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Sample records for normal mutation rates

  1. A simple algebraic cancer equation: calculating how cancers may arise with normal mutation rates

    Directory of Open Access Journals (Sweden)

    Shibata Darryl

    2010-01-01

    Full Text Available Abstract Background The purpose of this article is to present a relatively easy to understand cancer model where transformation occurs when the first cell, among many at risk within a colon, accumulates a set of driver mutations. The analysis of this model yields a simple algebraic equation, which takes as inputs the number of stem cells, mutation and division rates, and the number of driver mutations, and makes predictions about cancer epidemiology. Methods The equation [p = 1 - (1 - (1 - (1 - udkNm ] calculates the probability of cancer (p and contains five parameters: the number of divisions (d, the number of stem cells (N × m, the number of critical rate-limiting pathway driver mutations (k, and the mutation rate (u. In this model progression to cancer "starts" at conception and mutations accumulate with cell division. Transformation occurs when a critical number of rate-limiting pathway mutations first accumulates within a single stem cell. Results When applied to several colorectal cancer data sets, parameter values consistent with crypt stem cell biology and normal mutation rates were able to match the increase in cancer with aging, and the mutation frequencies found in cancer genomes. The equation can help explain how cancer risks may vary with age, height, germline mutations, and aspirin use. APC mutations may shorten pathways to cancer by effectively increasing the numbers of stem cells at risk. Conclusions The equation illustrates that age-related increases in cancer frequencies may result from relatively normal division and mutation rates. Although this equation does not encompass all of the known complexity of cancer, it may be useful, especially in a teaching setting, to help illustrate relationships between small and large cancer features.

  2. Studies of human mutation rates: Progress report

    International Nuclear Information System (INIS)

    Neel, J.V.

    1988-01-01

    Progress was recorded between January 1 and July 1, 1987 on a project entitled ''Studies of Human Mutation Rates''. Studies underway include methodology for studying mutation at the DNA level, algorithms for automated analyses of two-dimensional polyacrylamide DNA gels, theoretical and applied population genetics, and studies of mutation frequency in A-bomb survivors

  3. Spontaneous mutation rates and the rate-doubling dose

    International Nuclear Information System (INIS)

    Von Borstel, R.C.; Moustaccki, E.; Latarjet, R.

    1978-01-01

    The amount of radiation required to double the frequency of mutations or tumours over the rate of those that occur spontaneously is called the rate-doubling dose. An equivalent concept has been proposed for exposure to other environmental mutagens. The doubling dose concept is predicated on the assumption that all human populations have the same spontaneous mutation rate, and that this spontaneous mutation rate is known. It is now established for prokaryotes and lower eukaryotes that numerous genes control the spontaneous mutation rate, and it is likely that the same is true for human cells as well. Given that the accepted mode of evolution of human populatons is from small, isolated groups of individuals, it seems likely that each population would have a different spontaneous mutation rate. Given that a minimum of twenty genes control or affect the spontaneous mutation rate, and that each of these in turn is susceptible to spontaneously arising or environmentally induced mutations, it seems likely that every individual within a population (except for siblings from identical multiple births) will have a unique spontaneous mutation rate. If each individual in a population does have a different spontaneous mutation rate, the doubling dose concept, in rigorous terms, is fallacious. Therefore, as with other concepts of risk evaluation, the doubling dose concept is subject to criticism. Nevertheless, until we know individual spontaneous mutation rates with precision, and can evaluate risks based on this information, the doubling dose concept has a heuristic value and is needed for practical assessment of risks for defined populations. (author)

  4. Mutation Rates of STR Systems in Danes

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Bøttcher, Susanne Gammelgaard; Christensen, Susanne

    Danish paternity cases in the period 1999 to 2005 were investigated regarding mutation rates in STR loci. STR-typing was performed by the Applied Biosystems AmplfStr Profiler Plus kit in the period 1999 to early 2005, hereafter named the PP9, and by Applied Biosystems AmplfStr Identifier kit for ...... and kits. Sex and STR locus specific mutation rates were estimated with 95% confidence limits by the method of Clopper and Pearson (1934)....

  5. Experimental evolution and the dynamics of genomic mutation rate modifiers.

    Science.gov (United States)

    Raynes, Y; Sniegowski, P D

    2014-11-01

    Because genes that affect mutation rates are themselves subject to mutation, mutation rates can be influenced by natural selection and other evolutionary forces. The population genetics of mutation rate modifier alleles has been a subject of theoretical interest for many decades. Here, we review experimental contributions to our understanding of mutation rate modifier dynamics. Numerous evolution experiments have shown that mutator alleles (modifiers that elevate the genomic mutation rate) can readily rise to high frequencies via genetic hitchhiking in non-recombining microbial populations. Whereas these results certainly provide an explanatory framework for observations of sporadically high mutation rates in pathogenic microbes and in cancer lineages, it is nonetheless true that most natural populations have very low mutation rates. This raises the interesting question of how mutator hitchhiking is suppressed or its phenotypic effect reversed in natural populations. Very little experimental work has addressed this question; with this in mind, we identify some promising areas for future experimental investigation.

  6. Exchange rate arrangements: From extreme to "normal"

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    Beker Emilija

    2006-01-01

    Full Text Available The paper studies theoretical and empirical location dispersion of exchange rate arrangements - rigid-intermediate-flexible regimes, in the context of extreme arrangements of a currency board, dollarization and monetary union moderate characteristics of intermediate arrangements (adjustable pegs crawling pegs and target zones and imperative-process "normalization" in the form of a managed or clean floating system. It is established that de iure and de facto classifications generate "fear of floating" and "fear of pegging". The "impossible trinity" under the conditions of capital liberalization and globalization creates a bipolar view or hypothesis of vanishing intermediate exchange rate regimes.

  7. Precise estimates of mutation rate and spectrum in yeast

    Science.gov (United States)

    Zhu, Yuan O.; Siegal, Mark L.; Hall, David W.; Petrov, Dmitri A.

    2014-01-01

    Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae. PMID:24847077

  8. Avoiding dangerous missense: thermophiles display especially low mutation rates.

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    John W Drake

    2009-06-01

    Full Text Available Rates of spontaneous mutation have been estimated under optimal growth conditions for a variety of DNA-based microbes, including viruses, bacteria, and eukaryotes. When expressed as genomic mutation rates, most of the values were in the vicinity of 0.003-0.004 with a range of less than two-fold. Because the genome sizes varied by roughly 10(4-fold, the mutation rates per average base pair varied inversely by a similar factor. Even though the commonality of the observed genomic rates remains unexplained, it implies that mutation rates in unstressed microbes reach values that can be finely tuned by evolution. An insight originating in the 1920s and maturing in the 1960s proposed that the genomic mutation rate would reflect a balance between the deleterious effect of the average mutation and the cost of further reducing the mutation rate. If this view is correct, then increasing the deleterious impact of the average mutation should be countered by reducing the genomic mutation rate. It is a common observation that many neutral or nearly neutral mutations become strongly deleterious at higher temperatures, in which case they are called temperature-sensitive mutations. Recently, the kinds and rates of spontaneous mutations were described for two microbial thermophiles, a bacterium and an archaeon. Using an updated method to extrapolate from mutation-reporter genes to whole genomes reveals that the rate of base substitutions is substantially lower in these two thermophiles than in mesophiles. This result provides the first experimental support for the concept of an evolved balance between the total genomic impact of mutations and the cost of further reducing the basal mutation rate.

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

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    Kathleen Sprouffske

    2018-04-01

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

  10. Minisatellite germline mutation rate in the Techa River population

    Energy Technology Data Exchange (ETDEWEB)

    Dubrova, Yuri E. [Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH (United Kingdom)]. E-mail: yed2@le.ac.uk; Ploshchanskaya, Olga G. [Urals Research Centre for Radiation Medicine, Medgorodok, Chelyabinsk 454076 (Russian Federation); Department of Radiobiology, Chelyabinsk State University, Chelyabinsk 454021 (Russian Federation); Kozionova, Olga S. [Urals Research Centre for Radiation Medicine, Medgorodok, Chelyabinsk 454076 (Russian Federation); Department of Radiobiology, Chelyabinsk State University, Chelyabinsk 454021 (Russian Federation); Akleyev, Alexander V. [Urals Research Centre for Radiation Medicine, Medgorodok, Chelyabinsk 454076 (Russian Federation); Department of Radiobiology, Chelyabinsk State University, Chelyabinsk 454021 (Russian Federation)

    2006-12-01

    Germline mutation at eight minisatellite loci has been studied among the irradiated families from the Techa River population and non-exposed families from the rural area of the Chelyabinsk and Kurgan Oblasts. The groups were matched by ethnicity, parental age, occupation and smoking habit. A statistically significant 1.7-fold increase in mutation rate was found in the germline of irradiated fathers, whereas maternal germline mutation rate in the exposed families was not elevated. Most of the minisatellite loci showed an elevated paternal mutation rate in the exposed group, indicating a generalised increase in minisatellite germline mutation rate in the Techa River population. These data suggest that the elevated minisatellite mutation rate can be attributed to radioactive exposure. The spectra of paternal mutation seen in the unexposed and exposed families were indistinguishable.

  11. Minisatellite germline mutation rate in the Techa River population

    International Nuclear Information System (INIS)

    Dubrova, Yuri E.; Ploshchanskaya, Olga G.; Kozionova, Olga S.; Akleyev, Alexander V.

    2006-01-01

    Germline mutation at eight minisatellite loci has been studied among the irradiated families from the Techa River population and non-exposed families from the rural area of the Chelyabinsk and Kurgan Oblasts. The groups were matched by ethnicity, parental age, occupation and smoking habit. A statistically significant 1.7-fold increase in mutation rate was found in the germline of irradiated fathers, whereas maternal germline mutation rate in the exposed families was not elevated. Most of the minisatellite loci showed an elevated paternal mutation rate in the exposed group, indicating a generalised increase in minisatellite germline mutation rate in the Techa River population. These data suggest that the elevated minisatellite mutation rate can be attributed to radioactive exposure. The spectra of paternal mutation seen in the unexposed and exposed families were indistinguishable

  12. Sexual selection, germline mutation rate and sperm competition

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    Møller AP

    2003-04-01

    Full Text Available Abstract Background An important component of sexual selection arises because females obtain viability benefits for their offspring from their mate choice. Females choosing extra-pair fertilization generally favor males with exaggerated secondary sexual characters, and extra-pair paternity increases the variance in male reproductive success. Furthermore, females are assumed to benefit from 'good genes' from extra-pair sires. How additive genetic variance in such viability genes is maintained despite strong directional selection remains an evolutionary enigma. We propose that sexual selection is associated with elevated mutation rates, changing the balance between mutation and selection, thereby increasing variance in fitness and hence the benefits to be obtained from good genes sexual selection. Two hypotheses may account for such elevated mutation: (1 Increased sperm production associated with sperm competition may increase mutation rate. (2 Mutator alleles increase mutation rates that are revealed by the expression of condition-dependent secondary sexual characters used by choosy females during their mate choice. M Petrie has independently developed the idea that mutator alleles may account for the maintenance of genetic variation in viability despite strong directional selection. Results A comparative study of birds revealed a positive correlation between mutation rate at minisatellite loci and extra-pair paternity, but not between mutation rate and relative testes mass which is a measure of relative sperm production. Minisatellite mutation rates were not related to longevity, suggesting a meiotic rather than a mitotic origin of mutations. Conclusion We found evidence of increased mutation rate in species with more intense sexual selection. Increased mutation was not associated with increased sperm production, and we suggest that species with intense sexual selection may maintain elevated mutation rates because sexual selection continuously

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

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    Michael Stich

    2010-06-01

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

  14. Estimating spontaneous mutation rates at enzyme loci in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Mukai, Terumi; Yamazaki, Tsuneyuki; Harada, Ko; Kusakabe, Shin-ichi

    1990-04-01

    Spontaneous mutations were accumulated for 1,620,826 allele-generations on chromosomes that originated from six stem second chromosomes of Drosophila melanogaster. Only null-electromorph mutations were detected. Band-electromorph mutations were not found. The average rate of null-electromorph mutations was 2.71 x 10 -5 per locus per generation. The 95% confidence interval (μ n ) was 1.97 x 10 -5 n -5 per locus per generation. The upper 95% confidence limit of the band-electromorph mutation rate (μ B ) was 2.28 x 10 -6 per locus per generation. It appeared that null mutations were induced by movable genetic elements and that the mutation rates were different from chromosome to chromosome. (author)

  15. High mutation rates limit evolutionary adaptation in Escherichia coli

    Science.gov (United States)

    Wagner, Andreas

    2018-01-01

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

  16. The study of human mutation rates

    International Nuclear Information System (INIS)

    Neel, J.V.

    1992-01-01

    We will describe recent developments regarding the question of induced mutations in the survivors of the atomic bombings of Hiroshima and Nagasaki. As part of that work we, describe some developments with respect to the Amerindian blood samples collected under DoE sponsorship between 1964 and 1982. Then developments regarding the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to the study of genetic variation and mutation affecting protein characteristics. In particular, we will report on the identification and isolation of genes of especial interest as reflected in the behavior of the proteins which they encode

  17. An evolutionary reduction principle for mutation rates at multiple Loci.

    Science.gov (United States)

    Altenberg, Lee

    2011-06-01

    A model of mutation rate evolution for multiple loci under arbitrary selection is analyzed. Results are obtained using techniques from Karlin (Evolutionary Biology, vol. 14, pp. 61-204, 1982) that overcome the weak selection constraints needed for tractability in prior studies of multilocus event models.A multivariate form of the reduction principle is found: reduction results at individual loci combine topologically to produce a surface of mutation rate alterations that are neutral for a new modifier allele. New mutation rates survive if and only if they fall below this surface-a generalization of the hyperplane found by Zhivotovsky et al. (Proc. Natl. Acad. Sci. USA 91, 1079-1083, 1994) for a multilocus recombination modifier. Increases in mutation rates at some loci may evolve if compensated for by decreases at other loci. The strength of selection on the modifier scales in proportion to the number of germline cell divisions, and increases with the number of loci affected. Loci that do not make a difference to marginal fitnesses at equilibrium are not subject to the reduction principle, and under fine tuning of mutation rates would be expected to have higher mutation rates than loci in mutation-selection balance.Other results include the nonexistence of 'viability analogous, Hardy-Weinberg' modifier polymorphisms under multiplicative mutation, and the sufficiency of average transmission rates to encapsulate the effect of modifier polymorphisms on the transmission of loci under selection. A conjecture is offered regarding situations, like recombination in the presence of mutation, that exhibit departures from the reduction principle. Constraints for tractability are: tight linkage of all loci, initial fixation at the modifier locus, and mutation distributions comprising transition probabilities of reversible Markov chains.

  18. Estimating the Per-Base-Pair Mutation Rate in the Yeast Saccharomyces cerevisiae

    OpenAIRE

    Lang, Gregory I.; Murray, Andrew W.

    2008-01-01

    Although mutation rates are a key determinant of the rate of evolution they are difficult to measure precisely and global mutations rates (mutations per genome per generation) are often extrapolated from the per-base-pair mutation rate assuming that mutation rate is uniform across the genome. Using budding yeast, we describe an improved method for the accurate calculation of mutation rates based on the fluctuation assay. Our analysis suggests that the per-base-pair mutation rates at two genes...

  19. How much do we know about spontaneous human mutation rates

    Energy Technology Data Exchange (ETDEWEB)

    Crow, J.F. (Univ. of Wisconsin, Madison, WI (United States))

    1993-01-01

    The much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes on the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane in his classical study of X-linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate. The total mutation rate in Drosophila males of genes causing minor reduction in viability is at least 0.4 per sperm and may be considerably higher. The great mutation load implied by a rate of [approx] 1 per zygote can be greatly ameliorated by quasi-transition selection. Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 10[sup 2] new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known. Statistical evidence in Drosophilia shows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50-100 generations. 31 refs., 3 figs., 2 tabs.

  20. Variation in RNA virus mutation rates across host cells.

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    Marine Combe

    2014-01-01

    Full Text Available It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10(-6 to 10(-4 substitutions per nucleotide per round of copying (s/n/r and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV, which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10(-5 s/n/r. Cell immortalization through p53 inactivation and oxygen levels (1-21% did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature.

  1. Evolutionary rescue of a parasite population by mutation rate evolution.

    Science.gov (United States)

    Greenspoon, Philip B; Mideo, Nicole

    2017-10-01

    The risk of antibiotic resistance evolution in parasites is a major problem for public health. Identifying factors which promote antibiotic resistance evolution is thus a priority in evolutionary medicine. The rate at which new mutations enter the parasite population is one important predictor; however, mutation rate is not necessarily a fixed quantity, as is often assumed, but can itself evolve. Here we explore the possible impacts of mutation rate evolution on the fate of a disease circulating in a host population, which is being treated with drugs, the use of which varies over time. Using an evolutionary rescue framework, we find that mutation rate evolution provides a dramatic increase in the probability that a parasite population survives treatment in only a limited region, while providing little or no advantage in other regions. Both epidemiological features, such as the virulence of infection, and population genetic parameters, such as recombination rate, play important roles in determining the probability of evolutionary rescue and whether mutation rate evolution enhances the probability of evolutionary rescue or not. While efforts to curtail mutation rate evolution in parasites may be worthwhile under some circumstances, our results suggest that this need not always be the case. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Elevated mutation rate during meiosis in Saccharomyces cerevisiae.

    Science.gov (United States)

    Rattray, Alison; Santoyo, Gustavo; Shafer, Brenda; Strathern, Jeffrey N

    2015-01-01

    Mutations accumulate during all stages of growth, but only germ line mutations contribute to evolution. While meiosis contributes to evolution by reassortment of parental alleles, we show here that the process itself is inherently mutagenic. We have previously shown that the DNA synthesis associated with repair of a double-strand break is about 1000-fold less accurate than S-phase synthesis. Since the process of meiosis involves many programmed DSBs, we reasoned that this repair might also be mutagenic. Indeed, in the early 1960's Magni and Von Borstel observed elevated reversion of recessive alleles during meiosis, and found that the revertants were more likely to be associated with a crossover than non-revertants, a process that they called "the meiotic effect." Here we use a forward mutation reporter (CAN1 HIS3) placed at either a meiotic recombination coldspot or hotspot near the MAT locus on Chromosome III. We find that the increased mutation rate at CAN1 (6 to 21 -fold) correlates with the underlying recombination rate at the locus. Importantly, we show that the elevated mutation rate is fully dependent upon Spo11, the protein that introduces the meiosis specific DSBs. To examine associated recombination we selected for random spores with or without a mutation in CAN1. We find that the mutations isolated this way show an increased association with recombination (crossovers, loss of crossover interference and/or increased gene conversion tracts). Polζ appears to contribute about half of the mutations induced during meiosis, but is not the only source of mutations for the meiotic effect. We see no difference in either the spectrum or distribution of mutations between mitosis and meiosis. The correlation of hotspots with elevated mutagenesis provides a mechanism for organisms to control evolution rates in a gene specific manner.

  3. Monotonicity of fitness landscapes and mutation rate control.

    Science.gov (United States)

    Belavkin, Roman V; Channon, Alastair; Aston, Elizabeth; Aston, John; Krašovec, Rok; Knight, Christopher G

    2016-12-01

    A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms.

  4. Asymptotics of steady states of a selection–mutation equation for small mutation rate

    KAUST Repository

    Calsina, Àngel

    2013-12-01

    We consider a selection-mutation equation for the density of individuals with respect to a continuous phenotypic evolutionary trait. We assume that the competition term for an individual with a given trait depends on the traits of all the other individuals, therefore giving an infinite-dimensional nonlinearity. Mutations are modelled by means of an integral operator. We prove existence of steady states and show that, when the mutation rate goes to zero, the asymptotic profile of the population is a Cauchy distribution. © Royal Society of Edinburgh 2013.

  5. Asymptotics of steady states of a selection–mutation equation for small mutation rate

    KAUST Repository

    Calsina, À ngel; Cuadrado, Sí lvia; Desvillettes, Laurent; Raoul, Gaë l

    2013-01-01

    We consider a selection-mutation equation for the density of individuals with respect to a continuous phenotypic evolutionary trait. We assume that the competition term for an individual with a given trait depends on the traits of all the other individuals, therefore giving an infinite-dimensional nonlinearity. Mutations are modelled by means of an integral operator. We prove existence of steady states and show that, when the mutation rate goes to zero, the asymptotic profile of the population is a Cauchy distribution. © Royal Society of Edinburgh 2013.

  6. Strong effects of ionizing radiation from Chernobyl on mutation rates

    OpenAIRE

    M?ller, Anders Pape; Mousseau, Timothy A.

    2015-01-01

    In this paper we use a meta-analysis to examine the relationship between radiation and mutation rates in Chernobyl across 45 published studies, covering 30 species. Overall effect size of radiation on mutation rates estimated as Pearson's product-moment correlation coefficient was very large (E = 0.67; 95% confidence intervals (CI) 0.59 to 0.73), accounting for 44.3% of the total variance in an unstructured random-effects model. Fail-safe calculations reflecting the number of unpublished null...

  7. Radiation in relation to mutation rate, mutational damage and human ill-health

    International Nuclear Information System (INIS)

    Roberts, P.B.

    1976-09-01

    The effect of radiation in increasing the frequency of gene mutations is now reasonably understood. We discuss first how an increase in the mutation rate is reflected in the mutational damage expressed in populations. It is shown that the mutational damage, assessed by the loss of fitness in a population or the number of eventual gene extinctions, is equal to the number of new mutations arising per generation or the mutation rate. In a population of stable size, a dose of 1 rem given to 10 6 people leads to roughly 600 gene extinctions when summed over all ensuing generations if the dose is applied to only one generation; this number of extinctions will occur in each succeeding generation if the dose is given to every generation. However, the concept of genetic extinction, although quantifiable, is of limited value in assessing radiation risks since its impact on human ill-health is very speculative. In particular, no estimate can be made of the total cost of effects which are minor in each individual in which they arise, but which, because they are so minor, persist in the population for many generations. The best current estimate is for 14-140 obvious defects in the first few generations following exposure of 10 6 people to a dose of 1 rem. (auth.)

  8. Prospects for DNA methods to measure human heritable mutation rates

    International Nuclear Information System (INIS)

    Mendelsohn, M.L.

    1985-01-01

    A workshop cosponsored by ICPEMC and the US Department of Energy was held in Alta, Utah, December 9-13, 1984 to examine the extent to which DNA-oriented methods might provide new approaches to the important but intractable problem of measuring mutation rates in control and exposed human populations. The workshop identified and analyzed six DNA methods for detection of human heritable mutation, including several created at the meeting, and concluded that none of the methods combine sufficient feasibility and efficiency to be recommended for general application. 8 refs

  9. The rate of spontaneous mutations in human myeloid cells

    International Nuclear Information System (INIS)

    Araten, David J.; Krejci, Ondrej; DiTata, Kimberly; Wunderlich, Mark; Sanders, Katie J.; Zamechek, Leah; Mulloy, James C.

    2013-01-01

    Highlights: • We provide the first measurement of the mutation rate (μ) in human myeloid cells. • μ is measured to be 3.6–23 × 10 −7 per cell division. • The AML-ETO and MLL-AF9 fusions do not seem to increase μ. • Cooperating mutations in NRAS, FLT3 and p53 not seem to increase μ. • Hypermutability may be required to explain leukemogenesis. - Abstract: The mutation rate (μ) is likely to be a key parameter in leukemogenesis, but historically, it has been difficult to measure in humans. The PIG-A gene has some advantages for the detection of spontaneous mutations because it is X-linked, and therefore only one mutation is required to disrupt its function. Furthermore, the PIG-A-null phenotype is readily detected by flow cytometry. Using PIG-A, we have now provided the first in vitro measurement of μ in myeloid cells, using cultures of CD34+ cells that are transduced with either the AML-ETO or the MLL-AF9 fusion genes and expanded with cytokines. For the AML-ETO cultures, the median μ value was ∼9.4 × 10 −7 (range ∼3.6–23 × 10 −7 ) per cell division. In contrast, few spontaneous mutations were observed in the MLL-AF9 cultures. Knockdown of p53 or introduction of mutant NRAS or FLT3 alleles did not have much of an effect on μ. Based on these data, we provide a model to predict whether hypermutability must occur in the process of leukemogenesis

  10. TP53 mutations in clinically normal mucosa adjacent to oral carcinomas

    DEFF Research Database (Denmark)

    Thode, Christenze; Bilde, Anders; von Buchwald, Christian

    2010-01-01

    BACKGROUND: The tumour-suppressor protein p53 often accumulates in histologically normal epithelium adjacent to oral squamous cell carcinomas (OSCC). We investigated whether this was associated with mutations in TP53, the gene for p53, and might implicate impending malignancy. METHODS: Specimens...... products were separated by denatured gradient gel electrophoresis. Fragments with a deviant DGEE pattern were sequenced. RESULTS: TP53 mutations were found in six of 18 tumours. Fourteen specimens contained histologically normal mucosa adjacent to the tumour; 13 of these showed small clusters of p53...

  11. Strong effects of ionizing radiation from Chernobyl on mutation rates.

    Science.gov (United States)

    Møller, Anders Pape; Mousseau, Timothy A

    2015-02-10

    In this paper we use a meta-analysis to examine the relationship between radiation and mutation rates in Chernobyl across 45 published studies, covering 30 species. Overall effect size of radiation on mutation rates estimated as Pearson's product-moment correlation coefficient was very large (E = 0.67; 95% confidence intervals (CI) 0.59 to 0.73), accounting for 44.3% of the total variance in an unstructured random-effects model. Fail-safe calculations reflecting the number of unpublished null results needed to eliminate this average effect size showed the extreme robustness of this finding (Rosenberg's method: 4135 at p = 0.05). Indirect tests did not provide any evidence of publication bias. The effect of radiation on mutations varied among taxa, with plants showing a larger effect than animals. Humans were shown to have intermediate sensitivity of mutations to radiation compared to other species. Effect size did not decrease over time, providing no evidence for an improvement in environmental conditions. The surprisingly high mean effect size suggests a strong impact of radioactive contamination on individual fitness in current and future generations, with potentially significant population-level consequences, even beyond the area contaminated with radioactive material.

  12. Reduced Mutation Rate and Increased Transformability of Transposon-Free Acinetobacter baylyi ADP1-ISx.

    Science.gov (United States)

    Suárez, Gabriel A; Renda, Brian A; Dasgupta, Aurko; Barrick, Jeffrey E

    2017-09-01

    The genomes of most bacteria contain mobile DNA elements that can contribute to undesirable genetic instability in engineered cells. In particular, transposable insertion sequence (IS) elements can rapidly inactivate genes that are important for a designed function. We deleted all six copies of IS 1236 from the genome of the naturally transformable bacterium Acinetobacter baylyi ADP1. The natural competence of ADP1 made it possible to rapidly repair deleterious point mutations that arose during strain construction. In the resulting ADP1-ISx strain, the rates of mutations inactivating a reporter gene were reduced by 7- to 21-fold. This reduction was higher than expected from the incidence of new IS 1236 insertions found during a 300-day mutation accumulation experiment with wild-type ADP1 that was used to estimate spontaneous mutation rates in the strain. The extra improvement appears to be due in part to eliminating large deletions caused by IS 1236 activity, as the point mutation rate was unchanged in ADP1-ISx. Deletion of an error-prone polymerase ( dinP ) and a DNA damage response regulator ( umuD Ab [the umuD gene of A. baylyi ]) from the ADP1-ISx genome did not further reduce mutation rates. Surprisingly, ADP1-ISx exhibited increased transformability. This improvement may be due to less autolysis and aggregation of the engineered cells than of the wild type. Thus, deleting IS elements from the ADP1 genome led to a greater than expected increase in evolutionary reliability and unexpectedly enhanced other key strain properties, as has been observed for other clean-genome bacterial strains. ADP1-ISx is an improved chassis for metabolic engineering and other applications. IMPORTANCE Acinetobacter baylyi ADP1 has been proposed as a next-generation bacterial host for synthetic biology and genome engineering due to its ability to efficiently take up DNA from its environment during normal growth. We deleted transposable elements that are capable of copying themselves

  13. 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.

  14. Cellular and molecular effects for mutation induction in normal human cells irradiated with accelerated neon ions

    International Nuclear Information System (INIS)

    Suzuki, Masao; Tsuruoka, Chizuru; Kanai, Tatsuaki; Kato, Takeshi; Yatagai, Fumio; Watanabe, Masami

    2006-01-01

    We investigated the linear energy transfer (LET) dependence of mutation induction on the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in normal human fibroblast-like cells irradiated with accelerated neon-ion beams. The cells were irradiated with neon-ion beams at various LETs ranging from 63 to 335 keV/μm. Neon-ion beams were accelerated by the Riken Ring Cyclotron at the Institute of Physical and Chemical Research in Japan. Mutation induction at the HPRT locus was detected to measure 6-thioguanine-resistant clones. The mutation spectrum of the deletion pattern of exons of mutants was analyzed using the multiplex polymerase chain reaction (PCR). The dose-response curves increased steeply up to 0.5 Gy and leveled off or decreased between 0.5 and 1.0 Gy, compared to the response to 137 Cs γ-rays. The mutation frequency increased up to 105 keV/μm and then there was a downward trend with increasing LET values. The deletion pattern of exons was non-specific. About 75-100% of the mutants produced using LETs ranging from 63 to 335 keV/μm showed all or partial deletions of exons, while among γ-ray-induced mutants 30% showed no deletions, 30% partial deletions and 40% complete deletions. These results suggested that the dose-response curves of neon-ion-induced mutations were dependent upon LET values, but the deletion pattern of DNA was not

  15. Mutation rate estimation for 15 autosomal STR loci in a large population from Mainland China.

    Science.gov (United States)

    Zhao, Zhuo; Zhang, Jie; Wang, Hua; Liu, Zhi-Peng; Liu, Ming; Zhang, Yuan; Sun, Li; Zhang, Hui

    2015-09-01

    STR, short tandem repeats, are well known as a type of powerful genetic marker and widely used in studying human population genetics. Compared with the conventional genetic markers, the mutation rate of STR is higher. Additionally, the mutations of STR loci do not lead to genetic inconsistencies between the genotypes of parents and children; therefore, the analysis of STR mutation is more suited to assess the population mutation. In this study, we focused on 15 autosomal STR loci. DNA samples from a total of 42,416 unrelated healthy individuals (19,037 trios) from the population of Mainland China collected between Jan 2012 and May 2014 were successfully investigated. In our study, the allele frequencies, paternal mutation rates, maternal mutation rates and average mutation rates were detected. Furthermore, we also investigated the relationship between paternal ages, maternal ages, area, the time of pregnancy and average mutation rate. We found that the paternal mutation rate was higher than the maternal mutation rate and the paternal, maternal, and average mutation rates had a positive correlation with paternal age, maternal age and the time of pregnancy respectively. Additionally, the average mutation rate of coastal areas was higher than that of inland areas.

  16. Mutation rates at 42 Y chromosomal short tandem repeats in Chinese Han population in Eastern China.

    Science.gov (United States)

    Wu, Weiwei; Ren, Wenyan; Hao, Honglei; Nan, Hailun; He, Xin; Liu, Qiuling; Lu, Dejian

    2018-01-31

    Mutation analysis of 42 Y chromosomal short tandem repeats (Y-STRs) loci was performed using a sample of 1160 father-son pairs from the Chinese Han population in Eastern China. The results showed that the average mutation rate across the 42 Y-STR loci was 0.0041 (95% CI 0.0036-0.0047) per locus per generation. The locus-specific mutation rates varied from 0.000 to 0.0190. No mutation was found at DYS388, DYS437, DYS448, DYS531, and GATA_H4. DYS627, DYS570, DYS576, and DYS449 could be classified as rapidly mutating Y-STRs, with mutation rates higher than 1.0 × 10 -2 . DYS458, DYS630, and DYS518 were moderately mutating Y-STRs, with mutation rates ranging from 8 × 10 -3 to 1 × 10 -2 . Although the characteristics of the Y-STR mutations were consistent with those in previous studies, mutation rate differences between our data and previous published data were found at some rapidly mutating Y-STRs. The single-copy loci located on the short arm of the Y chromosome (Yp) showed relatively higher mutation rates more frequently than the multi-copy loci. These results will not only extend the data for Y-STR mutations but also be important for kinship analysis, paternal lineage identification, and family relationship reconstruction in forensic Y-STR analysis.

  17. Exact, time-independent estimation of clone size distributions in normal and mutated cells.

    Science.gov (United States)

    Roshan, A; Jones, P H; Greenman, C D

    2014-10-06

    Biological tools such as genetic lineage tracing, three-dimensional confocal microscopy and next-generation DNA sequencing are providing new ways to quantify the distribution of clones of normal and mutated cells. Understanding population-wide clone size distributions in vivo is complicated by multiple cell types within observed tissues, and overlapping birth and death processes. This has led to the increased need for mathematically informed models to understand their biological significance. Standard approaches usually require knowledge of clonal age. We show that modelling on clone size independent of time is an alternative method that offers certain analytical advantages; it can help parametrize these models, and obtain distributions for counts of mutated or proliferating cells, for example. When applied to a general birth-death process common in epithelial progenitors, this takes the form of a gambler's ruin problem, the solution of which relates to counting Motzkin lattice paths. Applying this approach to mutational processes, alternative, exact, formulations of classic Luria-Delbrück-type problems emerge. This approach can be extended beyond neutral models of mutant clonal evolution. Applications of these approaches are twofold. First, we resolve the probability of progenitor cells generating proliferating or differentiating progeny in clonal lineage tracing experiments in vivo or cell culture assays where clone age is not known. Second, we model mutation frequency distributions that deep sequencing of subclonal samples produce.

  18. Studies of human mutation rates, December 1, 1985--November 30, 1986

    International Nuclear Information System (INIS)

    Neel, J.V.

    1985-01-01

    This program seeks to quantify native human mutation rates and to determine how man's activities may affect these rates. The program is divided into six tasks, i.e. The American Indian mutation rate, monitoring populations for frequency of mutation by electrophoresis of blood proteins, application of molecular biological approaches to the detection and study of mutational events in human populations, development of two-dimensional electrophoresis for identification of mutant proteins, co-operative program with the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan, and statistical problems associated with the estimation of mutation rates. Progress of each of the above tasks is related in detail. (DT)

  19. Optimized reaction mechanism rate rules for ignition of normal alkanes

    KAUST Repository

    Cai, Liming

    2016-08-11

    The increasing demand for cleaner combustion and reduced greenhouse gas emissions motivates research on the combustion of hydrocarbon fuels and their surrogates. Accurate detailed chemical kinetic models are an important prerequisite for high fidelity reacting flow simulations capable of improving combustor design and operation. The development of such models for many new fuel components and/or surrogate molecules is greatly facilitated by the application of reaction classes and rate rules. Accurate and versatile rate rules are desirable to improve the predictive accuracy of kinetic models. A major contribution in the literature is the recent work by Bugler et al. (2015), which has significantly improved rate rules and thermochemical parameters used in kinetic modeling of alkanes. In the present study, it is demonstrated that rate rules can be used and consistently optimized for a set of normal alkanes including n-heptane, n-octane, n-nonane, n-decane, and n-undecane, thereby improving the predictive accuracy for all the considered fuels. A Bayesian framework is applied in the calibration of the rate rules. The optimized rate rules are subsequently applied to generate a mechanism for n-dodecane, which was not part of the training set for the optimized rate rules. The developed mechanism shows accurate predictions compared with published well-validated mechanisms for a wide range of conditions.

  20. The (1+λ) evolutionary algorithm with self-adjusting mutation rate

    DEFF Research Database (Denmark)

    Doerr, Benjamin; Witt, Carsten; Gießen, Christian

    2017-01-01

    We propose a new way to self-adjust the mutation rate in population-based evolutionary algorithms. Roughly speaking, it consists of creating half the offspring with a mutation rate that is twice the current mutation rate and the other half with half the current rate. The mutation rate is then upd......We propose a new way to self-adjust the mutation rate in population-based evolutionary algorithms. Roughly speaking, it consists of creating half the offspring with a mutation rate that is twice the current mutation rate and the other half with half the current rate. The mutation rate...... is then updated to the rate used in that subpopulation which contains the best offspring. We analyze how the (1 + A) evolutionary algorithm with this self-adjusting mutation rate optimizes the OneMax test function. We prove that this dynamic version of the (1 + A) EA finds the optimum in an expected optimization...... time (number of fitness evaluations) of O(nA/log A + n log n). This time is asymptotically smaller than the optimization time of the classic (1 + A) EA. Previous work shows that this performance is best-possible among all A-parallel mutation-based unbiased black-box algorithms. This result shows...

  1. General anesthesia suppresses normal heart rate variability in humans

    Science.gov (United States)

    Matchett, Gerald; Wood, Philip

    2014-06-01

    The human heart normally exhibits robust beat-to-beat heart rate variability (HRV). The loss of this variability is associated with pathology, including disease states such as congestive heart failure (CHF). The effect of general anesthesia on intrinsic HRV is unknown. In this prospective, observational study we enrolled 100 human subjects having elective major surgical procedures under general anesthesia. We recorded continuous heart rate data via continuous electrocardiogram before, during, and after anesthesia, and we assessed HRV of the R-R intervals. We assessed HRV using several common metrics including Detrended Fluctuation Analysis (DFA), Multifractal Analysis, and Multiscale Entropy Analysis. Each of these analyses was done in each of the four clinical phases for each study subject over the course of 24 h: Before anesthesia, during anesthesia, early recovery, and late recovery. On average, we observed a loss of variability on the aforementioned metrics that appeared to correspond to the state of general anesthesia. Following the conclusion of anesthesia, most study subjects appeared to regain their normal HRV, although this did not occur immediately. The resumption of normal HRV was especially delayed on DFA. Qualitatively, the reduction in HRV under anesthesia appears similar to the reduction in HRV observed in CHF. These observations will need to be validated in future studies, and the broader clinical implications of these observations, if any, are unknown.

  2. Wilms’ Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

    Science.gov (United States)

    Paschka, Peter; Marcucci, Guido; Ruppert, Amy S.; Whitman, Susan P.; Mrózek, Krzysztof; Maharry, Kati; Langer, Christian; Baldus, Claudia D.; Zhao, Weiqiang; Powell, Bayard L.; Baer, Maria R.; Carroll, Andrew J.; Caligiuri, Michael A.; Kolitz, Jonathan E.; Larson, Richard A.; Bloomfield, Clara D.

    2008-01-01

    Purpose To analyze the prognostic impact of Wilms’ tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC. Results Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITDnegative/NPM1mutated as low risk v FLT3-ITDpositive and/or NPM1wild-type as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count. Conclusion We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML. PMID:18559874

  3. Proliferation in the normal FTE is a hallmark of the follicular phase, not BRCA mutation status.

    Science.gov (United States)

    George, Sophia H L; Milea, Anca; Shaw, Patricia A

    2012-11-15

    Women who have inherited germline mutations of BRCA1/BRCA2 are at increased risk of developing high-grade serous carcinoma, and many of these cancers arise in the distal fimbriated end of the fallopian tube. We have previously shown that the fallopian tube epithelia of BRCA1 mutation carriers (FTE-BRCA) have altered signaling pathways compared to nonmutation carriers. In this study, we sought to determine whether these differences result in a proliferative advantage to the epithelia in this high-risk patient population and to investigate whether the postovulation environment of the FTE-BRCA compared to FTE from nonmutation carriers experiences a differential abundance of immune cells. Immunohistochemistry for Ki67, CD3, CD8, CD20, and CD68 was performed on histologically normal tubal epithelium (ampulla, n = 83), fimbria (n = 18) with known ovarian cycle status and germline mutation status and for Ki67 on fimbrial epithelium from women (n = 144) with and without BRCA1 or BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO). Serous tubal intraepithelial carcinomas (STIC) with concomitant cancer (n = 15) were also analyzed for presence of immune infiltrates. All slides were digitized and analyzed using automated image analysis software. There was no significant difference in the proliferative index in histologically normal FTE between BRCA1/BRCA2 and non-BRCA, in 144 fimbriae and 83 ampullae. The FTE-BRCA1 epithelia did not exhibit a differential presence of lymphocytes or macrophages, however more macrophages were present in the luteal phase compared to the follicular phase epithelia. In STICs macrophages were more abundant than lymphocytes with an incremental increase noted with disease progression. BRCA1/2 mutation carriers exhibited no significant increase in proliferation in the fallopian tube epithelial cells either in the ampulla or fimbriated ends of the tube. Rather, a significant proliferative increase was defined in the cases determined

  4. Mitochondrial Mutation Rate, Spectrum and Heteroplasmy in Caenorhabditis elegans Spontaneous Mutation Accumulation Lines of Differing Population Size.

    Science.gov (United States)

    Konrad, Anke; Thompson, Owen; Waterston, Robert H; Moerman, Donald G; Keightley, Peter D; Bergthorsson, Ulfar; Katju, Vaishali

    2017-06-01

    Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial mutations in small populations in the absence and presence of selection, we evolved mutation accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial mutation rate was estimated at 1.05 × 10-7/site/generation. A strong G/C→A/T mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Estimates of the rate and distribution of fitness effects of spontaneous mutation in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Zeyl, C.; Visser, de J.A.G.M.

    2001-01-01

    The per-genome, per-generation rate of spontaneous mutation affecting fitness (U) and the mean fitness cost per mutation (s) are important parameters in evolutionary genetics, but have been estimated for few species. We estimated U and sh (the heterozygous effect of mutations) for two diploid yeast

  6. Chromosomal Aberrations in Normal and AT Cells Exposed to High Dose of Low Dose Rate Irradiation

    Science.gov (United States)

    Kawata, T.; Shigematsu, N.; Kawaguchi, O.; Liu, C.; Furusawa, Y.; Hirayama, R.; George, K.; Cucinotta, F.

    2011-01-01

    Ataxia telangiectasia (A-T) is a human autosomally recessive syndrome characterized by cerebellar ataxia, telangiectases, immune dysfunction, and genomic instability, and high rate of cancer incidence. A-T cell lines are abnormally sensitive to agents that induce DNA double strand breaks, including ionizing radiation. The diverse clinical features in individuals affected by A-T and the complex cellular phenotypes are all linked to the functional inactivation of a single gene (AT mutated). It is well known that cells deficient in ATM show increased yields of both simple and complex chromosomal aberrations after high-dose-rate irradiation, but, less is known on how cells respond to low-dose-rate irradiation. It has been shown that AT cells contain a large number of unrejoined breaks after both low-dose-rate irradiation and high-dose-rate irradiation, however sensitivity for chromosomal aberrations at low-dose-rate are less often studied. To study how AT cells respond to low-dose-rate irradiation, we exposed confluent normal and AT fibroblast cells to up to 3 Gy of gamma-irradiation at a dose rate of 0.5 Gy/day and analyzed chromosomal aberrations in G0 using fusion PCC (Premature Chromosomal Condensation) technique. Giemsa staining showed that 1 Gy induces around 0.36 unrejoined fragments per cell in normal cells and around 1.35 fragments in AT cells, whereas 3Gy induces around 0.65 fragments in normal cells and around 3.3 fragments in AT cells. This result indicates that AT cells can rejoin breaks less effectively in G0 phase of the cell cycle? compared to normal cells. We also analyzed chromosomal exchanges in normal and AT cells after exposure to 3 Gy of low-dose-rate rays using a combination of G0 PCC and FISH techniques. Misrejoining was detected in the AT cells only? When cells irradiated with 3 Gy were subcultured and G2 chromosomal aberrations were analyzed using calyculin-A induced PCC technique, the yield of unrejoined breaks decreased in both normal and AT

  7. The application of a linear algebra to the analysis of mutation rates.

    Science.gov (United States)

    Jones, M E; Thomas, S M; Clarke, K

    1999-07-07

    Cells and bacteria growing in culture are subject to mutation, and as this mutation is the ultimate substrate for selection and evolution, the factors controlling the mutation rate are of some interest. The mutational event is not observed directly, but is inferred from the phenotype of the original mutant or of its descendants; the rate of mutation is inferred from the number of such mutant phenotypes. Such inference presumes a knowledge of the probability distribution for the size of a clone arising from a single mutation. We develop a mathematical formulation that assists in the design and analysis of experiments which investigate mutation rates and mutant clone size distribution, and we use it to analyse data for which the classical Luria-Delbrück clone-size distribution must be rejected. Copyright 1999 Academic Press.

  8. Hybridization alters spontaneous mutation rates in a parent-of-origin-dependent fashion in Arabidopsis.

    Science.gov (United States)

    Bashir, Tufail; Sailer, Christian; Gerber, Florian; Loganathan, Nitin; Bhoopalan, Hemadev; Eichenberger, Christof; Grossniklaus, Ueli; Baskar, Ramamurthy

    2014-05-01

    Over 70 years ago, increased spontaneous mutation rates were observed in Drosophila spp. hybrids, but the genetic basis of this phenomenon is not well understood. The model plant Arabidopsis (Arabidopsis thaliana) offers unique opportunities to study the types of mutations induced upon hybridization and the frequency of their occurrence. Understanding the mutational effects of hybridization is important, as many crop plants are grown as hybrids. Besides, hybridization is important for speciation and its effects on genome integrity could be critical, as chromosomal rearrangements can lead to reproductive isolation. We examined the rates of hybridization-induced point and frameshift mutations as well as homologous recombination events in intraspecific Arabidopsis hybrids using a set of transgenic mutation detector lines that carry mutated or truncated versions of a reporter gene. We found that hybridization alters the frequency of different kinds of mutations. In general, Columbia (Col)×Cape Verde Islands and Col×C24 hybrid progeny had decreased T→G and T→A transversion rates but an increased C→T transition rate. Significant changes in frameshift mutation rates were also observed in some hybrids. In Col×C24 hybrids, there is a trend for increased homologous recombination rates, except for the hybrids from one line, while in Col×Cape Verde Islands hybrids, this rate is decreased. The overall genetic distance of the parents had no influence on mutation rates in the progeny, as closely related accessions on occasion displayed higher mutation rates than accessions that are separated farther apart. However, reciprocal hybrids had significantly different mutation rates, suggesting parent-of-origin-dependent effects on the mutation frequency.

  9. The rate and effects of spontaneous mutation on fitness traits in the social amoeba, Dictyostelium discoideum.

    Science.gov (United States)

    Hall, David W; Fox, Sara; Kuzdzal-Fick, Jennie J; Strassmann, Joan E; Queller, David C

    2013-07-08

    We performed a mutation accumulation (MA) experiment in the social amoeba Dictyostelium discoideum to estimate the rate and distribution of effects of spontaneous mutations affecting eight putative fitness traits. We found that the per-generation mutation rate for most fitness components is 0.0019 mutations per haploid genome per generation or larger. This rate is an order of magnitude higher than estimates for fitness components in the unicellular eukaryote Saccharomyces cerevisiae, even though the base-pair substitution rate is two orders of magnitude lower. The high rate of fitness-altering mutations observed in this species may be partially explained by a large mutational target relative to S. cerevisiae. Fitness-altering mutations also may occur primarily at simple sequence repeats, which are common throughout the genome, including in coding regions, and may represent a target that is particularly likely to give fitness effects upon mutation. The majority of mutations had deleterious effects on fitness, but there was evidence for a substantial fraction, up to 40%, being beneficial for some of the putative fitness traits. Competitive ability within the multicellular slug appears to be under weak directional selection, perhaps reflecting the fact that slugs are sometimes, but not often, comprised of multiple clones in nature. Evidence for pleiotropy among fitness components across MA lines was absent, suggesting that mutations tend to act on single fitness components.

  10. The allele-frequency spectrum in a decoupled Moran model with mutation, drift, and directional selection, assuming small mutation rates.

    Science.gov (United States)

    Vogl, Claus; Clemente, Florian

    2012-05-01

    We analyze a decoupled Moran model with haploid population size N, a biallelic locus under mutation and drift with scaled forward and backward mutation rates θ(1)=μ(1)N and θ(0)=μ(0)N, and directional selection with scaled strength γ=sN. With small scaled mutation rates θ(0) and θ(1), which is appropriate for single nucleotide polymorphism data in highly recombining regions, we derive a simple approximate equilibrium distribution for polymorphic alleles with a constant of proportionality. We also put forth an even simpler model, where all mutations originate from monomorphic states. Using this model we derive the sojourn times, conditional on the ancestral and fixed allele, and under equilibrium the distributions of fixed and polymorphic alleles and fixation rates. Furthermore, we also derive the distribution of small samples in the diffusion limit and provide convenient recurrence relations for calculating this distribution. This enables us to give formulas analogous to the Ewens-Watterson estimator of θ for biased mutation rates and selection. We apply this theory to a polymorphism dataset of fourfold degenerate sites in Drosophila melanogaster. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.

    Directory of Open Access Journals (Sweden)

    Miguel Aste-Amézaga

    2010-02-01

    Full Text Available Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target.Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD, and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR. The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50 values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL. In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell

  12. Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Haslam, K

    2012-02-01

    BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

  13. Determining Y-STR mutation rates in deep-routing genealogies: Identification of haplogroup differences.

    Science.gov (United States)

    Claerhout, Sofie; Vandenbosch, Michiel; Nivelle, Kelly; Gruyters, Leen; Peeters, Anke; Larmuseau, Maarten H D; Decorte, Ronny

    2018-05-01

    Knowledge of Y-chromosomal short tandem repeat (Y-STR) mutation rates is essential to determine the most recent common ancestor (MRCA) in familial searching or genealogy research. Up to now, locus-specific mutation rates have been extensively examined especially for commercially available forensic Y-STRs, while haplogroup specific mutation rates have not yet been investigated in detail. Through 450 patrilineally related namesakes distributed over 212 deep-rooting genealogies, the individual mutation rates of 42 Y-STR loci were determined, including 27 forensic Y-STR loci from the Yfiler ® Plus kit and 15 additional Y-STR loci (DYS388, DYS426, DYS442, DYS447, DYS454, DYS455, DYS459a/b, DYS549, DYS607, DYS643, DYS724a/b and YCAIIa/b). At least 726 mutations were observed over 148,596 meiosis and individual Y-STR mutation rates varied from 2.83 × 10 -4 to 1.86 × 10 -2 . The mutation rate was significantly correlated with the average allele size, the complexity of the repeat motif sequence and the age of the father. Significant differences in average Y-STR mutations rates were observed when haplogroup 'I & J' (4.03 × 10 -3 mutations/generation) was compared to 'R1b' (5.35 × 10 -3 mutations/generation) and to the overall mutation rate (5.03 × 10 -3 mutations/generation). A difference in allele size distribution was identified as the only cause for these haplogroup specific mutation rates. The haplogroup specific mutation rates were also present within the commercially available Y-STR kits (Yfiler ® , PowerPlex ® Y23 System and Yfiler ® Plus). This observation has consequences for applications where an average Y-STR mutation rate is used, e.g. tMRCA estimations in familial searching and genealogy research. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. A Constant Rate of Spontaneous Mutation in DNA-Based Microbes

    Science.gov (United States)

    Drake, John W.

    1991-08-01

    In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by ≈6500-fold. Their average mutation rates per base pair vary by ≈16,000-fold, whereas their mutation rates per genome vary by only ≈2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.

  15. Critical mutation rate has an exponential dependence on population size in haploid and diploid populations.

    Directory of Open Access Journals (Sweden)

    Elizabeth Aston

    Full Text Available Understanding the effect of population size on the key parameters of evolution is particularly important for populations nearing extinction. There are evolutionary pressures to evolve sequences that are both fit and robust. At high mutation rates, individuals with greater mutational robustness can outcompete those with higher fitness. This is survival-of-the-flattest, and has been observed in digital organisms, theoretically, in simulated RNA evolution, and in RNA viruses. We introduce an algorithmic method capable of determining the relationship between population size, the critical mutation rate at which individuals with greater robustness to mutation are favoured over individuals with greater fitness, and the error threshold. Verification for this method is provided against analytical models for the error threshold. We show that the critical mutation rate for increasing haploid population sizes can be approximated by an exponential function, with much lower mutation rates tolerated by small populations. This is in contrast to previous studies which identified that critical mutation rate was independent of population size. The algorithm is extended to diploid populations in a system modelled on the biological process of meiosis. The results confirm that the relationship remains exponential, but show that both the critical mutation rate and error threshold are lower for diploids, rather than higher as might have been expected. Analyzing the transition from critical mutation rate to error threshold provides an improved definition of critical mutation rate. Natural populations with their numbers in decline can be expected to lose genetic material in line with the exponential model, accelerating and potentially irreversibly advancing their decline, and this could potentially affect extinction, recovery and population management strategy. The effect of population size is particularly strong in small populations with 100 individuals or less; the

  16. Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident

    International Nuclear Information System (INIS)

    Dubrova, Yuri E.; Buard, Jerome; Jeffreys, Alec J.; Nesterov, Valeri N.; Krouchinsky, Nicolay G.; Ostapenko, Vladislav A.; Vergnaud, Gilles; Giraudeau, Fabienne

    1997-01-01

    Analysis of germline mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite germline mutation rate in the Belarus families. Within the Belarus cohort, mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of germline mutation. The spectra of mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite mutation

  17. A consideration of two biochemical approaches to monitoring human populations for a change in germ cell mutation rates

    International Nuclear Information System (INIS)

    Neel, J.V.; Mohrenweiser, H.; Satoh, Chiyoko; Hamilton, H.B.

    1978-10-01

    This report presents two different strategies for monitoring increased mutation rates resulting from exposure to an environmental mutagen, both of which are based on the detection of biochemical variants of polypeptides. Using the first strategy, one monitors a defined population continuously for the rate at which children with such a variant are born to normal parents. An increase in this rate implies increasing exposure to a mutagen. With the second strategy, one contrasts the findings in the children born to a control group or groups with the findings in the children born to an exposed group, however this is defined. An example of each strategy is included. The alternatives to mutation which must be considered when a child with a variant is found to have nonaffected parents are considered. The numbers of individuals necessary to detect an increase of a specified magnitude are discussed. (author)

  18. Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans.

    Directory of Open Access Journals (Sweden)

    Arbel Harpak

    2016-12-01

    Full Text Available The site frequency spectrum (SFS has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the "phylogenetically-conditioned SFS" or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC, combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. In summary, we show that variable mutation rates are key determinants of the SFS in humans.

  19. From molecular genetics to phylodynamics: evolutionary relevance of mutation rates across viruses.

    Directory of Open Access Journals (Sweden)

    Rafael Sanjuán

    Full Text Available Although evolution is a multifactorial process, theory posits that the speed of molecular evolution should be directly determined by the rate at which spontaneous mutations appear. To what extent these two biochemical and population-scale processes are related in nature, however, is largely unknown. Viruses are an ideal system for addressing this question because their evolution is fast enough to be observed in real time, and experimentally-determined mutation rates are abundant. This article provides statistically supported evidence that the mutation rate determines molecular evolution across all types of viruses. Properties of the viral genome such as its size and chemical composition are identified as major determinants of these rates. Furthermore, a quantitative analysis reveals that, as expected, evolution rates increase linearly with mutation rates for slowly mutating viruses. However, this relationship plateaus for fast mutating viruses. A model is proposed in which deleterious mutations impose an evolutionary speed limit and set an extinction threshold in nature. The model is consistent with data from replication kinetics, selection strength and chemical mutagenesis studies.

  20. Wiskott-Aldrich Syndrome With Normal-Sized Platelets in an Eighteen-Month-Old Boy: A Rare Mutation

    Directory of Open Access Journals (Sweden)

    Jayitri Mazumdar

    2015-07-01

    Full Text Available Introduction: Wiskott-Aldrich syndrome (WAS is an X-linked recessive disorder characterized by thrombocytopenia, eczema, and recurrent infections. The disease is usually associated with small defective platelets. Case Presentation: We described an 18-month-old boy who presented with lower gastrointestinal bleeding, eczema, and recurrent infections. There was pancytopenia with normal-sized platelets. In addition, the CD4 count was significantly low and serum IgA and IgE levels were increased. The diagnosis of WAS was confirmed by detecting a mutation of WAS gene, which was due to a deletion mutation resulting in frameshift (c.177DelT. Conclusions: Usually microplatelets with mean platelet volume of 4-5 fL are seen in WAS, but in this case, the patient had normal-sized platelets with a rare mutation of WAS gene. Therefore, high index of clinical suspicion is needed to diagnose WAS.

  1. The influence of DNA repair inhibitors on the mutation rate

    International Nuclear Information System (INIS)

    Auzinger, Th.; Hruby, R.

    1980-12-01

    The simultaneous influence of gamma-radiation and DNA-repair inhibiting substances on the mutation frequency of mice was investigated in vivo with the micronucleus test. The detergens Tween 80, vitamin A, and the antiphlogisticum phenylbutazone were used as DNA-repair inhibiting substances. Using the same irradiation doses, a statistic significant increase of mutagenicity respectively micronucleus frequency was found in high concentrations of Tween 80 and in all used dosages of vitamin A, but not in phenylbutazone and in low concentrations of tween. (auth.)

  2. Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates.

    Science.gov (United States)

    Werner, Benjamin; Sottoriva, Andrea

    2018-06-01

    The immortal strand hypothesis poses that stem cells could produce differentiated progeny while conserving the original template strand, thus avoiding accumulating somatic mutations. However, quantitating the extent of non-random DNA strand segregation in human stem cells remains difficult in vivo. Here we show that the change of the mean and variance of the mutational burden with age in healthy human tissues allows estimating strand segregation probabilities and somatic mutation rates. We analysed deep sequencing data from healthy human colon, small intestine, liver, skin and brain. We found highly effective non-random DNA strand segregation in all adult tissues (mean strand segregation probability: 0.98, standard error bounds (0.97,0.99)). In contrast, non-random strand segregation efficiency is reduced to 0.87 (0.78,0.88) in neural tissue during early development, suggesting stem cell pool expansions due to symmetric self-renewal. Healthy somatic mutation rates differed across tissue types, ranging from 3.5 × 10-9/bp/division in small intestine to 1.6 × 10-7/bp/division in skin.

  3. Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates.

    Directory of Open Access Journals (Sweden)

    Benjamin Werner

    2018-06-01

    Full Text Available The immortal strand hypothesis poses that stem cells could produce differentiated progeny while conserving the original template strand, thus avoiding accumulating somatic mutations. However, quantitating the extent of non-random DNA strand segregation in human stem cells remains difficult in vivo. Here we show that the change of the mean and variance of the mutational burden with age in healthy human tissues allows estimating strand segregation probabilities and somatic mutation rates. We analysed deep sequencing data from healthy human colon, small intestine, liver, skin and brain. We found highly effective non-random DNA strand segregation in all adult tissues (mean strand segregation probability: 0.98, standard error bounds (0.97,0.99. In contrast, non-random strand segregation efficiency is reduced to 0.87 (0.78,0.88 in neural tissue during early development, suggesting stem cell pool expansions due to symmetric self-renewal. Healthy somatic mutation rates differed across tissue types, ranging from 3.5 × 10-9/bp/division in small intestine to 1.6 × 10-7/bp/division in skin.

  4. Speech Rate Normalization and Phonemic Boundary Perception in Cochlear-Implant Users

    Science.gov (United States)

    Jaekel, Brittany N.; Newman, Rochelle S.; Goupell, Matthew J.

    2017-01-01

    Purpose: Normal-hearing (NH) listeners rate normalize, temporarily remapping phonemic category boundaries to account for a talker's speech rate. It is unknown if adults who use auditory prostheses called cochlear implants (CI) can rate normalize, as CIs transmit degraded speech signals to the auditory nerve. Ineffective adjustment to rate…

  5. Optimal mutation rates for the (1+λ) EA on OneMax

    DEFF Research Database (Denmark)

    Gießen, Christian; Witt, Carsten

    2016-01-01

    We study the (1 + λ) EA with mutation probability c/n, where c > 0 is a constant, on the ONEMAX problem. Using an improved variable drift theorem, we show that upper and lower bounds on the expected runtime of the (1+λ) EA obtained from variable drift theorems are at most apart by a small lower...... mutation rates for the (1+λ) EA for various parameter settings of c and λ and also for moderate sizes of n. This makes the need for potentially lengthy and costly experiments in order to optimize the parameters unnecessary. Interestingly, even for moderate n and not too small λ it turns out that mutation...... rates up to 10% larger than the asymptotically optimal rate 1/n minimize the expected runtime. However, in absolute terms the expected runtime does not change by much when replacing 1/n with the optimal mutation rate....

  6. The rate of beneficial mutations surfing on the wave of a range expansion.

    Directory of Open Access Journals (Sweden)

    Rémi Lehe

    Full Text Available Many theoretical and experimental studies suggest that range expansions can have severe consequences for the gene pool of the expanding population. Due to strongly enhanced genetic drift at the advancing frontier, neutral and weakly deleterious mutations can reach large frequencies in the newly colonized regions, as if they were surfing the front of the range expansion. These findings raise the question of how frequently beneficial mutations successfully surf at shifting range margins, thereby promoting adaptation towards a range-expansion phenotype. Here, we use individual-based simulations to study the surfing statistics of recurrent beneficial mutations on wave-like range expansions in linear habitats. We show that the rate of surfing depends on two strongly antagonistic factors, the probability of surfing given the spatial location of a novel mutation and the rate of occurrence of mutations at that location. The surfing probability strongly increases towards the tip of the wave. Novel mutations are unlikely to surf unless they enjoy a spatial head start compared to the bulk of the population. The needed head start is shown to be proportional to the inverse fitness of the mutant type, and only weakly dependent on the carrying capacity. The precise location dependence of surfing probabilities is derived from the non-extinction probability of a branching process within a moving field of growth rates. The second factor is the mutation occurrence which strongly decreases towards the tip of the wave. Thus, most successful mutations arise at an intermediate position in the front of the wave. We present an analytic theory for the tradeoff between these factors that allows to predict how frequently substitutions by beneficial mutations occur at invasion fronts. We find that small amounts of genetic drift increase the fixation rate of beneficial mutations at the advancing front, and thus could be important for adaptation during species invasions.

  7. Speech rate normalization used to improve speaker verification

    CSIR Research Space (South Africa)

    Van Heerden, CJ

    2006-11-01

    Full Text Available the normalized durations is then compared with the EER using unnormalized durations, and also with the EER when duration information is not employed. 2. Proposed phoneme duration modeling 2.1. Choosing parametric models Since the duration of a phoneme... the known transcription and the speaker-specific acoustic model described above. Only one pronunciation per word was allowed, thus resulting in 49 triphones. To decide which parametric model to use for the duration density func- tions of the triphones...

  8. Characterization of ultraviolet light-induced diphtheria toxin-resistant mutations in normal and Xeroderma pigmentosum human fibroblasts

    International Nuclear Information System (INIS)

    Glover, T.W.

    1979-01-01

    Quantitative mutagenesis studies in human cells have been severely limited by the lack of reliable genetic markers. Experiments were therefore performed to develop and characterize a better quantitative mutation assay for human cells. The uv-induction of diphtheria toxin resistant (DT/sup r/) mutations in normal and excision repair defective xeroderma pigmentosum (XP) fibroblasts has been quantitatively characterized. A concentration of diphtheria toxin to use in the selection of resistant mutants was determined whereby DT/sup r/ cells are cross-resistant to Pseudomonas aeurginosa exotoxin A, indicating mutants have altered elongation factor-2 (EF-2) which is not susceptible to ADP-ribosylation by either toxin. Results of this study indicate that XP fibroblasts have higher uv-induced mutation frequencies per unit uv-dose but similar frequencies per unit survival compared to normal cells as measured using a new genetic marker for quantitative mutagenesis. Furthermore, these results support a prediction of the mutation theory of cancer, namely, that cells from individuals with certain human syndromes that predispose the individual to cancer will have higher induced mutation frequencies than cells from non-susceptible individuals. This newly characterized genetic marker should be useful in quantitative mutagenesis studies in human cells

  9. Coordinated Changes in Mutation and Growth Rates Induced by Genome Reduction

    Directory of Open Access Journals (Sweden)

    Issei Nishimura

    2017-07-01

    Full Text Available Genome size is determined during evolution, but it can also be altered by genetic engineering in laboratories. The systematic characterization of reduced genomes provides valuable insights into the cellular properties that are quantitatively described by the global parameters related to the dynamics of growth and mutation. In the present study, we analyzed a small collection of W3110 Escherichia coli derivatives containing either the wild-type genome or reduced genomes of various lengths to examine whether the mutation rate, a global parameter representing genomic plasticity, was affected by genome reduction. We found that the mutation rates of these cells increased with genome reduction. The correlation between genome length and mutation rate, which has been reported for the evolution of bacteria, was also identified, intriguingly, for genome reduction. Gene function enrichment analysis indicated that the deletion of many of the genes encoding membrane and transport proteins play a role in the mutation rate changes mediated by genome reduction. Furthermore, the increase in the mutation rate with genome reduction was highly associated with a decrease in the growth rate in a nutrition-dependent manner; thus, poorer media showed a larger change that was of higher significance. This negative correlation was strongly supported by experimental evidence that the serial transfer of the reduced genome improved the growth rate and reduced the mutation rate to a large extent. Taken together, the global parameters corresponding to the genome, growth, and mutation showed a coordinated relationship, which might be an essential working principle for balancing the cellular dynamics appropriate to the environment.

  10. Germline mutation rates at tandem repeat loci in DNA-repair deficient mice

    International Nuclear Information System (INIS)

    Barber, Ruth C.; Miccoli, Laurent; Buul, Paul P.W. van; Burr, Karen L.-A.; Duyn-Goedhart, Annemarie van; Angulo, Jaime F.; Dubrova, Yuri E.

    2004-01-01

    Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of non-exposed and irradiated severe combined immunodeficient (scid) and poly(ADP-ribose) polymerase (PARP-1 -/- ) deficient male mice. Non-exposed scid and PARP -/- male mice showed considerably elevated ESTR mutation rates, far higher than those in wild-type isogenic mice and other inbred strains. The irradiated scid and PARP-1 -/- male mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated wild-type isogenic males. ESTR mutation spectra in the scid and PARP-1 -/- strains did not differ from those in the isogenic wild-type strains. Considering these data and the results of previous studies, we propose that a delay in repair of DNA damage in scid and PARP-1 -/- mice could result in replication fork pausing which, in turn, may affect ESTR mutation rate in the non-irradiated males. The lack of mutation induction in irradiated scid and PARP-1 -/- can be explained by the high cell killing effects of irradiation on the germline of deficient mice

  11. Low Base-Substitution Mutation Rate in the Germline Genome of the Ciliate Tetrahymena thermophila

    Science.gov (United States)

    2016-09-15

    Tetrahymena thermophila, a model eukaryote. PLoS Biol. 4:e286. Farlow A, et al. 2015. The spontaneous mutation rate in the fission yeast Schizosaccharomyces...spontane- ous mutations in yeast . Proc Natl Acad Sci U S A. 105:9272–9277. Lynn DH, Doerder FP. 2012. The life and times of Tetrahymena. Methods Cell...Low Base-Substitution Mutation Rate in the Germline Genome of the Ciliate Tetrahymena thermophila Hongan Long1,2,y, David J. Winter3,*,y, Allan Y.-C

  12. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Directory of Open Access Journals (Sweden)

    Virijevic Marijana

    2016-12-01

    Full Text Available Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2 genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK. The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up.

  13. Optimized reaction mechanism rate rules for ignition of normal alkanes

    KAUST Repository

    Cai, Liming; Pitsch, Heinz; Mohamed, Samah; Raman, Venkat; Bugler, John; Curran, Henry; Sarathy, Mani

    2016-01-01

    fidelity reacting flow simulations capable of improving combustor design and operation. The development of such models for many new fuel components and/or surrogate molecules is greatly facilitated by the application of reaction classes and rate rules

  14. Constraining slip rates and spacings for active normal faults

    Science.gov (United States)

    Cowie, Patience A.; Roberts, Gerald P.

    2001-12-01

    Numerous observations of extensional provinces indicate that neighbouring faults commonly slip at different rates and, moreover, may be active over different time intervals. These published observations include variations in slip rate measured along-strike of a fault array or fault zone, as well as significant across-strike differences in the timing and rates of movement on faults that have a similar orientation with respect to the regional stress field. Here we review published examples from the western USA, the North Sea, and central Greece, and present new data from the Italian Apennines that support the idea that such variations are systematic and thus to some extent predictable. The basis for the prediction is that: (1) the way in which a fault grows is fundamentally controlled by the ratio of maximum displacement to length, and (2) the regional strain rate must remain approximately constant through time. We show how data on fault lengths and displacements can be used to model the observed patterns of long-term slip rate where measured values are sparse. Specifically, we estimate the magnitude of spatial variation in slip rate along-strike and relate it to the across-strike spacing between active faults.

  15. Predicting protein folding rate change upon point mutation using residue-level coevolutionary information.

    Science.gov (United States)

    Mallik, Saurav; Das, Smita; Kundu, Sudip

    2016-01-01

    Change in folding kinetics of globular proteins upon point mutation is crucial to a wide spectrum of biological research, such as protein misfolding, toxicity, and aggregations. Here we seek to address whether residue-level coevolutionary information of globular proteins can be informative to folding rate changes upon point mutations. Generating residue-level coevolutionary networks of globular proteins, we analyze three parameters: relative coevolution order (rCEO), network density (ND), and characteristic path length (CPL). A point mutation is considered to be equivalent to a node deletion of this network and respective percentage changes in rCEO, ND, CPL are found linearly correlated (0.84, 0.73, and -0.61, respectively) with experimental folding rate changes. The three parameters predict the folding rate change upon a point mutation with 0.031, 0.045, and 0.059 standard errors, respectively. © 2015 Wiley Periodicals, Inc.

  16. Non-uniform Mutation Rates for Problems with Unknown Solution Lengths

    DEFF Research Database (Denmark)

    Cathabard, Stephan; Lehre, Per Kristian; Yao, Xin

    2011-01-01

    Many practical optimisation problems allow candidate solu- tions of varying lengths, and where the length of the opti- mal solution is thereby a priori unknown. We suggest that non-uniform mutation rates can be beneficial when solving such problems. In particular, we consider a mutation oper- ator...... that flips each bit with a probability that is inversely proportional to the bit position, rather than the bitstring length. The runtime of the (1+1) EA using this mutation operator is analysed rigorously on standard example func- tions. Furthermore, the behaviour of the new mutation op- erator...... distribution, and show that the new operator can yield exponentially faster runtimes for some parameters of this distribution. The experimental results show that the new mutation operator leads to dramatically shorter runtimes on a class of instances of the software engi- neering problem that is conjectured...

  17. Early Embryonic Heart Rate in Normal Pregnancies In Memory of ...

    African Journals Online (AJOL)

    To determine the appearance and development of embryonic heart rate a total of n = 317 Nigerian pregnant women were studied in the very early pregnancy from 23 – 56 days from the onset of last menstrual period (LMP). All pregnancies had a subsequent successful outcome. Transvaginal ultrasonography was ...

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

    Science.gov (United States)

    Frenoy, Antoine; Bonhoeffer, Sebastian

    2018-05-01

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

  19. High mitochondrial mutation rates estimated from deep-rooting Costa Rican pedigrees

    Science.gov (United States)

    Madrigal, Lorena; Melendez-Obando, Mauricio; Villegas-Palma, Ramon; Barrantes, Ramiro; Raventos, Henrieta; Pereira, Reynaldo; Luiselli, Donata; Pettener, Davide; Barbujani, Guido

    2012-01-01

    Estimates of mutation rates for the noncoding hypervariable Region I (HVR-I) of mitochondrial DNA (mtDNA) vary widely, depending on whether they are inferred from phylogenies (assuming that molecular evolution is clock-like) or directly from pedigrees. All pedigree-based studies so far were conducted on populations of European origin. In this paper we analyzed 19 deep-rooting pedigrees in a population of mixed origin in Costa Rica. We calculated two estimates of the HVR-I mutation rate, one considering all apparent mutations, and one disregarding changes at sites known to be mutational hot spots and eliminating genealogy branches which might be suspected to include errors, or unrecognized adoptions along the female lines. At the end of this procedure, we still observed a mutation rate equal to 1.24 × 10−6, per site per year, i.e., at least three-fold as high as estimates derived from phylogenies. Our results confirm that mutation rates observed in pedigrees are much higher than estimated assuming a neutral model of long-term HVRI evolution. We argue that, until the cause of these discrepancies will be fully understood, both lower estimates (i.e., those derived from phylogenetic comparisons) and higher, direct estimates such as those obtained in this study, should be considered when modeling evolutionary and demographic processes. PMID:22460349

  20. High Mutation Levels are Compatible with Normal Embryonic Development in Mlh1-Deficient Mice.

    Science.gov (United States)

    Fan, Xiaoyan; Li, Yan; Zhang, Yulong; Sang, Meixiang; Cai, Jianhui; Li, Qiaoxia; Ozaki, Toshinori; Ono, Tetsuya; He, Dongwei

    2016-10-01

    To elucidate the role of the mismatch repair gene Mlh1 in genome instability during the fetal stage, spontaneous mutations were studied in Mlh1-deficient lacZ-transgenic mouse fetuses. Mutation levels were high at 9.5 days post coitum (dpc) and gradually increased during the embryonic stage, after which they remained unchanged. In addition, mutations that were found in brain, liver, spleen, small intestine and thymus showed similar levels and no statistically significant difference was found. The molecular nature of mutations at 12.5 dpc in fetuses of Mlh1 +/+ and Mlh1 -/- mice showed their own unique spectra, suggesting that deletion mutations were the main causes in the deficiency of the Mlh1 gene. Of note, fetuses of irradiated mice exhibited marked differences such as post-implantation loss and Mendelian distribution. Collectively, these results strongly suggest that high mutation ofMlh1 -/- -deficient fetuses has little effect on the fetuses during their early developmental stages, whereas Mlh1 -/- -deficient fetuses from X-ray irradiated mothers are clearly effected.

  1. Mutation and evolutionary rates in adélie penguins from the antarctic.

    Directory of Open Access Journals (Sweden)

    Craig D Millar

    2008-10-01

    Full Text Available Precise estimations of molecular rates are fundamental to our understanding of the processes of evolution. In principle, mutation and evolutionary rates for neutral regions of the same species are expected to be equal. However, a number of recent studies have shown that mutation rates estimated from pedigree material are much faster than evolutionary rates measured over longer time periods. To resolve this apparent contradiction, we have examined the hypervariable region (HVR I of the mitochondrial genome using families of Adélie penguins (Pygoscelis adeliae from the Antarctic. We sequenced 344 bps of the HVR I from penguins comprising 508 families with 915 chicks, together with both their parents. All of the 62 germline heteroplasmies that we detected in mothers were also detected in their offspring, consistent with maternal inheritance. These data give an estimated mutation rate (micro of 0.55 mutations/site/Myrs (HPD 95% confidence interval of 0.29-0.88 mutations/site/Myrs after accounting for the persistence of these heteroplasmies and the sensitivity of current detection methods. In comparison, the rate of evolution (k of the same HVR I region, determined using DNA sequences from 162 known age sub-fossil bones spanning a 37,000-year period, was 0.86 substitutions/site/Myrs (HPD 95% confidence interval of 0.53 and 1.17. Importantly, the latter rate is not statistically different from our estimate of the mutation rate. These results are in contrast to the view that molecular rates are time dependent.

  2. Automatic heart rate normalization for accurate energy expenditure normalization : an analysis of activities of daily living and heart rate features

    NARCIS (Netherlands)

    Altini, M.; Penders, J.; Vullers, R.J.M.; Amft, O.D.

    2014-01-01

    Introduction: This article is part of the Focus Theme of Methods of Information in Medicine on "Pervasive Intelligent Technologies for Health". Background: Energy Expenditure (EE) estimation algorithms using Heart Rate (HR) or a combination of accelerometer and HR data suffer from large error due to

  3. Germline mutation rates in families residing in high level natural radiation areas of Kerala coast in southwest India

    International Nuclear Information System (INIS)

    Das, Birajalaxmi; Ghosh, Anu; Ahmad, Shazia; Saini, DivyaIakshmi; Chauhan, P.S.; Seshadri, M.

    2010-01-01

    For this study, 200 nuclear families have been analyzed using over 40 mini- and microsatellite markers. Cord blood samples for the child and peripheral blood samples for the parent(s) were collected in EDTA vacuutainers from the hospital units located in High Level Natural Radiation Areas (HLNRA) and Normal Level Natural Radiation Areas (NLNRA). Both the parents of the newborn were exposed to the background dose. The families were grouped into four distinct dose groups - NLNRA group 5.00 mGy/year. An overall mutation rate of 2.08 X 10 -3 per cell per generation was observed for NLNRA and 2.12 X 10 -3 per cell per generation for HLNRA families. No radiation induced dose response was observed for the stratified groups. Thus, this study shows that mutation rates at mini- and microsatellites in the off springs of the parents living in the high background radiation areas of Kerala does not vary with radiation exposure. This is the first report to understand germline mutation rates at hypervariable loci in families residing in high level natural radiation areas of the world

  4. Single genome retrieval of context-dependent variability in mutation rates for human germline.

    Science.gov (United States)

    Sahakyan, Aleksandr B; Balasubramanian, Shankar

    2017-01-13

    Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome. The rates are characterised through rate constants in a time-domain, and are made available through a dedicated program (Trek) and a stand-alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG-independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human. The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes.

  5. Increase of the spontaneous mutation rate in a long-term experiment with Drosophila melanogaster.

    Science.gov (United States)

    Avila, Victoria; Chavarrías, David; Sánchez, Enrique; Manrique, Antonio; López-Fanjul, Carlos; García-Dorado, Aurora

    2006-05-01

    In a previous experiment, the effect of 255 generations of mutation accumulation (MA) on the second chromosome viability of Drosophila melanogaster was studied using 200 full-sib MA1 lines and a large C1 control, both derived from a genetically homogeneous base population. At generation 265, one of those MA1 lines was expanded to start 150 new full-sib MA2 lines and a new C2 large control. After 46 generations, the rate of decline in mean viability in MA2 was approximately 2.5 times that estimated in MA1, while the average degree of dominance of mutations was small and nonsignificant by generation 40 and moderate by generation 80. In parallel, the inbreeding depression rate for viability and the amount of additive variance for two bristle traits in C2 were 2-3 times larger than those in C1. The results are consistent with a mutation rate in the line from which MA2 and C2 were derived about 2.5 times larger than that in MA1. The mean viability of C2 remained roughly similar to that of C1, but the rate of MA2 line extinction increased progressively, leading to mutational collapse, which can be ascribed to accelerated mutation and/or synergy after important deleterious accumulation.

  6. Spontaneous mutation rate in Chinese hamster cell clones differing in UV-sensitivity

    International Nuclear Information System (INIS)

    Manuilova, E.S.; Bagrova, A.M.; Moskovskij Gosudarstvennyj Univ.

    1983-01-01

    The spontaneous rate of appearance of mutations to 6-mercaptopurine (6 MP) resistence in the cells of CHR2 and CHs2 clones dofferent in sensitivity to lethal and matagenous effect of UV-rays, is investigated. Increased UV-sensitivity of CHs2 clone is caused by the violation of postreplicative DNA reparation. It is established that the purity of spontaneously occuring mutations in both clones turns out to be similar, i.e. (1.5-1.8)x10 -5 for the cell pergeneration. It is shown that the effect of postreplicative DNA reparation in the cells of chinese hamster is not connected with the increase of spontaneous mutation ability. The problem on the possible role of reparation in the mechanism of appearance of spontaneous and induced mutations in the cells of Chinese hamster with increased UV-sensitivity is discussed

  7. Germline mutation rates in mice following in utero exposure to diesel exhaust particles by maternal inhalation

    DEFF Research Database (Denmark)

    Ritz, Caitlin; Ruminski, Wojciech; Hougaard, Karin S.

    2011-01-01

    (PAPs) from industrial environments cause DNA damage and mutations in the sperm of adult male mice. Effects on the female and male germline during critical stages of development (in utero) are unknown. In mice, previous studies have shown that expanded simple tandem repeat (ESTR) loci exhibit high rates......The induction of inherited DNA sequence mutations arising in the germline (i.e., sperm or egg) of mice exposed in utero to diesel exhaust particles (DEPs) via maternal inhalation compared to unexposed controls was investigated in this study. Previous work has shown that particulate air pollutants...... of spontaneous mutation, making this endpoint a valuable tool for studying inherited mutation and genomic instability. In the present study, pregnant C57Bl/6 mice were exposed to 19mg/m3 DEP from gestational day 7 through 19, alongside air exposed controls. Male and female F1 offspring were raised to maturity...

  8. A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty

    Science.gov (United States)

    Arroyo, Armando; Pernasetti, Flavia; Vasilyev, Vyacheslav V.; Amato, Paula; Yen, Samuel S. C.; Mellon, Pamela L.

    2010-01-01

    Summary We report a 28-year-old-female who presented with primary amenorrhoea, absence of puberty, obesity and normal stature. The subject was clearly short as a child, with a height more than 2 SD below normal until the age of 15 years. The pubertal growth spurt failed to develop. She continued growing at a prepubertal rate until growth ceased at the age of 20 years, reaching her final adult height of 157 cm (SDS −0.86) without hormonal treatment. A combined pituitary hormone stimulation test of anterior pituitary function showed deficiencies of GH, LH and FSH, and low normal serum levels of TSH and PRL. Magnetic resonance imaging revealed a hypoplastic pituitary with markedly reduced pituitary height. In addition, a whole body dual energy X-ray absorptiometry scan showed high levels of body fat (54%). Combined pituitary hormone deficiencies with a hypoplastic pituitary suggested the diagnosis of a Prophet of Pit-1 (PROP1) gene mutation. Normal stature in this case, however, confounded this diagnosis. Sequencing of PROP1 revealed homozygosity for a single base-pair substitution (C to T), resulting in the replacement of an Arg by a Cys at codon 120 (R120C) in the third helix of the homeodomain of the Prop-1 protein. To our knowledge, this is the first report of a patient with a mutation in the PROP1 gene that attained normal height without hormonal treatment, indicating a new variability in the PROP1 phenotype, with important implications for the diagnosis of these patients. We suggest that this can be explained by (i) the presence of low levels of GH in the circulation during childhood and adolescence; (ii) the lack of circulating oestrogen delaying epiphyseal fusion, resulting in growth beyond the period of normal growth; and (iii) fusion of the epiphyseal plates, possibly as a result of circulating oestrogens originating from peripheral conversion of androgens by adipose tissue. PMID:12153609

  9. Male Mutation Bias Is the Main Force Shaping Chromosomal Substitution Rates in Monotreme Mammals.

    Science.gov (United States)

    Link, Vivian; Aguilar-Gómez, Diana; Ramírez-Suástegui, Ciro; Hurst, Laurence D; Cortez, Diego

    2017-09-01

    In many species, spermatogenesis involves more cell divisions than oogenesis, and the male germline, therefore, accumulates more DNA replication errors, a phenomenon known as male mutation bias. The extent of male mutation bias (α) is estimated by comparing substitution rates of the X, Y, and autosomal chromosomes, as these chromosomes spend different proportions of their time in the germlines of the two sexes. Male mutation bias has been characterized in placental and marsupial mammals as well as birds, but analyses in monotremes failed to detect any such bias. Monotremes are an ancient lineage of egg-laying mammals with distinct biological properties, which include unique germline features. Here, we sought to assess the presence and potential characteristics of male mutation bias in platypus and the short-beaked echidna based on substitution rate analyses of X, Y, and autosomes. We established the presence of moderate male mutation bias in monotremes, corresponding to an α value of 2.12-3.69. Given that it has been unclear what proportion of the variation in substitution rates on the different chromosomal classes is really due to differential number of replications, we analyzed the influence of other confounding forces (selection, replication-timing, etc.) and found that male mutation bias is the main force explaining the between-chromosome classes differences in substitution rates. Finally, we estimated the proportion of variation at the gene level in substitution rates that is owing to replication effects and found that this phenomenon can explain >68% of these variations in monotremes, and in control species, rodents, and primates. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  10. Age and sex effects on human mutation rates. An old problem with new complexities

    International Nuclear Information System (INIS)

    Crow, James F.

    2006-01-01

    Base substitution mutations are far more common in human males than in females, and the frequency increases with paternal age. Both can be accounted for by the greater number of pre-meiotic cell divisions in males, especially old ones. In contrast, small deletions do not show any important age effect and occur with approximately equal frequency in the two sexes. Mutations in most genes include both types, and the sex and paternal age effect depends on the proportion of the two types. A few traits, of which Apert Syndrome is best understood, are mutation hot spots with all the mutations occurring in one or two codons, usually at one nucleotide. They occur with very high frequency almost exclusively in males and the frequency increases rapidly with paternal age. It has been suggested that the mutant cells have a selective advantage in the male germ-line prior to meiosis. Evidence for this surprising, but important, hypothesis is discussed. A possible mechanism is the conversion of asymmetrical stem-cell divisions into symmetric ones. Some traits with complex etiology show a slight paternal age effect. There is also a short discussion of the high deleterious mutation rate and the role of sexual reproduction in reducing the consequent mutation load. (author)

  11. Increased heart rate variability but normal resting metabolic rate in hypocretin/orexin-deficient human narcolepsy.

    NARCIS (Netherlands)

    Fronczek, R.; Overeem, S.; Reijntjes, R.; Lammers, G.J.; Dijk, J.G.M.; Pijl, H.

    2008-01-01

    STUDY OBJECTIVES: We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects. METHODS: Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were

  12. Y-chromosome-specific microsatellite mutation rates re-examined using a minisatellite, MSY1.

    Science.gov (United States)

    Jobling, M A; Heyer, E; Dieltjes, P; de Knijff, P

    1999-10-01

    Polymorphic Y-chromosome-specific microsatellites are becoming increasingly used in evolutionary and forensic studies and, in particular, in dating the origins of Y-chromosomal lineages. Previously, haplotyping of Y chromosomes from males belonging to a set of deep-rooting pedigrees was used to estimate a conservative average Y-chromosomal microsatellite mutation rate of 2.1 x 10(-3)per locus per generation. A number of males showed multiple differences in haplotypes compared with other males within their pedigrees, and these were excluded from the calculation of this estimate, on the grounds that non-paternity was a more probable explanation than multiple mutation within a lineage. Here we reanalyse the pedigrees using an independent highly polymorphic system, the Y-specific minisatellite, MSY1. This supports the hypothesis of non-paternity where more than one microsatellite difference was observed, provides further support for the previously deduced microsatellite mutation rate and throws light on the mutation dynamics of MSY1 itself, suggesting that single-step changes are not the only mode of mutation.

  13. Chronical influence of radiation and lead on mutation rates in plants of Arabidopsis Thaliana (L.) Heynh

    International Nuclear Information System (INIS)

    Kryukov, V.I.; Shishkin, V.A.; Sokolenko, S.F.

    1996-01-01

    Plants of Arabidopsis thaliana were grown in a laboratory conditions on the soil (black earth, chernozem) which was polluted with a radioactive isotopes of cesium, 134+137 Cs. Increase in specific activity of samples from 217 to 1025 and 2529 Bq/kg resulted in increase of embryonic mutation rate in Arabidopsis from 8.2 to 20.2 and 51.6 % respectively. Bringing Pb 2+ in a dose of 16 mg into the soil resulted in statistically significant decrease in mutation rate. Further increase of lead concentration in radioactive soils to 32, 64, 96, 160 and 320 mg/kg resulted in growth of the mutation rates in the plants which were grown on the soil with low and middle specific activity of cesium, and in decrease of the mutation rates in the plants which were grown on the soil with high specific radioactivity. The last process apparently was connected with the intensive growth in the number of sterile seeds in the pods. 19 refs.; 2 figs.; 4 tabs

  14. The rate and potential relevance of new mutations in a colonizing plant lineage.

    Directory of Open Access Journals (Sweden)

    Moises Exposito-Alonso

    2018-02-01

    Full Text Available By following the evolution of populations that are initially genetically homogeneous, much can be learned about core biological principles. For example, it allows for detailed studies of the rate of emergence of de novo mutations and their change in frequency due to drift and selection. Unfortunately, in multicellular organisms with generation times of months or years, it is difficult to set up and carry out such experiments over many generations. An alternative is provided by "natural evolution experiments" that started from colonizations or invasions of new habitats by selfing lineages. With limited or missing gene flow from other lineages, new mutations and their effects can be easily detected. North America has been colonized in historic times by the plant Arabidopsis thaliana, and although multiple intercrossing lineages are found today, many of the individuals belong to a single lineage, HPG1. To determine in this lineage the rate of substitutions-the subset of mutations that survived natural selection and drift-, we have sequenced genomes from plants collected between 1863 and 2006. We identified 73 modern and 27 herbarium specimens that belonged to HPG1. Using the estimated substitution rate, we infer that the last common HPG1 ancestor lived in the early 17th century, when it was most likely introduced by chance from Europe. Mutations in coding regions are depleted in frequency compared to those in other portions of the genome, consistent with purifying selection. Nevertheless, a handful of mutations is found at high frequency in present-day populations. We link these to detectable phenotypic variance in traits of known ecological importance, life history and growth, which could reflect their adaptive value. Our work showcases how, by applying genomics methods to a combination of modern and historic samples from colonizing lineages, we can directly study new mutations and their potential evolutionary relevance.

  15. Hepatocyte nuclear factor 1-alpha mutation in normal glucose-tolerant subjects and early-onset type 2 diabetic patients

    OpenAIRE

    Lim, Dong Mee; Huh, Nam; Park, Keun Yong

    2008-01-01

    Background/Aims The prevalence of diabetes in Korea is reported to be approximately 10%, but cases of maturity-onset diabetes of the young (MODY) are rare in Korea. A diagnostic technique for autosomal dominant MODY is being actively sought. In this regard, we used a DNA chip to investigate the frequency of mutations of the MODY3 gene (hepatocyte nuclear factor-1?) in Korean patients with early-onset type 2 diabetes. Methods The genomic DNA of 30 normal individuals [age, 24.9?8.6 years] and 2...

  16. Genetic influence of radiation measured by the effect on the mutation rate of human minisatellite genes

    International Nuclear Information System (INIS)

    Kodaira, Mieko

    2002-01-01

    Human minisatellite genes are composed from 0.1-30 kb with a high frequency of polymorphism. The genes exist in mammalian genomes and mice's ones are well studied after irradiation of their gonad cells by X-ray and γ-ray. Following five reports concerning the significant and/or insignificant increases of the mutation rate of the genes post A-bomb exposure, Chernobyl accident and nuclear weapons test in Semipalatinsk are reviewed and discussed on the subject number, exposed dose, problems of the control group, regions examined of loci and exposure conditions. Genetic influences of radiation examined by the author's facility are not recognized in the mutation rate (3.21% vs 4.94% in the control) of minisatellite genes in children of A-bomb survivors and their parents. The mutation rates are 4.27 vs 2.52% (positive influence) and 4.2-6.01% vs 3.5-6.34% in Chernobyl, and 4.3 (parents) and 3.8% (F 1 ) vs 2.5% (positive). Mutation of human minisatellite genes can be an important measure of genetic influences at the medical level. (K.H.)

  17. Experimental estimation of mutation rates in a wheat population with a gene genealogy approach.

    Science.gov (United States)

    Raquin, Anne-Laure; Depaulis, Frantz; Lambert, Amaury; Galic, Nathalie; Brabant, Philippe; Goldringer, Isabelle

    2008-08-01

    Microsatellite markers are extensively used to evaluate genetic diversity in natural or experimental evolving populations. Their high degree of polymorphism reflects their high mutation rates. Estimates of the mutation rates are therefore necessary when characterizing diversity in populations. As a complement to the classical experimental designs, we propose to use experimental populations, where the initial state is entirely known and some intermediate states have been thoroughly surveyed, thus providing a short timescale estimation together with a large number of cumulated meioses. In this article, we derived four original gene genealogy-based methods to assess mutation rates with limited bias due to relevant model assumptions incorporating the initial state, the number of new alleles, and the genetic effective population size. We studied the evolution of genetic diversity at 21 microsatellite markers, after 15 generations in an experimental wheat population. Compared to the parents, 23 new alleles were found in generation 15 at 9 of the 21 loci studied. We provide evidence that they arose by mutation. Corresponding estimates of the mutation rates ranged from 0 to 4.97 x 10(-3) per generation (i.e., year). Sequences of several alleles revealed that length polymorphism was only due to variation in the core of the microsatellite. Among different microsatellite characteristics, both the motif repeat number and an independent estimation of the Nei diversity were correlated with the novel diversity. Despite a reduced genetic effective size, global diversity at microsatellite markers increased in this population, suggesting that microsatellite diversity should be used with caution as an indicator in biodiversity conservation issues.

  18. Hemispherical dominance of glucose metabolic rate in the brain of the 'normal' ageing population

    NARCIS (Netherlands)

    Cutts, DA; Maguire, RP; Leenders, KL; Spyrou, NM

    2004-01-01

    In the 'normal' ageing brain a decrease in the cerebral metabolic rate has been determined across many brain regions. This study determines whether age differences would affect metabolic rates in regions and different hemispheres of the brain. The regional metabolic rate of glucose (rCMRGlu) was

  19. An approximate stationary solution for multi-allele neutral diffusion with low mutation rates.

    Science.gov (United States)

    Burden, Conrad J; Tang, Yurong

    2016-12-01

    We address the problem of determining the stationary distribution of the multi-allelic, neutral-evolution Wright-Fisher model in the diffusion limit. A full solution to this problem for an arbitrary K×K mutation rate matrix involves solving for the stationary solution of a forward Kolmogorov equation over a (K-1)-dimensional simplex, and remains intractable. In most practical situations mutations rates are slow on the scale of the diffusion limit and the solution is heavily concentrated on the corners and edges of the simplex. In this paper we present a practical approximate solution for slow mutation rates in the form of a set of line densities along the edges of the simplex. The method of solution relies on parameterising the general non-reversible rate matrix as the sum of a reversible part and a set of (K-1)(K-2)/2 independent terms corresponding to fluxes of probability along closed paths around faces of the simplex. The solution is potentially a first step in estimating non-reversible evolutionary rate matrices from observed allele frequency spectra. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism

    Directory of Open Access Journals (Sweden)

    Kyleen Luhrs

    2017-01-01

    Full Text Available The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n=62, de novo deletion copy number variations (DEL, n=74, de novo likely gene-disrupting mutations (LGDM, n=267, and children without a known genetic etiology (NON, n=2111. Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.

  1. Distinct Contributions of Replication and Transcription to Mutation Rate Variation of Human Genomes

    KAUST Repository

    Cui, Peng; Ding, Feng; Lin, Qiang; Zhang, Lingfang; Li, Ang; Zhang, Zhang; Hu, Songnian; Yu, Jun

    2012-01-01

    Here, we evaluate the contribution of two major biological processes—DNA replication and transcription—to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.

  2. Distinct Contributions of Replication and Transcription to Mutation Rate Variation of Human Genomes

    KAUST Repository

    Cui, Peng

    2012-03-23

    Here, we evaluate the contribution of two major biological processes—DNA replication and transcription—to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.

  3. Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed?

    Directory of Open Access Journals (Sweden)

    Agnieszka Ługowska

    Full Text Available BACKGROUND: Metachromatic leukodystrophy (MLD is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data. METHODOLOGY: We studied two independently ascertained cohorts from the Polish background population (N∼3000 each and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1 and c.459+1G>A, p.I179S (cohort 2. PRINCIPAL FINDINGS: Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses was estimated as 4.0/100,000 and 4.1/100,000, respectively for the 1(st and the 2(nd cohort with a pooled estimate of 4.1/100,000 (CI: 1.8-9.4 which was higher than the estimate of 0.38 per 100,000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients. CONCLUSIONS/SIGNIFICANCE: The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms.

  4. Heart rate variability in normal-weight patients with polycystic ovary syndrome

    OpenAIRE

    Kilit, Celal; Kilit, T?rkan Pa?al?

    2017-01-01

    Objective: Polycystic ovary syndrome (PCOS) is an endocrine disease closely related to several risk factors of cardiovascular disease. Obese women with PCOS show altered autonomic modulation. The results of studies investigating cardiac autonomic functions of normal-weight women with PCOS are conflicting. The aim of the study was to assess the reactivity of cardiac sympathovagal balance in normal-weight women with PCOS by heart rate variability analysis. Methods: We examined the heart rate va...

  5. Quantitative assessment of thallium myocardial washout rate: Importance of peak heart rate and lung thallium uptake in defining normal values

    International Nuclear Information System (INIS)

    Nishimura, Tsunehiko; Uehara, Toshiisa; Hayashida, Kohei; Kozuka, Takahiro; Saito, Muneyasu; Sumiyoshi, Tetsuya; National Cardiovascular Center, Suita, Osaka

    1987-01-01

    Traditionally, the results of exercise thallium scintigraphy were interpreted by transient defect analysis using initial and delayed images. Recently, washout rate analysis has been used for the relative quantification of exercise thallium scintigraphy. A diffuse slow washout from all myocardial regions has been defined as the indicator of extensive coronary artery disease. However, slow washout has occasionally been observed in normal cases and in healthy myocardial segments which are not supplied by a stenosed artery in patients with single or double vessel disease. We evaluate the factors influencing washout rate in 100 normal patients and 63 patients with angina pectoris (33 cases of single vessel disease and 30 cases of double vessel disease). The washout rates were calculated using circumferential profile analysis. In normal patients, washout rate was closely related to peak heart rate (r=0.72) and inversely related to lung thallium uptake (r=-0.56). A diffuse slow washout was observed in seven (7%) of 100 normal patients, six (18%) of 33 cases of single vessel disease and eight (24%) of 30 cases of double vessel disease. The patients with diffuse slow washout showed significantly higher lung thallium uptake values and lower peak heart rates than those without diffuse slow washout (P<0.01). Thus, this false positive slow washout should be considered in the interpretation of quantitative exercise thallium scintigraphy. (orig.)

  6. Radiation-induced cell mutations as a function of dose rate

    International Nuclear Information System (INIS)

    Kiefer, J.

    1987-01-01

    A brief review of the data in the literature is presented and forms the background of the experimental data given by the author obtained with exponential long-term cultures of V79 hamster cells exposed over a period of up to 35 days to different dose rates of gamma radiation. The experimental results show that at a dose rate of 40 mGy/hour the number of induced mutations is reduced, - which is in agreement with literature data - , but a dose rate of less than 30 mGy/hour makes the induced mutations leap to a value clearly higher than those induced by acute irradiation. As in addition to the mutations recombination is a significant factor of the radiation risk, experiments with a heterozygotic yeast strain have been made, as there is to date no reliable mammalian cell system available for this kind of research. Long-term radiation exposure of the yeast cells over a period of six weeks drastically increased the rate of recombinations, to a value higher by a factor of about 4 than that induced by acute irradiation. (orig.) [de

  7. A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data.

    Science.gov (United States)

    Bertl, Johanna; Guo, Qianyun; Juul, Malene; Besenbacher, Søren; Nielsen, Morten Muhlig; Hornshøj, Henrik; Pedersen, Jakob Skou; Hobolth, Asger

    2018-04-19

    Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration. To take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures. We find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model

  8. Erratum Haldane and the first estimates of the human mutation rate

    Indian Academy of Sciences (India)

    Published on the Web: 1 December 2008. Erratum. Haldane and the first estimates of the human mutation rate. (A commentary on J.B.S. Haldane 1935 J. Genet. 31, 317–326; reprinted in volume 83, 235–244 as a J. Genet. classic). Michael W. Nachman. J. Genet. 83, 231–233. Page 1, right column, para 1, line 6 from ...

  9. Fast maximum likelihood estimation of mutation rates using a birth-death process.

    Science.gov (United States)

    Wu, Xiaowei; Zhu, Hongxiao

    2015-02-07

    Since fluctuation analysis was first introduced by Luria and Delbrück in 1943, it has been widely used to make inference about spontaneous mutation rates in cultured cells. Under certain model assumptions, the probability distribution of the number of mutants that appear in a fluctuation experiment can be derived explicitly, which provides the basis of mutation rate estimation. It has been shown that, among various existing estimators, the maximum likelihood estimator usually demonstrates some desirable properties such as consistency and lower mean squared error. However, its application in real experimental data is often hindered by slow computation of likelihood due to the recursive form of the mutant-count distribution. We propose a fast maximum likelihood estimator of mutation rates, MLE-BD, based on a birth-death process model with non-differential growth assumption. Simulation studies demonstrate that, compared with the conventional maximum likelihood estimator derived from the Luria-Delbrück distribution, MLE-BD achieves substantial improvement on computational speed and is applicable to arbitrarily large number of mutants. In addition, it still retains good accuracy on point estimation. Published by Elsevier Ltd.

  10. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

    DEFF Research Database (Denmark)

    Giannoulatou, Eleni; McVean, Gilean; Taylor, Indira B

    2013-01-01

    Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed...

  11. Age-related increase in the rate of spontaneou and γ-ray-induced hprt mutations in mouse spleen lymphocytes

    International Nuclear Information System (INIS)

    Gazlev, A.I.; Podlutskii, A.Ya.; Bradbury, R.

    1994-01-01

    Endogenous and exogenous factors continually afflict DNA of cells of organisms. A certain amount of the damage is accumulated causing mutations, increasing the risk of malignacies, impairing cell functions, and upsetting the body's homeostasis. The research reported here studies the rates of spontaneous hprt nmutationsand those induced you ggammairradiation in the splenocytes of mice at various ages. The rate of spontaneous and induced hprt gene mutations increases with aging. In gamma irradiated mice the rate of radiation-induced mutations depended on the absorbed dose and age, with the rate 2.3-3.0 fold higher in 104-110 week old mice than in younger pups. 15 refs., 1 tab

  12. Analysis of a Dynamic Viscoelastic Contact Problem with Normal Compliance, Normal Damped Response, and Nonmonotone Slip Rate Dependent Friction

    Directory of Open Access Journals (Sweden)

    Mikaël Barboteu

    2016-01-01

    Full Text Available We consider a mathematical model which describes the dynamic evolution of a viscoelastic body in frictional contact with an obstacle. The contact is modelled with a combination of a normal compliance and a normal damped response law associated with a slip rate-dependent version of Coulomb’s law of dry friction. We derive a variational formulation and an existence and uniqueness result of the weak solution of the problem is presented. Next, we introduce a fully discrete approximation of the variational problem based on a finite element method and on an implicit time integration scheme. We study this fully discrete approximation schemes and bound the errors of the approximate solutions. Under regularity assumptions imposed on the exact solution, optimal order error estimates are derived for the fully discrete solution. Finally, after recalling the solution of the frictional contact problem, some numerical simulations are provided in order to illustrate both the behavior of the solution related to the frictional contact conditions and the theoretical error estimate result.

  13. Quantitative evaluation of DNA damage and mutation rate by atmospheric and room-temperature plasma (ARTP) and conventional mutagenesis.

    Science.gov (United States)

    Zhang, Xue; Zhang, Chong; Zhou, Qian-Qian; Zhang, Xiao-Fei; Wang, Li-Yan; Chang, Hai-Bo; Li, He-Ping; Oda, Yoshimitsu; Xing, Xin-Hui

    2015-07-01

    DNA damage is the dominant source of mutation, which is the driving force of evolution. Therefore, it is important to quantitatively analyze the DNA damage caused by different mutagenesis methods, the subsequent mutation rates, and their relationship. Atmospheric and room temperature plasma (ARTP) mutagenesis has been used for the mutation breeding of more than 40 microorganisms. However, ARTP mutagenesis has not been quantitatively compared with conventional mutation methods. In this study, the umu test using a flow-cytometric analysis was developed to quantify the DNA damage in individual viable cells using Salmonella typhimurium NM2009 as the model strain and to determine the mutation rate. The newly developed method was used to evaluate four different mutagenesis systems: a new ARTP tool, ultraviolet radiation, 4-nitroquinoline-1-oxide (4-NQO), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) mutagenesis. The mutation rate was proportional to the corresponding SOS response induced by DNA damage. ARTP caused greater DNA damage to individual living cells than the other conventional mutagenesis methods, and the mutation rate was also higher. By quantitatively comparing the DNA damage and consequent mutation rate after different types of mutagenesis, we have shown that ARTP is a potentially powerful mutagenesis tool with which to improve the characteristics of microbial cell factories.

  14. A comparison of chewing rate between overweight and normal BMI individuals.

    Science.gov (United States)

    White, Amy Kristin; Venn, Bernard; Lu, Louise Weiwei; Rush, Elaine; Gallo, Luigi Maria; Yong, Janet Lee Ching; Farella, Mauro

    2015-06-01

    Previous attempts to identify an 'obese eating style' have led to conflicting findings. This observational study compared the chewing features of overweight or obese young adults with those of normal range BMI. We hypothesised that chewing features are individual-specific and differ between participants of a normal BMI and high BMI. Fourteen overweight to obese participants (BMI≥25.0) were pairwise matched with 14 normal range BMI participants (18.5chewing episodes, including rate, duration, and power. Masticatory performance was assessed by a sieve test and was expressed as the percentage of particles ≤2mm after a standardised chewing test. Regardless of the meal, chewing rate was remarkably consistent among participants (ICC=0.89; 95% CI=0.79-0.94). Chewing rate did not differ between high and normal BMI participants (p>0.05), whereas chewing power was significantly higher in high BMI participants (pchewing characteristics were found between BMI groups. Participants chewed at similar rate in the natural environment (pizza) and in the laboratory (rice) setting (p>0.05). Masticatory performance did not differ significantly (p>0.05) between the high (55.9%) and normal (52.4%) BMI groups. Within the limitations of the present study, chewing characteristics appear to be individual-specific with wide variability. Overweight participants chew at a similar rate to control participants, albeit slightly stronger. Our preliminary findings need to be replicated in larger samples. Copyright © 2015. Published by Elsevier Inc.

  15. Heart rate variability in normal-weight patients with polycystic ovary syndrome.

    Science.gov (United States)

    Kilit, Celal; Paşalı Kilit, Türkan

    2017-05-01

    Polycystic ovary syndrome (PCOS) is an endocrine disease closely related to several risk factors of cardiovascular disease. Obese women with PCOS show altered autonomic modulation. The results of studies investigating cardiac autonomic functions of normal-weight women with PCOS are conflicting. The aim of the study was to assess the reactivity of cardiac sympathovagal balance in normal-weight women with PCOS by heart rate variability analysis. We examined the heart rate variability in 60 normal-weight women with PCOS and compared them with that in 60 age-matched healthy women having a similar metabolic profile. Time and frequency domain parameters of heart rate variability were analyzed based on 5-min-long continuous electrocardiography recordings for the following 3 periods: (1) during rest in supine position, (2) during controlled breathing, and (3) during isometric handgrip exercise. Time and frequency domain parameters of heart rate variability for the 3 periods assessed were similar in the two groups. Although modified Ferriman-Gallwey score and serum testosterone and luteinizing hormone levels were significantly higher in women with PCOS, homeostatic model assessment-insulin resistance (HOMA-IR) was not different the between the PCOS and control groups. There were no significant correlations between serum testosterone levels and heart rate variability parameters among the study population. The findings of this study suggest that the reactivity of cardiac sympathovagal balance is not altered in normal-weight women with PCOS having a normal HOMA-IR.

  16. Genome-Wide Mutation Rate Response to pH Change in the Coral Reef Pathogen Vibrio shilonii AK1.

    Science.gov (United States)

    Strauss, Chloe; Long, Hongan; Patterson, Caitlyn E; Te, Ronald; Lynch, Michael

    2017-08-22

    Recent application of mutation accumulation techniques combined with whole-genome sequencing (MA/WGS) has greatly promoted studies of spontaneous mutation. However, such explorations have rarely been conducted on marine organisms, and it is unclear how marine habitats have influenced genome stability. This report resolves the mutation rate and spectrum of the coral reef pathogen Vibrio shilonii , which causes coral bleaching and endangers the biodiversity maintained by coral reefs. We found that its mutation rate and spectrum are highly similar to those of other studied bacteria from various habitats, despite the saline environment. The mutational properties of this marine bacterium are thus controlled by other general evolutionary forces such as natural selection and genetic drift. We also found that as pH drops, the mutation rate decreases and the mutation spectrum is biased in the direction of generating G/C nucleotides. This implies that evolutionary features of this organism and perhaps other marine microbes might be altered by the increasingly acidic ocean water caused by excess CO 2 emission. Nonetheless, further exploration is needed as the pH range tested in this study was rather narrow and many other possible mutation determinants, such as carbonate increase, are associated with ocean acidification. IMPORTANCE This study explored the pH dependence of a bacterial genome-wide mutation rate. We discovered that the genome-wide rates of appearance of most mutation types decrease linearly and that the mutation spectrum is biased in generating more G/C nucleotides with pH drop in the coral reef pathogen V. shilonii . Copyright © 2017 Strauss et al.

  17. Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

    Directory of Open Access Journals (Sweden)

    Meagan B. Myers

    2016-04-01

    Full Text Available Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs, examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E. As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10−3 to 4.6 × 10−2 in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells.

  18. Effects of Sublethal Fungicides on Mutation Rates and Genomic Variation in Fungal Plant Pathogen, Sclerotinia sclerotiorum.

    Science.gov (United States)

    Amaradasa, B Sajeewa; Everhart, Sydney E

    2016-01-01

    Pathogen exposure to sublethal doses of fungicides may result in mutations that may represent an important and largely overlooked mechanism of introducing new genetic variation into strictly clonal populations, including acquisition of fungicide resistance. We tested this hypothesis using the clonal plant pathogen, Sclerotinia sclerotiorum. Nine susceptible isolates were exposed independently to five commercial fungicides with different modes of action: boscalid (respiration inhibitor), iprodione (unclear mode of action), thiophanate methyl (inhibition of microtubulin synthesis) and azoxystrobin and pyraclostrobin (quinone outside inhibitors). Mycelium of each isolate was inoculated onto a fungicide gradient and sub-cultured from the 50-100% inhibition zone for 12 generations and experiment repeated. Mutational changes were assessed for all isolates at six neutral microsatellite (SSR) loci and for a subset of isolates using amplified fragment length polymorphisms (AFLPs). SSR analysis showed 12 of 85 fungicide-exposed isolates had a total of 127 stepwise mutations with 42 insertions and 85 deletions. Most stepwise deletions were in iprodione- and azoxystrobin-exposed isolates (n = 40/85 each). Estimated mutation rates were 1.7 to 60-fold higher for mutated loci compared to that expected under neutral conditions. AFLP genotyping of 33 isolates (16 non-exposed control and 17 fungicide exposed) generated 602 polymorphic alleles. Cluster analysis with principal coordinate analysis (PCoA) and discriminant analysis of principal components (DAPC) identified fungicide-exposed isolates as a distinct group from non-exposed control isolates (PhiPT = 0.15, P = 0.001). Dendrograms based on neighbor-joining also supported allelic variation associated with fungicide-exposure. Fungicide sensitivity of isolates measured throughout both experiments did not show consistent trends. For example, eight isolates exposed to boscalid had higher EC50 values at the end of the experiment, and

  19. Effects of Sublethal Fungicides on Mutation Rates and Genomic Variation in Fungal Plant Pathogen, Sclerotinia sclerotiorum.

    Directory of Open Access Journals (Sweden)

    B Sajeewa Amaradasa

    Full Text Available Pathogen exposure to sublethal doses of fungicides may result in mutations that may represent an important and largely overlooked mechanism of introducing new genetic variation into strictly clonal populations, including acquisition of fungicide resistance. We tested this hypothesis using the clonal plant pathogen, Sclerotinia sclerotiorum. Nine susceptible isolates were exposed independently to five commercial fungicides with different modes of action: boscalid (respiration inhibitor, iprodione (unclear mode of action, thiophanate methyl (inhibition of microtubulin synthesis and azoxystrobin and pyraclostrobin (quinone outside inhibitors. Mycelium of each isolate was inoculated onto a fungicide gradient and sub-cultured from the 50-100% inhibition zone for 12 generations and experiment repeated. Mutational changes were assessed for all isolates at six neutral microsatellite (SSR loci and for a subset of isolates using amplified fragment length polymorphisms (AFLPs. SSR analysis showed 12 of 85 fungicide-exposed isolates had a total of 127 stepwise mutations with 42 insertions and 85 deletions. Most stepwise deletions were in iprodione- and azoxystrobin-exposed isolates (n = 40/85 each. Estimated mutation rates were 1.7 to 60-fold higher for mutated loci compared to that expected under neutral conditions. AFLP genotyping of 33 isolates (16 non-exposed control and 17 fungicide exposed generated 602 polymorphic alleles. Cluster analysis with principal coordinate analysis (PCoA and discriminant analysis of principal components (DAPC identified fungicide-exposed isolates as a distinct group from non-exposed control isolates (PhiPT = 0.15, P = 0.001. Dendrograms based on neighbor-joining also supported allelic variation associated with fungicide-exposure. Fungicide sensitivity of isolates measured throughout both experiments did not show consistent trends. For example, eight isolates exposed to boscalid had higher EC50 values at the end of the

  20. Effects of Sublethal Fungicides on Mutation Rates and Genomic Variation in Fungal Plant Pathogen, Sclerotinia sclerotiorum

    Science.gov (United States)

    Amaradasa, B. Sajeewa

    2016-01-01

    Pathogen exposure to sublethal doses of fungicides may result in mutations that may represent an important and largely overlooked mechanism of introducing new genetic variation into strictly clonal populations, including acquisition of fungicide resistance. We tested this hypothesis using the clonal plant pathogen, Sclerotinia sclerotiorum. Nine susceptible isolates were exposed independently to five commercial fungicides with different modes of action: boscalid (respiration inhibitor), iprodione (unclear mode of action), thiophanate methyl (inhibition of microtubulin synthesis) and azoxystrobin and pyraclostrobin (quinone outside inhibitors). Mycelium of each isolate was inoculated onto a fungicide gradient and sub-cultured from the 50–100% inhibition zone for 12 generations and experiment repeated. Mutational changes were assessed for all isolates at six neutral microsatellite (SSR) loci and for a subset of isolates using amplified fragment length polymorphisms (AFLPs). SSR analysis showed 12 of 85 fungicide-exposed isolates had a total of 127 stepwise mutations with 42 insertions and 85 deletions. Most stepwise deletions were in iprodione- and azoxystrobin-exposed isolates (n = 40/85 each). Estimated mutation rates were 1.7 to 60-fold higher for mutated loci compared to that expected under neutral conditions. AFLP genotyping of 33 isolates (16 non-exposed control and 17 fungicide exposed) generated 602 polymorphic alleles. Cluster analysis with principal coordinate analysis (PCoA) and discriminant analysis of principal components (DAPC) identified fungicide-exposed isolates as a distinct group from non-exposed control isolates (PhiPT = 0.15, P = 0.001). Dendrograms based on neighbor-joining also supported allelic variation associated with fungicide-exposure. Fungicide sensitivity of isolates measured throughout both experiments did not show consistent trends. For example, eight isolates exposed to boscalid had higher EC50 values at the end of the experiment

  1. The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline

    International Nuclear Information System (INIS)

    Burr, Karen L-A.; Duyn-Goedhart, Annemarie van; Hickenbotham, Peter; Monger, Karen; Buul, Paul P.W. van; Dubrova, Yuri E.

    2007-01-01

    Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of mismatch repair deficient Msh2 knock-out mice. Spontaneous mutation rates in homozygous Msh2 -/- males were significantly higher than those in isogenic wild-type (Msh2 +/+ ) and heterozygous (Msh2 +/- ) mice. In contrast, the irradiated Msh2 -/- mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated Msh2 +/+ and Msh2 +/- animals. Considering these data and the results of other publications, we propose that the Msh2-deficient mice possess a mutator phenotype in their germline and somatic tissues while the loss of a single Msh2 allele does not affect the stability of heterozygotes

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

    Science.gov (United States)

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

    2011-01-01

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

  3. Dermal fibroblasts from patients with Parkinson’s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Lucy M Collins

    2018-02-01

    Full Text Available Background: Recently, the development of Parkinson’s disease (PD has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA mutations. Methods: We investigated PD and Gaucher Disease (GD patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

  4. An alternative derivation of the stationary distribution of the multivariate neutral Wright-Fisher model for low mutation rates with a view to mutation rate estimation from site frequency data.

    Science.gov (United States)

    Schrempf, Dominik; Hobolth, Asger

    2017-04-01

    Recently, Burden and Tang (2016) provided an analytical expression for the stationary distribution of the multivariate neutral Wright-Fisher model with low mutation rates. In this paper we present a simple, alternative derivation that illustrates the approximation. Our proof is based on the discrete multivariate boundary mutation model which has three key ingredients. First, the decoupled Moran model is used to describe genetic drift. Second, low mutation rates are assumed by limiting mutations to monomorphic states. Third, the mutation rate matrix is separated into a time-reversible part and a flux part, as suggested by Burden and Tang (2016). An application of our result to data from several great apes reveals that the assumption of stationarity may be inadequate or that other evolutionary forces like selection or biased gene conversion are acting. Furthermore we find that the model with a reversible mutation rate matrix provides a reasonably good fit to the data compared to the one with a non-reversible mutation rate matrix. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. Microsatellite frequencies vary with body mass and body temperature in mammals, suggesting correlated variation in mutation rate

    Directory of Open Access Journals (Sweden)

    William Amos

    2014-11-01

    Full Text Available Substitution rate is often found to correlate with life history traits such as body mass, a predictor of population size and longevity, and body temperature. The underlying mechanism is unclear but most models invoke either natural selection or factors such as generation length that change the number of mutation opportunities per unit time. Here we use published genome sequences from 69 mammals to ask whether life history traits impact another form of genetic mutation, the high rates of predominantly neutral slippage in microsatellites. We find that the length-frequency distributions of three common dinucleotide motifs differ greatly between even closely related species. These frequency differences correlate with body mass and body temperature and can be used to predict the phenotype of an unknown species. Importantly, different length microsatellites show complicated patterns of excess and deficit that cannot be explained by a simple model where species with short generation lengths have experienced more mutations. Instead, the patterns probably require changes in mutation rate that impact alleles of different length to different extents. Body temperature plausibly influences mutation rate by modulating the propensity for slippage. Existing hypotheses struggle to account for a link between body mass and mutation rate. However, body mass correlates inversely with population size, which in turn predicts heterozygosity. We suggest that heterozygote instability, HI, the idea that heterozygous sites show increased mutability, could provide a plausible link between body mass and mutation rate.

  6. Dose rate effect of 125I irradiation on normal rabbit eyes and experimental choroidal melanoma

    International Nuclear Information System (INIS)

    Yang, C.M.; Olsen, K.R.; Schwade, J.G.; Houdek, P.V.; Markoe, A.M.; Pisciotta, V.; Xiaodong Wu

    1993-01-01

    The dose rate effect of radiation by 125 I plaque on choroidal melanoma and normal intraocular tissue was studied. In the first part of the experiment, high activity plaques (HAP) and low activity plagues (LAP) were implanted on rabbit eyes with experimental Greene choroidal melanoma to deliver a total dose of 10 000 cGy to the tumor apex. The mean dose rate calculated at 0.5 mm from the inner sclera in eight eyes with high activity plaques was 3341.5 cGy hr -1 while that in ten eyes with low activity plaques was 239.9 cGy hr -1 . For tumors less than 1.0 mm in height, both groups showed complete tumor regression at the tumor implantation site after plaque treatment. For tumours more than 1.0 mm in height, two out of two eyes in the low activity plaque group and one of four eyes in the high activity plaque group failed to show complete tumor regression. In the second part of the experiment, 125 I plaques were implanted on the sclera of 12 normal rabbits' eyes. Six received high dose rate plaque treatment, while the other six received low dose rate plaque treatment. Clinical and histologic examinations demonstrated more damaging effects to the normal chorioretinal tissues at the plaque implantation site in the high dose rate plaque group. These results suggest that high dose rate plaques are more effective than low dose rate plaques when tumor height is statistically controlled. (Author)

  7. Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase that increases the production rate of D-tagatose.

    Science.gov (United States)

    Kim, H-J; Kim, J-H; Oh, H-J; Oh, D-K

    2006-07-01

    Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase used to increase the production rate of D-tagatose. A mutated gene was obtained by an error-prone polymerase chain reaction using L-arabinose isomerase gene from G. stearothermophilus as a template and the gene was expressed in Escherichia coli. The expressed mutated L-arabinose isomerase exhibited the change of three amino acids (Met322-->Val, Ser393-->Thr, and Val408-->Ala), compared with the wild-type enzyme and was then purified to homogeneity. The mutated enzyme had a maximum galactose isomerization activity at pH 8.0, 65 degrees C, and 1.0 mM Co2+, while the wild-type enzyme had a maximum activity at pH 8.0, 60 degrees C, and 1.0-mM Mn2+. The mutated L-arabinose isomerase exhibited increases in D-galactose isomerization activity, optimum temperature, catalytic efficiency (kcat/Km) for D-galactose, and the production rate of D-tagatose from D-galactose. The mutated L-arabinose isomerase from G. stearothermophilus is valuable for the commercial production of D-tagatose. This work contributes knowledge on the characterization of a mutated L-arabinose isomerase, and allows an increased production rate for D-tagatose from D-galactose using the mutated enzyme.

  8. Adaptive Convergence Rates of a Dirichlet Process Mixture of Multivariate Normals

    OpenAIRE

    Tokdar, Surya T.

    2011-01-01

    It is shown that a simple Dirichlet process mixture of multivariate normals offers Bayesian density estimation with adaptive posterior convergence rates. Toward this, a novel sieve for non-parametric mixture densities is explored, and its rate adaptability to various smoothness classes of densities in arbitrary dimension is demonstrated. This sieve construction is expected to offer a substantial technical advancement in studying Bayesian non-parametric mixture models based on stick-breaking p...

  9. Divergence times in Caenorhabditis and Drosophila inferred from direct estimates of the neutral mutation rate.

    Science.gov (United States)

    Cutter, Asher D

    2008-04-01

    Accurate inference of the dates of common ancestry among species forms a central problem in understanding the evolutionary history of organisms. Molecular estimates of divergence time rely on the molecular evolutionary prediction that neutral mutations and substitutions occur at the same constant rate in genomes of related species. This underlies the notion of a molecular clock. Most implementations of this idea depend on paleontological calibration to infer dates of common ancestry, but taxa with poor fossil records must rely on external, potentially inappropriate, calibration with distantly related species. The classic biological models Caenorhabditis and Drosophila are examples of such problem taxa. Here, I illustrate internal calibration in these groups with direct estimates of the mutation rate from contemporary populations that are corrected for interfering effects of selection on the assumption of neutrality of substitutions. Divergence times are inferred among 6 species each of Caenorhabditis and Drosophila, based on thousands of orthologous groups of genes. I propose that the 2 closest known species of Caenorhabditis shared a common ancestor <24 MYA (Caenorhabditis briggsae and Caenorhabditis sp. 5) and that Caenorhabditis elegans diverged from its closest known relatives <30 MYA, assuming that these species pass through at least 6 generations per year; these estimates are much more recent than reported previously with molecular clock calibrations from non-nematode phyla. Dates inferred for the common ancestor of Drosophila melanogaster and Drosophila simulans are roughly concordant with previous studies. These revised dates have important implications for rates of genome evolution and the origin of self-fertilization in Caenorhabditis.

  10. Attentional Processing and Teacher Ratings in Hyperactive, Learning Disabled and Normal Boys.

    Science.gov (United States)

    Brown, Ronald T.; Wynne, Martha Ellen

    Sustained attention and inhibitory control of 15 nonhyperactive, learning disabled (LD) boys, 15 hyperactive but not LD boys, and 15 normal boys (11-12 years old) were studied, on teacher ratings of impulse control in the classroom and testing results. Coming to attention, decision making, sustained attention, and attention-concentration were…

  11. Major floods, poor land use delay return of sedimentation to normal rates

    Science.gov (United States)

    Henry W. Anderson

    1972-01-01

    Recovery from flood-accelerated sedimentation affects both estimates of long-term average deposition and short-term monitoring of changes. "Years to return to normal" for 10 watersheds in northern California after a major flood accelerated sediment concentrations were analyzed. Returns to normalcy took from 0 to 9 years; rate of decline was related to both...

  12. Population data and mutation rates of 20 autosomal STR loci in a Chinese Han population from Yunnan Province, Southwest China.

    Science.gov (United States)

    Zhang, Xiufeng; Liu, Linlin; Xie, Runfang; Wang, Guiyi; Shi, Yuan; Gu, Tao; Hu, Liping; Nie, Shengjie

    2018-07-01

    The genetic polymorphisms of 20 autosomal short tandem repeat (STR) loci included in the PowerPlex® 21 kit were evaluated from 2068 unrelated, healthy individuals from the Chinese Han population of Yunnan Province in southwest China. All of the loci reached Hardy-Weinberg equilibrium. These loci were examined to determine allele frequencies and forensic statistical parameters. The genetic relationships among the Yunnan Han and other Chinese populations were also estimated. The combined discrimination power and probability of excluding paternity of the 20 STR loci were 0.99999999999999999999999126 and 0.999999975, respectively. In addition, mutation rates from 4363 parentage cases (2215 trios and 2148 duos) were investigated in this study. A total of 164 mutations were observed in 6578 meioses from the 20 loci. The highest mutation rate was observed in D12S391 (0.30%), and the lowest mutation rates were observed in D13S317 (0.03%) and TPOX (0.03%). The average mutation rate for the 20 loci was estimated to be 1.246 × 10 -3 per meiosis. The mutations were primarily single-step and paternal mutations.

  13. Acoustic properties of naturally produced clear speech at normal speaking rates

    Science.gov (United States)

    Krause, Jean C.; Braida, Louis D.

    2004-01-01

    Sentences spoken ``clearly'' are significantly more intelligible than those spoken ``conversationally'' for hearing-impaired listeners in a variety of backgrounds [Picheny et al., J. Speech Hear. Res. 28, 96-103 (1985); Uchanski et al., ibid. 39, 494-509 (1996); Payton et al., J. Acoust. Soc. Am. 95, 1581-1592 (1994)]. While producing clear speech, however, talkers often reduce their speaking rate significantly [Picheny et al., J. Speech Hear. Res. 29, 434-446 (1986); Uchanski et al., ibid. 39, 494-509 (1996)]. Yet speaking slowly is not solely responsible for the intelligibility benefit of clear speech (over conversational speech), since a recent study [Krause and Braida, J. Acoust. Soc. Am. 112, 2165-2172 (2002)] showed that talkers can produce clear speech at normal rates with training. This finding suggests that clear speech has inherent acoustic properties, independent of rate, that contribute to improved intelligibility. Identifying these acoustic properties could lead to improved signal processing schemes for hearing aids. To gain insight into these acoustical properties, conversational and clear speech produced at normal speaking rates were analyzed at three levels of detail (global, phonological, and phonetic). Although results suggest that talkers may have employed different strategies to achieve clear speech at normal rates, two global-level properties were identified that appear likely to be linked to the improvements in intelligibility provided by clear/normal speech: increased energy in the 1000-3000-Hz range of long-term spectra and increased modulation depth of low frequency modulations of the intensity envelope. Other phonological and phonetic differences associated with clear/normal speech include changes in (1) frequency of stop burst releases, (2) VOT of word-initial voiceless stop consonants, and (3) short-term vowel spectra.

  14. Increasing Nucleosome Occupancy Is Correlated with an Increasing Mutation Rate so Long as DNA Repair Machinery Is Intact

    Science.gov (United States)

    Taylor, Jared F.; Khattab, Omar S.; Chen, Yu-Han; Chen, Yumay; Jacobsen, Steven E.; Wang, Ping H.

    2015-01-01

    Deciphering the multitude of epigenomic and genomic factors that influence the mutation rate is an area of great interest in modern biology. Recently, chromatin has been shown to play a part in this process. To elucidate this relationship further, we integrated our own ultra-deep sequenced human nucleosomal DNA data set with a host of published human genomic and cancer genomic data sets. Our results revealed, that differences in nucleosome occupancy are associated with changes in base-specific mutation rates. Increasing nucleosome occupancy is associated with an increasing transition to transversion ratio and an increased germline mutation rate within the human genome. Additionally, cancer single nucleotide variants and microindels are enriched within nucleosomes and both the coding and non-coding cancer mutation rate increases with increasing nucleosome occupancy. There is an enrichment of cancer indels at the theoretical start (74 bp) and end (115 bp) of linker DNA between two nucleosomes. We then hypothesized that increasing nucleosome occupancy decreases access to DNA by DNA repair machinery and could account for the increasing mutation rate. Such a relationship should not exist in DNA repair knockouts, and we thus repeated our analysis in DNA repair machinery knockouts to test our hypothesis. Indeed, our results revealed no correlation between increasing nucleosome occupancy and increasing mutation rate in DNA repair knockouts. Our findings emphasize the linkage of the genome and epigenome through the nucleosome whose properties can affect genome evolution and genetic aberrations such as cancer. PMID:26308346

  15. Increasing Nucleosome Occupancy Is Correlated with an Increasing Mutation Rate so Long as DNA Repair Machinery Is Intact.

    Directory of Open Access Journals (Sweden)

    Puya G Yazdi

    Full Text Available Deciphering the multitude of epigenomic and genomic factors that influence the mutation rate is an area of great interest in modern biology. Recently, chromatin has been shown to play a part in this process. To elucidate this relationship further, we integrated our own ultra-deep sequenced human nucleosomal DNA data set with a host of published human genomic and cancer genomic data sets. Our results revealed, that differences in nucleosome occupancy are associated with changes in base-specific mutation rates. Increasing nucleosome occupancy is associated with an increasing transition to transversion ratio and an increased germline mutation rate within the human genome. Additionally, cancer single nucleotide variants and microindels are enriched within nucleosomes and both the coding and non-coding cancer mutation rate increases with increasing nucleosome occupancy. There is an enrichment of cancer indels at the theoretical start (74 bp and end (115 bp of linker DNA between two nucleosomes. We then hypothesized that increasing nucleosome occupancy decreases access to DNA by DNA repair machinery and could account for the increasing mutation rate. Such a relationship should not exist in DNA repair knockouts, and we thus repeated our analysis in DNA repair machinery knockouts to test our hypothesis. Indeed, our results revealed no correlation between increasing nucleosome occupancy and increasing mutation rate in DNA repair knockouts. Our findings emphasize the linkage of the genome and epigenome through the nucleosome whose properties can affect genome evolution and genetic aberrations such as cancer.

  16. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

    Science.gov (United States)

    Mandelker, Diana; Zhang, Liying; Kemel, Yelena; Stadler, Zsofia K; Joseph, Vijai; Zehir, Ahmet; Pradhan, Nisha; Arnold, Angela; Walsh, Michael F; Li, Yirong; Balakrishnan, Anoop R; Syed, Aijazuddin; Prasad, Meera; Nafa, Khedoudja; Carlo, Maria I; Cadoo, Karen A; Sheehan, Meg; Fleischut, Megan H; Salo-Mullen, Erin; Trottier, Magan; Lipkin, Steven M; Lincoln, Anne; Mukherjee, Semanti; Ravichandran, Vignesh; Cambria, Roy; Galle, Jesse; Abida, Wassim; Arcila, Marcia E; Benayed, Ryma; Shah, Ronak; Yu, Kenneth; Bajorin, Dean F; Coleman, Jonathan A; Leach, Steven D; Lowery, Maeve A; Garcia-Aguilar, Julio; Kantoff, Philip W; Sawyers, Charles L; Dickler, Maura N; Saltz, Leonard; Motzer, Robert J; O'Reilly, Eileen M; Scher, Howard I; Baselga, Jose; Klimstra, David S; Solit, David B; Hyman, David M; Berger, Michael F; Ladanyi, Marc; Robson, Mark E; Offit, Kenneth

    2017-09-05

    Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of

  17. The Effects of a Normal Rate versus a Slow Intervalled Rate of Oral Nutrient Intake and Intravenous Low Rate Macronutrient Application on Psychophysical Function – Two Pilot Studies

    Directory of Open Access Journals (Sweden)

    Melanie Y. Denzer-Lippmann

    2017-06-01

    Full Text Available Stomach distension and energy per time are factors influencing satiety. Moreover, different rates of nutrient intake induce different stomach distension. The goal of our studies was to elucidate the influence of different oral rates of nutrient intake (normal rate versus slow intervalled rate; study I and intravenous low rate macronutrient application (protein, carbohydrate, fat or placebo (study II on psychophysical function. The pilot studies investigated the effects of 1 study I: a mixed nutrient solution (1/3 protein, 1/3 fat, 1/3 carbohydrates 2 study II: intravenous macronutrient infusions (protein, carbohydrate, fat or placebo on psychophysical function (mood, hunger, food craving, alertness, smell intensity ratings and hedonic ratings in human subjects. In study I 10 male subjects (age range: 21–30 years completed the study protocol participating in both test conditions and in study II 20 male subjects (age range: 19–41 years completed the study protocol participating in all test conditions. Additionally, metabolic function was analyzed and cognitive and olfactory tests were conducted twice starting 100 min before the beginning of the intervention and 240 min after. Psychophysical (mood, hunger, fat-, protein-, carbohydrate-, sweets- and vegetable-craving, alertness and metabolic function tests were performed seven times on each examination day. Greater effects on hunger and food cravings were observed for normal rate of intake compared to slow intervalled rate of intake and intravenous low rate macronutrient application. Our findings potentially confirm that volume of the food ingested and a higher rate of energy per time contribute to satiety during normal rate of food intake, while slow intervalled rate of food intake and intravenous low rate macronutrient application showed no effects on satiation. Our results motivate the view that a certain amount of volume of the food ingested and a certain energy per time ratio are necessary

  18. Accurate and fast methods to estimate the population mutation rate from error prone sequences

    Directory of Open Access Journals (Sweden)

    Miyamoto Michael M

    2009-08-01

    Full Text Available Abstract Background The population mutation rate (θ remains one of the most fundamental parameters in genetics, ecology, and evolutionary biology. However, its accurate estimation can be seriously compromised when working with error prone data such as expressed sequence tags, low coverage draft sequences, and other such unfinished products. This study is premised on the simple idea that a random sequence error due to a chance accident during data collection or recording will be distributed within a population dataset as a singleton (i.e., as a polymorphic site where one sampled sequence exhibits a unique base relative to the common nucleotide of the others. Thus, one can avoid these random errors by ignoring the singletons within a dataset. Results This strategy is implemented under an infinite sites model that focuses on only the internal branches of the sample genealogy where a shared polymorphism can arise (i.e., a variable site where each alternative base is represented by at least two sequences. This approach is first used to derive independently the same new Watterson and Tajima estimators of θ, as recently reported by Achaz 1 for error prone sequences. It is then used to modify the recent, full, maximum-likelihood model of Knudsen and Miyamoto 2, which incorporates various factors for experimental error and design with those for coalescence and mutation. These new methods are all accurate and fast according to evolutionary simulations and analyses of a real complex population dataset for the California seahare. Conclusion In light of these results, we recommend the use of these three new methods for the determination of θ from error prone sequences. In particular, we advocate the new maximum likelihood model as a starting point for the further development of more complex coalescent/mutation models that also account for experimental error and design.

  19. Genetic polymorphisms and mutation rates of 27 Y-chromosomal STRs in a Han population from Guangdong Province, Southern China.

    Science.gov (United States)

    Wang, Ying; Zhang, Yong-Ji; Zhang, Chu-chu; Li, Ran; Yang, Yang; Ou, Xue-Ling; Tong, Da-yue; Sun, Hong-Yu

    2016-03-01

    In this study, we collected blood samples from 1033 father-son pairs of a Han population from Guangdong Province, Southern China, of which 1007 fathers were unrelated male individuals. All together, 2040 male individuals were analyzed at 27 Y-chromosomal short tandem repeats (Y-STRs) with Yfiler(®) Plus system. A total of 1003 different haplotypes were observed among 1007 unrelated fathers, with the overall haplotype diversity (HD) 0.999992 and discrimination capacity (DC) 0.996. The gene diversity (GD) values for the 27 Y-STR loci ranged from 0.4400 at DYS438 to 0.9597 at DYS385a/b. 11 off-ladder alleles and 25 copy number variants were detected in 1007 males. Population relationships were analyzed by comparison with 19 other worldwide populations. With 27,920 allele transfers in 1033 father-son pairs, 124 mutation events occurred, of which 118 were one-step mutations and 6 were two-step mutations. Eleven father-son pairs were found to have mutations at two loci, while one pair at three loci. The estimated locus-specific mutation rates varied from 0 to 1.74×10(-2), with an average estimated mutation rate 4.4×10(-3) (95%CI: 3.7×10(-3) to 5.3×10(-3)). Mutations were most frequently observed at three rapidly mutating Y-STRs (RM Y-STRs), DYS576, DYS518 and DYS627. However, at DYS570, DYS449 and DYF387S1 loci, which were also described as RM Y-STRs, the mutation rates in Guangdong Han population were not as high as estimated in other populations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Parallel Evolution of High-Level Aminoglycoside Resistance in Escherichia coli Under Low and High Mutation Supply Rates

    Directory of Open Access Journals (Sweden)

    Claudia Ibacache-Quiroga

    2018-03-01

    Full Text Available Antibiotic resistance is a major concern in public health worldwide, thus there is much interest in characterizing the mutational pathways through which susceptible bacteria evolve resistance. Here we use experimental evolution to explore the mutational pathways toward aminoglycoside resistance, using gentamicin as a model, under low and high mutation supply rates. Our results show that both normo and hypermutable strains of Escherichia coli are able to develop resistance to drug dosages > 1,000-fold higher than the minimal inhibitory concentration for their ancestors. Interestingly, such level of resistance was often associated with changes in susceptibility to other antibiotics, most prominently with increased resistance to fosfomycin. Whole-genome sequencing revealed that all resistant derivatives presented diverse mutations in five common genetic elements: fhuA, fusA and the atpIBEFHAGDC, cyoABCDE, and potABCD operons. Despite the large number of mutations acquired, hypermutable strains did not pay, apparently, fitness cost. In contrast to recent studies, we found that the mutation supply rate mainly affected the speed (tempo but not the pattern (mode of evolution: both backgrounds acquired the mutations in the same order, although the hypermutator strain did it faster. This observation is compatible with the adaptive landscape for high-level gentamicin resistance being relatively smooth, with few local maxima; which might be a common feature among antibiotics for which resistance involves multiple loci.

  1. Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate

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    Ihssane El Bouchikhi

    2016-12-01

    Full Text Available Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.

  2. Determinants of global left ventricular peak diastolic filling rate during rest and exercise in normal volunteers

    International Nuclear Information System (INIS)

    Filiberti, A.W.; Bianco, J.A.; Baker, S.P.; Doherty; Nalivaika, L.A.; King, M.A.; Alpert, J.S.

    1984-01-01

    Early peak diastolic filling rate (PFR) of the left ventricle (LV) is said to be a sensitive index of LV dysfunction in patients with coronary disease, hypertension and hypertrophic cardiomyopathy. Radionuclide (RN0 multigated PFR was measured in 20 normal volunteers (13 males, 7 females, mean age 31 yrs., range 20-43) at rest and during supine bicycle exercise conducted to a symptomatic end-point. At rest, RN PFR was 3.4 +- SD 0.4 end-diastolic vols./sec (range 3.1 - 3.6). During exercise all normal volunteers had a progressive and numerically and statistically significant increase in PFR. Stepwise multiple linear regression (BMPD2R) was applied to the rest and exercise PFR data to develop a linear model describing the main determinants of the RN PFR. The potential independent variables which were included in the model were heart rate (HR), ejection fraction (EF), systolic arterial pressure, systolic ejection rate and exercise stage. Ranking of variables for prediction of RN PFR, and exclusion of less important variables, was done by F value criteria. The final multivariate equation was: LVPFR = -3.84437 + 0.03834 HR + 0.07537 LVEF. The model fit was highly significant (p<0.001), and accounted for 89 per cent of variability in the PFR. The authors conclude that the left ventricular peak filling rate is critically determined by heart rate and by ejection fraction at rest and during exercise

  3. Hemispherical dominance of glucose metabolic rate in the brain of the 'normal' ageing population

    International Nuclear Information System (INIS)

    Cutts, D.A.; Spyrou, N.M.

    2004-01-01

    In the 'normal' ageing brain a decrease in the cerebral metabolic rate has been determined across many brain regions. It is determined whether age differences would affect metabolic rates in regions and different hemispheres of the brain. The regional metabolic rate of glucose (rCMRGlu) was examined in a group of 72 subjects, ages 22 to 82 years, with 36 regions of interest chosen from both hemispheres of the cortex, midbrain and cerebellum. To determine metabolic rates the in-vivo technique of positron emission tomography (PET) was employed. Three age groups were chosen to compare hemispherical differences. In both young and intermediate age groups the left hemisphere had higher rCMRGlu values than those of the right for the majority of regions with, although less pronounced in the intermediate group. Importantly, the older age group displayed little difference between hemispheres. (author)

  4. Using wavelength-normalized optical spectroscopy to improve the accuracy of bacteria growth rate quantification

    Science.gov (United States)

    McBirney, Samantha E.; Trinh, Kristy; Wong-Beringer, Annie; Armani, Andrea M.

    2017-02-01

    One of the fundamental analytical measurements performed in microbiology is monitoring and characterizing cell concentration in culture media. Measurement error will give rise to reproducibility problems in a wide range of applications, from biomanufacturing to basic research. Therefore, it is critical that the generated results are consistent. Single wavelength optical density (OD) measurements have become the preferred approach. Here, we compare the conventional OD600 technique with a multi-wavelength normalized scattering optical spectroscopy method to measure the growth rates of Pseudomonas aeruginosa and Staphylococcus aureus, two of the leading nosocomial pathogens with proven abilities to develop resistance. The multi-wavelength normalization process minimizes the impact of bacteria byproducts and environmental noise on the signal, thereby accurately quantifying growth rates with high fidelity at low concentrations. In contrast, due to poor absorbance and scattering at 600 nm, the classic OD600 measurement method is able to detect bacteria but cannot quantify the growth rate reliably. Our wavelength-normalization protocol to detect bacteria growth rates can be readily and easily adopted by research labs, given that it only requires the use of a standard spectrophotometer and implementation of straightforward data analysis. Measuring and monitoring bacteria growth rates play a critical role in a wide range of settings, spanning from therapeutic design and development to diagnostics and disease prevention. Having a full understanding of the growth cycles of bacteria known to cause severe infections and diseases will lead to a better understanding of the pathogenesis of these illnesses, leading to better treatment and, ultimately, the development of a cure.

  5. Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.

    Directory of Open Access Journals (Sweden)

    Navin Elango

    2008-02-01

    Full Text Available Transitions at CpG dinucleotides, referred to as "CpG substitutions", are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates. We show that CpG substitutions occur approximately 15 times more frequently than other single nucleotide substitutions in primate genomes, and that they exhibit substantial regional variation. Patterns of CpG rate variation are consistent with differences in methylation level and susceptibility to subsequent deamination. In particular, we propose a "distance-decaying" hypothesis, positing that due to the molecular mechanism of a CpG substitution, rates are correlated with the stability of double-stranded DNA surrounding each CpG dinucleotide, and the effect of local DNA stability may decrease with distance from the CpG dinucleotide.Consistent with our "distance-decaying" hypothesis, rates of CpG substitution are strongly (negatively correlated with regional G+C content. The influence of G+C content decays as the distance from the target CpG site increases. We estimate that the influence of local G+C content extends up to 1,500 approximately 2,000 bps centered on each CpG site. We also show that the distance-decaying relationship persisted when we controlled for the effect of long-range homogeneity of nucleotide composition. GpC sites, in contrast, do not exhibit such "distance-decaying" relationship. Our results highlight an example of the distinctive properties of methylation-dependent substitutions versus substitutions mostly arising from errors during DNA replication. Furthermore

  6. Cortical volumes and atrophy rates in FTD-3 CHMP2B mutation carriers and related non-carriers

    DEFF Research Database (Denmark)

    Eskildsen, Simon F; Østergaard, Lasse R; Rodell, Anders B

    2008-01-01

    with a mean interval of 16 months and surface based cortical segmentation we measured cortical thickness and volume, and quantified atrophy rates. Cortical thickness and atrophy rates were averaged within major lobes and focal effects were determined by parametric statistical maps. The volumetric atrophy...... in the frontal and occipital lobes, and in the left temporal lobe. Results indicated that cortical thickness has a higher sensitivity for detecting small changes than whole-brain volumetric measures. Comparing mutation carriers with non-carriers revealed increased atrophy rates in mutation carriers bilaterally...

  7. Mutation rate heterogeneity and the generation of allele diversity at the human minisatellite MS205 (D16S309).

    Science.gov (United States)

    May, C A; Jeffreys, A J; Armour, J A

    1996-11-01

    Many tandemly repeated minisatellite loci display extreme levels of length variation as a consequence of high rates of spontaneous germline mutation altering repeat copy number. Direct screening for new allele lengths by small-pool PCR has shown that instability at the human minisatellite locus MS205 (D16S309) is largely germline specific and usually results in the gain or loss of just a few repeat units. Structural analysis of the order of variant repeats has shown that these events occur preferentially at one end of the tandem array and can result in complex rearrangements including the inter-allelic transfer of repeat units. In contrast, putative mutants recovered from somatic DNA occur at a substantially lower rate and are simple and non-polar in nature. Germline mutation rates vary considerably between alleles, consistent with regulation occurring in cis. Although examination of DNA sequence polymorphisms immediately flanking the minisatellite reveals no definitive associations with germline mutation rate variation, differences in rate may be paralleled by changes in mutation spectrum. These findings help to explain the diversity of MS205 allele structures in modern humans and suggest a common mutation pathway with some other minisatellites.

  8. Reducing Error Rates for Iris Image using higher Contrast in Normalization process

    Science.gov (United States)

    Aminu Ghali, Abdulrahman; Jamel, Sapiee; Abubakar Pindar, Zahraddeen; Hasssan Disina, Abdulkadir; Mat Daris, Mustafa

    2017-08-01

    Iris recognition system is the most secured, and faster means of identification and authentication. However, iris recognition system suffers a setback from blurring, low contrast and illumination due to low quality image which compromises the accuracy of the system. The acceptance or rejection rates of verified user depend solely on the quality of the image. In many cases, iris recognition system with low image contrast could falsely accept or reject user. Therefore this paper adopts Histogram Equalization Technique to address the problem of False Rejection Rate (FRR) and False Acceptance Rate (FAR) by enhancing the contrast of the iris image. A histogram equalization technique enhances the image quality and neutralizes the low contrast of the image at normalization stage. The experimental result shows that Histogram Equalization Technique has reduced FRR and FAR compared to the existing techniques.

  9. Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy

    Directory of Open Access Journals (Sweden)

    Nardone Anna

    2004-04-01

    Full Text Available Abstract Background Cystic fibrosis (CF is a multisystem disorder characterised by mutations of the CFTR gene, which encodes for an important component in the coordination of electrolyte movement across of epithelial cell membranes. Symptoms are pulmonary disease, pancreatic exocrine insufficiency, male infertility and elevated sweat concentrations. The CFTR gene has numerous mutations (>1000 and functionally important polymorphisms (>200. Early identification is important to provide appropriate therapeutic interventions, prognostic and genetic counselling and to ensure access to specialised medical services. However, molecular diagnosis by direct mutation screening has proved difficult in certain ethnic groups due to allelic heterogeneity and variable frequency of causative mutations. Methods We applied a gene scanning approach using DHPLC system for analysing specifically all CFTR exons and characterise sequence variations in a subgroup of CF Italian patients from the Lazio region (Central Italy characterised by an extensive allelic heterogeneity. Results We have identified a total of 36 different mutations representing 88% of the CF chromosomes. Among these are two novel CFTR mutations, including one missense (H199R and one microdeletion (4167delCTAAGCC. Conclusion Using this approach, we were able to increase our standard power rate of mutation detection of about 11% (77% vs. 88%.

  10. Effects of track structure and cell inactivation on the calculation of heavy ion mutation rates in mammalian cells

    Science.gov (United States)

    Cucinotta, F. A.; Wilson, J. W.; Shavers, M. R.; Katz, R.

    1996-01-01

    It has long been suggested that inactivation severely effects the probability of mutation by heavy ions in mammalian cells. Heavy ions have observed cross sections of inactivation that approach and sometimes exceed the geometric size of the cell nucleus in mammalian cells. In the track structure model of Katz the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated using the dose-response of the system to gamma-rays and the radial dose of the ions and may be equal to unity at small impact parameters for some ions. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections from heavy ions in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT mutations in Chinese hamster cells and good agreement is found. The resulting calculations qualitatively show that mutation cross sections for heavy ions display minima at velocities where inactivation cross sections display maxima. Also, calculations show the high probability of mutation by relativistic heavy ions due to the radial extension of ions track from delta-rays in agreement with the microlesion concept. The effects of inactivation on mutations rates make it very unlikely that a single parameter such as LET or Z*2/beta(2) can be used to specify radiation quality for heavy ion bombardment.

  11. High rate of mutation K103N causing resistance to nevirapine in Indian children with acquired immunodeficiency syndrome

    Directory of Open Access Journals (Sweden)

    Sehgal S

    2008-01-01

    Full Text Available In north India the number of paediatric cases with acquired immunodeficiency syndrome (AIDS is on the rise. Most drug combinations used for treatment of AIDS incorporate nevirapine, resistance to which develops very fast if given singly or because of unplanned interruptions. This paper investigates presence of mutations at codon 103 and codon 215 of the HIV pol gene causing resistance to nevirapine and zidovudine (AZT respectively in 25 children with AIDS. Mutations T215Y and K103N were detected by a nested cum amplification refractory mutation system polymerase chain reaction (ARMS PCR and the results were confirmed by direct sequencing in five randomly selected cases. Nineteen patients had received nevirapine containing regimen and six were drug naive. Mutation K103N was observed in 56% (14/25 of the children while mutation T215Y was found in none. Two of the six drug naοve children also showed K103N mutation. Thus, Indian children drug naοve or treated with nevirapine containing regimens show a high rate of mutation conferring resistance to nevirapine which calls for a judicious use of nevirapine both in antenatal and postnatal setting.

  12. Compression-rate-dependent nonlinear mechanics of normal and impaired porcine knee joints.

    Science.gov (United States)

    Rodriguez, Marcel Leonardo; Li, LePing

    2017-11-14

    The knee joint performs mechanical functions with various loading and unloading processes. Past studies have focused on the kinematics and elastic response of the joint with less understanding of the rate-dependent load response associated with viscoelastic and poromechanical behaviors. Forty-five fresh porcine knee joints were used in the present study to determine the loading-rate-dependent force-compression relationship, creep and relaxation of normal, dehydrated and meniscectomized joints. The mechanical tests of all normal intact joints showed similar strong compression-rate-dependent behavior: for a given compression-magnitude up to 1.2 mm, the reaction force varied 6 times over compression rates. While the static response was essentially linear, the nonlinear behavior was boosted with the increased compression rate to approach the asymptote or limit at approximately 2 mm/s. On the other hand, the joint stiffness varied approximately 3 times over different joints, when accounting for the maturity and breed of the animals. Both a loss of joint hydration and a total meniscectomy greatly compromised the load support in the joint, resulting in a reduction of load support as much as 60% from the corresponding intact joint. However, the former only weakened the transient load support, but the latter also greatly weakened the equilibrium load support. A total meniscectomy did not diminish the compression-rate-dependence of the joint though. These findings are consistent with the fluid-pressurization loading mechanism, which may have a significant implication in the joint mechanical function and cartilage mechanobiology.

  13. Influence of peak exercise heart rate on normal thallium-201 myocardial clearance

    International Nuclear Information System (INIS)

    Kaul, S.; Chesler, D.A.; Pohost, G.M.; Strauss, H.W.; Okada, R.D.; Boucher, C.A.

    1986-01-01

    Measurement of myocardial clearance rates between initial and delayed images is a major justification for adding computer quantification to the interpretation of exercise 201 TI images. To clarify the range of normal thallium clearance and its relationship to the level of exercise achieved, exercise thallium images in 89 normal subjects were analyzed: 45 asymptomatic subjects with less than 1% probability of coronary artery disease (CAD) (Group I), and 44 patients with chest pain found to have no significant CAD on angiography (Group II). Mean initial regional thallium uptake was similar in the two groups, but myocardial thallium clearance (mean +/- 1 s.d.) was slower in Group II, expressed as a longer half-life in the myocardium (8.2 +/- 7.6 hr compared with 3.4 +/- 0.7 hr p less than 0.001). Analysis of variance using ten clinical and exercise variables as covariates showed that the slower clearance in Group II was related to a lower peak exercise heart rate (HR) (154 +/- 27 compared with 183 +/- 11, respectively, p less than 0.001). By linear regression analysis, a decrease in peak HR of 1 beat/min was associated with a slower thallium clearance (longer half-life) of 0.05 hr. Using this formula, the clearance value in each patient was then corrected for peak exercise heart rate by decreasing measured clearance by 0.05 hr multiplied by the amount peak exercise heart rate which was below 183 (the mean value in Group I). There were no differences in the corrected clearance between the two groups. We conclude that thallium myocardial clearance after exercise is related in part to factors other than the presence of CAD, being slower when peak exercise HR is lower. Therefore, thallium clearance rates alone uncorrected for peak exercise heart rate should be used with caution when diagnosing CAD

  14. The effect of a change in mutation rate on the incidence of dominant and X-linked recessive disorders in man

    International Nuclear Information System (INIS)

    Childs, J.D.

    1981-01-01

    In order to assess the impact on man of a sustained change in mutation rate that might be caused by ionizing radiation or a chemical mutagen in the environment, it is important to determine the current incidence of genetic disease, the rate at which deleterious mutations arise and the number of generations that mutations persist before eliminated by selection. From these data it should be possible to estimate both the increase in genetic disease in the first generation following the increase in mutation rate, and the rate at which a new equilibrium between mutation and selection would occur. In this paper the results of a survey to determine birth frequency, mutation rate and reproductive fitness for each of the important dominant and X-linked recessive disorders are described. It is estimated that these disorders affect about 0.6% of live-born individuals, including 0.1% of live-borns who carry a newly-arising mutation. (orig.)

  15. Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students.

    Science.gov (United States)

    Hinney, Anke; Hoch, Anne; Geller, Frank; Schäfer, Helmut; Siegfried, Wolfgang; Goldschmidt, Hanspeter; Remschmidt, Helmut; Hebebrand, Johannes

    2002-06-01

    Ghrelin induces obesity via central and peripheral mechanisms. Administration of ghrelin leads to increased food intake and decreased fat utilisation in rodents. Ghrelin levels are decreased in obese individuals. Recently, a polymorphism (Arg-51-Gln) within the ghrelin gene (GHRL) was described to be associated with obesity. We screened the GHRL coding region in 215 extremely obese German Children and adolescents (study group 1) and 93 normal weight students (study group 2) by single strand conformation polymorphism analysis (SSCP). We found the two previously described single nucleotide polymorphisms (SNP: Arg-51-Gln and Leu-72-Met) in similar frequencies in study groups 1 and 2 (allele frequencies were: 0.019 and 0.016 for the 51-Gln allele and 0.091 and 0.086 for the 72-Met allele, respectively). Hence, we could not confirm the previous finding. Additionally, two novel variants were identified within the coding region: (1) We detected one healthy normal weight individual with a frameshift mutation (2bp deletion at codon 34). This frameshift mutation affects the coding region of the mature ghrelin. Hence, it is highly likely that the normal weight student is haplo-insufficient for ghrelin. (2) An A to T transversion leads to an amino acid exchange from Gln to Leu at amino acid position 90. The frequency of the 90-Leu allele was significantly higher in the extremely obese children and adolescents (0.063) than in the normal weight students (0.016; nominal p = 0.011). Additionally, we genotyped 134 underweight students and 44 normal weight adults for this SNP. Genotype frequencies were similar in extremely obese children and adolescents, underweight students and normal weight adults (p > 0.8). In conclusion, we identified four sequence variants in the coding region of the ghrelin gene in individuals belonging to different weight extremes. A frameshift mutation was detected in a normal weight individual. None of the variants seem to influence weight regulation.

  16. Intrinsic washout rates of thallium-201 in normal and ischemic myocardium after dipyridamole-induced vasodilation

    International Nuclear Information System (INIS)

    Beller, G.A.; Holzgrefe, H.H.; Watson, D.D.

    1985-01-01

    Infusion of dipyridamole has been suggested as an alternative to exercise stress for myocardial perfusion imaging for detection of ischemia, but the mechanism and significance of thallium-201 ( 201 Tl) redistribution after administration of dipyridamole are uncertain. If disparate intrinsic cellular efflux rates of 201 Tl from normal and relatively underperfused myocardium in response to dipyridamole-induced vasodilation were observed, this could explain delayed 201 Tl redistribution. We investigated the effect of an intravenous infusion of 0.15 mg/kg dipyridamole on the intrinsic myocardial washout rate of 201 Tl as measured with a gamma-detector probe after intracoronary injection (50 muCi) of the radionuclide in open-chested anesthetized dogs. In six normal dogs the t 1/2 for intrinsic 201 Tl washout from the myocardium was 89 +/- 11 min (SE) at control conditions and became more rapid at 59 +/- 10 min (p . .0001) after dipyridamole. This corresponded to a significant increase in microsphere-determined epicardial (0.95 +/- 0.11 to 2.23 +/- 0.46 ml/min/g; p . .01) and endocardial (0.86 +/- 0.10 to 1.53 +/- 0.27; p . .029) flows. In 12 dogs with a critical coronary stenosis, the 201 Tl intrinsic washout rate slowed from 70 +/- 5 to 104 +/- 6 min (p . .0001) after production of the stenosis and slowed even further to 169 +/- 21 min (p . .003) after dipyridamole

  17. Measuring the prevalence of regional mutation rates: an analysis of silent substitutions in mammals, fungi, and insects

    Directory of Open Access Journals (Sweden)

    Tuch Brian B

    2008-06-01

    Full Text Available Abstract Background The patterns of mutation vary both within and across genomes. It has been shown for a few mammals that mutation rates vary within the genome, while for unknown reasons, the sensu stricto yeasts have uniform rates instead. The generality of these observations has been unknown. Here we examine silent site substitutions in a more expansive set (20 mammals, 27 fungi, 4 insects to determine why some genomes demonstrate this mosaic distribution and why others are uniform. Results We applied several intragene and intergene correlation tests to measure regional substitution patterns. Assuming that silent sites are a reasonable approximation to neutrally mutating sequence, our results show that all multicellular eukaryotes exhibit mutational heterogeneity. In striking contrast, all fungi are mutationally uniform – with the exception of three Candida species: C. albicans, C. dubliniensis, and C. tropicalis. We speculate that aspects of replication timing may be responsible for distinguishing these species. Our analysis also reveals classes of genes whose silent sites behave anomalously with respect to the mutational background in many species, indicating prevalent selective pressures. Genes associated with nucleotide binding or gene regulation have consistently low silent substitution rates in every mammalian species, as well as multiple fungi. On the other hand, receptor genes repeatedly exhibit high silent substitution rates, suggesting they have been influenced by diversifying selection. Conclusion Our findings provide a framework for understanding the regional mutational properties of eukaryotes, revealing a sharp difference between fungi and multicellular species. They also elucidate common selective pressures acting on eukaryotic silent sites, with frequent evidence for both purifying and diversifying selection.

  18. The Rate and Spectrum of Spontaneous Mutations in Mycobacterium smegmatis, a Bacterium Naturally Devoid of the Postreplicative Mismatch Repair Pathway.

    Science.gov (United States)

    Kucukyildirim, Sibel; Long, Hongan; Sung, Way; Miller, Samuel F; Doak, Thomas G; Lynch, Michael

    2016-07-07

    Mycobacterium smegmatis is a bacterium that is naturally devoid of known postreplicative DNA mismatch repair (MMR) homologs, mutS and mutL, providing an opportunity to investigate how the mutation rate and spectrum has evolved in the absence of a highly conserved primary repair pathway. Mutation accumulation experiments of M. smegmatis yielded a base-substitution mutation rate of 5.27 × 10(-10) per site per generation, or 0.0036 per genome per generation, which is surprisingly similar to the mutation rate in MMR-functional unicellular organisms. Transitions were found more frequently than transversions, with the A:T→G:C transition rate significantly higher than the G:C→A:T transition rate, opposite to what is observed in most studied bacteria. We also found that the transition-mutation rate of M. smegmatis is significantly lower than that of other naturally MMR-devoid or MMR-knockout organisms. Two possible candidates that could be responsible for maintaining high DNA fidelity in this MMR-deficient organism are the ancestral-like DNA polymerase DnaE1, which contains a highly efficient DNA proofreading histidinol phosphatase (PHP) domain, and/or the existence of a uracil-DNA glycosylase B (UdgB) homolog that might protect the GC-rich M. smegmatis genome against DNA damage arising from oxidation or deamination. Our results suggest that M. smegmatis has a noncanonical Dam (DNA adenine methylase) methylation system, with target motifs differing from those previously reported. The mutation features of M. smegmatis provide further evidence that genomes harbor alternative routes for improving replication fidelity, even in the absence of major repair pathways. Copyright © 2016 Kucukyildirim et al.

  19. The Rate and Spectrum of Spontaneous Mutations in Mycobacterium smegmatis, a Bacterium Naturally Devoid of the Postreplicative Mismatch Repair Pathway

    Directory of Open Access Journals (Sweden)

    Sibel Kucukyildirim

    2016-07-01

    Full Text Available Mycobacterium smegmatis is a bacterium that is naturally devoid of known postreplicative DNA mismatch repair (MMR homologs, mutS and mutL, providing an opportunity to investigate how the mutation rate and spectrum has evolved in the absence of a highly conserved primary repair pathway. Mutation accumulation experiments of M. smegmatis yielded a base-substitution mutation rate of 5.27 × 10−10 per site per generation, or 0.0036 per genome per generation, which is surprisingly similar to the mutation rate in MMR-functional unicellular organisms. Transitions were found more frequently than transversions, with the A:T→G:C transition rate significantly higher than the G:C→A:T transition rate, opposite to what is observed in most studied bacteria. We also found that the transition-mutation rate of M. smegmatis is significantly lower than that of other naturally MMR-devoid or MMR-knockout organisms. Two possible candidates that could be responsible for maintaining high DNA fidelity in this MMR-deficient organism are the ancestral-like DNA polymerase DnaE1, which contains a highly efficient DNA proofreading histidinol phosphatase (PHP domain, and/or the existence of a uracil-DNA glycosylase B (UdgB homolog that might protect the GC-rich M. smegmatis genome against DNA damage arising from oxidation or deamination. Our results suggest that M. smegmatis has a noncanonical Dam (DNA adenine methylase methylation system, with target motifs differing from those previously reported. The mutation features of M. smegmatis provide further evidence that genomes harbor alternative routes for improving replication fidelity, even in the absence of major repair pathways.

  20. L-Carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts

    International Nuclear Information System (INIS)

    Shao Lan; Li Qinghuan; Tan Zheng

    2004-01-01

    Telomere is the repetitive DNA sequence at the end of chromosomes, which shortens progressively with cell division and limits the replicative potential of normal human somatic cells. L-Carnosine, a naturally occurring dipeptide, has been reported to delay the replicative senescence, and extend the lifespan of cultured human diploid fibroblasts. In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine. We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine

  1. Quantification of pulmonary thallium-201 activity after upright exercise in normal persons: importance of peak heart rate and propranolol usage in defining normal values

    International Nuclear Information System (INIS)

    Brown, K.A.; Boucher, C.A.; Okada, R.D.; Strauss, H.W.; Pohost, G.M.

    1984-01-01

    Fifty-nine normal patients (34 angiographically normal and 25 clinically normal by Bayesian analysis) underwent thallium-201 imaging after maximal upright exercise. Lung activity was quantitated relative to myocardial activity and a lung/myocardial activity ratio was determined for each patient. Stepwise regression analysis was then used to examine the influence of patient clinical characteristics and exercise variables on the lung/myocardium ratio. Peak heart rate during exercise and propranolol usage both showed significant negative regression coefficients (p less than 0.001). No other patient data showed a significant relation. Using the regression equation and the estimated variance, a 95% confidence level upper limit of normal could be determined for a give peak heart rate and propranolol status. Sixty-one other patients were studied to validate the predicted upper limits of normal based on this model. None of the 27 patients without coronary artery disease had an elevated lung/myocardial ratio, compared with 1 of 8 with 1-vessel disease (difference not significant), 6 of 14 with 2-vessel disease (p less than 0.005), and 6 of 12 with 3-vessel disease (p less than 0.0001). Thus, lung activity on upright exercise thallium-201 studies can be quantitated relative to myocardial activity, and is inversely related to peak heart rate and propranolol use. Use of a regression analysis allows determination of a 95% confidence upper limit of normal to be anticipated in an individual patient

  2. The Effect of Coexistence of a Pair of Mutated Oncogenes on the Survival Rate of Invasive Breast Carcinoma Patients

    Science.gov (United States)

    Nair, D. R.

    2017-12-01

    The purpose of this project was to determine the effect of two mutated oncogenes on the survival rate from invasive breast carcinoma when in comparison to the mutation of a single oncogene on the survival rate. An oncogene is defined as a gene, that when mutated, can lead to cancer. The two oncogenes used in this project were human epidermal growth factor receptor 2 (HER2) and c-myc (MYC). HER2 and MYC are both oncogenes that contribute to the formation of cancer. HER2 proteins are receptors on breast cells, and when the HER2 gene is mutated, there is an overexpression of HER2 protein on the breast cell. This makes the breast cells proliferate uncontrollably. MYC is a gene that codes for a transcription factor that plays a role in cell cycle progression. The overexpression of MYC also leads to the proliferation of cells. I hypothesized that if there is a mutation in both the MYC and HER2 genes, then the survival rate of invasive breast carcinoma patients will be lower compared to patients with the mutations of only MYC or HER2. To test this hypothesis, we conducted individual gene searches in CBioPortal for HER2 in the datasets from the studies titled TCGA Nature 2012, TCGA Cell 2015, and TCGA Provisional. We conducted individual gene searches in CBioPortal for MYC in the same datasets. The survival rate data was then exported and analyzed for patients with mutations of either HER2 or MYC and with mutations of both genes. To determine the cases that had both HER2 and MYC mutations, we found the overlapping cases in both HER2 and MYC groups for all three datasets. We calculated the median of the survival data for cases where either HER2 or MYC was mutated and cases where both MYC and HER2 were mutated. From the first dataset, the median of MYC data was 95.53, HER2 data was 95.83, and both HER2 and MYC data was 91.24. In the second dataset, the median of MYC data was 92.17 , HER2 data was 93.5, and both HER2 and MYC data was 87.95 . In the third dataset, the median

  3. The Norwegian PMS2 founder mutation c.989-1G > T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry.

    Science.gov (United States)

    Grindedal, Eli Marie; Aarset, Harald; Bjørnevoll, Inga; Røyset, Elin; Mæhle, Lovise; Stormorken, Astrid; Heramb, Cecilie; Medvik, Heidi; Møller, Pål; Sjursen, Wenche

    2014-01-01

    Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions. All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm. Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers. The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males.

  4. Optimal Mutation Rates for the (1+lambda) EA on OneMax Through Asymptotically Tight Drift Analysis

    DEFF Research Database (Denmark)

    Gießen, Christian; Witt, Carsten

    2018-01-01

    We study the (1+) EA, a classical population-based evolutionary algorithm, with mutation probability c / n, where and are constant, on the benchmark function OneMax, which counts the number of 1-bits in a bitstring. We improve a well-established result that allows to determine the first hitting t...... that mutation rates up to 10% larger than the asymptotically optimal rate 1 / n minimize the expected runtime. However, in absolute terms the expected runtime does not change by much when replacing 1 / n with the optimal mutation rate....... drift is known. This reduces the analysis of expected optimization time to finding an exact expression for the drift. We then give an exact closed-form expression for the drift and develop a method to approximate it very efficiently, enabling us to determine approximate optimal mutation rates for the (1......+) EA for various parameter settings of c and and also for moderate sizes of n. This makes the need for potentially lengthy and costly experiments in order to optimize c for fixed n and for the optimization of OneMax unnecessary. Interestingly, even for moderate n and not too small it turns out...

  5. Unravelling the Mysteries of Slip Histories, Validating Cosmogenic 36Cl Derived Slip Rates on Normal Faults

    Science.gov (United States)

    Goodall, H.; Gregory, L. C.; Wedmore, L.; Roberts, G.; Shanks, R. P.; McCaffrey, K. J. W.; Amey, R.; Hooper, A. J.

    2017-12-01

    The cosmogenic isotope chlorine-36 (36Cl) is increasingly used as a tool to investigate normal fault slip rates over the last 10-20 thousand years. These slip histories are being used to address complex questions, including investigating slip clustering and understanding local and large scale fault interaction. Measurements are time consuming and expensive, and as a result there has been little work done validating these 36Cl derived slip histories. This study aims to investigate if the results are repeatable and therefore reliable estimates of how normal faults have been moving in the past. Our approach is to test if slip histories derived from 36Cl are the same when measured at different points along the same fault. As normal fault planes are progressively exhumed from the surface they accumulate 36Cl. Modelling these 36Cl concentrations allows estimation of a slip history. In a previous study, samples were collected from four sites on the Magnola fault in the Italian Apennines. Remodelling of the 36Cl data using a Bayesian approach shows that the sites produced disparate slip histories, which we interpret as being due to variable site geomorphology. In this study, multiple sites have been sampled along the Campo Felice fault in the central Italian Apennines. Initial results show strong agreement between the sites we have processed so far and a previous study. This indicates that if sample sites are selected taking the geomorphology into account, then 36Cl derived slip histories will be highly similar when sampled at any point along the fault. Therefore our study suggests that 36Cl derived slip histories are a consistent record of fault activity in the past.

  6. Blood pressure and heart rate variability analysis of orthostatic challenge in normal human pregnancies.

    Science.gov (United States)

    Heiskanen, Nonna; Saarelainen, Heli; Valtonen, Pirjo; Lyyra-Laitinen, Tiina; Laitinen, Tomi; Vanninen, Esko; Heinonen, Seppo

    2008-11-01

    The aim of the present study was to evaluate pregnancy-related changes in autonomic regulatory functions in healthy subjects. We studied cardiovascular autonomic responses to head-up tilt (HUT) in 28 pregnant women during the third trimester of pregnancy and 3 months after parturition. The maternal ECG and non-invasive beat-to-beat blood pressure were recorded in the horizontal position (left-lateral position) and during HUT in the upright position. Stroke volume was assessed from blood pressure signal by using the arterial pulse contour method. Heart rate variability (HRV) was analysed in frequency domain, and baroreflex sensitivity by the cross-spectral and the sequence methods. In the horizontal position, all frequency components of HRV were lower during pregnancy than 3 months after parturition (P pregnancy had no influence on normalized low frequency and high frequency powers. During pregnancy haemodynamics was well balanced with only minor changes in response to postural change while haemodynamic responses to HUT were more remarkable after parturition. In pregnant women HRV and especially its very low frequency component increased in response to HUT, whereas at 3 months after parturition the direction of these changes was opposite. Parasympathetic deactivation towards term is likely to contribute to increased heart rate and cardiac output at rest, whereas restored sympathetic modulation with modest responses may contribute stable peripheral resistance and sufficient placental blood supply under stimulated conditions. It is important to understand cardiovascular autonomic nervous system and haemodynamic control in normal pregnancy before being able to judge whether they are dysregulated in complicated pregnancies.

  7. Ultraviolet-induced mutations in Cockayne syndrome cells are primarily caused by cyclobutane dimer photoproducts while repair of other photoproducts is normal

    International Nuclear Information System (INIS)

    Parris, C.N.; Kraemer, K.H.

    1993-01-01

    The authors compared the contribution to mutagenesis on Cockayne syndrome (CS) cells of the major class of UV photoproducts, the cyclobutane pyrimidine dimer, to that of other DNA photoproducts by using the mutagenesis shuttle vector pZ189. Lymphoblastoid cell lines from the DNA repair-deficient disorders CS and xeroderma pigmentosum (XP) and a normal line were transfected with UV-treated pZ189. Cyclobutane dimers were selectively removed before transfection by photoreactivation (PR), leaving nondimer photoproducts intact. After UV exposure and replication in CS and XP cells, plasmid survival was abnormally elevated. After PR, plasmid survival increased and mutation frequency in CS cells decreased to normal levels but remained abnormal in XP cells. Sequence analysis of >200 mutant plasmids showed that with CS cells a major mutational hot spot was caused by unrepaired cyclobutane dimers. These data indicate that with both CS and XP cyclobutane dimers are major photoproducts generating reduced plasmid survival and increased mutation frequency. However, unlike XP, CS cells are proficient in repair of nondimer photoproducts. Since XP but not CS patients have a high frequency of UV-induced skin cancers, the data suggest that prevention of UV-induced skin cancers is associated with proficient repair of nondimer photoproducts. 38 refs., 3 figs., 2 tabs

  8. Effect of dose-rate on the frequency of X-linked lethal mutation in the nematode Panagrellus redivivus

    International Nuclear Information System (INIS)

    Ager, D.

    1984-01-01

    A total X-ray dose of 50 Gy was applied to the nematode Panagrellus redivivus using dose-rates ranging from 0.23 Gy/min to 10.49 Gy/min, and the frequency of lethal X-chromosomes was determined. This frequency ranged from approximately 1.6% at the lower dose-rate to 4.3% at the highest dose-rate, indicating a dose-rate dependency of mutation frequency in the spermatogonia and oogonia of this organism. (orig.)

  9. Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain of function mutations

    DEFF Research Database (Denmark)

    Galan-Diez, Marta; Isa, Adiba; Ponzetti, Marco

    2016-01-01

    of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5...... mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation...... of β-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM...

  10. Mild achondroplasia/hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation.

    Science.gov (United States)

    Couser, Natario L; Pande, Chetna K; Turcott, Christie M; Spector, Elaine B; Aylsworth, Arthur S; Powell, Cynthia M

    2017-04-01

    Pathogenic allelic variants in the fibroblast growth factor receptor 3 (FGFR3) gene have been associated with a number of phenotypes including achondroplasia, hypochondroplasia, thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome), and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). Crouzon syndrome with acanthosis nigricans is caused by the pathogenic variant c.1172C>A (p.Ala391Glu) in the FGFR3 gene. The p.Lys650Thr pathogenic variant in FGFR3 has been linked to acanthosis nigricans without significant craniofacial or skeletal abnormalities. Recently, an infant with achondroplasia and a novel p.Ser348Cys FGFR3 mutation was reported. We describe the clinical history of an 8-year-old child with a skeletal dysplasia in the achondroplasia-hypochondroplasia spectrum, acanthosis nigricans, typical development, and the recently described p.Ser348Cys FGFR3 mutation. © 2017 Wiley Periodicals, Inc.

  11. The erratic mitochondrial clock: variations of mutation rate, not population size, affect mtDNA diversity across birds and mammals

    Directory of Open Access Journals (Sweden)

    Galtier Nicolas

    2009-03-01

    Full Text Available Abstract Background During the last ten years, major advances have been made in characterizing and understanding the evolution of mitochondrial DNA, the most popular marker of molecular biodiversity. Several important results were recently reported using mammals as model organisms, including (i the absence of relationship between mitochondrial DNA diversity and life-history or ecological variables, (ii the absence of prominent adaptive selection, contrary to what was found in invertebrates, and (iii the unexpectedly large variation in neutral substitution rate among lineages, revealing a possible link with species maximal longevity. We propose to challenge these results thanks to the bird/mammal comparison. Direct estimates of population size are available in birds, and this group presents striking life-history trait differences with mammals (higher mass-specific metabolic rate and longevity. These properties make birds the ideal model to directly test for population size effects, and to discriminate between competing hypotheses about the causes of substitution rate variation. Results A phylogenetic analysis of cytochrome b third-codon position confirms that the mitochondrial DNA mutation rate is quite variable in birds, passerines being the fastest evolving order. On average, mitochondrial DNA evolves slower in birds than in mammals of similar body size. This result is in agreement with the longevity hypothesis, and contradicts the hypothesis of a metabolic rate-dependent mutation rate. Birds show no footprint of adaptive selection on cytochrome b evolutionary patterns, but no link between direct estimates of population size and cytochrome b diversity. The mutation rate is the best predictor we have of within-species mitochondrial diversity in birds. It partly explains the differences in mitochondrial DNA diversity patterns observed between mammals and birds, previously interpreted as reflecting Hill-Robertson interferences with the W

  12. Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death.

    Science.gov (United States)

    Erichsen, Martina M; Løvås, Kristian; Fougner, Kristian J; Svartberg, Johan; Hauge, Erik R; Bollerslev, Jens; Berg, Jens P; Mella, Bjarne; Husebye, Eystein S

    2009-02-01

    Primary adrenal insufficiency (Addison's disease) is a rare autoimmune disease. Until recently, life expectancy in Addison's disease patients was considered normal. To determine the mortality rate in Addison's disease patients. i) Patients registered with Addison's disease in Norway during 1943-2005 were identified through search in hospital diagnosis registries. Scrutiny of the medical records provided diagnostic accuracy and age at diagnosis. ii) The patients who had died were identified from the National Directory of Residents. iii) Background mortality data were obtained from Statistics Norway, and standard mortality rate (SMR) calculated. iv) Death diagnoses were obtained from the Norwegian Death Cause Registry. Totally 811 patients with Addison's disease were identified, of whom 147 were deceased. Overall SMR was 1.15 (95% confidence intervals (CI) 0.96-1.35), similar in females (1.18 (0.92-1.44)) and males (1.10 (0.80-1.39)). Patients diagnosed before the age of 40 had significantly elevated SMR at 1.50 (95% CI 1.09-2.01), most pronounced in males (2.03 (1.19-2.86)). Acute adrenal failure was a major cause of death; infection and sudden death were more common than in the general population. The mean ages at death for females (75.7 years) and males (64.8 years) were 3.2 and 11.2 years less than the estimated life expectancy. Addison's disease is still a potentially lethal condition, with excess mortality in acute adrenal failure, infection, and sudden death in patients diagnosed at young age. Otherwise, the prognosis is excellent for patients with Addison's disease.

  13. The Normalized-Rate Iterative Algorithm: A Practical Dynamic Spectrum Management Method for DSL

    Directory of Open Access Journals (Sweden)

    Statovci Driton

    2006-01-01

    Full Text Available We present a practical solution for dynamic spectrum management (DSM in digital subscriber line systems: the normalized-rate iterative algorithm (NRIA. Supported by a novel optimization problem formulation, the NRIA is the only DSM algorithm that jointly addresses spectrum balancing for frequency division duplexing systems and power allocation for the users sharing a common cable bundle. With a focus on being implementable rather than obtaining the highest possible theoretical performance, the NRIA is designed to efficiently solve the DSM optimization problem with the operators' business models in mind. This is achieved with the help of two types of parameters: the desired network asymmetry and the desired user priorities. The NRIA is a centralized DSM algorithm based on the iterative water-filling algorithm (IWFA for finding efficient power allocations, but extends the IWFA by finding the achievable bitrates and by optimizing the bandplan. It is compared with three other DSM proposals: the IWFA, the optimal spectrum balancing algorithm (OSBA, and the bidirectional IWFA (bi-IWFA. We show that the NRIA achieves better bitrate performance than the IWFA and the bi-IWFA. It can even achieve performance almost as good as the OSBA, but with dramatically lower requirements on complexity. Additionally, the NRIA can achieve bitrate combinations that cannot be supported by any other DSM algorithm.

  14. The Normalized-Rate Iterative Algorithm: A Practical Dynamic Spectrum Management Method for DSL

    Science.gov (United States)

    Statovci, Driton; Nordström, Tomas; Nilsson, Rickard

    2006-12-01

    We present a practical solution for dynamic spectrum management (DSM) in digital subscriber line systems: the normalized-rate iterative algorithm (NRIA). Supported by a novel optimization problem formulation, the NRIA is the only DSM algorithm that jointly addresses spectrum balancing for frequency division duplexing systems and power allocation for the users sharing a common cable bundle. With a focus on being implementable rather than obtaining the highest possible theoretical performance, the NRIA is designed to efficiently solve the DSM optimization problem with the operators' business models in mind. This is achieved with the help of two types of parameters: the desired network asymmetry and the desired user priorities. The NRIA is a centralized DSM algorithm based on the iterative water-filling algorithm (IWFA) for finding efficient power allocations, but extends the IWFA by finding the achievable bitrates and by optimizing the bandplan. It is compared with three other DSM proposals: the IWFA, the optimal spectrum balancing algorithm (OSBA), and the bidirectional IWFA (bi-IWFA). We show that the NRIA achieves better bitrate performance than the IWFA and the bi-IWFA. It can even achieve performance almost as good as the OSBA, but with dramatically lower requirements on complexity. Additionally, the NRIA can achieve bitrate combinations that cannot be supported by any other DSM algorithm.

  15. Improvement of mutation rate and reduction of somatic effects by double treatment of chemical mutagens in barley

    International Nuclear Information System (INIS)

    Koo, B.C.; Maluszynski, M.

    1996-01-01

    Mutation techniques inducing more useful mutations and reducing somatic effects need to be improved for crop breeding. Seeds of barley varieties; Dema, Grosso were treated with two types of mutagens; 1) chemical treatment: single treatment or double treatment of two mutagens (N-nitroso-N-methylurea ; MNH, Sodium Azide; NaN 3 ) 2) gamma ray irradiation treatment. After treatment, half of seeds were used for germination test and half of seeds were sown to the field. With the higher dose of mutagen both chemical and gamma ray were plants treated, the higher rate of growth reduction rate was in M 1 seedling. In chemical treatment, germination rate of seeds, growth rate of coleoptile and root in double treatment of chemical mutagens were better than single treatments, especially in same dose. Growth inhibition rate of plant in double treatment of 1.0 mM MNH (0.5 mM MNH + 0.5 mM MNH), for example, were less than one of plants of single treatment of 1.0 mM MNH in pot and petri dish test. Growth reduction rate of culm and fertility rate in M 1 plants double treated in same dose of single treatment were also less than single one. With the higher dose of mutagen both chemical and gamma ray were plants treated, the higher frequency of chlorophyll mutants was in M 2 seedling. The rate of chlorophyll mutants in double treatment of chemical mutagens were higher than single treatment. Double treatment methods can be a improved method for induction of new good mutants, which were induced more useful mutations and reduced harmful somatic effects

  16. Scaling of normalized mean energy and scalar dissipation rates in a turbulent channel flow

    Science.gov (United States)

    Abe, Hiroyuki; Antonia, Robert Anthony

    2011-05-01

    Non-dimensional parameters for the mean energy and scalar dissipation rates Cɛ and Cɛθ are examined using direct numerical simulation (DNS) data obtained in a fully developed turbulent channel flow with a passive scalar (Pr = 0.71) at several values of the Kármán (Reynolds) number h+. It is shown that Cɛ and Cɛθ are approximately equal in the near-equilibrium region (viz., y+ = 100 to y/h = 0.7) where the production and dissipation rates of either the turbulent kinetic energy or scalar variance are approximately equal and the magnitudes of the diffusion terms are negligibly small. The magnitudes of Cɛ and Cɛθ are about 2 and 1 in the logarithmic and outer regions, respectively, when h+ is sufficiently large. The former value is about the same for the channel, pipe, and turbulent boundary layer, reflecting the similarity between the mean velocity and temperature distributions among these three canonical flows. The latter value is, on the other hand, about twice as large as in homogeneous isotropic turbulence due to the existence of the large-scale u structures in the channel. The behaviour of Cɛ and Cɛθ impacts on turbulence modeling. In particular, the similarity between Cɛ and Cɛθ leads to a simple relation for the scalar variance to turbulent kinetic energy time-scale ratio, an important ingredient in the eddy diffusivity model. This similarity also yields a relation between the Taylor and Corrsin microscales and analogous relations, in terms of h+, for the Taylor microscale Reynolds number and Corrsin microscale Peclet number. This dependence is reasonably well supported by both the DNS data at small to moderate h+ and the experimental data of Comte-Bellot [Ph. D. thesis (University of Grenoble, 1963)] at larger h+. It does not however apply to a turbulent boundary layer where the mean energy dissipation rate, normalized on either wall or outer variables, is about 30% larger than for the channel flow.

  17. Influence of radiation exposure rate on somatic mutation frequency and loss of reproductive integrity in tradescantia stamen hairs

    International Nuclear Information System (INIS)

    Ichikawa, S.; Nauman, C.H.; Sparrow, A.H.; Takahashi, C.S.

    1978-01-01

    Inflorescences of Tradescantia clone 02 (2n=12), hetero- or hemi-zygous for flower color, were exposed to a series of γ-ray exposures at two different exposure rates, 29.3 R/min and 0.026-0.52 R/min. Pink mutation-response curves, and survival curves based on reproductive integrity, were constructed for each of the exposure rates. Loss of reproductive integrity was also assessed at high (256 R/min) and low (0.52-4.17 R/min) γ-ray exposure rates in T. blossfeldiana (2n=72). All observations were made on stamen hairs. The higher exposure rate was 1.3-1.7 times more effective in inducing pink mutations in clone 02. A greater efficiency of the higher exposure rate was also found for both taxa at the loss of reproductive integrity endpoint. The D 0 values obtained at the higher exposure rates, 154 R for clone 02 and 720 R for T. blossfeldiana, were significantly lower than the corresponding values of 270 R and 1880 R obtained at the lower exposure rates. These D 0 's differ by factors of 1.75 and 2.61 for clone 02 and T. blossfeldiana, respectively. D 0 's for the two taxa were found to be inversely correlated with their interphase chromosome volumes. (Auth.)

  18. Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes

    Directory of Open Access Journals (Sweden)

    Christina L. Zheng

    2014-11-01

    Full Text Available Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER, thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.

  19. Laboratory determination of normal operating flow rates with enlarged outlet fittings -- BDF reactors

    Energy Technology Data Exchange (ETDEWEB)

    Waters, E.D.

    1960-02-02

    Experiments have been conducted in the Hydraulics Laboratory, at the request of IPD`s Mechanical Development-A Operation, to determine the energy losses of various enlarged outlet fitting combinations. These experiments were conducted an steady state runs and allow the determination of the normal operating point (flow rate) of a reactor process channel under selected conditions of front header pressure and fuel charge. No attempt is made to make a mechanical or economic evaluation of the particular fitting combinations, although observations were noted which might bear on this evaluation. It is very important for the reader to bear in mind that changing outlet fittings will definitely affect the reactor tube power limits and outlet vater temperature limits. The size of the outlet fittings largely determines the present outlet temperature limits of the old reactors. The flow characteristics of these present fittings cause some degree of pressurization to suppress boiling on the fuel charge and also cause dual Panellit trip protection for certain flow changes and for power surges. Enlargement of the outlet fittings may actually reduce the allowable outlet coolant temperature limits. Since these effects cannot be determined on the apparatus used in these experiments, a complete discussion of this point is not included in this report. However, the seriousness of these effects should be known and carefully analyzed before a final selection of enlarged outlet fittings in made. This report will be one of a series. New reports in the series will be issued as data are obtained for other such outlet fitting combinations or for new concepts of outlet fitting assemblies such as the new nozzle being developed by C. E. Trantz for use on F-reactor stuck gunbarrel tubes.

  20. Cultured cells from a severe combined immunodeficient mouse have a slower than normal rate of repair of potentially lethal damage sensitive to hypertonic treatment

    International Nuclear Information System (INIS)

    Kimura, H.; Terado, T.; Ikebuchi, M.; Aoyama, T.; Komatsu, K.; Nozawa, A.

    1995-01-01

    The effects of hypertonic 0.5 M NaCl treatment after irradiation on the repair of DNA damage were examined in fibroblasts of the severe combined immunodeficient (scid) mouse. These cells are hypersensitive to ionizing radiation because of a deficiency in the repair of double-strand breaks. Hypertonic treatment caused radiosensitization due to a fixation of potentially lethal damage (PLD) in scid cells, demonstrating that scid cells normally repair PLD. To assess the kinetics of the repair of PLD, hypertonic treatment was delayed for various times after irradiation. Potentially lethal damage was repaired during these times in isotonic medium at 37 degrees C. It was found that the rate of repair of PLD was much slower in scid cells than in BALB/c 3T3 cells, which have a open-quotes wild-typeclose quotes level of radiosensitivity. This fact indicates that the scid mutation affects the type of repair of PLD that is sensitive to 0.5 M NaCl treatment. In scid hybrid cells containing fragments of human chromosome 8, which complements the radiosensitivity of the scid cells, the rate of repair was restored to a normal level. An enzyme encoded by a gene on chromosome 8 may also be connected with PLD which is sensitive to hypertonic treatment. 29 refs., 3 figs

  1. Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations.

    Science.gov (United States)

    Galán-Díez, Marta; Isa, Adiba; Ponzetti, Marco; Nielsen, Morten Frost; Kassem, Moustapha; Kousteni, Stavroula

    2016-03-01

    Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of β-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of β-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require β-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of β-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate β-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. Published

  2. Use of scintigraphy for the determination of mucociliary clearance rates in normal, sedated, diseased and exercised horses.

    Science.gov (United States)

    Willoughby, R A; Ecker, G L; McKee, S L; Riddolls, L J

    1991-01-01

    Mucociliary clearance rates from the trachea were determined in normal, sedated, diseased and exercised horses from scintigraphs obtained after an injection of technetium-99m sulphide colloid into the tracheal lumen. The group mean tracheal clearance rate of eight clinically normal horses during 42 trials was 2.06 +/- 0.38 cm/min. Significant between horse differences were found (p less than 0.05). When six and seven of these horses were given xylazine and detomidine hydrochloride, respectively, mean group tracheal clearance rates dropped significantly (p less than 0.05). The decreases from each normal horse's mean tracheal clearance rate ranged from 18 to 54%. There did not appear to be a difference between the tracheal clearance rates (TCRs) of the normal horses and those with chronic respiratory disease. Postexercise evaluations were not significantly different from the pre-exercise TCRs in three clinically normal horses and three horses with chronic obstructive pulmonary disease (p greater than 0.05). This minimally invasive scintigraphic technique for determining TCRs has proved to be useful and reliable. Images Fig. 1. PMID:1790485

  3. The role of weak selection and high mutation rates in nearly neutral evolution.

    Science.gov (United States)

    Lawson, Daniel John; Jensen, Henrik Jeldtoft

    2009-04-21

    Neutral dynamics occur in evolution if all types are 'effectively equal' in their reproductive success, where the definition of 'effectively equal' depends on the population size and the details of mutations. Empirically observed neutral genetic evolution in extremely large clonal populations can only be explained under current models if selection is completely absent. Such models typically consider the case where population dynamics occurs on a different timescale to evolution. However, this assumption is invalid when mutations are not rare in a whole population. We show that this has important consequences for the occurrence of neutral evolution in clonal populations. In highly connected type spaces, neutral dynamics can occur for all population sizes despite significant selective differences, via the forming of effectively neutral networks connecting rare neutral types. Biological implications include an explanation for the high diversity of rare types that survive in large clonal populations, and a theoretical justification for the use of neutral null models.

  4. A Site Specific Model And Analysis Of The Neutral Somatic Mutation Rate In Whole-Genome Cancer Data

    DEFF Research Database (Denmark)

    Bertl, Johanna; Guo, Qianyun; Rasmussen, Malene Juul

    2017-01-01

    Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation ra...

  5. Large-scale analyses of synonymous substitution rates can be sensitive to assumptions about the process of mutation.

    Science.gov (United States)

    Aris-Brosou, Stéphane; Bielawski, Joseph P

    2006-08-15

    A popular approach to examine the roles of mutation and selection in the evolution of genomes has been to consider the relationship between codon bias and synonymous rates of molecular evolution. A significant relationship between these two quantities is taken to indicate the action of weak selection on substitutions among synonymous codons. The neutral theory predicts that the rate of evolution is inversely related to the level of functional constraint. Therefore, selection against the use of non-preferred codons among those coding for the same amino acid should result in lower rates of synonymous substitution as compared with sites not subject to such selection pressures. However, reliably measuring the extent of such a relationship is problematic, as estimates of synonymous rates are sensitive to our assumptions about the process of molecular evolution. Previous studies showed the importance of accounting for unequal codon frequencies, in particular when synonymous codon usage is highly biased. Yet, unequal codon frequencies can be modeled in different ways, making different assumptions about the mutation process. Here we conduct a simulation study to evaluate two different ways of modeling uneven codon frequencies and show that both model parameterizations can have a dramatic impact on rate estimates and affect biological conclusions about genome evolution. We reanalyze three large data sets to demonstrate the relevance of our results to empirical data analysis.

  6. Bacterias con alta tasa de mutación: los riesgos de una vida acelerada High mutation rate bacteria: Risks of a high-speed life

    Directory of Open Access Journals (Sweden)

    JUAN CARLOS GALÁN

    2006-03-01

    Full Text Available El proceso evolutivo de un ser vivo se acelera cuanto mayor sea su capacidad para producir variabilidad genética, bien por mutación, bien por recombinación. Sin embargo, cuanto mayor sea esta capacidad, mayor también será el riesgo de acumular mutaciones del etéreas. La variabilidad genética es, por tanto, un proceso altamente regulado, de tal manera que las bacterias tienden a mantener una baja tasa de mutación. En diferentes poblaciones bacterianas analizadas hay siempre un porcentaje variable de cepas con una tasa de mutación superior a la frecuencia modal del resto de la población. Existe una relación directa entre la proporción de cepas que mutan y el grado de estrés del ambiente. Así, en los procesos infecciosos crónicos, en los que el tratamiento antibiótico es constante durante períodos prolongados, se observan los mayores porcentajes de bacterias que mutan, cercano al 50% de la población. Esta selección positiva de bacterias que mutan es debida al enorme potencial que presentan para desarrollar resistencia antibiótica (100 veces superior a una bacteria normal. Esta capacidad ha sido explotada, en algunos centros de investigación, como un modelo natural de evolución acelerada para predecir la facilidad con la que determinadas variantes resistentes pueden aparecer, saber qué posiciones serán las más susceptibles a los cambios y cuál será el costo para la bacteria. El laboratorio de microbiología debe hacer un esfuerzo por detectar estas cepas mutadoras antes de que desarrollen mecanismos de resistencia e induzcan el fracaso terapéutico.The potential of producing genetic variability, either by mutation or by recombination, is the driving force of evolution in a living organism. Genetic variability is a quite regulated process in which bacteria tend to maintain a low mutation rate. However, a variable proportion of bacteria with a higher mutation rate than that of the modal is always present in any population

  7. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing

    DEFF Research Database (Denmark)

    Martin, P; Heiskari, N; Zhou, J

    1998-01-01

    -amplified and sequenced from DNA of 50 randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mutation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Although it could not be determined whether the remaining...

  8. Homozygous mutation of focal adhesion kinase in embryonic stem cell derived neurons: normal electrophysiological and morphological properties in vitro

    Directory of Open Access Journals (Sweden)

    Komiyama NH

    2006-06-01

    Full Text Available Abstract Background Genetically manipulated embryonic stem (ES cell derived neurons (ESNs provide a powerful system with which to study the consequences of gene manipulation in mature, synaptically connected neurons in vitro. Here we report a study of focal adhesion kinase (FAK, which has been implicated in synapse formation and regulation of ion channels, using the ESN system to circumvent the embryonic lethality of homozygous FAK mutant mice. Results Mouse ES cells carrying homozygous null mutations (FAK-/- were generated and differentiated in vitro into neurons. FAK-/- ESNs extended axons and dendrites and formed morphologically and electrophysiologically intact synapses. A detailed study of NMDA receptor gated currents and voltage sensitive calcium currents revealed no difference in their magnitude, or modulation by tyrosine kinases. Conclusion FAK does not have an obligatory role in neuronal differentiation, synapse formation or the expression of NMDA receptor or voltage-gated calcium currents under the conditions used in this study. The use of genetically modified ESNs has great potential for rapidly and effectively examining the consequences of neuronal gene manipulation and is complementary to mouse studies.

  9. High mutation rates explain low population genetic divergence at copy-number-variable loci in Homo sapiens.

    Science.gov (United States)

    Hu, Xin-Sheng; Yeh, Francis C; Hu, Yang; Deng, Li-Ting; Ennos, Richard A; Chen, Xiaoyang

    2017-02-22

    Copy-number-variable (CNV) loci differ from single nucleotide polymorphic (SNP) sites in size, mutation rate, and mechanisms of maintenance in natural populations. It is therefore hypothesized that population genetic divergence at CNV loci will differ from that found at SNP sites. Here, we test this hypothesis by analysing 856 CNV loci from the genomes of 1184 healthy individuals from 11 HapMap populations with a wide range of ancestry. The results show that population genetic divergence at the CNV loci is generally more than three times lower than at genome-wide SNP sites. Populations generally exhibit very small genetic divergence (G st  = 0.05 ± 0.049). The smallest divergence is among African populations (G st  = 0.0081 ± 0.0025), with increased divergence among non-African populations (G st  = 0.0217 ± 0.0109) and then among African and non-African populations (G st  = 0.0324 ± 0.0064). Genetic diversity is high in African populations (~0.13), low in Asian populations (~0.11), and intermediate in the remaining 11 populations. Few significant linkage disequilibria (LDs) occur between the genome-wide CNV loci. Patterns of gametic and zygotic LDs indicate the absence of epistasis among CNV loci. Mutation rate is about twice as large as the migration rate in the non-African populations, suggesting that the high mutation rates play dominant roles in producing the low population genetic divergence at CNV loci.

  10. Rate of Visual Information Pick-Up in Learning Disabled and Normal Boys.

    Science.gov (United States)

    Bryant, Susan K.; And Others

    1983-01-01

    A span-of-apprehension task and a backward masking technique were combined to allow measurement of the apprehension span of a sample of 34 learning disabled and normal boys about 8 to 13 years old at various time intervals following stimulus presentation. (Author/SW)

  11. Mutation frequencies in male mice and the estimation of genetic hazards of radiation in men: (specific-locus mutations/dose-rate effect/doubling dose/risk estimation)

    International Nuclear Information System (INIS)

    Russell, W.L.; Kelly, E.M.

    1982-01-01

    Estimation of the genetic hazards of ionizing radiation in men is based largely on the frequency of transmitted specific-locus mutations induced in mouse spermatogonial stem cells at low radiation dose rates. The publication of new data on this subject has permitted a fresh review of all the information available. The data continue to show no discrepancy from the interpretation that, although mutation frequency decreases markedly as dose rate is decreased from 90 to 0.8 R/min (1 R = 2.6 X 10 -4 coulombs/kg) there seems to be no further change below 0.8 R/min over the range from that dose rate to 0.0007 R/min. Simple mathematical models are used to compute: (a) a maximum likelihood estimate of the induced mutation frequency at the low dose rates, and (b) a maximum likelihood estimate of the ratio of this to the mutation frequency at high dose rates in the range of 72 to 90 R/min. In the application of these results to the estimation of genetic hazards of radiation in man, the former value can be used to calculate a doubling dose - i.e., the dose of radiation that induces a mutation frequency equal to the spontaneous frequency. The doubling dose based on the low-dose-rate data compiled here is 110 R. The ratio of the mutation frequency at low dose rate to that at high dose rate is useful when it becomes necessary to extrapolate from experimental determinations, or from human data, at high dose rates to the expected risk at low dose rates. The ratio derived from the present analysis is 0.33

  12. Probing the effect of human normal sperm morphology rate on cycle outcomes and assisted reproductive methods selection.

    Directory of Open Access Journals (Sweden)

    Bo Li

    Full Text Available Sperm morphology is the best predictor of fertilization potential, and the critical predictive information for supporting assisted reproductive methods selection. Given its important predictive value and the declining reality of semen quality in recent years, the threshold of normal sperm morphology rate (NSMR is being constantly corrected and controversial, from the 4th edition (14% to the 5th version (4%. We retrospectively analyzed 4756 cases of infertility patients treated with conventional-IVF(c-IVF or ICSI, which were divided into three groups according to NSMR: ≥14%, 4%-14% and <4%. Here, we demonstrate that, with decrease in NSMR(≥14%, 4%-14%, <4%, in the c-IVF group, the rate of fertilization, normal fertilization, high-quality embryo, multi-pregnancy and birth weight of twins gradually decreased significantly (P<0.05, while the miscarriage rate was significantly increased (p<0.01 and implantation rate, clinical pregnancy rate, ectopic pregnancy rate, preterm birth rate, live birth rate, sex ratio, and birth weight(Singleton showed no significant change. In the ICSI group, with decrease in NSMR (≥14%, 4%-14%, <4%, high-quality embryo rate, multi-pregnancy rate and birth weight of twins were gradually decreased significantly (p<0.05, while other parameters had no significant difference. Considering the clinical assisted methods selection, in the NFMR ≥14% group, normal fertilization rate of c-IVF was significantly higher than the ICSI group (P<0.05, in the 4%-14% group, birth weight (twins of c-IVF were significantly higher than the ICSI group, in the <4% group, miscarriage of IVF was significantly higher than the ICSI group. Therefore, we conclude that NSMR is positively related to embryo reproductive potential, and when NSMR<4% (5th edition, ICSI should be considered first, while the NSMR≥4%, c-IVF assisted reproduction might be preferred.

  13. The effect of inertia, viscous damping, temperature and normal stress on chaotic behaviour of the rate and state friction model

    Science.gov (United States)

    Sinha, Nitish; Singh, Arun K.; Singh, Trilok N.

    2018-04-01

    A fundamental understanding of frictional sliding at rock surfaces is of practical importance for nucleation and propagation of earthquakes and rock slope stability. We investigate numerically the effect of different physical parameters such as inertia, viscous damping, temperature and normal stress on the chaotic behaviour of the two state variables rate and state friction (2sRSF) model. In general, a slight variation in any of inertia, viscous damping, temperature and effective normal stress reduces the chaotic behaviour of the sliding system. However, the present study has shown the appearance of chaos for the specific values of normal stress before it disappears again as the normal stress varies further. It is also observed that magnitude of system stiffness at which chaotic motion occurs, is less than the corresponding value of critical stiffness determined by using the linear stability analysis. These results explain the practical observation why chaotic nucleation of an earthquake is a rare phenomenon as reported in literature.

  14. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes

    NARCIS (Netherlands)

    Ruijs, M.W.G.; Verhoef, S.; Rookus, M.A.; Pruntel, R.; van der Hout, A.H.; Hogervorst, F.B.L.; Kluijt, I.; Sijmons, R.H.; Aalfs, C.M.; Wagner, A.; Ausems, M.G.E.M.; Hoogerbrugge, N.; van Asperen, C.J.; Gómez García, E.B.; Meijers-Heijboer, H.; ten Kate, L.P.; Menko, F.H.; van 't Veer, L.J.

    2010-01-01

    Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria

  15. Application of specific gravity method for normalization of urinary excretion rates of radionuclides

    International Nuclear Information System (INIS)

    Thakur, Smita S.; Yadav, J.R.; Rao, D.D.

    2015-01-01

    In vitro bioassay monitoring is based on the determination of activity concentration in biological samples excreted from the body and is most suitable for alpha and beta emitters. For occupational workers handling actinides in reprocessing facilities possibility of internal exposure exists and urine assay is preferred method for monitoring such exposure. Urine samples collected for 24 h duration, is the true representative of bioassay sample and hence in the case of insufficient collection time, specific gravity applied method of normalization of urine sample is used. The present study reports the data of specific gravity generated for controlled group of Indian population by the use of densitometer and its application in urinary sample activity normalization. The average specific gravity value obtained for the controlled group was 1.008±0.005 gm/ml. (author)

  16. The influence of dose fractionation and dose rate on normal tissue responses

    International Nuclear Information System (INIS)

    Barendsen, G.W.

    1982-01-01

    An analysis of responses of a variety of normal tissues in animals to fractionated irradiations has been made with the aim of developing a formalism for the prediction of tolerance doses as a function of the dose per fraction and the overall treatment time. An important feature of the formalism is that it is directly based on radiological insights and therefore provides a logical concept to account for the diversity of tissue responses. (Auth.)

  17. Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals.

    Directory of Open Access Journals (Sweden)

    Simon L Girard

    Full Text Available De novo mutations (DNM are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots.

  18. ENU mutagenesis screening for dominant behavioral mutations based on normal control data obtained in home-cage activity, open-field, and passive avoidance tests.

    Science.gov (United States)

    Wada, Yumiko; Furuse, Tamio; Yamada, Ikuko; Masuya, Hiroshi; Kushida, Tomoko; Shibukawa, Yoko; Nakai, Yuji; Kobayashi, Kimio; Kaneda, Hideki; Gondo, Yoichi; Noda, Tetsuo; Shiroishi, Toshihiko; Wakana, Shigeharu

    2010-01-01

    To establish the cutoff values for screening ENU-induced behavioral mutations, normal variations in mouse behavioral data were examined in home-cage activity (HA), open-field (OF), and passive-avoidance (PA) tests. We defined the normal range as one that included more than 95% of the normal control values. The cutoffs were defined to identify outliers yielding values that deviated from the normal by less than 5% for C57BL/6J, DBA/2J, DBF(1), and N(2) (DXDB) progenies. Cutoff values for G1-phenodeviant (DBF(1)) identification were defined based on values over +/- 3.0 SD from the mean of DBF(1) for all parameters assessed in the HA and OF tests. For the PA test, the cutoff values were defined based on whether the mice met the learning criterion during the 2nd (at a shock intensity of 0.3 mA) or the 3rd (at a shock intensity of 0.15 mA) retention test. For several parameters, the lower outliers were undetectable as the calculated cutoffs were negative values. Based on the cutoff criteria, we identified 275 behavioral phenodeviants among 2,646 G1 progeny. Of these, 64 were crossed with wild-type DBA/2J individuals, and the phenotype transmission was examined in the G2 progeny using the cutoffs defined for N(2) mice. In the G2 mice, we identified 15 novel dominant mutants exhibiting behavioral abnormalities, including hyperactivity in the HA or OF tests, hypoactivity in the OF test, and PA deficits. Genetic and detailed behavioral analysis of these ENU-induced mutants will provide novel insights into the molecular mechanisms underlying behavior.

  19. Decrease in the CGG{sub n} trinucleotide repeat mutation of the fragile X syndrome to normal size range during paternal transmission

    Energy Technology Data Exchange (ETDEWEB)

    Vaeisaenen, M.L.; Haataja, R.; Leisti, J. [Oulu Univ. Hospital (Finland)

    1996-09-01

    The fragile X syndrome, the most common inherited form of mental retardation, is caused by the expansion of a CGG{sub n} trinucleotide repeat in the FMR-1 gene. Although the repeat number usually increases during transmission, few cases with reduction of an expanded CGG{sub n} repeat back to the normal size range have been reported. We describe for the first time a family in which such reduction has occurred in the paternal transmission. The paternal premutation ({Delta} = 300 hp) was not detected in one of the five daughters or in the son of this daughter, although he had the grandpaternal RFLP haplotype. Instead, fragments indicating the normal CGG{sub n} repeat size were seen on a Southern blot probed with StB12.3. PCR analysis of the CGG{sub n} repeat confirmed this; in addition to a maternal allele of 30 repeats, an allele of 34 repeats was detected in the daughter and, further, in her son. Sequencing of this new allele revealed a pure CGG{sub n} repeat configuration without AGG interruptions. No evidence for a somatic mosaicism of a premutation allele in the daughter or a normal allele in her father was detected when investigating DNA derived from blood lymphocytes and skin fibroblasts. Another unusual finding in this family was lack of the PCR product of the microsatellite marker RS46 (DXS548) in one of the grandmaternal X chromosomes, detected as incompatible inheritance of RS46 alleles. The results suggest an intergenerational reduction in the CGG{sub n} repeat from premutation size to the normal size range and stable transmission of the contracted repeat to the next generation. However, paternal germ-line mosaicism could not be excluded as an alternative explanation for the reverse mutation. 37 refs., 4 figs.

  20. The experience of mutation rate quantitative evaluation in connection with environmental pollution (based on studies of congenital anomalies in human populations).

    Science.gov (United States)

    Antipenko YeN; Kogut, N N

    1993-10-01

    For 3 years genetic monitoring of congenital anomalies (CA) has been carried out in three Ukrainian towns essentially different in the level of air pollution: the most polluted, Mariupol (M.); medium polluted, Zaporozhye (Z.); and relatively clean, Simpheropol (S.). In this work we present the results of this study. Eighteen CAs being used in the International Clearinghouse program were registered during the first year of life. For each case of CA an individual questionnaire was filled in. It included practically all known causes of malformations. Similar questionnaires were filled in for cases of normal birth outcome. The estimation of newborns of control groups was made according to a score of 9-10 on the Apgar scale. The questionnaires were completed by physicians in all maternity hospitals and children's clinics and based on the information obtained from mothers. Multiple malformations, dominant and X-linked CA in M. were 2.6-3.1 times more frequent than in S. The frequency of new mutations was 0.45-0.95 and 0.17-0.47 per 10(3) births respectively. No differences in multifactorial and recessive CA were noted. The mathematical method (so-called statusmetrical analysis) was used to indirectly determine the part of CAs of unknown etiology (probably of mutation origin) in the total number of CAs. Their quota in Z. and M. was 1.2-1.5 times more than in S. The advantage of statusmetrical analysis lies in the absence of any restrictions connected with a large number of parameters which describe the object's status. It makes it possible to analyze tens, even hundreds of factors (along with the increased number of parameters the reliability of the conclusions increases) and range them in accordance with their validity. Genetic consequences of chemical pollution were estimated in biological equivalents Röntgen (BER). In M. they were equal to the effect of irradiation at doses of 180-300 BER (230 BER, central estimate) over 30 years. In the polluted towns (M. and Z.) the

  1. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Sluimer, Jasper D. [VU University Medical Centre, Department of Diagnostic Radiology, Amsterdam (Netherlands); VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Diagnostic Radiology and Alzheimer Centre, PO Box 7057, Amsterdam (Netherlands); Flier, Wiesje M. van der; Scheltens, Philip [VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Neurology, Amsterdam (Netherlands); Karas, Giorgos B.; Barkhof, Frederik [VU University Medical Centre, Department of Diagnostic Radiology, Amsterdam (Netherlands); VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); Schijndel, Ronald van [VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Informatics, Amsterdam (Netherlands); Barnes, Josephine; Boyes, Richard G. [UCL, Institute of Neurology, Dementia Research Centre, London (United Kingdom); Cover, Keith S. [VU University Medical Centre, Department of Physics and Medical Technology, Amsterdam (Netherlands); Olabarriaga, Silvia D. [University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam (Netherlands); Fox, Nick C. [VU University Medical Centre, Department of Neurology, Amsterdam (Netherlands); UCL, Institute of Neurology, Dementia Research Centre, London (United Kingdom); Vrenken, Hugo [VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Physics and Medical Technology, Amsterdam (Netherlands)

    2009-12-15

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 {+-} 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. (orig.)

  2. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    International Nuclear Information System (INIS)

    Sluimer, Jasper D.; Flier, Wiesje M. van der; Scheltens, Philip; Karas, Giorgos B.; Barkhof, Frederik; Schijndel, Ronald van; Barnes, Josephine; Boyes, Richard G.; Cover, Keith S.; Olabarriaga, Silvia D.; Fox, Nick C.; Vrenken, Hugo

    2009-01-01

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 ± 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. (orig.)

  3. Rates of convergence and asymptotic normality of curve estimators for ergodic diffusion processes

    NARCIS (Netherlands)

    J.H. van Zanten (Harry)

    2000-01-01

    textabstractFor ergodic diffusion processes, we study kernel-type estimators for the invariant density, its derivatives and the drift function. We determine rates of convergence and find the joint asymptotic distribution of the estimators at different points.

  4. Modification of a hydrophobic layer by a point mutation in syntaxin 1A regulates the rate of synaptic vesicle fusion.

    Directory of Open Access Journals (Sweden)

    Robert D Lagow

    2007-04-01

    Full Text Available Both constitutive secretion and Ca(2+-regulated exocytosis require the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE complexes. At present, little is known about how the SNARE complexes mediating these two distinct pathways differ in structure. Using the Drosophila neuromuscular synapse as a model, we show that a mutation modifying a hydrophobic layer in syntaxin 1A regulates the rate of vesicle fusion. Syntaxin 1A molecules share a highly conserved threonine in the C-terminal +7 layer near the transmembrane domain. Mutation of this threonine to isoleucine results in a structural change that more closely resembles those found in syntaxins ascribed to the constitutive secretory pathway. Flies carrying the I254 mutant protein have increased levels of SNARE complexes and dramatically enhanced rate of both constitutive and evoked vesicle fusion. In contrast, overexpression of the T254 wild-type protein in neurons reduces vesicle fusion only in the I254 mutant background. These results are consistent with molecular dynamics simulations of the SNARE core complex, suggesting that T254 serves as an internal brake to dampen SNARE zippering and impede vesicle fusion, whereas I254 favors fusion by enhancing intermolecular interaction within the SNARE core complex.

  5. Radiation-induced dominant skeletal mutations in mice: mutation rate, characteristics, and usefulness in estimating genetic hazard to humans from radiation

    International Nuclear Information System (INIS)

    Selby, P.B.

    1979-01-01

    The work discussed in this paper represents a major advance in the difficult task of trying to estimate the effects that an increase in mutation frequency would have on human health. Male mice were bred to three females prior to being killed and skeleton studies made. Guidelines were instituted for checking progeny mutations. Surprising results showed a mutation frequency of 1.4% per gamete where none would have been expected. It is now clear that mice can be greatly deformed without showing external effects

  6. Identification of citrullinaemia carrier and detection of a new silent mutation at 240bp position in ASS1 gene of normal Holstein cattle

    Directory of Open Access Journals (Sweden)

    Kotikalapudi Rosaiah

    2014-01-01

    Full Text Available The autosomal recessive genetic disorders are regularly investigated especially in Indian Holstein and Holstein Crossbred bulls before they entered in semen collection so that a defective gene should not be transmitted to future generations. Bovine citrullinaemia first reported in Australia is a metabolic disorder as one of the enzymes, Argininosuccinate synthetase (ASS involved in urea cycle is impaired in function. The mutation responsible for citrullinemia has been characterized as a single-base substitution at 256bp (C>T in coding exon 3 of argininosuccinate synthetase 1 (ASS1 gene, which converts the CGA (arginine at 86 codon to TGA (stop codon. A Holstein bull during routine molecular screening was found to be carrier for Citrullinaemia that was confirmed by sequencing. This is a fresh case of Citrullinaemia carrier in addition to three cases reported earlier in India. Partial sequencing of coding exon 3 of a normal Holstein revealed a new silent polymorphism at 240bp position that does not change amino acid (Sarine AGC>AGT at 80 codon within exon 3 of ASS1 gene. The sequence of exon 3 of ASS1 gene in a normal Holstein exhibiting a new polymorphism was submitted to NCBI with accession No. KF933365. The presence of citrullinaemia carriers in Indian Holstein, though in very low frequency, emphasizing to continue the investigation of mutant gene in cattle population.

  7. Normalized impact factor (NIF): an adjusted method for calculating the citation rate of biomedical journals.

    Science.gov (United States)

    Owlia, P; Vasei, M; Goliaei, B; Nassiri, I

    2011-04-01

    The interests in journal impact factor (JIF) in scientific communities have grown over the last decades. The JIFs are used to evaluate journals quality and the papers published therein. JIF is a discipline specific measure and the comparison between the JIF dedicated to different disciplines is inadequate, unless a normalization process is performed. In this study, normalized impact factor (NIF) was introduced as a relatively simple method enabling the JIFs to be used when evaluating the quality of journals and research works in different disciplines. The NIF index was established based on the multiplication of JIF by a constant factor. The constants were calculated for all 54 disciplines of biomedical field during 2005, 2006, 2007, 2008 and 2009 years. Also, ranking of 393 journals in different biomedical disciplines according to the NIF and JIF were compared to illustrate how the NIF index can be used for the evaluation of publications in different disciplines. The findings prove that the use of the NIF enhances the equality in assessing the quality of research works produced by researchers who work in different disciplines. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Measurement of urinary albumin excretion rate (AER) in normal and diabetic subjects

    International Nuclear Information System (INIS)

    Giampetro, O.; Clerico, A.; Cruschelli, L.; Miccoli, R.; Dipalma, L.; Navalesi, R.

    1987-01-01

    The chemico-clinical characteristics of two commercial RIA kits for the measurement of urinary albumin excretion in normal and diabetic subjects were compared. The chief difference between the two methods concerns the bound/free separation of the antigen, since one employs the second antybody plus PEG (Sclavo Kit), while the other uses the solid phase [antiserum bound to sepharose (Pharmacia kit)]. The two RIA methods have demonstrated a similar degree of sensitivity, feasibility and cost. The precision of the two RIAs was also similar, although the Sclavo kit has shown a better precision for lower albumin concentrations and the Pharmacia kit for higher values. In diabetic patients, elevated urinary albumin concentrations (>60 mg/L) have been found more frequently than low values (<5 mg/L); hence the Pharmacia kit seems to be preferable, because it less frequently needs dilution of urinary sample for measuring with a better precision supranormal urinary albumin values. A significant bias (about 15%) was found between the two RIAs. Bias between different albumin RIA methods could partially explain the differences of normal values previously reported in the literature

  9. Population data and mutation rates of 19 STR loci in seven provinces from China based on Goldeneye™ DNA ID System 20A.

    Science.gov (United States)

    Liu, Qiu-Ling; Chen, Ye-Fei; Huang, Xiao-Ling; Liu, Kai-Yan; Zhao, Hu; Lu, De-Jian

    2017-05-01

    Short tandem repeat (STR) analysis is a primary tool in forensic casework. Population data and mutation rates of STRs are very important for paternity testing and forensic genetics. However, the population data and mutation rates of STRs in Han nationality based on large samples have still not been fully described in China. In this study, the allelic frequencies, forensic parameters, and mutation rate of 19 STR loci (D19S433, D5S818, D21S11, D18S51, D6S1043, D3S1358, D13S317, D7S820, D16S539, CSFIPO, PentaD, vWA, D8S1179, TPOX, Penta E, TH01, D12S391, D2S1338, and FGA) based on the Goldeneye™ DNA ID System 20A in Southern China Han nationality among seven provinces were investigated. Furthermore, population stratification of Southern China Han nationality among seven provinces was established. The multidimensional scaling (MDS) plot based on genetic distances (Fst) showed that the studied populations can be clustered into two major groups. However, relationships among populations were weak (Fst < 0.0043). A total of 376 cases of mutation were detected from the 19 selected loci in 15,396 meioses. The average mutation rate for the 19 loci was estimated to be 1.3 × 10 -3 per meiosis. The mutation was mainly single step; the paternal mutation rate was higher than the maternal; and paternal mutation rate increases with paternal age.

  10. Running on empty: does mitochondrial DNA mutation limit replicative lifespan in yeast?: Mutations that increase the division rate of cells lacking mitochondrial DNA also extend replicative lifespan in Saccharomyces cerevisiae.

    Science.gov (United States)

    Dunn, Cory D

    2011-10-01

    Mitochondrial DNA (mtDNA) mutations escalate with increasing age in higher organisms. However, it has so far been difficult to experimentally determine whether mtDNA mutation merely correlates with age or directly limits lifespan. A recent study shows that budding yeast can also lose functional mtDNA late in life. Interestingly, independent studies of replicative lifespan (RLS) and of mtDNA-deficient cells show that the same mutations can increase both RLS and the division rate of yeast lacking the mitochondrial genome. These exciting, parallel findings imply a potential causal relationship between mtDNA mutation and replicative senescence. Furthermore, these results suggest more efficient methods for discovering genes that determine lifespan. Copyright © 2011 WILEY Periodicals, Inc.

  11. Efficient Computation of Transition State Resonances and Reaction Rates from a Quantum Normal Form

    NARCIS (Netherlands)

    Schubert, Roman; Waalkens, Holger; Wiggins, Stephen

    2006-01-01

    A quantum version of a recent formulation of transition state theory in phase space is presented. The theory developed provides an algorithm to compute quantum reaction rates and the associated Gamov-Siegert resonances with very high accuracy. The algorithm is especially efficient for

  12. 46 CFR 401.428 - Basic rates and charges for carrying a U.S. pilot beyond normal change point or for boarding at...

    Science.gov (United States)

    2010-10-01

    ... boarding point, the ship shall pay at the rate of $719 per day or part thereof, plus reasonable travel... normal change point or for boarding at other than the normal boarding point. 401.428 Section 401.428... carrying a U.S. pilot beyond normal change point or for boarding at other than the normal boarding point...

  13. The rate of DNA synthesis in normal human and ataxia telangiectasia cells after exposure to X-irradiation

    International Nuclear Information System (INIS)

    Wit, J. de; Bootsma, D.; Jaspers, N.G.J.; Rijksverdedigingsorganisatie TNO, Rijswijk

    1981-01-01

    The rate of DNA synthesis was studied in normal cell strains and in strains from patients suffering from the inherited disorder ataxia telangiectasia (AT). After exposure to relatively low doses of oxic X-rays (0- 4 krad) DNA synthesis was depressed in AT cell strains to a significantly lesser extent than in normal cells. This response was observed in both an excision-deficient and an excision-proficient strain. In contrast, there was no difference in DNA-synthesis inhibition between AT and normal cells after UV exposure. After X-irradiation of cells from patients with xeroderma pigmentosum, both complementation group A and XP variants, the observed rate of DNA synthesis was equal to that in normal cells. An exception was the strain XP3BR which has been shown to be X-ray-sensitive. This strain exhibited diminished DNA synthesis inhibition after X-ray doses below 1 krad. These data suggest a relationship between hypersensitivity to X-rays and diminished depression of DNA synthesis. (orig.)

  14. Frequency modulation excursion and rate discrimination in normal-hearing and hearing-impaired listeners

    DEFF Research Database (Denmark)

    Schindwolf, Isabel; Vatti, Marianna; Santurette, Sébastien

    Most natural sounds contain frequency fluctuations over time such as changes in their fundamental frequency, non-periodic speech formant transitions, or periodic fluctuations like musical vibrato. These are sometimes characterized as frequency modulation (FM) with a given excursion (FMe) and rate......, this study investigated the effects of age and SNHL on FMe and FMr difference limens (DLs) for reference values typical of frequency fluctuations observed in speech and music signals....

  15. Durability predictions from rate of diffusion testing of normal portland cement, fly ash, and slag concrete

    International Nuclear Information System (INIS)

    Philipose, K.E.

    1991-09-01

    A waste repository for the belowground disposal of low-level radioactive waste, labelled IRUS (Intrusion Resistant Underground Structure), is planned at the Chalk River Laboratories. It relies greatly on the durability of concrete for a minimum of 500 years of service life. A research program based on laboratory testing to design a durable concrete and predict its useful engineered service life is in progress. The durability of concrete depends on its resistance to deterioration from both internal and external causes. Since the rate of degradation depends to a major extent on the rate of ingress of aggressive ions into concrete, laboratory testing is in progress to establish the diffusion rates of chlorides and sulphate ions. A total of 1000 concrete specimens and 500 paste specimens are being exposed at 22 degrees and 45 degrees C to twenty-five different combinations of corrosive agents, including CO 2 . Procedures to measure the ionic penetration profile and to determine the factors controlling diffusion of ions in the various concretes have been developed. The paper presents the initial results from the research program and the longevity predictions to qualify concretes for the IRUS waste repository, based on 16 months of diffusion testing on laboratory specimens

  16. Albino mutation rates in red mangroves (Rhizophora mangle L.) as a bioassay of contamination history in Tampa Bay, Florida, USA

    Science.gov (United States)

    Proffitt, C.E.; Travis, S.E.

    2005-01-01

    We assessed the sensitivity of a viviparous estuarine tree species, Rhizophora mangle, to historic sublethal mutagenic stress across a fine spatial scale by comparing the frequency of trees producing albino propagules in historically contaminated (n=4) and uncontaminated (n=11) forests in Tampa Bay, Florida, USA. Data from uncontaminated forests were used to provide estimates of background mutation rates. We also determined whether other fitness parameters were negatively correlated with mutagenic stress (e.g., degree of outcrossing and numbers of reproducing trees km-1). Contaminated sites in Tampa Bay had significantly higher frequencies of trees that were heterozygous for albinism per 1000 total reproducing trees (FHT) than uncontaminated forests (mean ?? SE: 11.4 ?? 4.3 vs 4.3 ?? 0.73, P 25 yrs of subsequent recruitment and tree replacement may have allowed an initial elevation in the FHT to decay. Patterns of FHT were not explained by distance from the bay mouth or the degree of urbanization. However, there was a significant positive relationship between tree size and FHT (r=0.83, Pbioassay for the effects of mutagens will facilitate future monitoring of contamination events and comparisons of bay-wide recovery in future decades. Development of a database of FHT values for a range of subtropical and tropical estuaries is underway that will provide a baseline against which to compare mutational consequences of global change. ?? 2005, The Society of Wetland Scientists.

  17. Generation time, life history and the substitution rate of neutral mutations.

    Science.gov (United States)

    Lehtonen, Jussi; Lanfear, Robert

    2014-11-01

    Our understanding of molecular evolution is hampered by a lack of quantitative predictions about how life-history (LH) traits should correlate with substitution rates. Comparative studies have shown that neutral substitution rates vary substantially between species, and evidence shows that much of this diversity is associated with variation in LH traits. However, while these studies often agree, some unexplained and contradictory results have emerged. Explaining these results is difficult without a clear theoretical understanding of the problem. In this study, we derive predictions for the relationships between LH traits and substitution rates in iteroparous species by using demographic theory to relate commonly measured life-history traits to genetic generation time, and by implication to neutral substitution rates. This provides some surprisingly simple explanations for otherwise confusing patterns, such as the association between fecundity and substitution rates. The same framework can be applied to more complex life histories if full life-tables are available. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  18. HLW disposal by fission reactors; calculation of trans-mutation rate and recycle

    International Nuclear Information System (INIS)

    Mulyanto

    1997-01-01

    Transmutation of MA (Minor actinide) and LLFPS (long-lived fission products) into stable nuclide or short-lived isotopes by fission reactors seem to become an alternative technology for HLW disposal. in this study, transmutation rate and recycle calculation were developed in order to evaluate transmutation characteristics of MA and LLFPs in the fission reactors. inventory of MA and LLFPs in the transmutation reactors were determined by solving of criticality equation with 1-D cylindrical geometry of multigroup diffusion equations at the beginning of cycle (BOC). transmutation rate and burn-up was determined by solving of depletion equation. inventory of MA and LLFPs was calculated for 40 years recycle. From this study, it was concluded that characteristics of MA and LLFPs in the transmutation reactors can be evaluated by recycle calculation. by calculation of transmutation rate, performance of fission reactor for transmutation of MA or LLFPs can be discussed

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

    International Nuclear Information System (INIS)

    Russell, W.L.

    1979-01-01

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

  20. Comparison of Detection Rate and Mutational Pattern of Drug-Resistant Mutations Between a Large Cohort of Genotype B and Genotype C Hepatitis B Virus-Infected Patients in North China.

    Science.gov (United States)

    Li, Xiaodong; Liu, Yan; Xin, Shaojie; Ji, Dong; You, Shaoli; Hu, Jinhua; Zhao, Jun; Wu, Jingjing; Liao, Hao; Zhang, Xin-Xin; Xu, Dongping

    2017-06-01

    The study aimed to investigate the association of prevalent genotypes in China (HBV/C and HBV/B) with HBV drug-resistant mutations. A total of 13,847 nucleos(t)ide analogue (NA)-treated patients with chronic HBV infection from North China were enrolled. HBV genotypes and resistant mutations were determined by direct sequencing and confirmed by clonal sequencing if necessary. HBV/B, HBV/C, and HBV/D occupied 14.3%, 84.9%, and 0.8% across the study population, respectively. NA usage had no significant difference between HBV/B- and HBV/C-infected patients. Lamivudine-resistant mutations were more frequently detected in HBV/C-infected patients, compared with HBV/B-infected patients (31.67% vs. 25.26%, p M250 V/I/L substitution (0.67% vs. 1.46%, p < 0.01). Multidrug-resistant mutations (defined as coexistence of mutation to nucleoside and nucleotide analogues) were detected in 104 patients. HBV/C-infected patients had a higher detection rate of multidrug-resistant mutation than HBV/B-infected patients (0.83% vs. 0.35%, p < 0.05). The study for the first time clarified that HBV/C-infected patients had a higher risk to develop multidrug-resistant mutations, compared with HBV/B-infected patients; and HBV/C- and HBV/B-infected patients had different inclinations in the ETV-resistant mutational pattern.

  1. Mutations in Cas9 Enhance the Rate of Acquisition of Viral Spacer Sequences during the CRISPR-Cas Immune Response.

    Science.gov (United States)

    Heler, Robert; Wright, Addison V; Vucelja, Marija; Bikard, David; Doudna, Jennifer A; Marraffini, Luciano A

    2017-01-05

    CRISPR loci and their associated (Cas) proteins encode a prokaryotic immune system that protects against viruses and plasmids. Upon infection, a low fraction of cells acquire short DNA sequences from the invader. These sequences (spacers) are integrated in between the repeats of the CRISPR locus and immunize the host against the matching invader. Spacers specify the targets of the CRISPR immune response through transcription into short RNA guides that direct Cas nucleases to the invading DNA molecules. Here we performed random mutagenesis of the RNA-guided Cas9 nuclease to look for variants that provide enhanced immunity against viral infection. We identified a mutation, I473F, that increases the rate of spacer acquisition by more than two orders of magnitude. Our results highlight the role of Cas9 during CRISPR immunization and provide a useful tool to study this rare process and develop it as a biotechnological application. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. MutS and MutL are dispensable for maintenance of the genomic mutation rate in the halophilic archaeon Halobacterium salinarum NRC-1.

    Directory of Open Access Journals (Sweden)

    Courtney R Busch

    Full Text Available BACKGROUND: The genome of the halophilic archaeon Halobacterium salinarum NRC-1 encodes for homologs of MutS and MutL, which are key proteins of a DNA mismatch repair pathway conserved in Bacteria and Eukarya. Mismatch repair is essential for retaining the fidelity of genetic information and defects in this pathway result in the deleterious accumulation of mutations and in hereditary diseases in humans. METHODOLOGY/PRINCIPAL FINDINGS: We calculated the spontaneous genomic mutation rate of H. salinarum NRC-1 using fluctuation tests targeting genes of the uracil monophosphate biosynthesis pathway. We found that H. salinarum NRC-1 has a low incidence of mutation suggesting the presence of active mechanisms to control spontaneous mutations during replication. The spectrum of mutational changes found in H. salinarum NRC-1, and in other archaea, appears to be unique to this domain of life and might be a consequence of their adaption to extreme environmental conditions. In-frame targeted gene deletions of H. salinarum NRC-1 mismatch repair genes and phenotypic characterization of the mutants demonstrated that the mutS and mutL genes are not required for maintenance of the observed mutation rate. CONCLUSIONS/SIGNIFICANCE: We established that H. salinarum NRC-1 mutS and mutL genes are redundant to an alternative system that limits spontaneous mutation in this organism. This finding leads to the puzzling question of what mechanism is responsible for maintenance of the low genomic mutation rates observed in the Archaea, which for the most part do not have MutS and MutL homologs.

  3. A fast simulation method for the Log-normal sum distribution using a hazard rate twisting technique

    KAUST Repository

    Rached, Nadhir B.

    2015-06-08

    The probability density function of the sum of Log-normally distributed random variables (RVs) is a well-known challenging problem. For instance, an analytical closed-form expression of the Log-normal sum distribution does not exist and is still an open problem. A crude Monte Carlo (MC) simulation is of course an alternative approach. However, this technique is computationally expensive especially when dealing with rare events (i.e. events with very small probabilities). Importance Sampling (IS) is a method that improves the computational efficiency of MC simulations. In this paper, we develop an efficient IS method for the estimation of the Complementary Cumulative Distribution Function (CCDF) of the sum of independent and not identically distributed Log-normal RVs. This technique is based on constructing a sampling distribution via twisting the hazard rate of the original probability measure. Our main result is that the estimation of the CCDF is asymptotically optimal using the proposed IS hazard rate twisting technique. We also offer some selected simulation results illustrating the considerable computational gain of the IS method compared to the naive MC simulation approach.

  4. A fast simulation method for the Log-normal sum distribution using a hazard rate twisting technique

    KAUST Repository

    Rached, Nadhir B.; Benkhelifa, Fatma; Alouini, Mohamed-Slim; Tempone, Raul

    2015-01-01

    The probability density function of the sum of Log-normally distributed random variables (RVs) is a well-known challenging problem. For instance, an analytical closed-form expression of the Log-normal sum distribution does not exist and is still an open problem. A crude Monte Carlo (MC) simulation is of course an alternative approach. However, this technique is computationally expensive especially when dealing with rare events (i.e. events with very small probabilities). Importance Sampling (IS) is a method that improves the computational efficiency of MC simulations. In this paper, we develop an efficient IS method for the estimation of the Complementary Cumulative Distribution Function (CCDF) of the sum of independent and not identically distributed Log-normal RVs. This technique is based on constructing a sampling distribution via twisting the hazard rate of the original probability measure. Our main result is that the estimation of the CCDF is asymptotically optimal using the proposed IS hazard rate twisting technique. We also offer some selected simulation results illustrating the considerable computational gain of the IS method compared to the naive MC simulation approach.

  5. Prediction of the time-dependent failure rate for normally operating components taking into account the operational history

    International Nuclear Information System (INIS)

    Vrbanic, I.; Simic, Z.; Sljivac, D.

    2008-01-01

    The prediction of the time-dependent failure rate has been studied, taking into account the operational history of a component used in applications such as system modeling in a probabilistic safety analysis in order to evaluate the impact of equipment aging and maintenance strategies on the risk measures considered. We have selected a time-dependent model for the failure rate which is based on the Weibull distribution and the principles of proportional age reduction by equipment overhauls. Estimation of the parameters that determine the failure rate is considered, including the definition of the operational history model and likelihood function for the Bayesian analysis of parameters for normally operating repairable components. The operational history is provided as a time axis with defined times of overhauls and failures. An example for demonstration is described with prediction of the future behavior for seven different operational histories. (orig.)

  6. Performance improvement of two-dimensional EUV spectroscopy based on high frame rate CCD and signal normalization method

    International Nuclear Information System (INIS)

    Zhang, H.M.; Morita, S.; Ohishi, T.; Goto, M.; Huang, X.L.

    2014-01-01

    In the Large Helical Device (LHD), the performance of two-dimensional (2-D) extreme ultraviolet (EUV) spectroscopy with wavelength range of 30-650A has been improved by installing a high frame rate CCD and applying a signal intensity normalization method. With upgraded 2-D space-resolved EUV spectrometer, measurement of 2-D impurity emission profiles with high horizontal resolution is possible in high-density NBI discharges. The variation in intensities of EUV emission among a few discharges is significantly reduced by normalizing the signal to the spectral intensity from EUV_—Long spectrometer which works as an impurity monitor with high-time resolution. As a result, high resolution 2-D intensity distribution has been obtained from CIV (384.176A), CV(2x40.27A), CVI(2x33.73A) and HeII(303.78A). (author)

  7. Compositional and mutational rate heterogeneity in mitochondrial genomes and its effect on the phylogenetic inferences of Cimicomorpha (Hemiptera: Heteroptera).

    Science.gov (United States)

    Yang, Huanhuan; Li, Teng; Dang, Kai; Bu, Wenjun

    2018-04-18

    Mitochondrial genome (mt-genome) data can potentially return artefactual relationships in the higher-level phylogenetic inference of insects due to the biases of accelerated substitution rates and compositional heterogeneity. Previous studies based on mt-genome data alone showed a paraphyly of Cimicomorpha (Insecta, Hemiptera) due to the positions of the families Tingidae and Reduviidae rather than the monophyly that was supported based on morphological characters, morphological and molecular combined data and large scale molecular datasets. Various strategies have been proposed to ameliorate the effects of potential mt-genome biases, including dense taxon sampling, removal of third codon positions or purine-pyrimidine coding and the use of site-heterogeneous models. In this study, we sequenced the mt-genomes of five additional Tingidae species and discussed the compositional and mutational rate heterogeneity in mt-genomes and its effect on the phylogenetic inferences of Cimicomorpha by implementing the bias-reduction strategies mentioned above. Heterogeneity in nucleotide composition and mutational biases were found in mt protein-coding genes, and the third codon exhibited high levels of saturation. Dense taxon sampling of Tingidae and Reduviidae and the other common strategies mentioned above were insufficient to recover the monophyly of the well-established group Cimicomorpha. When the sites with weak phylogenetic signals in the dataset were removed, the remaining dataset of mt-genomes can support the monophyly of Cimicomorpha; this support demonstrates that mt-genomes possess strong phylogenetic signals for the inference of higher-level phylogeny of this group. Comparison of the ratio of the removal of amino acids for each PCG showed that ATP8 has the highest ratio while CO1 has the lowest. This pattern is largely congruent with the evolutionary rate of 13 PCGs that ATP8 represents the highest evolutionary rate, whereas CO1 appears to be the lowest. Notably

  8. Effects of adipose tissue distribution on maximum lipid oxidation rate during exercise in normal-weight women.

    Science.gov (United States)

    Isacco, L; Thivel, D; Duclos, M; Aucouturier, J; Boisseau, N

    2014-06-01

    Fat mass localization affects lipid metabolism differently at rest and during exercise in overweight and normal-weight subjects. The aim of this study was to investigate the impact of a low vs high ratio of abdominal to lower-body fat mass (index of adipose tissue distribution) on the exercise intensity (Lipox(max)) that elicits the maximum lipid oxidation rate in normal-weight women. Twenty-one normal-weight women (22.0 ± 0.6 years, 22.3 ± 0.1 kg.m(-2)) were separated into two groups of either a low or high abdominal to lower-body fat mass ratio [L-A/LB (n = 11) or H-A/LB (n = 10), respectively]. Lipox(max) and maximum lipid oxidation rate (MLOR) were determined during a submaximum incremental exercise test. Abdominal and lower-body fat mass were determined from DXA scans. The two groups did not differ in aerobic fitness, total fat mass, or total and localized fat-free mass. Lipox(max) and MLOR were significantly lower in H-A/LB vs L-A/LB women (43 ± 3% VO(2max) vs 54 ± 4% VO(2max), and 4.8 ± 0.6 mg min(-1)kg FFM(-1)vs 8.4 ± 0.9 mg min(-1)kg FFM(-1), respectively; P normal-weight women, a predominantly abdominal fat mass distribution compared with a predominantly peripheral fat mass distribution is associated with a lower capacity to maximize lipid oxidation during exercise, as evidenced by their lower Lipox(max) and MLOR. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Maximum Likelihood based comparison of the specific growth rates for P. aeruginosa and four mutator strains

    DEFF Research Database (Denmark)

    Philipsen, Kirsten Riber; Christiansen, Lasse Engbo; Mandsberg, Lotte Frigaard

    2008-01-01

    with an exponentially decaying function of the time between observations is suggested. A model with a full covariance structure containing OD-dependent variance and an autocorrelation structure is compared to a model with variance only and with no variance or correlation implemented. It is shown that the model...... are used for parameter estimation. The data is log-transformed such that a linear model can be applied. The transformation changes the variance structure, and hence an OD-dependent variance is implemented in the model. The autocorrelation in the data is demonstrated, and a correlation model...... that best describes data is a model taking into account the full covariance structure. An inference study is made in order to determine whether the growth rate of the five bacteria strains is the same. After applying a likelihood-ratio test to models with a full covariance structure, it is concluded...

  10. Normal IncA Expression and Fusogenicity of Inclusions in Chlamydia trachomatis Isolates with the incA I47T Mutation

    OpenAIRE

    Pannekoek, Yvonne; van der Ende, Arie; Eijk, Paul P.; van Marle, Jan; de Witte, Moniek A.; Ossewaarde, Jacobus M.; van den Brule, Adriaan J. C.; Morré, Servaas A.; Dankert, Jacob

    2001-01-01

    To investigate the correlation between the incA I47T mutation in Chlamydia trachomatis and the nonfusogenic phenotype, the incA genes of 25 isolates were sequenced. Four major sequence types were identified. Seven isolates (28%) had the I47T mutation. Isolates representing the four sequence types expressed IncA in the membrane of one large single inclusion. In conclusion, the incA I47T mutation is not associated with the nonfusogenic phenotype.

  11. Genomic instability in mutation induction on normal human fibroblasts irradiated with chronic low-dose radiations in heavy-ion radiation field

    International Nuclear Information System (INIS)

    Suzuki, M.; Tsuruoka, C.; Uchihori, Y.; Yasuda, H.; Fujitaka, K.

    2003-01-01

    Full text: At a time when manned space exploration is more a reality with the planned the International Space Station (ISS) underway, the potential exposure of crews in a spacecraft to chronic low-dose radiations in the field of low-flux galactic cosmic rays (GCR) and the subsequent biological effects have become one of the major concerns of space science. We have studied both in vitro life span and genomic instability in cellular effects in normal human skin fibroblasts irradiated with chronic low-dose radiations in heavy-ion radiation field. Cells were cultured in a CO2 incubator, which was set in the irradiation room for the biological study of heavy ions in the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences (NIRS), and irradiated with scattered radiations produced from heavy ions. Absorbed dose measured using a thermoluminescence dosimeter (TLD) and a Si-semiconductor detector was to be around 1.4 mGy per day when operating the HIMAC machine for biological experiments. The total population doubling number (tPDN) of low-dose irradiated cells was significantly smaller (79-93%) than that of unirradiated cells. The results indicate that the life span of the cell population shortens by irradiating with low-dose scattered radiations in the heavy-ion irradiation field. Genomic instability in cellular responses was examined to measure either cell killing or mutation induction in low-dose accumulated cells after exposing to X-ray challenging doses. The results showed that there was no enhanced effect on cell killing between low-dose accumulated and unirradiated cells after exposing to defined challenging doses of 200kV X rays. On the contrary, the mutation frequency on hprt locus of low-dose accumulated cells was much higher than that of unirradiated cells. The results suggested that genomic instability was induced in mutagenesis by the chronic low-dose irradiations in heavy-ion radiation field

  12. Albino mutation rates in red mangroves (Rhizophora mangle L.) as a bioassay of contamination history in Tampa Bay, Florida, USA

    Science.gov (United States)

    Proffitt, C.E.; Travis, S.E.

    2005-01-01

    We assessed the sensitivity of a viviparous estuarine tree species, Rhizophora mangle, to historic sublethal mutagenic stress across a fine spatial scale by comparing the frequency of trees producing albino propagules in historically contaminated (n=4) and uncontaminated (n=11) forests in Tampa Bay, Florida, USA. Data from uncontaminated forests were used to provide estimates of background mutation rates. We also determined whether other fitness parameters were negatively correlated with mutagenic stress (e.g., degree of outcrossing and numbers of reproducing trees km-1). Contaminated sites in Tampa Bay had significantly higher frequencies of trees that were heterozygous for albinism per 1000 total reproducing trees (FHT) than uncontaminated forests (mean ?? SE: 11.4 ?? 4.3 vs 4.3 ?? 0.73, P 25 yrs of subsequent recruitment and tree replacement may have allowed an initial elevation in the FHT to decay. Patterns of FHT were not explained by distance from the bay mouth or the degree of urbanization. However, there was a significant positive relationship between tree size and FHT (r=0.83, P<0.018), which suggests that forests with older or larger trees provide a more lasting record of cumulative mutagenic stress. No other fitness parameters correlated with FHT. There was a difference in FHT between two latitudes, as determined by comparing Tampa Bay with literature values for Puerto Rico. The sensitivity of this bioassay for the effects of mutagens will facilitate future monitoring of contamination events and comparisons of bay-wide recovery in future decades. Development of a database of FHT values for a range of subtropical and tropical estuaries is underway that will provide a baseline against which to compare mutational consequences of global change. ?? 2005, The Society of Wetland Scientists.

  13. Normal values of glomerular filtration rate in geriatrics in Bandung and its correlation with serum cystatin-C levels

    International Nuclear Information System (INIS)

    Resnaldi, A.; Yuliani, A.; Hidayat, B.; Kartamihardja, A.H.S.

    2007-01-01

    Full text: Determination of the normal values of glomerular filtration rate (GFR) is an essential part of the evaluation of patient with kidney disease. GFR almost linearly decreases with age at a mean annual rate of 0.8 ml/min/1.73 m2 over the age of 30 years old. According to NHANES III mean GFR for population with age > 60 years was 80 mL/min/1.73 m2. It is recommended for each centre to determine their own normal values of GFR for different age groups particularly in geriatric population. Recently, serum cystatin-C has been proposed as a new endogenous marker of glomerular filtration rate. Aim of the study was to determination of normal values of glomerular filtration rate (GFR) in geriatrics in Bandung and its correlation with serum Cystatin-C levels. Subjects were 24 males and 36 females (mean age 66.71 ± 6.7 years; range 60-87 yrs), without any renal and/or systemic disease. Creatinine clearance was estimated by using Cockroft-Gault formula and serum cystatin-C level were determined by using particle enhanced immunonephelometric method, while GFR values were determined by external body counting methods using Tc-99m DTPA ( Gates' methods ). Pearson correlation was used to determine correlation between variables and a P value < 0.05 is considered significant. Results and Discussion. Mean total GFR was 67.57 ml/min/1.73 m2 (SD ± 16.02), range from 45 to 100 ml/min/1.73 m2. Mean total GFR for male was 69.46 ml/min/1.73 m2, and female was 66.31 ml/min/1.73 m2, the difference was statistically significant (p < 0.05). The results were lower than NHANES III values. There was a better correlation between total GFR and cystatin-C level (r = -0.522 and p < 0.001) compared to total GFR and creatinine clearance (r 0.306 and p < 0.005). Mean creatinine clearance was 57.93 ml/min and serum cystatin-C was 0.97 mg/dl, the correlation was statistically significant (r -0.414 and p < 0.005). Conclusions: The normal values of GFR in geriatric population in Bandung were 69

  14. BAP1 missense mutation c.2054 A>T (p.E685V completely disrupts normal splicing through creation of a novel 5' splice site in a human mesothelioma cell line.

    Directory of Open Access Journals (Sweden)

    Arianne Morrison

    Full Text Available BAP1 is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal mela¬noma, malignant pleural mesothelioma (MPM, clear cell renal carcinoma, and cholangiocarcinoma. Recently, BAP1 germline mutations have been reported in families with combinations of these same cancers. A particular challenge for mutation screening is the classification of non-truncating BAP1 sequence variants because it is not known whether these subtle changes can affect the protein function sufficiently to predispose to cancer development. Here we report mRNA splicing analysis on a homozygous substitution mutation, BAP1 c. 2054 A&T (p.Glu685Val, identified in an MPM cell line derived from a mesothelioma patient. The mutation occurred at the 3rd nucleotide from the 3' end of exon 16. RT-PCR, cloning and subsequent sequencing revealed several aberrant splicing products not observed in the controls: 1 a 4 bp deletion at the end of exon 16 in all clones derived from the major splicing product. The BAP1 c. 2054 A&T mutation introduced a new 5' splice site (GU, which resulted in the deletion of 4 base pairs and presumably protein truncation; 2 a variety of alternative splicing products that led to retention of different introns: introns 14-16; introns 15-16; intron 14 and intron 16; 3 partial intron 14 and 15 retentions caused by activation of alternative 3' splice acceptor sites (AG in the introns. Taken together, we were unable to detect any correctly spliced mRNA transcripts in this cell line. These results suggest that aberrant splicing caused by this mutation is quite efficient as it completely abolishes normal splicing through creation of a novel 5' splice site and activation of cryptic splice sites. These data support the conclusion that BAP1 c.2054 A&T (p.E685V variant is a pathogenic mutation and contributes to MPM through disruption of normal splicing.

  15. Patient-dependent count-rate adaptive normalization for PET detector efficiency with delayed-window coincidence events

    International Nuclear Information System (INIS)

    Niu, Xiaofeng; Ye, Hongwei; Xia, Ting; Asma, Evren; Gagnon, Daniel; Wang, Wenli; Winkler, Mark

    2015-01-01

    Quantitative PET imaging is widely used in clinical diagnosis in oncology and neuroimaging. Accurate normalization correction for the efficiency of each line-of- response is essential for accurate quantitative PET image reconstruction. In this paper, we propose a normalization calibration method by using the delayed-window coincidence events from the scanning phantom or patient. The proposed method could dramatically reduce the ‘ring’ artifacts caused by mismatched system count-rates between the calibration and phantom/patient datasets. Moreover, a modified algorithm for mean detector efficiency estimation is proposed, which could generate crystal efficiency maps with more uniform variance. Both phantom and real patient datasets are used for evaluation. The results show that the proposed method could lead to better uniformity in reconstructed images by removing ring artifacts, and more uniform axial variance profiles, especially around the axial edge slices of the scanner. The proposed method also has the potential benefit to simplify the normalization calibration procedure, since the calibration can be performed using the on-the-fly acquired delayed-window dataset. (paper)

  16. Normal IncA expression and fusogenicity of inclusions in Chlamydia trachomatis isolates with the incA I47T mutation

    NARCIS (Netherlands)

    Pannekoek, Y.; van der Ende, A.; Eijk, P. P.; van Marle, J.; de Witte, M. A.; Ossewaarde, J. M.; van den Brule, A. J.; Morré, S. A.; Dankert, J.

    2001-01-01

    To investigate the correlation between the incA I47T mutation in Chlamydia trachomatis and the nonfusogenic phenotype, the incA genes of 25 isolates were sequenced. Four major sequence types were identified. Seven isolates (28%) had the I47T mutation. Isolates representing the four sequence types

  17. Mutation of the protein kinase C site in borna disease virus phosphoprotein abrogates viral interference with neuronal signaling and restores normal synaptic activity.

    Directory of Open Access Journals (Sweden)

    Christine M A Prat

    2009-05-01

    Full Text Available Understanding the pathogenesis of infection by neurotropic viruses represents a major challenge and may improve our knowledge of many human neurological diseases for which viruses are thought to play a role. Borna disease virus (BDV represents an attractive model system to analyze the molecular mechanisms whereby a virus can persist in the central nervous system (CNS and lead to altered brain function, in the absence of overt cytolysis or inflammation. Recently, we showed that BDV selectively impairs neuronal plasticity through interfering with protein kinase C (PKC-dependent signaling in neurons. Here, we tested the hypothesis that BDV phosphoprotein (P may serve as a PKC decoy substrate when expressed in neurons, resulting in an interference with PKC-dependent signaling and impaired neuronal activity. By using a recombinant BDV with mutated PKC phosphorylation site on P, we demonstrate the central role of this protein in BDV pathogenesis. We first showed that the kinetics of dissemination of this recombinant virus was strongly delayed, suggesting that phosphorylation of P by PKC is required for optimal viral spread in neurons. Moreover, neurons infected with this mutant virus exhibited a normal pattern of phosphorylation of the PKC endogenous substrates MARCKS and SNAP-25. Finally, activity-dependent modulation of synaptic activity was restored, as assessed by measuring calcium dynamics in response to depolarization and the electrical properties of neuronal networks grown on microelectrode arrays. Therefore, preventing P phosphorylation by PKC abolishes viral interference with neuronal activity in response to stimulation. Our findings illustrate a novel example of viral interference with a differentiated neuronal function, mainly through competition with the PKC signaling pathway. In addition, we provide the first evidence that a viral protein can specifically interfere with stimulus-induced synaptic plasticity in neurons.

  18. Effect of soft drinks on proximal plaque pH at normal and low salivary secretion rates.

    Science.gov (United States)

    Johansson, Ann-Katrin; Lingström, Peter; Birkhed, Dowen

    2007-11-01

    The aim of this study was to investigate the effect of different types of drinks on plaque pH during normal and drug-induced low salivary secretion rates. Three drinks were tested in 10 healthy adult subjects: 1) Coca-Cola regular, 2) Coca-Cola light, and 3) fresh orange juice. pH was measured in the maxillary incisor and premolar region with the microtouch method. The area under the pH curve (AUC) was calculated. During normal salivary condition, mouth-rinsing with Coca-Cola regular resulted in a slightly more pronounced drop in pH during the first few minutes than it did with orange juice. After this initial phase, both products showed similar and relatively slow pH recovery. Coca-Cola light also resulted in low pH values during the very first minutes, but thereafter in a rapid recovery back to baseline. During dry mouth conditions, the regular Cola drink showed a large initial drop in pH, and slightly more pronounced than for orange juice. After the initial phase, both products had a similar and slow recovery back to baseline. At most time-points, AUC was significantly greater in dry conditions compared to normal conditions for Coca-Cola regular and orange juice, but not for Coca-Cola light. Coca-Cola light generally showed a significantly smaller AUC than Coca-Cola regular and orange juice. The main conclusion from this study is that a low salivary secretion rate may accentuate the fall in pH in dental plaque after gentle mouth-rinsing with soft drinks.

  19. Estimation of mutation rates induced by large doses of gamma, proton and neutron irradiation of the X-chromosome of the nematode Panagrellus redivivus

    International Nuclear Information System (INIS)

    Denich, K.T.R.; Samoiloff, M.R.

    1984-01-01

    The radiation-resistant free-living nematode Panagrellus redivivus was used to study mutation rates in oocytes, following gamma, proton and neutron irradiation in the dose range 45-225 grays. γ-Radiation produced approximately 0.001 lethal X-chromosomes per gray over the range tested. Proton or neutron irradiation produced approximately 0.003 lethal X-chromosomes per gray at lower doses, with the mutation rate dropping to 0.001 lethal X-chromosome per gray at the higher doses. These results suggest a dose-dependent mutation-repair system. Cell lethality was also examined. γ-Radiation produced the greatest amount of cell lethality at all doses, while neutron irradiation had no cell lethal effect at any of the doses examined. (orig.)

  20. Radiobiological influence of megavoltage electron pulses of ultra-high pulse dose rate on normal tissue cells.

    Science.gov (United States)

    Laschinsky, Lydia; Karsch, Leonhard; Leßmann, Elisabeth; Oppelt, Melanie; Pawelke, Jörg; Richter, Christian; Schürer, Michael; Beyreuther, Elke

    2016-08-01

    Regarding the long-term goal to develop and establish laser-based particle accelerators for a future radiotherapeutic treatment of cancer, the radiobiological consequences of the characteristic short intense particle pulses with ultra-high peak dose rate, but low repetition rate of laser-driven beams have to be investigated. This work presents in vitro experiments performed at the radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance). This accelerator delivered 20-MeV electron pulses with ultra-high pulse dose rate of 10(10) Gy/min either at the low pulse frequency analogue to previous cell experiments with laser-driven electrons or at high frequency for minimizing the prolonged dose delivery and to perform comparison irradiation with a quasi-continuous electron beam analogue to a clinically used linear accelerator. The influence of the different electron beam pulse structures on the radiobiological response of the normal tissue cell line 184A1 and two primary fibroblasts was investigated regarding clonogenic survival and the number of DNA double-strand breaks that remain 24 h after irradiation. Thereby, no considerable differences in radiation response were revealed both for biological endpoints and for all probed cell cultures. These results provide evidence that the radiobiological effectiveness of the pulsed electron beams is not affected by the ultra-high pulse dose rates alone.

  1. Radiobiological influence of megavoltage electron pulses of ultra-high pulse dose rate on normal tissue cells

    International Nuclear Information System (INIS)

    Laschinsky, Lydia; Karsch, Leonhard; Schuerer, Michael; Lessmann, Elisabeth; Beyreuther, Elke; Oppelt, Melanie; Pawelke, Joerg; Richter, Christian

    2016-01-01

    Regarding the long-term goal to develop and establish laser-based particle accelerators for a future radiotherapeutic treatment of cancer, the radiobiological consequences of the characteristic short intense particle pulses with ultra-high peak dose rate, but low repetition rate of laser-driven beams have to be investigated. This work presents in vitro experiments performed at the radiation source ELBE (Electron Linac for beams with high Brilliance and low Emittance). This accelerator delivered 20-MeV electron pulses with ultra-high pulse dose rate of 10"1"0 Gy/min either at the low pulse frequency analogue to previous cell experiments with laser-driven electrons or at high frequency for minimizing the prolonged dose delivery and to perform comparison irradiation with a quasi-continuous electron beam analogue to a clinically used linear accelerator. The influence of the different electron beam pulse structures on the radiobiological response of the normal tissue cell line 184A1 and two primary fibroblasts was investigated regarding clonogenic survival and the number of DNA double-strand breaks that remain 24 h after irradiation. Thereby, no considerable differences in radiation response were revealed both for biological endpoints and for all probed cell cultures. These results provide evidence that the radiobiological effectiveness of the pulsed electron beams is not affected by the ultra-high pulse dose rates alone. (orig.)

  2. The effect of eating salt with iodine on the normal values of thyroid 131I uptake rate

    International Nuclear Information System (INIS)

    Zhang Chunyan; Wang Huawen; Li Guirong; Chen Chunmei; Zhang Lixia; Yu Yuehua

    2002-01-01

    131 I uptake rates of control group, which stop eating salt with iodine for over six weeks, eating salt with iodine group, the hyperthyroidism group are determined in 2 h, 6 h and 24 h respectively. The results show 131 I uptake rate of eating salt with iodine group are (7.7 +- 4.2)% in 2 h, (13.8 +- 5.3)% in 6 h and (21.9 +- 7.7)% in 24 h. There are no difference between sex. There is significance of difference (P 131 I uptake rates between the hyperthyroidism group of eating salt with iodine and control group is 5.0%, and eating salt with iodine group is 22.5%. To determine the thyroid iodine uptake rate in the patients who did not stop eating salt with iodine, the ranges of normal values must be defined. This result could be as a standard to diagnose the patients of hyperthyroidism of eating salt with iodine

  3. Mutational analysis of the glycosylphosphatidylinositol (GPI) anchor pathway demonstrates that GPI-anchored proteins are required for cell wall biogenesis and normal hyphal growth in Neurospora crassa.

    Science.gov (United States)

    Bowman, Shaun M; Piwowar, Amy; Al Dabbous, Mash'el; Vierula, John; Free, Stephen J

    2006-03-01

    Using mutational and proteomic approaches, we have demonstrated the importance of the glycosylphosphatidylinositol (GPI) anchor pathway for cell wall synthesis and integrity and for the overall morphology of the filamentous fungus Neurospora crassa. Mutants affected in the gpig-1, gpip-1, gpip-2, gpip-3, and gpit-1 genes, which encode components of the N. crassa GPI anchor biosynthetic pathway, have been characterized. GPI anchor mutants exhibit colonial morphologies, significantly reduced rates of growth, altered hyphal growth patterns, considerable cellular lysis, and an abnormal "cell-within-a-cell" phenotype. The mutants are deficient in the production of GPI-anchored proteins, verifying the requirement of each altered gene for the process of GPI-anchoring. The mutant cell walls are abnormally weak, contain reduced amounts of protein, and have an altered carbohydrate composition. The mutant cell walls lack a number of GPI-anchored proteins, putatively involved in cell wall biogenesis and remodeling. From these studies, we conclude that the GPI anchor pathway is critical for proper cell wall structure and function in N. crassa.

  4. Disparity mutagenesis model possesses the ability to realize both stable and rapid evolution in response to changing environments without altering mutation rates.

    Directory of Open Access Journals (Sweden)

    Ichiro Fujihara

    2016-08-01

    As long as the fidelity difference between the lagging and leading strand was kept high enough, the robustness of the disparity model was very high. The acceleration or slowdown of evolution can be unambiguously introduced only by environmental changes, and the seesawing mutation rate is not the necessary condition for changing the speed of evolution.

  5. Efficient inference of population size histories and locus-specific mutation rates from large-sample genomic variation data.

    Science.gov (United States)

    Bhaskar, Anand; Wang, Y X Rachel; Song, Yun S

    2015-02-01

    With the recent increase in study sample sizes in human genetics, there has been growing interest in inferring historical population demography from genomic variation data. Here, we present an efficient inference method that can scale up to very large samples, with tens or hundreds of thousands of individuals. Specifically, by utilizing analytic results on the expected frequency spectrum under the coalescent and by leveraging the technique of automatic differentiation, which allows us to compute gradients exactly, we develop a very efficient algorithm to infer piecewise-exponential models of the historical effective population size from the distribution of sample allele frequencies. Our method is orders of magnitude faster than previous demographic inference methods based on the frequency spectrum. In addition to inferring demography, our method can also accurately estimate locus-specific mutation rates. We perform extensive validation of our method on simulated data and show that it can accurately infer multiple recent epochs of rapid exponential growth, a signal that is difficult to pick up with small sample sizes. Lastly, we use our method to analyze data from recent sequencing studies, including a large-sample exome-sequencing data set of tens of thousands of individuals assayed at a few hundred genic regions. © 2015 Bhaskar et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients.

    Science.gov (United States)

    Jiang, Lichun; Liang, Xiaofang; Li, Yumei; Wang, Jing; Zaneveld, Jacques Eric; Wang, Hui; Xu, Shan; Wang, Keqing; Wang, Binbin; Chen, Rui; Sui, Ruifang

    2015-09-04

    Usher syndrome (USH) is the most common disease causing combined deafness and blindness. It is predominantly an autosomal recessive genetic disorder with occasionally digenic cases. Molecular diagnosis of USH patients is important for disease management. Few studies have tried to find the genetic cause of USH in Chinese patients. This study was designed to determine the mutation spectrum of Chinese USH patients. We applied next generation sequencing to characterize the mutation spectrum in 67 independent Chinese families with at least one member diagnosed with USH. Blood was collected at Peking Union Medical College Hospital. This cohort is one of the largest USH cohorts reported. We utilized customized panel and whole exome sequencing, variant analysis, Sanger validation and segregation tests to find disease causing mutations in these families. We identified biallelic disease causing mutations in known USH genes in 70 % (49) of our patients. As has been previously reported, MYO7A is the most frequently mutated gene in our USH type I patients while USH2A is the most mutated gene in our USH type II patients. In addition, we identify mutations in CLRN1, DFNB31, GPR98 and PCDH15 for the first time in Chinese USH patients. Together, mutations in CLRN1, DNFB31, GPR98 and PCDH15 account for 11.4 % of disease in our cohort. Interestingly, although the spectrum of disease genes is quite similar between our Chinese patient cohort and other patient cohorts from different (and primarily Caucasian) ethnic backgrounds, the mutations themselves are dramatically different. In particular, 76 % (52/68) of alleles found in this study have never been previously reported. Interestingly, we observed a strong enrichment for severe protein truncating mutations expected to have severe functional consequence on the protein in USH II patients compared to the reported mutation spectrum in RP patients, who often carry partial protein truncating mutations. Our study provides the first

  7. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease.

    Science.gov (United States)

    Gambardella, Stefano; Biagioni, Francesca; Ferese, Rosangela; Busceti, Carla L; Frati, Alessandro; Novelli, Giuseppe; Ruggieri, Stefano; Fornai, Francesco

    2016-01-01

    Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD.

  8. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease

    Science.gov (United States)

    Gambardella, Stefano; Biagioni, Francesca; Ferese, Rosangela; Busceti, Carla L.; Frati, Alessandro; Novelli, Giuseppe; Ruggieri, Stefano; Fornai, Francesco

    2016-01-01

    Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD. PMID:27932943

  9. The support of the ultrasonography of the shoulder in the diagnosis of polymyalgia rheumatica with normal erythrocyte sedimentation rate

    Directory of Open Access Journals (Sweden)

    G. Frisone

    2011-06-01

    Full Text Available The Polymyalgia Rheumatica (PMR is a cronic inflammatory syndrome that affects the elderly population and whose diagnosis is mainly based on clinical criteria taking little advantage of the latest innovatory methods of diagnostic imaging, for instance ultrasonography. Although it is generally characterised by increasing of inflammation values as well as pain and stiffness on the shoulder and pelvic girdles, there is a significant percentage of patients with PMR whose erythrocyte sedimentation rate (ESR is normal; in this case to make a diagnosis is difficult. The purpose of our study is to demonstrate how useful ultrasound investigations on the shoulders joints could be in order to make a diagnosis of PMR, especially for those patients with atypical normal ESR. Our case control study included 23 patients with atypical PMR and 88 patients with standard symptomatic PMR; both groups underwent shoulder ultrasound scans before receiving steroid therapy. As it has been previously shown, the ultrasound method is able to detect distinctive aspects in the joints and tissues of the patients with PMR; so that we could find that 90% of the patients with PMR of both groups suffered from bilateral subdeltoid bursitis. This disorder is seldom found in healthy people and consequently its presence could be considered a useful diagnostic test/check for/of PMR independently from ESR values.

  10. Heart rate variability and QT dispersion study in brain death patients and comatose patients with normal brainstem function

    International Nuclear Information System (INIS)

    Vakilian, A.R.; Iranmanesh, F.; Nadimi, A.E.; Kahnali, J.A.

    2011-01-01

    To compare heart rate variability (HRV) and QT dispersion in comatose patients with normal brainstem function and with brain death. Fourteen brain death patients with clinical signs of imminent brain death and 15 comatose patients were examined by neurologist in intensive care unit. HRV, RR interval and QT dispersion on ECG were assessed for 24 hours in both groups. Independent t-test and chi-square test were used for statistical analysis to determine significance which was set at p < 0.05. According to Holter findings, mean of standard deviation of RR-interval in the comatose and brain death groups was 48.33 and 35 respectively (p = 0.045). Mean of covariance coefficient of RR-interval was 0.065 in the comatose group and 0.043 in the brain deaths (p = 0.006). QT dispersion was not significant difference in two groups. HRV and RR-interval analysis appeared as an early finding for the diagnosis of brainstem death in comparison to comatose patients with normal brainstem function. QT dispersion had not significant in this regard. (author)

  11. MSH6 Mutations are Frequent in Hereditary Nonpolyposis Colorectal Cancer Families With Normal pMSH6 Expression as Detected by Immunohistochemistry

    DEFF Research Database (Denmark)

    Okkels, Henrik; Larsen, K.L.; Thorlacius-Ussing, O.

    2012-01-01

    INTRODUCTION:: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 2% to 4% of all colorectal cancer cases worldwide. Families with germ line mutations in 1 of 6 mismatch repair genes are known as Lynch syndrome families. The largest number...... this approach in Lynch families carrying mutations in MSH6. MATERIALS AND METHODS:: Results of the screening of the MSH6 gene in HNPCC families were compared with those obtained on immunohistochemical protein analysis. RESULTS:: In 56 (7%) of 815 families, at least 1 MSH6 mutation, 23 definitively pathogenic...... be detected, whereas in 34.5% pMSH6 was present and pMLH1/pPMS2 was absent. CONCLUSIONS:: If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified...

  12. Classification of caesarean section and normal vaginal deliveries using foetal heart rate signals and advanced machine learning algorithms.

    Science.gov (United States)

    Fergus, Paul; Hussain, Abir; Al-Jumeily, Dhiya; Huang, De-Shuang; Bouguila, Nizar

    2017-07-06

    Visual inspection of cardiotocography traces by obstetricians and midwives is the gold standard for monitoring the wellbeing of the foetus during antenatal care. However, inter- and intra-observer variability is high with only a 30% positive predictive value for the classification of pathological outcomes. This has a significant negative impact on the perinatal foetus and often results in cardio-pulmonary arrest, brain and vital organ damage, cerebral palsy, hearing, visual and cognitive defects and in severe cases, death. This paper shows that using machine learning and foetal heart rate signals provides direct information about the foetal state and helps to filter the subjective opinions of medical practitioners when used as a decision support tool. The primary aim is to provide a proof-of-concept that demonstrates how machine learning can be used to objectively determine when medical intervention, such as caesarean section, is required and help avoid preventable perinatal deaths. This is evidenced using an open dataset that comprises 506 controls (normal virginal deliveries) and 46 cases (caesarean due to pH ≤ 7.20-acidosis, n = 18; pH > 7.20 and pH machine-learning algorithms are trained, and validated, using binary classifier performance measures. The findings show that deep learning classification achieves sensitivity = 94%, specificity = 91%, Area under the curve = 99%, F-score = 100%, and mean square error = 1%. The results demonstrate that machine learning significantly improves the efficiency for the detection of caesarean section and normal vaginal deliveries using foetal heart rate signals compared with obstetrician and midwife predictions and systems reported in previous studies.

  13. The influence of continuous γ-irradiation at decreasing dose-rate on the survival rote and induction of gene mutations in cultured Chinese hamster cells

    International Nuclear Information System (INIS)

    Feoktistova, T.P.; Elisova, E.V.; Stavrakova, N.M.

    1991-01-01

    Continuous γ-irradiation at decreasing dose-rate was shown to be less effective than acute exposure with regard to the lethal effect and frequency of mutations of resistance to 6-thioguanine in cultured Chinese hamster cells. The cell population subjected to continuons irradiation was d more radioresistant than the intact one. Lethal and genetic effects of continuous irradiation at decreasing dose-rate were mainly determined by the contribution of the radiation dose received during the first 24 h of exposure

  14. High Rates of Psychiatric Disorders and Below Normal Mental Capacity Associated With Spastic Peroneal Flatfoot: A New Relationship.

    Science.gov (United States)

    Kılıçoğlu, Önder İsmet; Salduz, Ahmet; Birişik, Fevzi; Bilgili, Fuat; Polat, Gökhan; Kaya, İlyas; Süleyman, Funda; Coşkun, Murat

    Spastic peroneal flatfoot (SPFF) is a rare hindfoot pathology usually seen in the adolescent age group that is characterized by painful spasms in the peroneal muscles. We have clinically observed that patients with SPFF also have some behavioral and emotional difficulties and problems in their academic achievements. Because of these observations, we investigated the prevalence and patterns of psychiatric disorders and intellectual disability among young subjects with SPFF. Our cohort consisted of 16 patients with SPFF. Their mean age at presentation was 21 (range 13 to 31) years. Only 6 patients had a tarsal coalition as an underlying condition. The psychometric evaluation was conducted using validated instruments (Wechsler Intelligence Scale for Children-revised form, Stanford Binet intelligence quotient [IQ] test, and Cattell IQ test). Psychiatric disorders were assessed using a semistructured diagnostic instrument (Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version). The testers and psychiatrists were unaware of the orthopedic condition and the preliminary psychiatric diagnoses. The ethical committee approved the study protocol. The mean follow-up period was 41 (range 12 to 97) months. The mean IQ score of the patients was 75.1 ± 17.9 (range 52 to 107). Compared with the general population, the rate of intellectual disability was significantly greater (p = .0001) and the rate of normal intelligence significantly lower (p = .0015) in our patient group. Furthermore, according to the community schooling ratio, our cohort also had lower junior high and secondary education rates compared with the general population. The rate of most psychiatric disorders diagnosed in the SPFF patients was greater than that in the normal population. The most commonly identified psychiatric disorders were social phobia and attention deficit and hyperactivity disorder (75%). Timely interventions of the psychosocial and

  15. SU-F-J-45: Sparing Normal Tissue with Ultra-High Dose Rate in Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Y [DCH Reg. Medical Center, Tuscaloosa, AL (United States)

    2016-06-15

    Purpose: To spare normal tissue by reducing the location uncertainty of a moving target, we proposed an ultra-high dose rate system and evaluated. Methods: High energy electrons generated with a linear accelerator were injected into a storage ring to be accumulated. The number of the electrons in the ring was determined based on the prescribed radiation dose. The dose was delivered within a millisecond, when an online imaging system found that the target was in the position that was consistent with that in a treatment plan. In such a short time period, the displacement of the target was negligible. The margin added to the clinical target volume (CTV) could be reduced that was evaluated by comparing of volumes between CTV and ITV in 14 cases of lung stereotactic body radiation therapy (SBRT) treatments. A design of the ultra-high dose rate system was evaluated based clinical needs and the recent developments of low energy (a few MeV) electron storage ring. Results: This design of ultra-high dose rate system was feasible based on the techniques currently available. The reduction of a target volume was significant by reducing the margin that accounted the motion of the target. ∼50% volume reduction of the internal target volume (ITV) could be achieved in lung SBRT treatments. Conclusion: With this innovation of ultra-high dose rate system, the margin of target is able to be significantly reduced. It will reduce treatment time of gating and allow precisely specified gating window to improve the accuracy of dose delivering.

  16. Efficient Photometry In-Frame Calibration (EPIC) Gaussian Corrections for Automated Background Normalization of Rate-Tracked Satellite Imagery

    Science.gov (United States)

    Griesbach, J.; Wetterer, C.; Sydney, P.; Gerber, J.

    Photometric processing of non-resolved Electro-Optical (EO) images has commonly required the use of dark and flat calibration frames that are obtained to correct for charge coupled device (CCD) dark (thermal) noise and CCD quantum efficiency/optical path vignetting effects respectively. It is necessary to account/calibrate for these effects so that the brightness of objects of interest (e.g. stars or resident space objects (RSOs)) may be measured in a consistent manner across the CCD field of view. Detected objects typically require further calibration using aperture photometry to compensate for sky background (shot noise). For this, annuluses are measured around each detected object whose contained pixels are used to estimate an average background level that is subtracted from the detected pixel measurements. In a new photometric calibration software tool developed for AFRL/RD, called Efficient Photometry In-Frame Calibration (EPIC), an automated background normalization technique is proposed that eliminates the requirement to capture dark and flat calibration images. The proposed technique simultaneously corrects for dark noise, shot noise, and CCD quantum efficiency/optical path vignetting effects. With this, a constant detection threshold may be applied for constant false alarm rate (CFAR) object detection without the need for aperture photometry corrections. The detected pixels may be simply summed (without further correction) for an accurate instrumental magnitude estimate. The noise distribution associated with each pixel is assumed to be sampled from a Poisson distribution. Since Poisson distributed data closely resembles Gaussian data for parameterized means greater than 10, the data may be corrected by applying bias subtraction and standard-deviation division. EPIC performs automated background normalization on rate-tracked satellite images using the following technique. A deck of approximately 50-100 images is combined by performing an independent median

  17. Life span prediction from the rate of age-related DNA demethylation in normal and cancer cell lines.

    Science.gov (United States)

    Mazin, A L

    1995-01-01

    A method has been proposed for the Hayflick Limit prediction by the analysis of the 5-methylcytosine content in DNA at earlier and later cell passages. The following facts were used as the basis of the method: (i) the rate of m5C loss from DNA remains approximately constant during cell divisions and it does not depend on the cell donor age; (ii) this rate is inversely proportional to the Hayflick Limit as well as to the life span of cell donor species; (iii) the period corresponded to loss of all m5C residues from the genome coincides with or somewhat exceeds the Hayflick Limit of normal cells. The prognosis of the Hayflick Limit has usually been found in good agreement with the experimental evidences for various human, hamster, and mouse cell lines. The method proposed may be used for early detection of precrisis and cancer cells. The age-related m5C loss may result from accumulation of the m5C-->T+C transitions occurring with DNA methylation in every cell division.

  18. Weakly Deleterious Mutations and Low Rates of Recombination Limit the Impact of Natural Selection on Bacterial Genomes.

    Science.gov (United States)

    Price, Morgan N; Arkin, Adam P

    2015-12-15

    Free-living bacteria are usually thought to have large effective population sizes, and so tiny selective differences can drive their evolution. However, because recombination is infrequent, "background selection" against slightly deleterious alleles should reduce the effective population size (Ne) by orders of magnitude. For example, for a well-mixed population with 10(12) individuals and a typical level of homologous recombination (r/m = 3, i.e., nucleotide changes due to recombination [r] occur at 3 times the mutation rate [m]), we predict that Ne is selection should be sufficient to drive evolution if Ne × s is >1, where s is the selection coefficient. We found that this remains approximately correct if background selection is occurring or when population structure is present. Overall, we predict that even for free-living bacteria with enormous populations, natural selection is only a significant force if s is above 10(-7) or so. Because bacteria form huge populations with trillions of individuals, the simplest theoretical prediction is that the better allele at a site would predominate even if its advantage was just 10(-9) per generation. In other words, virtually every nucleotide would be at the local optimum in most individuals. A more sophisticated theory considers that bacterial genomes have millions of sites each and selection events on these many sites could interfere with each other, so that only larger effects would be important. However, bacteria can exchange genetic material, and in principle, this exchange could eliminate the interference between the evolution of the sites. We used simulations to confirm that during multisite evolution with realistic levels of recombination, only larger effects are important. We propose that advantages of less than 10(-7) are effectively neutral. Copyright © 2015 Price and Arkin.

  19. Global Bi-ventricular endocardial distribution of activation rate during long duration ventricular fibrillation in normal and heart failure canines.

    Science.gov (United States)

    Luo, Qingzhi; Jin, Qi; Zhang, Ning; Han, Yanxin; Wang, Yilong; Huang, Shangwei; Lin, Changjian; Ling, Tianyou; Chen, Kang; Pan, Wenqi; Wu, Liqun

    2017-04-13

    The objective of this study was to detect differences in the distribution of the left and right ventricle (LV & RV) activation rate (AR) during short-duration ventricular fibrillation (SDVF, 1 min) in normal and heart failure (HF) canine hearts. Ventricular fibrillation (VF) was electrically induced in six healthy dogs (control group) and six dogs with right ventricular pacing-induced congestive HF (HF group). Two 64-electrode basket catheters deployed in the LV and RV were used for global endocardium electrical mapping. The AR of VF was estimated by fast Fourier transform analysis from each electrode. In the control group, the LV was activated faster than the RV in the first 20 s, after which there was no detectable difference in the AR between them. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the posterior LV was activated fastest, while the anterior was slowest. In the HF group, a detectable AR gradient existed between the two ventricles within 3 min of VF, with the LV activating more quickly than the RV. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the septum of the LV was activated fastest, while the anterior was activated slowest. A global bi-ventricular endocardial AR gradient existed within the first 20 s of VF but disappeared in the LDVF in healthy hearts. However, the AR gradient was always observed in both SDVF and LDVF in HF hearts. The findings of this study suggest that LDVF in HF hearts can be maintained differently from normal hearts, which accordingly should lead to the development of different management strategies for LDVF resuscitation.

  20. Ultraviolet light induction of diphtheria toxin-resistant mutations in normal and DNA repair-deficient human and Chinese hamster fibroblasts

    International Nuclear Information System (INIS)

    Trosko, J.E.; Schultz, R.S.; Chang, C.C.; Glover, T.

    1980-01-01

    The role on unrepaired DNA lesions in the production of mutations is suspected of contributing to the initiation phase of carcinogenesis. Since the molecular basis of mutagenesis is not understood in eukaryotic cells, development of new genetic markers for quantitative in vitro measurement of mutations for mammalian cells is needed. Furthermore, mammalian cells, genetically deficient for various DNA repair enzymes, will be needed to study the role of unrepaired DNA lesions in mutagenesis. The results in this report relate to preliminary attempts to characterize the diphtheria toxin resistance marker as a useful quantitative genetic marker in human cells and to isolate and characterize various DNA repair-deficient Chinese hamster cells

  1. Screening for MPL mutations in essential thrombocythemia and primary myelofibrosis: normal Mpl expression and absence of constitutive STAT3 and STAT5 activation in MPLW515L-positive platelets.

    Science.gov (United States)

    Glembotsky, Ana C; Korin, Laura; Lev, Paola R; Chazarreta, Carlos D; Marta, Rosana F; Molinas, Felisa C; Heller, Paula G

    2010-05-01

    To evaluate the frequency of MPL W515L, W515K and S505N mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) and to determine whether MPLW515L leads to impaired Mpl expression, constitutive STAT3 and STAT5 activation and enhanced response to thrombopoietin (TPO). Mutation detection was performed by allele-specific PCR and sequencing. Platelet Mpl expression was evaluated by flow cytometry, immunoblotting and real-time RT-PCR. Activation of STAT3 and STAT5 before and after stimulation with increasing concentrations of TPO was studied by immunoblotting. Plasma TPO was measured by ELISA. MPLW515L was detected in 1 of 100 patients with ET and 1 of 11 with PMF. Platelets from the PMF patient showed 100% mutant allele, which was Mpl surface and total protein expression were normal, and TPO levels were mildly increased in the MPLW515L-positive ET patient, while MPL transcripts did not differ from controls in both MPLW515L-positive patients. Constitutive STAT3 and STAT5 phosphorylation was absent and dose response to TPO-induced phosphorylation was not enhanced. The low frequency of MPL mutations in this cohort is in agreement with previous studies. The finding of normal Mpl levels in MPLW515L-positive platelets indicates this mutation does not lead to dysregulated Mpl expression, as frequently shown for myeloproliferative neoplasms. The lack of spontaneous STAT3 and STAT5 activation and the normal response to TPO is unexpected as MPLW515L leads to constitutive receptor activation and hypersensitivity to TPO in experimental models.

  2. Intracellular trafficking of the free cholesterol derived from LDL cholesteryl ester is defective in vivo in Niemann-Pick C disease: insights on normal metabolism of HDL and LDL gained from the NP-C mutation.

    Science.gov (United States)

    Shamburek, R D; Pentchev, P G; Zech, L A; Blanchette-Mackie, J; Carstea, E D; VandenBroek, J M; Cooper, P S; Neufeld, E B; Phair, R D; Brewer, H B; Brady, R O; Schwartz, C C

    1997-12-01

    Niemann-Pick C disease (NP-C) is a rare inborn error of metabolism with hepatic involvement and neurological sequelae that usually manifest in childhood. Although in vitro studies have shown that the lysosomal distribution of LDL-derived cholesterol is defective in cultured cells of NP-C subjects, no unusual characteristics mark the plasma lipoprotein profiles. We set out to determine whether anomalies exist in vivo in the cellular distribution of newly synthesized, HDL-derived or LDL-derived cholesterol under physiologic conditions in NP-C subjects. Three affected and three normal male subjects were administered [14C]mevalonate as a tracer of newly synthesized cholesterol and [3H]cholesteryl linoleate in either HDL or LDL to trace the distribution of lipoprotein-derived free cholesterol. The rate of appearance of free [14C]- and free [3H]cholesterol in the plasma membrane was detected indirectly by monitoring their appearance in plasma and bile. The plasma disappearance of [3H]cholesteryl linoleate was slightly faster in NP-C subjects regardless of its lipoprotein origin. Appearance of free [14C] cholesterol ill the plasma (and in bile) was essentially identical in normal and affected individuals as was the initial appearance of free [3H]cholesterol derived from HDL, observed before extensive exchange occurred of the [3H]cholesteryl linoleate among lipoproteins. In contrast, the rate of appearance of LDL-derived free [3H]cholesterol in the plasma membrane of NP-C subjects, as detected in plasma and bile, was retarded to a similar extent that LDL cholesterol metabolism was defective in cultured fibroblasts of these affected subjects. These findings show that intracellular distribution of both newly synthesized and HDL-derived cholesterol are essentially unperturbed by the NP-C mutation, and therefore occur by lysosomal-independent paths. In contrast, in NP-C there is defective trafficking of LDL-derived cholesterol to the plasma membrane in vivo as well as in vitro

  3. Interpersonal Complementarity – Self-rated Behavior by Normal and Antisocial Adolescents with a Liked and Disliked Peer

    Directory of Open Access Journals (Sweden)

    Camilla Hakelind

    2007-12-01

    Full Text Available The principle of complementarity in interpersonal theory and the SASB model (Structural Analysis of Social Behavior as developed by Benjamin (1974 were used to study how adolescents in a normal group of 60 adolescents and a group of 42 adolescents with severe behavioural problems rated that they usually behaved in relation to a liked and disliked peer. The peer’s behaviour varied in a systematic way on the dimensions of affiliation and dominance. Complementary behavior was defined as the same behaviour from peer and self and anticomplementarity was defined as opposite behaviour from self in relation the peer’s behavior. Consistent over the two groups complementarity and anticomplementarity were influenced by both the peer’s behaviour and type of relationship with the peer. Friendly behaviour from a liked peer evoked much more complementary friendly behaviour compared to a disliked peer who with the same behaviour evoked almost as much anticomplementary hostile behaviour as complementary friendly behaviour. Hostile behaviour from a disliked peer evoked much more complementary hostile behaviour compared to a liked peer with the same kind of behavior. Autonomy granting from a liked peer evoked more complementary autonomous behaviour compared to a disliked peer. Differences between the two groups were small and only in relation with a disliked peer. The results were discussed in terms of interpersonal theory and the principle of complementarity with focus on kind of relationship.

  4. Late change of normal tissue treated either by high dose rate or low dose rate interstitial brachytherapy. A retrospective comparative study on oral and oropharyngeal mucosa

    International Nuclear Information System (INIS)

    Nose, Takayuki; Koizumi, Masahiko; Nishiyama, Kinji; Inoue, Toshihiko

    2002-01-01

    The purpose of this study was to compare late changes of normal tissue treated either by high dose rate (HDR) or low dose rate (LDR) interstitial brachytherapy. For HDR group, 22 oropharynx cancer patients who were treated by HDR Ir-192 interstitial brachytherapy with/without external beam radiotherapy in Osaka (Osaka Medical Center for Cancer and Cardiovascular Diseases and Osaka University Hospital) during June 1994 through April 2000 and came to the follow-up clinics during July 2000 through December 2000 were studied. For LDR group, 26 oropharynx cancer patients who were treated by LDR Ir-192 interstitial brachytherapy with/without external beam radiotherapy in Nancy (Centre Alexis Vautrin) during February 1989 through July 1998 and came to the follow-up clinics during April 1999 through July 1999 were studied. The standard HDR schedules were 54 Gy/9 fr/5-6 days for monotherapy and 18-24 Gy/3-4 fr/2-3 days following 45 Gy external beam radiotherapy. The standard LDR schedules were 65 Gy/5-6 days for monotherapy and 15-25 Gy/2-3 days following 50 Gy external beam radiotherapy. For evaluation of the late changes, we scored the mucosal and muscular changes inside the treated volume using the modified Dische score system and the RTOG/EORTC late radiation morbidity scoring scheme. For 6 items of the modified Dische score system, no significant difference was found between HDR and LDR groups. For the remaining 2 items (pallor, mobility impairment of faucial pillars), LDR group showed higher scores (p=0.010, 0.002). LDR group showed a trend toward higher scores for the RTOG/EORTC scheme (p=0.059). Some predict late effects by HDR interstitial brachytherapy to be severer than by LDR because no dose-rate effects can be expected. Our study, however, showed at least equivalent or even milder late changes by HDR. Appropriate fractionation schedule and extra geometrical sparing effects by optimized dose distribution of HDR group might result in milder late changes. With our

  5. Active site mutations in yeast protein disulfide isomerase cause dithiothreitol sensitivity and a reduced rate of protein folding in the endoplasmic reticulum

    DEFF Research Database (Denmark)

    Holst, B; Tachibana, C; Winther, Jakob R.

    1997-01-01

    Aspects of protein disulfide isomerase (PDI) function have been studied in yeast in vivo. PDI contains two thioredoxin-like domains, a and a', each of which contains an active-site CXXC motif. The relative importance of the two domains was analyzed by rendering each one inactive by mutation to SGAS....... Such mutations had no significant effect on growth. The domains however, were not equivalent since the rate of folding of carboxypeptidase Y (CPY) in vivo was reduced by inactivation of the a domain but not the a' domain. To investigate the relevance of PDI redox potential, the G and H positions of each CGHC......-deleted strains overexpressing the yeast PDI homologue EUG1 are viable. Exchanging the wild-type Eug1p C(L/I)HS active site sequences for C(L/I)HC increased the growth rate significantly, however, further highlighting the importance of the oxidizing function for optimal growth....

  6. Mutator activity in Schizophyllum commune

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-01-01

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

  7. Intrauterine growth-restricted piglets have similar gastric emptying rates but lower rectal temperatures and altered blood values when compared with normal-weight piglets at birth

    DEFF Research Database (Denmark)

    Williams, Charlotte Amdi; Klarlund, M. V.; Pedersen, Janni Hales

    2016-01-01

    Intrauterine growth-restricted (IUGR) piglets have lower survival rates and are more likely to have empty stomachs 24 h after birth than normal piglets. Although hypoglycemia may result from low colostrum intake per se, it is not known if slow gastric emptying may be an additional risk factor...... that the gastric emptying rate and blood glucose would be lower in IUGR piglets. We investigated gastric emptying rates in normal and IUGR piglets and blood glucose and rectal temperatures at birth and after 15, 30, 60, and 120 min. In addition, blood parameters relevant for metabolism were studied. Forty......-eight piglets (24 normal and 24 IUGR) were classified at birth as either normal or IUGR on the basis of head morphology. Piglets were removed from the sow at birth before suckling, and birth weight was recorded. Pooled porcine colostrum was tube-fed to all piglets at 12 mL/kg BW as soon as possible after birth...

  8. Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells

    NARCIS (Netherlands)

    Chan, M.F.; van Amerongen, R.; Nijjar, T.; Cuppen, E.; Jones, P.A.; Laird, P.W.

    2001-01-01

    Tumor suppressor gene inactivation is a crucial event in oncogenesis. Gene inactivation mechanisms include events resulting in loss of heterozygosity (LOH), gene mutation, and transcriptional silencing. The contribution of each of these different pathways varies among tumor suppressor genes and by

  9. Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure.

    Science.gov (United States)

    El Lakis, Mustapha; Nockel, Pavel; Guan, Bin; Agarwal, Sunita; Welch, James; Simonds, William F; Marx, Stephen; Li, Yulong; Nilubol, Naris; Patel, Dhaval; Yang, Lily; Merkel, Roxanne; Kebebew, Electron

    2018-01-01

    Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism. We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism. Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism. Published by Elsevier Inc.

  10. Type I error rates of rare single nucleotide variants are inflated in tests of association with non-normally distributed traits using simple linear regression methods.

    Science.gov (United States)

    Schwantes-An, Tae-Hwi; Sung, Heejong; Sabourin, Jeremy A; Justice, Cristina M; Sorant, Alexa J M; Wilson, Alexander F

    2016-01-01

    In this study, the effects of (a) the minor allele frequency of the single nucleotide variant (SNV), (b) the degree of departure from normality of the trait, and (c) the position of the SNVs on type I error rates were investigated in the Genetic Analysis Workshop (GAW) 19 whole exome sequence data. To test the distribution of the type I error rate, 5 simulated traits were considered: standard normal and gamma distributed traits; 2 transformed versions of the gamma trait (log 10 and rank-based inverse normal transformations); and trait Q1 provided by GAW 19. Each trait was tested with 313,340 SNVs. Tests of association were performed with simple linear regression and average type I error rates were determined for minor allele frequency classes. Rare SNVs (minor allele frequency < 0.05) showed inflated type I error rates for non-normally distributed traits that increased as the minor allele frequency decreased. The inflation of average type I error rates increased as the significance threshold decreased. Normally distributed traits did not show inflated type I error rates with respect to the minor allele frequency for rare SNVs. There was no consistent effect of transformation on the uniformity of the distribution of the location of SNVs with a type I error.

  11. Longitudinal Associations among Renal Urea Clearance-Corrected Normalized Protein Catabolic Rate, Serum Albumin, and Mortality in Patients on Hemodialysis.

    Science.gov (United States)

    Eriguchi, Rieko; Obi, Yoshitsugu; Streja, Elani; Tortorici, Amanda R; Rhee, Connie M; Soohoo, Melissa; Kim, Taehee; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

    2017-07-07

    There are inconsistent reports on the association of dietary protein intake with serum albumin and outcomes among patients on hemodialysis. Using a new normalized protein catabolic rate (nPCR) variable accounting for residual renal urea clearance, we hypothesized that higher baseline nPCR and rise in nPCR would be associated with higher serum albumin and better survival among incident hemodialysis patients. Among 36,757 incident hemodialysis patients in a large United States dialysis organization, we examined baseline and change in renal urea clearance-corrected nPCR as a protein intake surrogate and modeled their associations with serum albumin and mortality over 5 years (1/2007-12/2011). Median nPCRs with and without accounting for renal urea clearance at baseline were 0.94 and 0.78 g/kg per day, respectively (median within-patient difference, 0.14 [interquartile range, 0.07-0.23] g/kg per day). During a median follow-up period of 1.4 years, 8481 deaths were observed. Baseline renal urea clearance-corrected nPCR was associated with higher serum albumin and lower mortality in the fully adjusted model ( P trend urea clearance-corrected nPCR during the first 6 months was also associated with attaining high serum albumin (≥3.8 g/dl) and lower mortality ( P trend urea clearance, higher levels of renal urea clearance-corrected nPCR consistently showed lower mortality risk. Among incident hemodialysis patients, higher dietary protein intake represented by nPCR and its changes over time appear to be associated with increased serum albumin levels and greater survival. nPCR may be underestimated when not accounting for renal urea clearance. Compared with the conventional nPCR, renal urea clearance-corrected nPCR may be a better marker of mortality. Copyright © 2017 by the American Society of Nephrology.

  12. The effect of puberty on fat oxidation rates during exercise in overweight and normal-weight girls.

    Science.gov (United States)

    Chu, L; Riddell, M C; Schneiderman, J E; McCrindle, B W; Hamilton, J K

    2014-01-01

    Excess weight is often associated with insulin resistance (IR) and may disrupt fat oxidation during exercise. This effect is further modified by puberty. While studies have shown that maximal fat oxidation rates (FOR) during exercise decrease with puberty in normal-weight (NW) and overweight (OW) boys, the effect of puberty in NW and OW girls is unclear. Thirty-three NW and OW girls ages 8-18 yr old completed a peak aerobic capacity test on a cycle ergometer. FOR were calculated during progressive submaximal exercise. Body composition and Tanner stage were determined. For each participant, a best-fit polynomial curve was constructed using fat oxidation vs. exercise intensity to estimate max FOR. In a subset of the girls, IR derived from an oral glucose tolerance test (n = 20), and leptin and adiponectin levels (n = 11) were assessed in relation to FOR. NW pre-early pubertal girls had higher max FOR [6.9 ± 1.4 mg·kg fat free mass (FFM)(-1)·min(-1)] than NW mid-late pubertal girls (2.2 ± 0.9 mg·kg FFM(-1)·min(-1)) (P = 0.002), OW pre-early pubertal girls (3.8 ± 2.1 mg·kg FFM(-1)·min(-1)), and OW mid-late pubertal girls (3.3 ± 0.9 mg·kg FFM(-1)·min(-1)) (P puberty; however, this decrease associated with puberty was blunted in OW girls due to lower FOR in pre-early puberty. The presence of IR due to obesity potentially masks the effect of puberty on FOR during exercise in girls.

  13. Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates.

    Science.gov (United States)

    de Chantal, Marilyn; Diodati, Jean G; Nasmith, James B; Amyot, Robert; LeBlanc, A Robert; Schampaert, Erick; Pharand, Chantal

    2006-12-01

    ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.

  14. Comparison of the predictions of the LQ and CRE models for normal tissue damage due to biologically targeted radiotherapy with exponentially decaying dose rates

    International Nuclear Information System (INIS)

    O'Donoghue, J.A.; West of Schotland Health Boards, Glasgow

    1989-01-01

    For biologically targeted radiotherapy organ dose rates may be complex functions of time, related to the biodistribution kinetics of the delivery vehicle and radiolabel. The simples situation is where dose rates are exponentially decaying functions of time. Two normal tissue isoeffect models enable the effects of exponentially decaying dose rates to be addressed. These are the extension of the linear-quadratic model and the cumulative radiation effect model. This communication will compare the predictions of these models. (author). 14 refs.; 1 fig

  15. Mutation rate switch inside Eurasian mitochondrial haplogroups: impact of selection and consequences for dating settlement in Europe.

    Directory of Open Access Journals (Sweden)

    Denis Pierron

    Full Text Available R-lineage mitochondrial DNA represents over 90% of the European population and is significantly present all around the planet (North Africa, Asia, Oceania, and America. This lineage played a major role in migration "out of Africa" and colonization in Europe. In order to determine an accurate dating of the R lineage and its sublineages, we analyzed 1173 individuals and complete mtDNA sequences from Mitomap. This analysis revealed a new coalescence age for R at 54.500 years, as well as several limitations of standard dating methods, likely to lead to false interpretations. These findings highlight the association of a striking under-accumulation of synonymous mutations, an over-accumulation of non-synonymous mutations, and the phenotypic effect on haplogroup J. Consequently, haplogroup J is apparently not a Neolithic group but an older haplogroup (Paleolithic that was subjected to an underestimated selective force. These findings also indicated an under-accumulation of synonymous and non-synonymous mutations localized on coding and non-coding (HVS1 sequences for haplogroup R0, which contains the major haplogroups H and V. These new dates are likely to impact the present colonization model for Europe and confirm the late glacial resettlement scenario.

  16. Inactivation of CDK/pRb pathway normalizes survival pattern of lymphoblasts expressing the FTLD-progranulin mutation c.709-1G>A.

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    Carolina Alquezar

    Full Text Available BACKGROUND: Mutations in the progranulin (PGRN gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP, although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. METHODOLOGY/PRINCIPAL FINDINGS: We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. CONCLUSION/SIGNIFICANCE: The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP.

  17. Detection of Ultra-Rare Mitochondrial Mutations in Breast Stem Cells by Duplex Sequencing.

    Directory of Open Access Journals (Sweden)

    Eun Hyun Ahn

    Full Text Available Long-lived adult stem cells could accumulate non-repaired DNA damage or mutations that increase the risk of tumor formation. To date, studies on mutations in stem cells have concentrated on clonal (homoplasmic mutations and have not focused on rarely occurring stochastic mutations that may accumulate during stem cell dormancy. A major challenge in investigating these rare mutations is that conventional next generation sequencing (NGS methods have high error rates. We have established a new method termed Duplex Sequencing (DS, which detects mutations with unprecedented accuracy. We present a comprehensive analysis of mitochondrial DNA mutations in human breast normal stem cells and non-stem cells using DS. The vast majority of mutations occur at low frequency and are not detectable by NGS. The most prevalent point mutation types are the C>T/G>A and A>G/T>C transitions. The mutations exhibit a strand bias with higher prevalence of G>A, T>C, and A>C mutations on the light strand of the mitochondrial genome. The overall rare mutation frequency is significantly lower in stem cells than in the corresponding non-stem cells. We have identified common and unique non-homoplasmic mutations between non-stem and stem cells that include new mutations which have not been reported previously. Four mutations found within the MT-ND5 gene (m.12684G>A, m.12705C>T, m.13095T>C, m.13105A>G are present in all groups of stem and non-stem cells. Two mutations (m.8567T>C, m.10547C>G are found only in non-stem cells. This first genome-wide analysis of mitochondrial DNA mutations may aid in characterizing human breast normal epithelial cells and serve as a reference for cancer stem cell mutation profiles.

  18. Mutation induction in cultured human cells after low-dose and low-dose-rate γ-ray irradiation. Detection by LOH analysis

    International Nuclear Information System (INIS)

    Umebayashi, Yukihiro; Iwaki, Masaya; Yatagai, Fumio; Honma, Masamitsu; Suzuki, Masao; Suzuki, Hiromi; Shimazu, Toru; Ishioka, Noriaki

    2007-01-01

    To study the genetic effects of low-doses and low-dose-rate ionizing radiation (IR), human lymphoblastoid TK6 cells were exposed to 30 mGy of γ-rays at a dose-rate of 1.2 mGy/hr. The frequency of early mutations (EMs) in the thymidine kinase (TK) gene locus was determined to be 1.7 x 10 -6 , or 1.9-fold higher than the level seen in unirradiated controls. These mutations were analyzed with a loss of heterozygosity (LOH) detection system, a methodology which has been shown to be sensitive to the effects of radiation. Among the 15 EMs observed after IR exposure, 8 were small interstitial-deletion events restricted to the TK gene locus. However, this specific type of event was not found in unirradiated controls. Although these results were observed under the limited conditions, they strongly suggest that the LOH detection system can be used for estimating the genetic effects of a low-dose IR exposure delivered at a low-dose-rate. (author)

  19. A loss-of-function mutation in the nucleoporin AtNUP160 indicates that normal auxin signalling is required for a proper ethylene response in Arabidopsis

    Science.gov (United States)

    Robles, Linda M.; Deslauriers, Stephen D.; Alvarez, Ashley A.; Larsen, Paul B.

    2012-01-01

    As part of a continuing effort to elucidate mechanisms that regulate the magnitude of ethylene signalling, an Arabidopsis mutant with an enhanced ethylene response was identified. Subsequent characterization of this loss-of-function mutant revealed severe hypocotyl shortening in the presence of saturating ethylene along with increased expression in leaves of a subset of ethylene-responsive genes. It was subsequently determined by map-based cloning that the mutant (sar1-7) represents a loss-of-function mutation in the previously described nucleoporin AtNUP160 (At1g33410, SAR1). In support of previously reported results, the sar1-7 mutant partially restored auxin responsiveness to roots of an rce1 loss-of-function mutant, indicating that AtNUP160/SAR1 is required for proper expression of factors responsible for the repression of auxin signalling. Analysis of arf7-1/sar1-7 and arf19-1/sar1-7 double mutants revealed that mutations affecting either ARF7 or ARF19 function almost fully blocked manifestation of the sar1-7-dependent ethylene hypersensitivity phenotype, suggesting that ARF7- and ARF19-mediated auxin signalling is responsible for regulating the magnitude of and/or competence for the ethylene response in Arabidopsis etiolated hypocotyls. Consistent with this, addition of auxin to ethylene-treated seedlings resulted in severe hypocotyl shortening, reminiscent of that seen for other eer (enhanced ethylene response) mutants, suggesting that auxin functions in part synergistically with ethylene to control hypocotyl elongation and other ethylene-dependent phenomena. PMID:22238449

  20. Ehlers-Danlos syndrome type IV : unusual congenital anomalies in a mother and son with a COL3A1 mutation and a normal collagen III protein profile

    NARCIS (Netherlands)

    Kroes, HY; Pals, G; van Essen, AJ

    A mother and son with Ehlers-Danlos syndrome (EDS) type IV and unusual congenital anomalies are described. The congenital anomalies include, in the mother, amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly owing to normal-pressure hydrocephaly and, in the son, an

  1. Specific-locus mutation frequencies in mouse stem-cell spermatogonia at very low radiation dose rates, and their use in the estimation of genetic hazards of radiation in man

    International Nuclear Information System (INIS)

    Russell, W.L.; Kelly, E.M.

    1982-01-01

    Experiments were undertaken to augment the information on the lowest radiation dose rates feasible for scoring transmitted induced mutations detected by the specific-locus method in the mouse. This is the type of information most suitable for estimating genetic hazards of radiation in man. The results also aid in resolving conflicting possibilities about the relationship between mutation frequency and radiation dose at low dose rates

  2. Inhibiting effect of plasma from normal and tumour bearing mice on the mitotic rate of regenerating liver.

    Science.gov (United States)

    Echave Llanos, J M; Moreno, F R; Badrán, A F

    1986-01-01

    Plasma from normal mice and from mice bearing the ES2 transplantable malignant tumour was injected intraperitoneally at a dose of 0.01 ml/g body weight in partially hepatectomized mice. Control animals were injected with a solution of sodium citrate in saline. The recipients were killed at the first (14:00 hours/48 h). These times are the time of day and the number of h after partial hepatectomy and second (14:00 hours/72 h) peak times after partial hepatectomy. The number of colchicine metaphases per 1000 nuclei was determined for hepatocytes and litoral cells. A different effect was obtained with plasma from tumour-bearing compared with normal mice. Plasma from both sources when injected 26 h after partial hepatectomy (16:00 hours/26 h) inhibited the mitotic activity of hepatocytes at the next peak of regenerative activity (14:00 hours/48 h). The plasma from tumour-bearing mice also inhibited the peak on the following day (14:00 hours/72 h), whereas plasma from normal mice had no inhibitory effect and, indeed, a compensatory wave was observed at this time. Furthermore, plasma from tumour-bearing mice also showed an inhibitory effect at the first peak (14:00 hours/48 h) when injected at the time of partial hepatectomy (14:00 hours/00 h) or at 22 h before partial hepatectomy (16:00 hours/-22 h) whereas the injection of plasma from normal mice at these times had no inhibitory effect. In the litoral cells the injection of plasma from tumour-bearing mice made 22 h before hepatectomy (16:00 hours/-22 h) led to a stimulation of mitotic activity which was controlled at 14:00 hours/48 h.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Adaptive response to ionizing radiation in normal human skin fibroblasts. Enhancement of DNA repair rate and modulation of gene expression

    International Nuclear Information System (INIS)

    Toledo, S.M. de; Mitchel, R.E.J.; Azzam, E.; Ottawa Univ., ON; Raaphorst, G.P.

    1994-01-01

    Low doses and dose rates of ionizing radiation enhance the rate of DNA repair in human fibroblasts and protect the cells against radiation-induced micronucleus formation. Chronic exposures reduce the mRNA levels of the genes topoisomerase II and FACC-1 (Fanconi's anemia, group C). (authors). 11 refs., 1 tab., 2 figs

  4. Reflex control of heart rate in normal subjects in relation to age: a data base for cardiac vagal neuropathy

    NARCIS (Netherlands)

    Wieling, W.; van Brederode, J. F.; de Rijk, L. G.; Borst, C.; Dunning, A. J.

    1982-01-01

    We examined the heart rate changes induced by forced breathing and by standing up in 133 healthy subjects in the age range 10-65 years in order to establish a data base for studies on parasympathetic heart rate control in autonomic neuropathy. Test results declined with age. Log-transformation was

  5. Specific-locus experiments show that female mice exposed near the time of birth to low-LET ionizing radiation exhibit both a low mutational response and a dose-rate effect

    International Nuclear Information System (INIS)

    Selby, P.B.; Lee, S.S.; Kelly, E.M.; Bangham, J.W.; Raymer, G.D.; Hunsicker, P.R.

    1991-01-01

    Female mice were exposed to 300 R of 73-93 R/min X-radiation either as fetuses at 18.5d post conception (p.c.) or within 9h after birth. Combining the similar results from these 2 groups yielded a specific-locus mutation frequency of 9.4x10 -8 mutation/locus/R, which is statistically significantly higher than the historical-control mutation frequency, but much lower than the rate obtained by irradiating mature and maturing oocytes in adults. Other females, exposed at 18.5 days p.c. to 300 R of 0.79 R/min γ-radiation, yielded a mutation frequency that was statistically significantly lower than the frequency at high dose rates. The low-dose-rate group also had markedly higher fertility. It appears that the doe-rate effect for mutations induced near the time of birth may be more pronounced than that reported for mature and maturing oocytes of adults. A hypothesis sometimes advanced to explain low mutation frequencies recovered from cell populations that experience considerable radiation-induced cell killing is that there is selection against mutant cells. The reason for the relatively low mutational response following acute irradiation in the experiments is unknown; however, the finding of a dose-rate effect in these oocytes in the presence of only minor radiation-induced cell killing (as judged from fertility) makes it seem unlikely that selection was responsible for the low mutational response following acute exposure. Had selection been an important factor, the mutation frequency should have increased when oocyte killing was markedly reduced. (author). 32 refs.; 5 figs.; 5 tabs

  6. Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.

    Science.gov (United States)

    Meadowcroft, Mark D; Wang, Jianli; Purnell, Carson J; Peters, Douglas G; Eslinger, Paul J; Neely, Elizabeth B; Gill, David J; Vasavada, Megha; Ali-Rahmani, Fatima; Yang, Qing X; Connor, James R

    2016-12-01

    Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R 2 ) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R 2 compared to non-carriers within white matter association fibers in the brain. Similar R 2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R 2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R 2 within white matter tracts of both species is speculated to be multifaceted. The R 2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R 2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

  7. High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington's disease expansion mutation carriers shows normal mitochondrial respiratory function.

    Directory of Open Access Journals (Sweden)

    Eva Buck

    Full Text Available Alterations in mitochondrial respiration are an important hallmark of Huntington's disease (HD, one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human vastus lateralis muscle was measured by high-resolution respirometry (HRR in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (HdhQ111 as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.

  8. RADIA: RNA and DNA integrated analysis for somatic mutation detection.

    Directory of Open Access Journals (Sweden)

    Amie J Radenbaugh

    Full Text Available The detection of somatic single nucleotide variants is a crucial component to the characterization of the cancer genome. Mutation calling algorithms thus far have focused on comparing the normal and tumor genomes from the same individual. In recent years, it has become routine for projects like The Cancer Genome Atlas (TCGA to also sequence the tumor RNA. Here we present RADIA (RNA and DNA Integrated Analysis, a novel computational method combining the patient-matched normal and tumor DNA with the tumor RNA to detect somatic mutations. The inclusion of the RNA increases the power to detect somatic mutations, especially at low DNA allelic frequencies. By integrating an individual's DNA and RNA, we are able to detect mutations that would otherwise be missed by traditional algorithms that examine only the DNA. We demonstrate high sensitivity (84% and very high precision (98% and 99% for RADIA in patient data from endometrial carcinoma and lung adenocarcinoma from TCGA. Mutations with both high DNA and RNA read support have the highest validation rate of over 99%. We also introduce a simulation package that spikes in artificial mutations to patient data, rather than simulating sequencing data from a reference genome. We evaluate sensitivity on the simulation data and demonstrate our ability to rescue back mutations at low DNA allelic frequencies by including the RNA. Finally, we highlight mutations in important cancer genes that were rescued due to the incorporation of the RNA.

  9. Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection

    Science.gov (United States)

    Dudley, Matthew Z.; Sheen, Patricia; Gilman, Robert H.; Ticona, Eduardo; Friedland, Jon S.; Kirwan, Daniela E.; Caviedes, Luz; Rodriguez, Richard; Cabrera, Lilia Z.; Coronel, Jorge; Grandjean, Louis; Moore, David A. J.; Evans, Carlton A.; Huaroto, Luz; Chávez-Pérez, Víctor; Zimic, Mirko

    2016-01-01

    Hospital infection control measures are crucial to tuberculosis (TB) control strategies within settings caring for human immunodeficiency virus (HIV)–positive patients, as these patients are at heightened risk of developing TB. Pyrazinamide (PZA) is a potent drug that effectively sterilizes persistent Mycobacterium tuberculosis bacilli. However, PZA resistance associated with mutations in the nicotinamidase/pyrazinamidase coding gene, pncA, is increasing. A total of 794 patient isolates obtained from four sites in Lima, Peru, underwent spoligotyping and drug resistance testing. In one of these sites, the HIV unit of Hospital Dos de Mayo (HDM), an isolation ward for HIV/TB coinfected patients opened during the study as an infection control intervention: circulating genotypes and drug resistance pre- and postintervention were compared. All other sites cared for HIV-negative outpatients: genotypes and drug resistance rates from these sites were compared with those from HDM. HDM patients showed high concordance between multidrug resistance, PZA resistance according to the Wayne method, the two most common genotypes (spoligotype international type [SIT] 42 of the Latino American-Mediterranean (LAM)-9 clade and SIT 53 of the T1 clade), and the two most common pncA mutations (G145A and A403C). These associations were absent among community isolates. The infection control intervention was associated with 58–92% reductions in TB caused by SIT 42 or SIT 53 genotypes (odds ratio [OR] = 0.420, P = 0.003); multidrug-resistant TB (OR = 0.349, P < 0.001); and PZA-resistant TB (OR = 0.076, P < 0.001). In conclusion, pncA mutation typing, with resistance testing and spoligotyping, was useful in identifying a nosocomial TB outbreak and demonstrating its resolution after implementation of infection control measures. PMID:27928075

  10. Resistance mechanisms of linezolid-nonsusceptible enterococci in Korea: low rate of 23S rRNA mutations in Enterococcus faecium.

    Science.gov (United States)

    Lee, Sae-Mi; Huh, Hee Jae; Song, Dong Joon; Shim, Hyang Jin; Park, Kyung Sun; Kang, Cheol-In; Ki, Chang-Seok; Lee, Nam Yong

    2017-12-01

    To investigate linezolid-resistance mechanisms in linezolid-nonsusceptible enterococci (LNSE) isolated from a tertiary hospital in Korea. Enterococcal isolates exhibiting linezolid MICs ≥4 mg l -1 that were isolated between December 2011 and May 2016 were investigated by PCR and sequencing for mutations in 23S rRNA or ribosomal proteins (L3, L4 and L22) and for the presence of cfr, cfr(B) and optrA genes.Results/Key findings. Among 135 LNSE (87 Enterococcus faecium and 48 Enterococcus faecalis isolates), 39.1 % (34/87) of E. faecium and 18.8 % (9/48) of E. faecalis isolates were linezolid-resistant. The optrA carriage was the dominant mechanism in E. faecalis: 13 isolates, including 10 E. faecalis [70 % (7/10) linezolid-resistant and 30 % (3/10) linezolid-intermediate] and three E. faecium [33.3 % (1/3) linezolid-resistant and 66.7 % (2/3) linezolid-intermediate], contained the optrA gene. G2576T mutations in the 23S rRNA gene were detected only in E. faecium [14 isolates; 71.4 % (10/14) linezolid-resistant and 28.6 % (4/14) linezolid-intermediate]. One linezolid-intermediate E. faecium harboured a L22 protein alteration (Ser77Thr). No isolates contained cfr or cfr(B) genes and any L3 or L4 protein alterations. No genetic mechanism of resistance was identified for 67.6 % (23/34) of linezolid-resistant E. faecium. A low rate of 23S rRNA mutations and the absence of known linezolid-resistance mechanisms in the majority of E. faecium isolates suggest regional differences in the mechanisms of linezolid resistance and the possibility of additional mechanisms.

  11. Blood disappearance rate of /sup 198/Au-colloid and changes of hepatic blood flow during position change in normal persons and in patients with various hepatic diseases

    Energy Technology Data Exchange (ETDEWEB)

    Cho, B Y [Capital Armed Forces General Hospital, Seoul (Republic of Korea); Hong, K S; Koh, C S; Lee, M [Seoul National Univ., Seoul (Republic of Korea). Coll. of Medicine

    1977-01-01

    To evaluate the diagnostic significance of the blood disappearance rate of /sup 198/Au-colloid and to evaluate the change of hepatic blood flow during position change from supine to erect, we measured the half time of blood disappearance rate of 7,1/sup 98/Au-colloid using external counting method in 94 normal persons and in 77 patients with various hepatic diseases. The results obtained were as follows: 1. In normal control, the mean blood disappearance half time of /sup 198/Au-colloid in supine position was 2.7+-0.4 minutes. There was no significant difference of hepatic blood flow in age and sex. 2. In acute hepatitits, chronic hepatitis and hepatic cirrhosis, the mean blood disappearance half times in supine position were 3.0+-0.45, 3.5+-0.74, 7.2+-3.6 minutes respectively. The hepatic blood flow of the patients with chronic hepatitis and hepatic cirrhosis were significantly decreased than that of normal control. 3. In the normal control and acute hepatitis, the decreaces of the hepatic blood flow during the position change from supine to erect were 27.7% and 22.6% respectively.

  12. The blood disappearance rate of 198Au-colloid and changes of hepatic blood flow during position change in normal persons and in patients with various hepatic diseases

    International Nuclear Information System (INIS)

    Cho, B.Y.; Hong, K.S.; Koh, C.S.; Lee, M.

    1977-01-01

    To evaluate the diagnostic significance of the blood disappearance rate of 198 Au-colloid and to evaluate the change of hepatic blood flow during position change from supine to erect, we measured the half time of blood disappearance rate of 7,1 98 Au-colloid using external counting method in 94 normal persons and in 77 patients with various hepatic diseases. The results obtained were as follows: 1. In normal control, the mean blood disappearance half time of 198 Au-colloid in supine position was 2.7+-0.4 minutes. There was no significant difference of hepatic blood flow in age and sex. 2. In acute hepatitits, chronic hepatitis and hepatic cirrhosis, the mean blood disappearance half times in supine position were 3.0+-0.45, 3.5+-0.74, 7.2+-3.6 minutes respectively. The hepatic blood flow of the patients with chronic hepatitis and hepatic cirrhosis were significantly decreased than that of normal control. 3. In the normal control and acute hepatitis, the decreaces of the hepatic blood flow during the position change from supine to erect were 27.7% and 22.6% respectively. (author)

  13. The Blood Disappearance Rate of 198Au-Colloid and Changes of Hepatic Blood Flow During Position Change in Normal Persons and in Patients with Various Hepatic Diseases

    International Nuclear Information System (INIS)

    Cho, Bo Yeon; Hong, Kee Suk; Koh, Chang Soon; Lee, Mun Ho

    1977-01-01

    To evaluate the diagnostic significance of the blood disappearance rate of 198 Au-colloid and to evaluate the change of hepatic blood flow during position change from supine to erect, we measured the half time of blood disappearance rate of 198 Au-colloid using external counting method in 94 normal persons and in 77 patients with various hepatic diseases. The results obtained were as follows: 1) In normal control, the mean blood disappearance half time of 198 Au-colloid in supine position was 2.7±0.4 minutes. There was no significant difference of hepatic blood flow in age and sex. 2) In acute hepatitis, chronic hepatitis and hepatic cirrhosis, the mean blood disappearance half times in supine position were 3.0±0.45, 3.5±0.74, 7.2±3.6 minutes respectively. The hepatic blood flow of the patients with chronic hepatitis and hepatic cirrhosis were significantly decreased than that of normal control. 3) In the normal control and acute hepatitis, the decreases of the hepatic blood flow during the position change from supine to erect were 27.7% and 22.6% respectively.

  14. Ataxia Telangiectasia–Mutated Gene Polymorphisms and Acute Normal Tissue Injuries in Cancer Patients After Radiation Therapy: A Systematic Review and Meta-analysis

    International Nuclear Information System (INIS)

    Dong, Lihua; Cui, Jingkun; Tang, Fengjiao; Cong, Xiaofeng; Han, Fujun

    2015-01-01

    Purpose: Studies of the association between ataxia telangiectasia–mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results are inconsistent. We conducted the first meta-analysis to provide a systematic review of published findings. Methods and Materials: Publications were identified by searching PubMed up to April 25, 2014. Primary meta-analysis was performed for all acute radiation injuries, and subgroup meta-analyses were based on clinical endpoint. The influence of sample size and radiation injury incidence on genetic effects was estimated in sensitivity analyses. Power calculations were also conducted. Results: The meta-analysis was conducted on the ATM polymorphism rs1801516, including 5 studies with 1588 participants. For all studies, the cut-off for differentiating cases from controls was grade 2 acute radiation injuries. The primary meta-analysis showed a significant association with overall acute radiation injuries (allelic model: odds ratio = 1.33, 95% confidence interval: 1.04-1.71). Subgroup analyses detected an association between the rs1801516 polymorphism and a significant increase in urinary and lower gastrointestinal injuries and an increase in skin injury that was not statistically significant. There was no between-study heterogeneity in any meta-analyses. In the sensitivity analyses, small studies did not show larger effects than large studies. In addition, studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence. Power calculations revealed that the statistical power of the primary meta-analysis was borderline, whereas there was adequate power for the subgroup analysis of studies with high incidence of acute radiation injuries. Conclusions: Our meta-analysis showed a consistency of the results from the overall and subgroup analyses. We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was

  15. Morphological evolution of dissolving feldspar particles with anisotropic surface kinetics and implications for dissolution rate normalization and grain size dependence: A kinetic modeling study

    Science.gov (United States)

    Zhang, Li; Lüttge, Andreas

    2009-11-01

    With previous two-dimensional (2D) simulations based on surface-specific feldspar dissolution succeeding in relating the macroscopic feldspar kinetics to the molecular-scale surface reactions of Si and Al atoms ( Zhang and Lüttge, 2008, 2009), we extended our modeling effort to three-dimensional (3D) feldspar particle dissolution simulations. Bearing on the same theoretical basis, the 3D feldspar particle dissolution simulations have verified the anisotropic surface kinetics observed in the 2D surface-specific simulations. The combined effect of saturation state, pH, and temperature on the surface kinetics anisotropy has been subsequently evaluated, found offering diverse options for morphological evolution of dissolving feldspar nanoparticles with varying grain sizes and starting shapes. Among the three primary faces on the simulated feldspar surface, the (1 0 0) face has the biggest dissolution rate across an extensively wide saturation state range and thus acquires a higher percentage of the surface area upon dissolution. The slowest dissolution occurs to either (0 0 1) or (0 1 0) faces depending on the bond energies of Si-(O)-Si ( ΦSi-O-Si/ kT) and Al-(O)-Si ( ΦAl-O-Si/ kT). When the ratio of ΦSi-O-Si/ kT to ΦAl-O-Si/ kT changes from 6:3 to 7:5, the dissolution rates of three primary faces change from the trend of (1 0 0) > (0 1 0) > (0 0 1) to the trend of (1 0 0) > (0 0 1) > (0 1 0). The rate difference between faces becomes more distinct and accordingly edge rounding becomes more significant. Feldspar nanoparticles also experience an increasing degree of edge rounding from far-from-equilibrium to close-to-equilibrium. Furthermore, we assessed the connection between the continuous morphological modification and the variation in the bulk dissolution rate during the dissolution of a single feldspar particle. Different normalization treatments equivalent to the commonly used mass, cube assumption, sphere assumption, geometric surface area, and reactive

  16. Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate.

    Science.gov (United States)

    Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O'Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter

    2014-06-01

    Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Activation recovery intervals measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady-state pacing, whilst subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Hemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (P=0.001). APD decreased during the stressful parts of the film clip, for example, for global right ventricular activation recovery interval at end of film clip 193.8 ms (SD, 14) versus 198.0 ms (SD, 13) during the matched breathing control (end film left ventricle 199.8 ms [SD, 16] versus control 201.6 ms [SD, 15]; P=0.004). Respiration rate increased during the stressful part of the film clip (by 2 breaths per minute) and was well matched in the respective control period without any hemodynamic or activation recovery interval changes. Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular APD in conscious humans. The effect of mental challenge on APD was not secondary to emotionally induced altered respiration or heart rate. © 2014 American Heart Association, Inc.

  17. Clinical Application of Screening for GJB2 Mutations before Cochlear Implantation in a Heterogeneous Population with High Rate of Autosomal Recessive Nonsyndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Masoud Motasaddi Zarandy

    2011-01-01

    Full Text Available Clinical application of mutation screening and its effect on the outcome of cochlear implantation is widely debated. We investigated the effect of mutations in GJB2 gene on the outcome of cochlear implantation in a population with a high rate of consanguineous marriage and autosomal recessive nonsyndromic hearing loss. Two hundred and one children with profound prelingual sensorineural hearing loss were included. Forty-six patients had 35delG in GJB2. Speech awareness thresholds (SATs and speech recognition thresholds (SRTs improved following implantation, but there was no difference in performance between patients with GJB2-related deafness versus control (all >0.10. Both groups had produced their first comprehensible words within the same period of time following implantation (2.27 months in GJB2-related deaf versus 2.62 months in controls, =0.22. Although our findings demonstrate the need to uncover unidentified genetic causes of hereditary deafness, they do not support the current policy for genetic screening before cochlear implantation, nor prove a prognostic value.

  18. Different mutations of the human c-mpl gene indicate distinct haematopoietic diseases.

    Science.gov (United States)

    He, Xin; Chen, Zhigang; Jiang, Yangyan; Qiu, Xi; Zhao, Xiaoying

    2013-01-25

    The human c-mpl gene (MPL) plays an important role in the development of megakaryocytes and platelets as well as the self-renewal of haematopoietic stem cells. However, numerous MPL mutations have been identified in haematopoietic diseases. These mutations alter the normal regulatory mechanisms and lead to autonomous activation or signalling deficiencies. In this review, we summarise 59 different MPL mutations and classify these mutations into four different groups according to the associated diseases and mutation rates. Using this classification, we clearly distinguish four diverse types of MPL mutations and obtain a deep understand of their clinical significance. This will prove to be useful for both disease diagnosis and the design of individual therapy regimens based on the type of MPL mutations.

  19. Assessment of cardiac performance with quantitative radionuclide angiocardiography: sequential left ventricular ejection fraction, normalized left ventricular ejection rate, and regional wall motion

    International Nuclear Information System (INIS)

    Marshall, R.C.; Berger, H.J.; Costin, J.C.; Freedman, G.S.; Wolberg, J.; Cohen, L.S.; Gotischalk, A.; Zaret, B.L.

    1977-01-01

    Sequential quantitative first pass radionuclide angiocardiograms (RA) were used to measure left ventricular ejection fraction (LVEF) and left ventricular ejection rate (LVER), and to assess regional wall motion (RWM) in the anterior (ANT) and left anterior oblique (LAO) positions. Studies were obtained with a computerized multicrystal scintillation camera suitable for acquiring high count-rate data. Background was determined in a new fashion by selecting frames temporally from the left ventricular region of interest time-activity curve. A ''representative'' cardiac cycle was formed by summing together counts over three to six cardiac cycles. From this background corrected, high count-rate ''representative''cardiac cycle, LVEF, LVER, and RWM were determined. In 22 patients with normal sinus rhythm in the absence of significant valvular regurgitation, RA LVEF correlated well with that measured by contrast angiography (r = 0.95). LVER correlated well with LVEF measured at contrast angiography (r = 0.90) and allowed complete separation of those with normal (LVER = 3.4 +- 0.17 sec -1 ) and abnormal (LVER = 1.22 +- 0.11 sec -1 ) (P < 0.001) left ventricular performance. This separation was independent of background. Isoproterenol infusion in five normal subjects caused LVER to increase by 81 +- 17% while LVEF increased by 10 +- 2.0%. RWM was correctly defined in 21/22 patients and 89% of left ventricular segments with abnormal wall motion

  20. Radiobiological equivalent of low/high dose rate brachytherapy and evaluation of tumor and normal responses to the dose.

    Science.gov (United States)

    Manimaran, S

    2007-06-01

    The aim of this study was to compare the biological equivalent of low-dose-rate (LDR) and high-dose-rate (HDR) brachytherapy in terms of the more recent linear quadratic (LQ) model, which leads to theoretical estimation of biological equivalence. One of the key features of the LQ model is that it allows a more systematic radiobiological comparison between different types of treatment because the main parameters alpha/beta and micro are tissue-specific. Such comparisons also allow assessment of the likely change in the therapeutic ratio when switching between LDR and HDR treatments. The main application of LQ methodology, which focuses on by increasing the availability of remote afterloading units, has been to design fractionated HDR treatments that can replace existing LDR techniques. In this study, with LDR treatments (39 Gy in 48 h) equivalent to 11 fractions of HDR irradiation at the experimental level, there are increasing reports of reproducible animal models that may be used to investigate the biological basis of brachytherapy and to help confirm theoretical predictions. This is a timely development owing to the nonavailability of sufficient retrospective patient data analysis. It appears that HDR brachytherapy is likely to be a viable alternative to LDR only if it is delivered without a prohibitively large number of fractions (e.g., fewer than 11). With increased scientific understanding and technological capability, the prospect of a dose equivalent to HDR brachytherapy will allow greater utilization of the concepts discussed in this article.

  1. Enhancement of relaxation rates in the normal state of superconductor PuRhGa5:NQR relaxation study

    International Nuclear Information System (INIS)

    Sakai, H.; Kambe, S.; Tokunaga, Y.; Fujimoto, T.; Walstedt, R.E.; Yasuoka, H.; Aoki, D.; Homma, Y.; Yamamoto, E.; Nakamura, A.; Shiokawa, Y.; Nakajima, K.; Arai, Y.; Matsuda, T.D.; Haga, Y.; Onuki, Y.

    2007-01-01

    The spin-lattice relaxation rates (1/T 1 ) have been measured under zero field using nuclear quadrupole resonance (NQR) lines in superconductor PuRhGa 5 and Pauli-paramagnet LuCoGa 5 . In the reference LuCoGa 5 with fully-occupied 4f shell, the 1/T 1 shows the constant behavior of (T 1 T) -1 =0.495+/-0.002(sK) -1 . On the other hand, in PuRhGa 5 , 1/T 1 is much larger than in LuCoGa 5 and the 1/T 1 ∝T behavior below ∼30K is seen, where its (T 1 T) -1 value is 3.27+/-0.005(sK) -1 . These results suggest a development of coherent Fermi liquid state incorporated with 5f electrons below ∼30K in PuRhGa 5

  2. Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects? A Summary of Evidence.

    Science.gov (United States)

    Harvie, Michelle N; Howell, Tony

    2016-07-01

    Animal studies and human observational data link energy restriction (ER) to reduced rates of carcinogenesis. Most of these studies have involved continuous energy restriction (CER), but there is increasing public and scientific interest in the potential health and anticancer effects of intermittent energy restriction (IER) or intermittent fasting (IF), which comprise periods of marked ER or total fasting interspersed with periods of normal eating. This review summarizes animal studies that assessed tumor rates with IER and IF compared with CER or ad libitum feed consumption. The relevance of these animal data to human cancer is also considered by summarizing available human studies of the effects of IER or IF compared with CER on cancer biomarkers in obese, overweight, and normal-weight subjects. IER regimens that include periods of ER alternating with ad libitum feed consumption for 1, 2, or 3 wk have been reported to be superior to CER in reducing tumor rates in most spontaneous mice tumor models. Limited human data from short-term studies (≤6 mo) in overweight and obese subjects have shown that IER can lead to greater improvements in insulin sensitivity (homeostasis model assessment) than can CER, with comparable reductions in adipokines and inflammatory markers and minor changes in the insulin-like growth factor axis. There are currently no data comparing IER or IF with CER in normal-weight subjects. The benefits of IER in these short-term trials are of interest, but not sufficient evidence to recommend the use of IER above CER. Longer-term human studies of adherence to and efficacy and safety of IER are required in obese and overweight subjects, as well as normal-weight subjects. © 2016 American Society for Nutrition.

  3. [{sup 123}]FP-CIT SPECT scans initially rated as normal became abnormal over time in patients with probable dementia with Lewy bodies

    Energy Technology Data Exchange (ETDEWEB)

    Zande, J.J. van der; Scheltens, P.; Lemstra, A.W. [VU Medical Center Alzheimer Center, Amsterdam (Netherlands); Booij, J. [Academic Medical Center, Department of Nuclear Medicine, Amsterdam (Netherlands); Raijmakers, P.G.H.M. [VU Medical Center, Department of Nuclear Medicine, Amsterdam (Netherlands)

    2016-06-15

    Decreased striatal dopamine transporter (DAT) binding on SPECT imaging is a strong biomarker for the diagnosis of dementia with Lewy bodies (DLB). There is still a lot of uncertainty about patients meeting the clinical criteria for probable DLB who have a normal DAT SPECT scan (DLB/S-). The aim of this study was to describe the clinical and imaging follow-up in these patients, and compare them to DLB patients with abnormal baseline scans (DLB/S+). DLB patients who underwent DAT imaging ([{sup 123}I]FP-CIT SPECT) were selected from the Amsterdam Dementia Cohort. All [{sup 123}I]FP-CIT SPECT scans were evaluated independently by two nuclear medicine physicians and in patients with normal scans follow-up imaging was obtained. We matched DLB/S- patients for age and disease duration to DLB/S+ patients and compared their clinical characteristics. Of 67 [{sup 123}I]FP-CIT SPECT scans, 7 (10.4 %) were rated as normal. In five DLB/S- patients, a second [{sup 123}I]FP-CIT SPECT was performed (after on average 1.5 years) and these scans were all abnormal. No significant differences in clinical characteristics were found at baseline. DLB/S- patients could be expected to have a better MMSE score after 1 year. This study was the first to investigate DLB patients with the initial [{sup 123}I]FP-CIT SPECT scan rated as normal and subsequent scans during disease progression rated as abnormal. We hypothesize that DLB/S- scans could represent a relatively rare DLB subtype with possibly a different severity or spread of alpha-synuclein pathology (''neocortical predominant subtype''). In clinical practice, if an alternative diagnosis is not imminent in a DLB/S- patient, repeating [{sup 123}I]FP-CIT SPECT should be considered. (orig.)

  4. Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects? A Summary of Evidence12

    Science.gov (United States)

    2016-01-01

    Animal studies and human observational data link energy restriction (ER) to reduced rates of carcinogenesis. Most of these studies have involved continuous energy restriction (CER), but there is increasing public and scientific interest in the potential health and anticancer effects of intermittent energy restriction (IER) or intermittent fasting (IF), which comprise periods of marked ER or total fasting interspersed with periods of normal eating. This review summarizes animal studies that assessed tumor rates with IER and IF compared with CER or ad libitum feed consumption. The relevance of these animal data to human cancer is also considered by summarizing available human studies of the effects of IER or IF compared with CER on cancer biomarkers in obese, overweight, and normal-weight subjects. IER regimens that include periods of ER alternating with ad libitum feed consumption for 1, 2, or 3 wk have been reported to be superior to CER in reducing tumor rates in most spontaneous mice tumor models. Limited human data from short-term studies (≤6 mo) in overweight and obese subjects have shown that IER can lead to greater improvements in insulin sensitivity (homeostasis model assessment) than can CER, with comparable reductions in adipokines and inflammatory markers and minor changes in the insulin-like growth factor axis. There are currently no data comparing IER or IF with CER in normal-weight subjects. The benefits of IER in these short-term trials are of interest, but not sufficient evidence to recommend the use of IER above CER. Longer-term human studies of adherence to and efficacy and safety of IER are required in obese and overweight subjects, as well as normal-weight subjects. PMID:27422504

  5. Normalization of water flow rate for external fire fighting of the buildings in settlements with zone water supply

    Directory of Open Access Journals (Sweden)

    Deryushev Leonid Georgievich

    2014-12-01

    Full Text Available In the article the requirements for fire safety assurance are justified for the objects, in which water is supplied with account for serial and parallel area zoning. In the process of zoning the district is segregated into such parts, for which head rate in any point of selection of water from network will not exceed 6 bar. In the current regulatory rules the requirements for the calculation of the costs of water points are stated, as well as in case of extinguishing fires at the sites with water-supply systems zones. It is recommended to analyze each zone of the system of water-supply separately, without interrelation with the common water feeders, water consumers and services of fire extinguishing. Such an approach to assign water discharge for fire extinguishing results in the decrease of fire safety of an object, deforms calculation technique of outside systems of water-supply of the similar-type objects located in different parts of the terrain. Taking the number of fires and water consumption for fire suppression by the number of residents in each zone, we thus underestimate the capacity of the pipeline system. It is offered to make changes in Norms and Standards in force on fire safety of settlements. The recommendations on regulation of the number of fires and water flow for fire fighting in residential objects with zoned systems of water-supply are formulated.

  6. Self-rated driving habits among older adults with clinically-defined mild cognitive impairment, clinically-defined dementia, and normal cognition.

    Science.gov (United States)

    O'Connor, Melissa L; Edwards, Jerri D; Bannon, Yvonne

    2013-12-01

    Older adults with clinically-defined dementia may report reducing their driving more than cognitively normal controls. However, it is unclear how these groups compare to individuals with clinically-defined mild cognitive impairment (MCI) in terms of driving behaviors. The current study investigated self-reported driving habits among adults age 60 and older with clinical MCI (n=41), clinical mild dementia (n=40), and normal cognition (n=43). Participants reported their driving status, driving frequency (days per week), and how often they avoided accessing the community, making left turns, driving at night, driving in unfamiliar areas, driving on high-traffic roads, and driving in bad weather. After adjusting for education, a MANCOVA revealed that participants with MCI and dementia avoided unfamiliar areas and high-traffic roads significantly more than normal participants. Participants with dementia also avoided left turns and accessing the community more than those with normal cognition and MCI (pdriving variables did not significantly differ between groups. Thus, older adults with clinically-defined MCI, as well as those with dementia, avoided some complex driving situations more than cognitively intact adults. However, all diagnostic groups had similar rates of driving cessation and frequency. Future research should examine the safety implications of such findings. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Ab initio calculation of transition state normal mode properties and rate constants for the H(T)+CH4(CD4) abstraction and exchange reactions

    International Nuclear Information System (INIS)

    Schatz, G.C.; Walch, S.P.; Wagner, A.F.

    1980-01-01

    We present ab initio (GVB--POL--CI) calculations for enough of the region about the abstraction and exchange saddle points for H(T)+CH 4 (CD 4 ) to perform a full normal mode analysis of the transition states. The resulting normal mode frequencies are compared to four other published surfaces: an ab initio UHF--SCF calculation by Carsky and Zahradnik, a semiempirical surface by Raff, and two semiempirical surfaces by Kurylo, Hollinden, and Timmons. Significant quantitative and qualitative differences exist between the POL--CI results and those of the other surfaces. Transition state theory rate constants and vibrationally adiabatic reaction threshold energies were computed for all surfaces and compared to available experimental values. For abstraction, the POL--CI rates are in good agreement with experimental rates and in better agreement than are the rates of any of the other surfaces. For exchange, uncertainties in the experimental values and in the importance of vibrationally nonadiabatic effects cloud the comparison of theory to experiment. Tentative conclusions are that the POL--CI barrier is too low by several kcal. Unless vibrationaly nonadiabatic effects are severe, the POL--CI surface is still in better agreement with experiment than are the other surfaces. The rates for a simple 3-atom transition state theory model (where CH 3 is treated as an atom) are compared to the rates for the full 6-atom model. The kinetic energy coupling of reaction coordinate modes to methyl group modes is identified as being of primary importance in determining the accuracy of the 3-atom model for this system. Substantial coupling in abstraction, but not exchange, causes the model to fail for abstraction but succeed for exchange

  8. Dose-rate effects between 0.3 and 30 Gy/h in a normal and a malignant human cell line

    International Nuclear Information System (INIS)

    Amdur, R.J.; Bedford, J.S.

    1994-01-01

    This study used continuous open-quotes intermediateclose quotes dose rate irradiation (0.3-30 Gy/h) to compare the capacity for and repair of sublethal radiation damage in different cell lines growing in tissue culture. Two human cell lines were studied; one was derived from normal human fibroblasts (AG1522) and the other from a squamous cell carcinoma of the uterine cervix (HTB-35). Dose-response curves for clonogenic survival were determined following irradiation of plateau-phase cultures at five different dose rates: 22.6, 6.12, 3.65, 1.04, and 0.38 Gy/h. Subculture following irradiation was delayed for 8-24 h to allow for the full repair of open-quotes potentially lethal damage.close quotes A significant dose-rate effect was seen in both cell lines. For irradiation at the highest dose rate, survival at 2 Gy (SF2) and the α/β ratio were similar for the two cell lines (approximately 0.7 and 8.0 Gy, respectively) but the half-time of repair of sublethal damage was estimated to be approximately five times longer in the normal human fibroblast line (154 min) than in the carcinoma (31 min) cell line. These results indicate that measuring the dose-rate effect between 0.3 and 30 Gy/h is a useful way to identify and quantify differences in sublethal damage repair between cell lines. To the extent that in vitro and in vivo repair parameters are similar, and that representative tumor biopsy specimens can be examined in this way, this approach may provide a prospective way of determining the dose rate (brachytherapy) or fractionation schedule that will optimize the therapeutic ratio. 32 refs., 1 fig

  9. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate

    DEFF Research Database (Denmark)

    Mocroft, Amanda; Lundgren, Jens D; Ross, Michael

    2016-01-01

    BACKGROUND: Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration...... of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR). METHODS: In this prospective international cohort study, HIV-positive adult participants (aged ≥16 years) from the D......:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1·73 m(2) were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6...

  10. The effect of speaking rate on serial-order sound-level errors in normal healthy controls and persons with aphasia.

    Science.gov (United States)

    Fossett, Tepanta R D; McNeil, Malcolm R; Pratt, Sheila R; Tompkins, Connie A; Shuster, Linda I

    Although many speech errors can be generated at either a linguistic or motoric level of production, phonetically well-formed sound-level serial-order errors are generally assumed to result from disruption of phonologic encoding (PE) processes. An influential model of PE (Dell, 1986; Dell, Burger & Svec, 1997) predicts that speaking rate should affect the relative proportion of these serial-order sound errors (anticipations, perseverations, exchanges). These predictions have been extended to, and have special relevance for persons with aphasia (PWA) because of the increased frequency with which speech errors occur and because their localization within the functional linguistic architecture may help in diagnosis and treatment. Supporting evidence regarding the effect of speaking rate on phonological encoding has been provided by studies using young normal language (NL) speakers and computer simulations. Limited data exist for older NL users and no group data exist for PWA. This study tested the phonologic encoding properties of Dell's model of speech production (Dell, 1986; Dell,et al., 1997), which predicts that increasing speaking rate affects the relative proportion of serial-order sound errors (i.e., anticipations, perseverations, and exchanges). The effects of speech rate on the error ratios of anticipation/exchange (AE), anticipation/perseveration (AP) and vocal reaction time (VRT) were examined in 16 normal healthy controls (NHC) and 16 PWA without concomitant motor speech disorders. The participants were recorded performing a phonologically challenging (tongue twister) speech production task at their typical and two faster speaking rates. A significant effect of increased rate was obtained for the AP but not the AE ratio. Significant effects of group and rate were obtained for VRT. Although the significant effect of rate for the AP ratio provided evidence that changes in speaking rate did affect PE, the results failed to support the model derived predictions

  11. Saliva composition in three selected groups with normal stimulated salivary flow rates, but yet major differences in caries experience and dental erosion.

    Science.gov (United States)

    Bardow, Allan; Lykkeaa, Joan; Qvist, Vibeke; Ekstrand, Kim; Twetman, Svante; Fiehn, Niels-Erik

    2014-08-01

    It was hypothesized that, by comparing matched subjects with major differences in these dental diseases, but yet normal saliva flow rates, it would be possible to obtain data on the effect of saliva composition on dental disease isolated from the effect of the flow rate. Thus, the aim of the study was to compare the major physicochemical characteristics of stimulated whole saliva in three groups of 85 subjects, each with normal saliva flow rates and at least 24 remaining teeth. A group with very little dental disease (healthy), a group with dental erosion (erosion) and a group with very high caries experience (caries) were chosen. Furthermore, the aim was to determine whether differences among groups could also be found on an individual level. Although it was not possible to retrieve three groups whose members were completely identical, the present study points in the direction that, on a group level, subjects with very little dental disease seemed to have a more favorable physicochemical saliva composition with respect to higher calcium, phosphate, bicarbonate, pH, degree of saturation with respect to hydroxyapatite and a lower critical pH (p dental erosion (p dental caries and erosion in single individuals.

  12. New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits.

    Science.gov (United States)

    Rautaharju, Pentti M; Mason, Jay W; Akiyama, Toshio

    2014-07-01

    Existing formulas for rate-corrected QT (QTc) commonly fail to properly adjust the upper normal limits which are more critical than the mean QTc for evaluation of prolonged QT. Age- and sex-related differences in QTc are also often overlooked. Our goal was to establish criteria for prolonged QTc using formulas that minimize QTc bias at the upper normal limits. Strict criteria were used in selecting a study group of 57,595 persons aged 5 to 89 years (54% women) and to exclude electrocardiograms (ECG) with possible disease-associated changes. Two QT rate adjustment formulas were identified which both minimized rate-dependency in the 98 th percentile limits: QTcmod, based on an electrophysiological model (QTcMod = QTx(120 + HR)/180)), and QTcLogLin, a power function of the RR interval with exponents 0.37 for men and 0.38 for women. QTc shortened in men during adolescence and QTcMod became 13 ms shorter than in women at age 20-29 years. The sex difference was maintained through adulthood although decreasing with age. The criteria established for prolonged QTc were: Age < 40 years, men 430 ms, women 440 ms; Age 40 to 69, men 440 ms, women 450 ms; Age ≥ 70 years, men 455 ms, and women 460 ms. Sex difference in QTc originates from shortened QT in adolescent males. Upper normal limits for QTc vary substantially by age and sex, and it is essential to use age- and sex-specific criteria for evaluation of QT prolongation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Use of Sine Shaped High-Frequency Rhythmic Visual Stimuli Patterns for SSVEP Response Analysis and Fatigue Rate Evaluation in Normal Subjects

    Directory of Open Access Journals (Sweden)

    Ahmadreza Keihani

    2018-05-01

    Full Text Available Background: Recent EEG-SSVEP signal based BCI studies have used high frequency square pulse visual stimuli to reduce subjective fatigue. However, the effect of total harmonic distortion (THD has not been considered. Compared to CRT and LCD monitors, LED screen displays high-frequency wave with better refresh rate. In this study, we present high frequency sine wave simple and rhythmic patterns with low THD rate by LED to analyze SSVEP responses and evaluate subjective fatigue in normal subjects.Materials and Methods: We used patterns of 3-sequence high-frequency sine waves (25, 30, and 35 Hz to design our visual stimuli. Nine stimuli patterns, 3 simple (repetition of each of above 3 frequencies e.g., P25-25-25 and 6 rhythmic (all of the frequencies in 6 different sequences e.g., P25-30-35 were chosen. A hardware setup with low THD rate (<0.1% was designed to present these patterns on LED. Twenty two normal subjects (aged 23–30 (25 ± 2.1 yrs were enrolled. Visual analog scale (VAS was used for subjective fatigue evaluation after presentation of each stimulus pattern. PSD, CCA, and LASSO methods were employed to analyze SSVEP responses. The data including SSVEP features and fatigue rate for different visual stimuli patterns were statistically evaluated.Results: All 9 visual stimuli patterns elicited SSVEP responses. Overall, obtained accuracy rates were 88.35% for PSD and > 90% for CCA and LASSO (for TWs > 1 s. High frequency rhythmic patterns group with low THD rate showed higher accuracy rate (99.24% than simple patterns group (98.48%. Repeated measure ANOVA showed significant difference between rhythmic pattern features (P < 0.0005. Overall, there was no significant difference between the VAS of rhythmic [3.85 ± 2.13] compared to the simple patterns group [3.96 ± 2.21], (P = 0.63. Rhythmic group had lower within group VAS variation (min = P25-30-35 [2.90 ± 2.45], max = P35-25-30 [4.81 ± 2.65] as well as least individual pattern VAS (P25

  14. Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-05-01

    Full Text Available The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM, gadolinium (300 μM and 2-aminoethyl diphenylborinate (0.1 μM. The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal

  15. Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: a case series and literature review.

    Science.gov (United States)

    Heathcote, Karen L; Cockcroft, Donald W; Fladeland, Derek A; Fenton, Mark E

    2011-01-01

    Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

  16. Normal Expiratory Flow Rate and Lung Volumes in Patients with Combined Emphysema and Interstitial Lung Disease: A Case Series and Literature Review

    Directory of Open Access Journals (Sweden)

    Karen L Heathcote

    2011-01-01

    Full Text Available Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

  17. Investigation of analytical methods in thermal stratification analysis. Evaluation of flow rates through flow holes for normal and scram conditions of 40% power operation with AQUA code

    International Nuclear Information System (INIS)

    Doi, Yoshihiro; Muramatsu, Toshiharu

    1997-08-01

    Thermal stratification phenomena are observed in an upper plenum of liquid metal fast breeder reactors (LMFBRs) under reactor scram conditions, which give rise to thermal stress on structural components. Therefore it is important to evaluate characteristics of phenomena in the design of the internal structure in an LMFBR plenum. To evaluate flow rates through flow holes of the prototype fast breeder reactor, MONJU, numerical analyses were carried out with AQUA code for normal and scram conditions with 40% power operation. Through comparison of analysis results and measured temperature, thermal stratification phenomena in 300 second period after the scram was evaluated. Flow rate through the upper flow holes, the lower flow holes and annular gap between the inner barrel and the reactor vessel were evaluated with the measured temperature and the analysis results individually. (J.P.N.)

  18. Perception of a Sung Vowel as a Function of Frequency-Modulation Rate and Excursionin Normal-Hearing and Hearing-Impaired Listeners

    DEFF Research Database (Denmark)

    Vatti, Marianna; Santurette, Sébastien; Pontoppidan, Niels henrik

    2014-01-01

    Purpose: Frequency fluctuations in human voices can usually be described as coherent frequency modulation (FM). As listeners with hearing impairment (HI listeners) are typically less sensitive to FM than listeners with normal hearing (NH listeners), this study investigated whether hearing loss...... affects the perception of a sung vowel based on FM cues. Method: Vibrato maps were obtained in 14 NH and 12 HI listeners with different degrees of musical experience. The FM rate and FM excursion of a synthesized vowel, to which coherent FM was applied, were adjusted until a singing voice emerged. Results......: In NH listeners, adding FM to the steady vowel components produced perception of a singing voice for FM rates between 4.1 and 7.5 Hz and FM excursions between 17 and 83 cents on average. In contrast, HI listeners showed substantially broader vibrato maps. Individual differences in map boundaries were...

  19. Shear rate normalization is not essential for removing the dependency of flow-mediated dilation on baseline artery diameter: past research revisited

    International Nuclear Information System (INIS)

    Atkinson, Greg

    2014-01-01

    A ratio index (FMD%) is used ubiquitously to scale (by simple division) brachial artery flow-mediated dilation (D diff ) in direct proportion to baseline diameter (D base ). It is now known that D diff is inversely proportional to D base rendering FMD% wholly inappropriate. Consequently, FMD% is still substantially dependent on D base . Although this problem is grounded in statistics, normalization of FMD% for the change in arterial shear rate (ΔSR) has been proposed to remove this D base -dependency. It was hypothesized that, if the flow-mediated response is scaled properly to D base in the first place, shear rate normalization would not be needed to remove D base -dependency. Dedicated software (Digitizelt) was employed to extract the data from a seminal study on FMD% normalization. The underlying allometric relationship between D base and peak diameter (D peak ) was described. The re-analyses revealed that the absolute change in arterial diameter was strongly inversely proportional to D base (r= − 0.7, P < 0.0005). The allometric exponent for the D base –D peak relationship was 0.82 (95% CI: 0.78–0.86) rather than the value of 1 needed for appropriate use of FMD%. The allometric approach completely eliminated the originally reported dependency on D base without any need for ΔSR normalization (r=0.0, P=0.96). The correlation between ΔSR and FMD% reduced from 0.69 to 0.37, when adjusted for D base . In conclusion, this new re-analysis of data from an influential study demonstrates that the FMD%–D base correlation is caused by the inappropriate size-scaling properties of FMD% itself. Removal of D base -dependency via FMD%/ΔSR normalization is not essential at all if allometric scaling is applied to isolate the flow-mediated response in the first place. Consequently, the influence of ΔSR on this properly scaled response can also be isolated and quantified accurately without the confounding influence of D base . (paper)

  20. Use of Sine Shaped High-Frequency Rhythmic Visual Stimuli Patterns for SSVEP Response Analysis and Fatigue Rate Evaluation in Normal Subjects.

    Science.gov (United States)

    Keihani, Ahmadreza; Shirzhiyan, Zahra; Farahi, Morteza; Shamsi, Elham; Mahnam, Amin; Makkiabadi, Bahador; Haidari, Mohsen R; Jafari, Amir H

    2018-01-01

    Background: Recent EEG-SSVEP signal based BCI studies have used high frequency square pulse visual stimuli to reduce subjective fatigue. However, the effect of total harmonic distortion (THD) has not been considered. Compared to CRT and LCD monitors, LED screen displays high-frequency wave with better refresh rate. In this study, we present high frequency sine wave simple and rhythmic patterns with low THD rate by LED to analyze SSVEP responses and evaluate subjective fatigue in normal subjects. Materials and Methods: We used patterns of 3-sequence high-frequency sine waves (25, 30, and 35 Hz) to design our visual stimuli. Nine stimuli patterns, 3 simple (repetition of each of above 3 frequencies e.g., P25-25-25) and 6 rhythmic (all of the frequencies in 6 different sequences e.g., P25-30-35) were chosen. A hardware setup with low THD rate ( 90% for CCA and LASSO (for TWs > 1 s). High frequency rhythmic patterns group with low THD rate showed higher accuracy rate (99.24%) than simple patterns group (98.48%). Repeated measure ANOVA showed significant difference between rhythmic pattern features ( P rhythmic [3.85 ± 2.13] compared to the simple patterns group [3.96 ± 2.21], ( P = 0.63). Rhythmic group had lower within group VAS variation (min = P25-30-35 [2.90 ± 2.45], max = P35-25-30 [4.81 ± 2.65]) as well as least individual pattern VAS (P25-30-35). Discussion and Conclusion: Overall, rhythmic and simple pattern groups had higher and similar accuracy rates. Rhythmic stimuli patterns showed insignificantly lower fatigue rate than simple patterns. We conclude that both rhythmic and simple visual high frequency sine wave stimuli require further research for human subject SSVEP-BCI studies.

  1. A study of Huntington disease-like syndromes in black South African patients reveals a single SCA2 mutation and a unique distribution of normal alleles across five repeat loci.

    Science.gov (United States)

    Baine, Fiona K; Peerbhai, Nabeelah; Krause, Amanda

    2018-07-15

    Huntington disease (HD) is a progressive neurodegenerative disease, characterised by a triad of movement disorder, emotional and behavioural disturbances and cognitive impairment. The underlying cause is an expanded CAG repeat in the huntingtin gene. For a small proportion of patients presenting with HD-like symptoms, the mutation in this gene is not identified and they are said to have a HD "phenocopy". South Africa has the highest number of recorded cases of an African-specific phenocopy, Huntington disease-like 2 (HDL2), caused by a repeat expansion in the junctophilin-3 gene. However, a significant proportion of black patients with clinical symptoms suggestive of HD still test negative for HD and HDL2. This study thus aimed to investigate five other loci associated with HD phenocopy syndromes - ATN1, ATXN2, ATXN7, TBP and C9orf72. In a sample of patients in whom HD and HDL2 had been excluded, a single expansion was identified in the ATXN2 gene, confirming a diagnosis of Spinocerebellar ataxia 2. The results indicate that common repeat expansion disorders do not contribute significantly to the HD-like phenotype in black South African patients. Importantly, allele sizing reveals unique distributions of normal repeat lengths across the associated loci in the African population studied. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Insulin production rate in normal man as an estimate for calibration of continuous intravenous insulin infusion in insulin-dependent diabetic patients.

    Science.gov (United States)

    Waldhäusl, W K; Bratusch-Marrain, P R; Francesconi, M; Nowotny, P; Kiss, A

    1982-01-01

    This study examines the feasibility of deriving the 24-h insulin requirement of insulin-dependent diabetic patients who were devoid of any endogenous insulin release (IDD) from the insulin-production rate (IPR) of healthy man (basal, 17 mU/min; stimulated 1.35 U/12.5 g glucose). To this end, continuous intravenous insulin infusion (CIVII) was initiated at a precalculated rate of 41.2 +/- 4.6 (SD) U/24 h in IDD (N - 12). Blood glucose profiles were compared with those obtained during intermittent subcutaneous (s.c.) insulin therapy (IIT) and those of healthy controls (N = 7). Regular insulin (Hoechst CS) was infused with an adapted Mill Hill Infuser at a basal infusion rate of 1.6 U/h (6:00 a.m. to 8:00 p.m.), and of 0.8 U/h from 8:00 p.m. to 6:00 a.m. Preprandial insulin (3.2-6.4 U) was added for breakfast, lunch, and dinner. Daily individual food intake totaled 7688 +/- 784 kJ (1836 +/- 187 kcal)/24 h including 184 +/- 37 g of glucose. Proper control of blood glucose (BG) (mean BG 105 +/- 10 mg/dl; mean amplitude of glycemic excursions 54 +/- 18 mg/dl; and 1 h postprandial BG levels not exceeding 160 mg/dl) and of plasma concentrations of beta-hydroxybutyrate and lactate was maintained by 41.4 +/- 4.4 U insulin/24 h. Although BG values only approximated the upper normal range as seen in healthy controls, they were well within the range reported by others during CIVII. Therefore, we conclude that in adult IDD completely devoid of endogenous insulin (1) the IPR of normal man can be used during CIVII as an estimate for the patient's minimal insulin requirement per 24 h, and (2) this approach allows for a blood glucose profile close to the upper range of a normal control group. Thus, deriving a patient's daily insulin dose from the insulin production rate of healthy man may add an additional experimental protocol which aids in making general calculations of a necessary insulin dose instead of using trial and error or a closed-loop insulin infusion system.

  3. The molecular anatomy of spontaneous germline mutations in human testes.

    Directory of Open Access Journals (Sweden)

    Jian Qin

    2007-09-01

    Full Text Available The frequency of the most common sporadic Apert syndrome mutation (C755G in the human fibroblast growth factor receptor 2 gene (FGFR2 is 100-1,000 times higher than expected from average nucleotide substitution rates based on evolutionary studies and the incidence of human genetic diseases. To determine if this increased frequency was due to the nucleotide site having the properties of a mutation hot spot, or some other explanation, we developed a new experimental approach. We examined the spatial distribution of the frequency of the C755G mutation in the germline by dividing four testes from two normal individuals each into several hundred pieces, and, using a highly sensitive PCR assay, we measured the mutation frequency of each piece. We discovered that each testis was characterized by rare foci with mutation frequencies 10(3 to >10(4 times higher than the rest of the testis regions. Using a model based on what is known about human germline development forced us to reject (p < 10(-6 the idea that the C755G mutation arises more frequently because this nucleotide simply has a higher than average mutation rate (hot spot model. This is true regardless of whether mutation is dependent or independent of cell division. An alternate model was examined where positive selection acts on adult self-renewing Ap spermatogonial cells (SrAp carrying this mutation such that, instead of only replacing themselves, they occasionally produce two SrAp cells. This model could not be rejected given our observed data. Unlike the disease site, similar analysis of C-to-G mutations at a control nucleotide site in one testis pair failed to find any foci with high mutation frequencies. The rejection of the hot spot model and lack of rejection of a selection model for the C755G mutation, along with other data, provides strong support for the proposal that positive selection in the testis can act to increase the frequency of premeiotic germ cells carrying a mutation

  4. Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes.

    Science.gov (United States)

    Souza, C J H; McNeilly, A S; Benavides, M V; Melo, E O; Moraes, J C F

    2014-10-01

    Litter size (LS) in sheep is determined mainly by ovulation rate (OR). Several polymorphisms have been identified in the growth differentiation factor 9 (GDF9) gene that result in an increase in OR and prolificacy of sheep. Screening the databank of the Brazilian Sheep Breeders Association for triplet delivery, we identified flocks of prolific Ile de France ewes. After resequencing of GDF9, a point mutation (c.943C>T) was identified, resulting in a non-conservative amino acid change (p.Arg315Cys) in the cleavage site of the propeptide. This new allele was called Vacaria (FecG(v) ). A flock of half-sib ewes was evaluated for OR in the first three breeding seasons, and Vacaria heterozygotes had higher OR (P develop up to small antral stages, although with abnormal oocyte morphology and altered arrangement of granulosa cells. After the collapse of the oocyte in most follicles, the remaining cells formed clusters that persisted in the ovary. This SNP is useful to improve selection for dam prolificacy and also as a model to investigate GDF9 post-translation processing and the fate of the follicular cells that remain after the oocyte demise. © 2014 Stichting International Foundation for Animal Genetics.

  5. Evaluation of discriminating power of 13 Y chromosome markers with high rate of mutation (RM Y-STR) in the Costa Rican population

    International Nuclear Information System (INIS)

    Solano Matamoros, Carlos

    2014-01-01

    The Y chromosome microsatellites analysis has had among its purposes the obtaining of a male haplotype from mixtures with high prevalence of female genetic material, such as sexual offenses. The currently available markers set as AmpFISTR® Yfiler® have offered haplotype resolution to level of incomplete patrilineal line. This limitation has been particularly important when is needed to supplement paternity studies. The implementation expected of the 13 Y chromosome microsatellites with high mutation rate (RM Y-STR) recently described, has improved the discriminating power of microsatellite analysis of Y in the forensic context. However, for implemetation it has been necessary to obtain the frequencies of haplotypes in the Costa Rican population. In addition, the discriminating power of the new markers is evaluated and compared with current markers set, such as AmpFISTR® Yfile®, to determine whether the former have an advantage over the latter. The use of a powerful new tool has been claimed for a more efficient and effective application of justice in Costa Rica, specially in sexual offenses [es

  6. Rate of transformation and normal range about cardiac size and cardiothoracic ratio according to patient position and age at chest radiography of Korean adult man

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Young Cheol [Dept. of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Lim, Cheong Hwan; Jung, Hong Ryang [Dept. of Radiological Science, Hanseo University, Seosan (Korea, Republic of); Kim, Yun Min [Dept. of Radiotechnology, Wonkwang Health Science University, Iksan (Korea, Republic of); Hong, Dong Hee [Dept. of Radiological Science, Far East University, Eumseong (Korea, Republic of)

    2017-06-15

    Purpose of this study is present the normal range of cardiac size and cardiothoracic ratio according to patient position(chest PA and AP) and age of Korean adult male on digital chest X - ray, And to propose a mutually compatible conversion rate. 1,024 males were eligible for this study, among 1,300 normal chest patients who underwent chest PA and low-dose CT examinations on the same day at the 'S' Hospital Health Examination Center in Seoul From January to December 2014. CS and CTR were measured by Danzer (1919). The mean difference between CS and CTR was statistically significant (p<0.01) in Chest PA (CS 135.48 mm, CTR 43.99%) and Chest AP image (CS 155.96 mm, CTR 51.75%). There was no statistically significant difference between left and right heart in chest PA and AP images(p>0.05). CS showed statistically significant difference between Chest PA (p>0. 05) and Chest AP (p<0.05). The thorax size and CTR were statistically significant (p<0.01) in both age and chest PA and AP. Result of this study, On Chest AP image CS was magnified 15%, CTR was magnified 17% compare with Chest PA image. CS and CTR were about 10% difference by changing posture at all ages.

  7. SU-E-T-501: Normal Tissue Toxicities of Pulsed Low Dose Rate Radiotherapy and Conventional Radiotherapy: An in Vivo Total Body Irradiation Study

    Energy Technology Data Exchange (ETDEWEB)

    Cvetkovic, D; Zhang, P; Wang, B; Chen, L; Ma, C [Fox Chase Cancer Center, Philadelphia, PA (United States)

    2014-06-01

    Purpose: Pulsed low dose rate radiotherapy (PLDR) is a re-irradiation technique for therapy of recurrent cancers. We have previously shown a significant difference in the weight and survival time between the mice treated with conventional radiotherapy (CRT) and PLDR using total body irradiation (TBI). The purpose of this study was to investigate the in vivo effects of PLDR on normal mouse tissues.Materials and Methods: Twenty two male BALB/c nude mice, 4 months of age, were randomly assigned into a PLDR group (n=10), a CRT group (n=10), and a non-irradiated control group (n=2). The Siemens Artiste accelerator with 6 MV photon beams was used. The mice received a total of 18Gy in 3 fractions with a 20day interval. The CRT group received the 6Gy dose continuously at a dose rate of 300 MU/min. The PLDR group was irradiated with 0.2Gyx20 pulses with a 3min interval between the pulses. The mice were weighed thrice weekly and sacrificed 2 weeks after the last treatment. Brain, heart, lung, liver, spleen, gastrointestinal, urinary and reproductive organs, and sternal bone marrow were removed, formalin-fixed, paraffin-embedded and stained with H and E. Morphological changes were observed under a microscope. Results: Histopathological examination revealed atrophy in several irradiated organs. The degree of atrophy was mild to moderate in the PLDR group, but severe in the CRT group. The most pronounced morphological abnormalities were in the immune and hematopoietic systems, namely spleen and bone marrow. Brain hemorrhage was seen in the CRT group, but not in the PLDR group. Conclusions: Our results showed that PLDR induced less toxicity in the normal mouse tissues than conventional radiotherapy for the same dose and regimen. Considering that PLDR produces equivalent tumor control as conventional radiotherapy, it would be a good modality for treatment of recurrent cancers.

  8. Dosimetric Coverage of the Prostate, Normal Tissue Sparing, and Acute Toxicity with High-Dose-Rate Brachytherapy for Large Prostate Volumes

    Directory of Open Access Journals (Sweden)

    George Yang

    2015-06-01

    Full Text Available ABSTRACTPurposeTo evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes.Materials and MethodsOne hundred and two prostate cancer patients with prostate volumes >50 mL (range: 5-29 mL were treated with high-dose-rate (HDR brachytherapy ± intensity modulated radiation therapy (IMRT to 4,500 cGy in 25 daily fractions between 2009 and 2013. HDR brachytherapy monotherapy doses consisted of two 1,350-1,400 cGy fractions separated by 2-3 weeks, and HDR brachytherapy boost doses consisted of two 950-1,150 cGy fractions separated by 4 weeks. Twelve of 32 (38% unfavorable intermediate risk, high risk, and very high risk patients received androgen deprivation therapy. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.ResultsMedian follow-up was 14 months. Dosimetric goals were achieved in over 90% of cases. Three of 102 (3% patients developed Grade 2 acute proctitis. No variables were significantly associated with Grade 2 acute proctitis. Seventeen of 102 (17% patients developed Grade 2 acute urinary retention. American Urological Association (AUA symptom score was the only variable significantly associated with Grade 2 acute urinary retention (p=0.04. There was no ≥ Grade 3 acute toxicity.ConclusionsDosimetric coverage of the prostate and normal tissue sparing were adequate in patients with prostate volumes >50 mL. Higher pre-treatment AUA symptom scores increased the relative risk of Grade 2 acute urinary retention. However, the overall incidence of acute toxicity was acceptable in patients with large prostate volumes.

  9. Dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with high-dose-rate brachytherapy for large prostate volumes

    Energy Technology Data Exchange (ETDEWEB)

    Yang, George; Strom, Tobin J.; Shrinath, Kushagra; Mellon, Eric A.; Fernandez, Daniel C.; Biagioli, Matthew C. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Wilder, Richard B., E-mail: mcbiagioli@yahoo.com [Cancer Treatment Centers of America, Newnan, GA (United States)

    2015-05-15

    Purpose: to evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes. Materials and methods: one hundred and two prostate cancer patients with prostate volumes >50 mL (range: 5-29 mL) were treated with high-dose-rate (HDR) brachytherapy ± intensity modulated radiation therapy (IMRT) to 4,500 cGy in 25 daily fractions between 2009 and 2013. HDR brachytherapy monotherapy doses consisted of two 1,350-1,400 cGy fractions separated by 2-3 weeks, and HDR brachytherapy boost doses consisted of two 950-1,150 cGy fractions separated by 4 weeks. Twelve of 32 (38%) unfavorable intermediate risk, high risk, and very high risk patients received androgen deprivation therapy. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Results: median follow-up was 14 months. Dosimetric goals were achieved in over 90% of cases. Three of 102 (3%) patients developed Grade 2 acute proctitis. No variables were significantly associated with Grade 2 acute proctitis. Seventeen of 102 (17%) patients developed Grade 2 acute urinary retention. American Urological Association (AUA) symptom score was the only variable significantly associated with Grade 2 acute urinary retention (p-0.04). There was no ≥ Grade 3 acute toxicity. Conclusions: dosimetric coverage of the prostate and normal tissue sparing were adequate in patients with prostate volumes >50 mL. Higher pre-treatment AUA symptom scores increased the relative risk of Grade 2 acute urinary retention. However, the overall incidence of acute toxicity was acceptable in patients with large prostate volumes. (author)

  10. An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV(B)-inflamed and normal skin.

    Science.gov (United States)

    Schaffler, Klaus; Reeh, Peter; Duan, W Rachel; Best, Andrea E; Othman, Ahmed A; Faltynek, Connie R; Locke, Charles; Nothaft, Wolfram

    2013-02-01

    Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UV(B)-inflamed skin. This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO(2) -laser on normal and UV(B) -inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types. Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV(B)-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml(-1) for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings. TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation. © 2012 Abbott. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  11. Doubling the referral rate of monogenic diabetes through a nationwide information campaign--update on glucokinase gene mutations in a Polish cohort.

    Science.gov (United States)

    Borowiec, M; Fendler, W; Antosik, K; Baranowska, A; Gnys, P; Zmyslowska, A; Malecki, M; Mlynarski, W

    2012-12-01

    In order to improve recruitment efficiency of patients with monogenic diabetes in Poland, in September 2010 a nationwide advertising campaign was launched to inform multiple target groups interested or participating in pediatric diabetologic care. Promotional actions aimed at informing physicians, patients, parents and educators were carried out through nationwide newspapers, medical and patient-developed websites and educational conference presentations. Recruitment efficiency was compared between September 2010 (publication of the first report on project's results) and the following 12 months. The number of families and patients referred to genetic screening was increased by 92% and 96% respectively nearly reaching the numbers recruited throughout the initial 4 years of the project. Participation of non-academic centers was also significantly increased from 2.3% to 7.5% (p = 0.0005). DNA sequencing and Multiplex Ligation-dependant Probe Amplification of the glucokinase gene resulted in finding 50 different mutations. Among those mutations, 19 were novel variants, which included: 17 missense mutations (predicted to be pathogenic according to bioinformatic analysis), 1 nonsense mutation and 1 mutation affecting a consensus intronic splice site. Advertising actions directed at increasing recruitment efficiency are a powerful and possibly neglected tool in screening for rare genetic disorders with a clinically defined phenotype. © 2011 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  12. Vacuolar Protein Sorting genes in Parkinson’s Disease: a re-appraisal of mutations detection rate and neurobiology of disease

    Directory of Open Access Journals (Sweden)

    Stefano Gambardella

    2016-11-01

    Full Text Available Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN. Recently, retromers have been linked to Parkinson's Disease (PD since the identification of the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35 as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation, which represent critical steps in the molecular mechanisms of disease. Other slightly penetrant and mildly deleterious mutations in VPS genes have been reported in both sporadic and familial PD. Therefore, understanding the actual prevalence of the whole range of VPS gene mutations is key to understand the relevance of retromers impairment in PD. This scenario indicates a plethora of mutations occurring in different pathways (autophagy, mitophagy, proteasome, endosomes, protein misfolding all converging to cell clearing systems. This may explain how genetic predispositions to PD may derive from slightly deleterious mutations when combining with heterogeneous environmental factors. This manuscript is a re-appraisal of genetic data produced in the last five years redefining the prevalence of VPS mutations in PD. The prevalence of p.Asp620Asn in VPS35 is 0.286 of familial PD. This data increases up to 0.548 considering mutations affecting all VPS genes, thus representing the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the key role of retromers alterations in PD, strongly candidate environmentally-induced VPS alterations as key molecular mechanisms in the genesis of PD. rations as key molecular mechanisms in the genesis of PD.

  13. WHO-defined 'myelodysplastic syndrome with isolated del(5q)' in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations.

    Science.gov (United States)

    Patnaik, M M; Lasho, T L; Finke, C M; Gangat, N; Caramazza, D; Holtan, S G; Pardanani, A; Knudson, R A; Ketterling, R P; Chen, D; Hoyer, J D; Hanson, C A; Tefferi, A

    2010-07-01

    The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with 'myelodysplastic syndrome with isolated del(5q)' (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age >or=70 years (P=0.01), transfusion need at diagnosis (P=0.04) and dysgranulopoiesis (P=0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or >or=2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations.

  14. A loss-of-function mutation in the PAS kinase Rim15p is related to defective quiescence entry and high fermentation rates of Saccharomyces cerevisiae sake yeast strains.

    Science.gov (United States)

    Watanabe, Daisuke; Araki, Yuya; Zhou, Yan; Maeya, Naoki; Akao, Takeshi; Shimoi, Hitoshi

    2012-06-01

    Sake yeast cells have defective entry into the quiescent state, allowing them to sustain high fermentation rates. To reveal the underlying mechanism, we investigated the PAS kinase Rim15p, which orchestrates initiation of the quiescence program in Saccharomyces cerevisiae. We found that Rim15p is truncated at the carboxyl terminus in modern sake yeast strains as a result of a frameshift mutation. Introduction of this mutation or deletion of the full-length RIM15 gene in a laboratory strain led to a defective stress response, decreased synthesis of the storage carbohydrates trehalose and glycogen, and impaired G(1) arrest, which together closely resemble the characteristic phenotypes of sake yeast. Notably, expression of a functional RIM15 gene in a modern sake strain suppressed all of these phenotypes, demonstrating that dysfunction of Rim15p prevents sake yeast cells from entering quiescence. Moreover, loss of Rim15p or its downstream targets Igo1p and Igo2p remarkably improved the fermentation rate in a laboratory strain. This finding verified that Rim15p-mediated entry into quiescence plays pivotal roles in the inhibition of ethanol fermentation. Taken together, our results suggest that the loss-of-function mutation in the RIM15 gene may be the key genetic determinant of the increased ethanol production rates in modern sake yeast strains.

  15. Spontaneous mutation by mutagenic repair of spontaneous lesions in DNA

    International Nuclear Information System (INIS)

    Hastings, P.J.; Quah, S.-K.; Borstel, R.C. von

    1976-01-01

    It is stated that strains of yeast carrying mutations in many of the steps in pathways repairing radiation-induced damage to DNA have enhanced spontaneous mutation rates. Most strains isolated because they have enhanced spontaneous mutation carry mutations in DNA repair systems. This suggests that much spontaneous mutation arises by mutagenic repair of spontaneous lesions. (author)

  16. [Clinical significance of JAK2、CALR and MPL gene mutations in 1 648 Philadelphia chromosome negative myeloproliferative neoplasms patients from a single center].

    Science.gov (United States)

    Li, M Y; Chao, H Y; Sun, A N; Qiu, H Y; Jin, Z M; Tang, X W; Han, Y; Fu, C C; Chen, S N; Wu, D P

    2017-04-14

    Objective: To explore the prevalences of JAK2, CALR and MPL gene mutations and the mutation types in patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) , and to compare their clinical characteristics of different mutation types with each other and mutation negative group. Methods: The mutations of JAK2 V617F, JAK2 gene at exon 12, CALR gene at exon 9 and MPL gene at exon 10 in 1 648 Ph negative MPNs patients were detected by direct sequencing. Results: ① The JAK2V617F mutation was found in 471 (92.7%) of 508 PV patients, 819 (78.1%) of 1 049 ET patients and 74 (81.3%) of 91 PMF patients respectively, with the total mutation rate as 82.8% (1 364/1 648) . The JAK2 exon12 mutation was found in 9 (1.7%) of 508 PV patients, none was found in ET or PMF patients, with the total mutation rate as 0.5% (9/1 648) . The CALR mutation was found in 132 (12.6%) of 1 049 ET patients and 11 (12.1%) of 91 PMF patients respectively, with the total mutation rate as 8.7% (143/1 648) ; the MPL mutation was found in 9 (0.9%) of 1 049 ET patients and 1 (1.1%) of 91 PMF patients respectively, with the total mutation rate as 0.6% (10/1 648) . The co-occurrence of any two types of driver gene mutations was not detected by direct sequencing. ②The median onset age of patients with JAK2V617F[61 (15-95) y] was significant higher than of with JAK2 exon12 mutation[49 (33-62) y] or without mutations[42 (3-78) y] ( P MPL mutation[59 (22-71) y] ( P >0.05) . Patients with JAK2V617F had higher white blood cell count and hemoglobin level ( P MPL mutation ( P =0.013) . The platelet count of patients with CALR mutation was significantly higher than of with JAK2V617F[966 (400-2 069) ×10(9)/L vs 800 (198-3 730) ×10(9)/L, P MPL gene mutation revealed normal karyotype. Conclusions: Driver gene mutations detection could ensure the diagnosis and prognosis judgment of MPN more reliable, different subtypes of MPNs had different profiles of driver gene mutations, the latter

  17. Clarifying Normalization

    Science.gov (United States)

    Carpenter, Donald A.

    2008-01-01

    Confusion exists among database textbooks as to the goal of normalization as well as to which normal form a designer should aspire. This article discusses such discrepancies with the intention of simplifying normalization for both teacher and student. This author's industry and classroom experiences indicate such simplification yields quicker…

  18. Errors in Computing the Normalized Protein Catabolic Rate due to Use of Single-pool Urea Kinetic Modeling or to Omission of the Residual Kidney Urea Clearance.

    Science.gov (United States)

    Daugirdas, John T

    2017-07-01

    The protein catabolic rate normalized to body size (PCRn) often is computed in dialysis units to obtain information about protein ingestion. However, errors can manifest when inappropriate modeling methods are used. We used a variable volume 2-pool urea kinetic model to examine the percent errors in PCRn due to use of a 1-pool urea kinetic model or after omission of residual urea clearance (Kru). When a single-pool model was used, 2 sources of errors were identified. The first, dependent on the ratio of dialyzer urea clearance to urea distribution volume (K/V), resulted in a 7% inflation of the PCRn when K/V was in the range of 6 mL/min per L. A second, larger error appeared when Kt/V values were below 1.0 and was related to underestimation of urea distribution volume (due to overestimation of effective clearance) by the single-pool model. A previously reported prediction equation for PCRn was valid, but data suggest that it should be modified using 2-pool eKt/V and V coefficients instead of single-pool values. A third source of error, this one unrelated to use of a single-pool model, namely omission of Kru, was shown to result in an underestimation of PCRn, such that each ml/minute Kru per 35 L of V caused a 5.6% underestimate in PCRn. Marked overestimation of PCRn can result due to inappropriate use of a single-pool urea kinetic model, particularly when Kt/V <1.0 (as in short daily dialysis), or after omission of residual native kidney clearance. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  19. Mutations in the FHA-domain of ectopically expressed NBS1 lead to radiosensitization and to no increase in somatic mutation rates via a partial suppression of homologous recombination

    International Nuclear Information System (INIS)

    Ohara, Maki; Funyu, Yumi; Ebara, Shunsuke

    2014-01-01

    Ionizing radiation induces DNA double-strand breaks (DSBs). Mammalian cells repair DSBs through multiple pathways, and the repair pathway that is utilized may affect cellular radiation sensitivity. In this study, we examined effects on cellular radiosensitivity resulting from functional alterations in homologous recombination (HR). HR was inhibited by overexpression of the forkhead-associated (FHA) domain-mutated NBS1 (G27D/R28D: FHA-2D) protein in HeLa cells or in hamster cells carrying a human X-chromosome. Cells expressing FHA-2D presented partially (but significantly) HR-deficient phenotypes, which were assayed by the reduction of gene conversion frequencies measured with a reporter assay, a decrease in radiation-induced Mre11 foci formation, and hypersensitivity to camptothecin treatments. Interestingly, ectopic expression of FHA-2D did not increase the frequency of radiation-induced somatic mutations at the HPRT locus, suggesting that a partial reduction of HR efficiency has only a slight effect on genomic stability. The expression of FHA-2D rendered the exponentially growing cell population slightly (but significantly) more sensitive to ionizing radiation. This radiosensitization effect due to the expression of FHA-2D was enhanced when the cells were irradiated with split doses delivered at 24-h intervals. Furthermore, enhancement of radiation sensitivity by split dose irradiation was not seen in contact-inhibited G0/G1 populations, even though the cells expressed FHA-2D. These results suggest that the FHA domain of NBS1 might be an effective molecular target that can be used to induce radiosensitization using low molecular weight chemicals, and that partial inhibition of HR might improve the effectiveness of cancer radiotherapy. (author)

  20. Immunological responses during a virologically failing antiretroviral regimen are associated with in vivo synonymous mutation rates of HIV type-1 env

    DEFF Research Database (Denmark)

    Mens, Helene; Jørgensen, Louise Bruun; Kronborg, Gitte

    2009-01-01

    BACKGROUND: Little is known about the underlying causes of differences in immunological response to antiretroviral therapy during multidrug-resistant (MDR) HIV type-1 (HIV-1) infection. This study aimed to identify virological factors associated with immunological response during therapy failure...... for analysis. In a longitudinal mixed-effects model, plasma HIV-1 RNA only tended to predict immunological response (P=0.06), whereas minor protease inhibitor (PI) and nucleoside reverse transcriptase (NRTI) mutations at baseline correlated significantly with CD4+ T-cell count slopes (r= -0.56, P=0.04 and r......= -0.64, P=0.008, respectively). Interestingly, synonymous mutations of env correlated inversely with CD4+ T-cell count slopes (r=-0.60; P=0.01) and individuals with codons under positive selection had significantly better CD4+ T-cell responses than individuals without (0.42 versus -5.34; P=0...

  1. Biochemical mutations in the children of atomic bomb survivors

    International Nuclear Information System (INIS)

    Satoh, Chiyoko; Neel, J.V.

    1988-01-01

    Genetic effects of atomic bombs in children of survivors in Hiroshima and Nagasaki were studied using two biochemical indicators. Eligible children were classified as those born to parents exposed at up to 2,000 m from the hypocenter (Group I, n=13,052); and those born to either parents exposed at a distance of over 2,500 m or parents who were not in the cities (Group II, n=10,609). Thirty blood proteins were examined by one-dimensional gel electrophoresis. In Group I, 3 mutations altering electrophoretic mobility of proteins were identified among 667,404 locus tests. This corresponded to a mutation rate of 0.45 x 10 -5 per locus per generation. In Group II, 3 mutations among 466,881 locus tests were seen, yielding a mutation rate for electromorphs of 0.64 x 10 -5 per locus per generation. According to the dose schedule developed in 1965 (T65 DR), average gonal doses of gamma and neutrons were 16.9 and 3.4, respectively, for Hiroshima's fathers; 14.0 and 1.3 for Hiroshima's mothers; 26.2 and 0.3 for Nagasaki's fathers; and 19.7 and 0.1 for Nagasaki's mothers. A screening for variants in 9 erythrocyte enzymes with activity ≤66% of normal value revealed one mutation resulting in the loss of enzyme activity in 60,529 tests for Group I, but none of the mutations in 61,741 tests for Group II. The mutation rates in both groups are thus considered to be 0.60 and 0.64 x 10 -5 , respectively, per locus per generation. (Namekawa, K)

  2. Rapid detection of RB1 recurrent mutations in retinoblastoma by ...

    Indian Academy of Sciences (India)

    In about half of the patients, one mutation is inherited via the germinal cells, while in the .... mutational hot spots in the RB1 gene, making genetic testing complex and challenging ... by direct sequencing. High normal background in sequenc-.

  3. Stellar reaction rate for 22Mg+p→23Al from the asymptotic normalization coefficient in the mirror nuclear system 22Ne+n→23Ne

    International Nuclear Information System (INIS)

    Al-Abdullah, T.; Carstoiu, F.; Chen, X.; Clark, H. L.; Fu, C.; Gagliardi, C. A.; Lui, Y.-W.; Mukhamedzhanov, A.; Tabacaru, G.; Tokimoto, Y.; Trache, L.; Tribble, R. E.

    2010-01-01

    The production of 22 Na in ONe novae can be influenced by the 22 Mg(p,γ) 23 Al reaction. To investigate this reaction rate at stellar energies, we have determined the asymptotic normalization coefficient (ANC) for 22 Mg+p→ 23 Al through measurements of the ANCs in the mirror nuclear system 22 Ne+n→ 23 Ne. The peripheral neutron-transfer reactions 13 C( 12 C, 13 C) 12 C and 13 C( 22 Ne, 23 Ne) 12 C were studied. The identical entrance and exit channels of the first reaction make it possible to extract independently the ground-state ANC in 13 C. Our experiment gives C p 1/2 2 ( 13 C)=2.24±0.11 fm -1 , which agrees with the value obtained from several previous measurements. The weighted average for all the obtained C p 1/2 2 is 2.31±0.08 fm -1 . This value is adopted to be used in obtaining the ANCs in 23 Ne. The differential cross sections for the reaction 13 C( 22 Ne, 23 Ne) 12 C leading to the J π =5/2 + and 1/2 + states in 23 Ne have been measured at 12 MeV/u. Optical model parameters for use in the DWBA calculations were obtained from measurements of the elastic scatterings 22 Ne+ 13 C and 22 Ne+ 12 C. The extracted ANC for the ground state in 23 Ne, C d 5/2 2 =0.86±0.08±0.12 fm -1 , is converted to its corresponding value in 23 Al using mirror symmetry to give C d 5/2 2 ( 23 Al)=(4.63±0.77)x10 3 fm -1 . The astrophysical S factor S(0) for the 22 Mg(p,γ) reaction was determined to be 0.96±0.11 keV b. The consequences for nuclear astrophysics are discussed.

  4. The risk of extinction - the mutational meltdown or the overpopulation

    OpenAIRE

    Malarz, K.

    2006-01-01

    The phase diagrams survival-extinction for the Penna model with parameters: (mutations rate)-(birth rate), (mutation rate)-(harmful mutations threshold), (harmful mutation threshold)-(minimal reproduction age) are presented. The extinction phase may be caused by either mutational meltdown or overpopulation. When the Verhulst factor is responsible for removing only newly born babies and does not act on adults the overpopulation is avoided and only genetic factors may lead to species extinction.

  5. The risk of extinction - the mutational meltdown or the overpopulation.

    Science.gov (United States)

    Malarz, Krzysztof

    2007-04-01

    The phase diagrams survival-extinction for the Penna model with parameters: (mutations rate)-(birth rate), (mutation rate)-(harmful mutations threshold), (harmful mutation threshold)-(minimal reproduction age) are presented. The extinction phase may be caused by either mutational meltdown or overpopulation. When the Verhulst factor is responsible for removing only newly born babies and does not act on adults the overpopulation is avoided and only genetic factors may lead to species extinction.

  6. Radiation-induced mutation at minisatellite loci

    International Nuclear Information System (INIS)

    Dubrova, Y.E.; Nesterov, V.N.; Krouchinsky, N.G.

    1997-01-01

    We are studying the radiation-induced increase of mutation rate in minisatellite loci in mice and humans. Minisatellite mutations were scored by multilocus DNA fingerprint analysis in the progeny of γ-irradiated and non-irradiated mice. The frequency of mutation in offspring of irradiated males was 1.7 higher that in the control group. Germline mutation at human minisatellite loci was studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation assayed both by DNA fingerprinting and by eight single locus probes was found to be two times higher in the exposed families than in the control group. Furthermore, mutation rate was correlated with the parental radiation dose for chronic exposure 137 Cs, consistent with radiation-induction of germline mutation. The potential use of minisatellites in monitoring germline mutation in humans will be discussed

  7. Birkhoff normalization

    NARCIS (Netherlands)

    Broer, H.; Hoveijn, I.; Lunter, G.; Vegter, G.

    2003-01-01

    The Birkhoff normal form procedure is a widely used tool for approximating a Hamiltonian systems by a simpler one. This chapter starts out with an introduction to Hamiltonian mechanics, followed by an explanation of the Birkhoff normal form procedure. Finally we discuss several algorithms for

  8. The influence of surgical transection and anastomosis on the rate of cell proliferation in the colonic epithelium of normal and DMH-treated rats.

    Science.gov (United States)

    Barkla, D H; Tutton, P M

    1983-10-01

    Normal and DMH-treated male rats aged 18-20 weeks underwent surgical transection and anastomosis of the transverse colon. Animals were subsequently killed at intervals of 14, 30 and 72 days. Three hours prior to sacrifice animals were injected with vinblastine sulphate and mitotic indices were subsequently estimated in histological sections. Possible differences between experimental and control groups were tested using a Student's t-test. The results show that the accumulated mitotic indices in normal and DMH-treated colon are statistically similar. The results also show that transection and anastomosis stimulates cell division in both normal and DMH-treated colon and that the increase is of greater amplitude and more prolonged duration in the DMH-treated rats. Carcinomas developed close to the line of anastomosis in DMH-treated but not in control rats. The results support the hypothesis that non-specific injury to hyperplastic colonic epithelium promotes carcinogenesis.

  9. Perception of a Sung Vowel as a Function of Frequency-Modulation Rate and Excursion in Listeners with Normal Hearing and Hearing Impairment

    Science.gov (United States)

    Vatti, Marianna; Santurette, Sébastien; Pontoppidan, Niels Henrik; Dau, Torsten

    2014-01-01

    Purpose: Frequency fluctuations in human voices can usually be described as coherent frequency modulation (FM). As listeners with hearing impairment (HI listeners) are typically less sensitive to FM than listeners with normal hearing (NH listeners), this study investigated whether hearing loss affects the perception of a sung vowel based on FM…

  10. Apolipoprotein E Genotype and educational attainment predict the rate of cognitive decline in normal aging? A 12-year follow-up of the Maastricht Aging Study

    NARCIS (Netherlands)

    van Gerven, P.W.; van Boxtel, M.P.J.; Bekers, O.; Ausems, E.E.B.; Jolles, J.

    2012-01-01

    Objective: We investigated suspected longitudinal interaction effects of apolipoprotein E (APOE) genotype and educational attainment on cognitive decline in normal aging. Method: Our sample consisted of 571 healthy, nondemented adults aged between 49 and 82 years. Linear mixed-models analyses were

  11. The IARC TP53 mutation database: a resource for studying the significance of TP53 mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Magali Olivier

    2007-02-01

    yeast and human cells to measure the impact of these mutations on various protein properties: (1 transactivation activities (TA of mutant proteins on reporter genes placed under the control of various p53 responseelements, (2 capacity of mutant proteins to induce cellcycle arrest or apoptosis, (3 ability to exert dominantnegative effect (DNE over the wild-type protein, (4 activities of mutant proteins that are independent and unrelated to the wild-type protein (gain of function, GOF. Prediction models based on interspecies protein sequence conservation have also been developed to predict the functional impact of all possible single amino-acid substitutions.

    Normal">These data have been used to produce systematic functional classifications of mutant proteins and these classifications have been integrated in the IARC TP53 database. New tools have been implemented to visualize these data and analyze mutation frequencies in relation to their functional impact and intrinsic nucleotide substitution rates.

    Normal">Thus, the database allows systematic analyses of the factors that shape the patterns and influence the phenotype of missense mutations in human cancers. In a recent analysis of the database, we showed that that loss of TA capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. TA capacity of inherited missense mutations was also found to be related the age at onset of specific tumor types, mutations with total loss of TA being associated with earlier cancer onset cancers compared to mutations that retain partial trans-activation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE over wildtype p53, compared to only 45% of

  12. Mutations of NPM1 gene in de novo acute myeloid leukaemia: determination of incidence, distribution pattern and identification of two novel mutations in Indian population.

    Science.gov (United States)

    Ahmad, Firoz; Mandava, Swarna; Das, Bibhu Ranjan

    2009-06-01

    Mutations in the nucleophosmin (NPM1) gene have been recently described to occur in about one-third of acute myeloid leukaemias (AMLs) and represent the most frequent genetic alteration currently known in this subset, specially in those with normal karyotype. This study explored the prevalence and clinical profile of NPM1 mutations in a cohort of 200 Indian adult and children with AML. NPM1 mutations were observed in 19.5% of all population and 34.2% of those with normal karyotype. Adults had a significantly higher incidence of NPM1 mutations than children [38 of 161 (23.6%) vs. 1 of 39 (2.5%), p = 0.002]. NPM1 mutations were significantly associated with normal karyotype (p = 0.001), high WBC count (p = 0.034), AML-M4 subtype (p = 0.039) and a gradient increase of mutation rate with the increase in age groups. Sequence analysis of 39 mutated cases revealed typical mutations (types A, B, D, Nm and H*) as well as two novel variations (types F1 and F2). Majority of the patients had mutation type A (69.2%), followed by B (5.1%), D (15.3%), H* (2.5%) and Nm (2.5%) all involving COOH terminal of the NPM1 protein. In conclusion, this study represents the first report of NPM1 mutation from Indian population and confirms that the incidence of NPM1 mutations varies considerably globally, with slightly lower incidence in Indian population compared to western countries. The current study also served to identify two novel NPM1 mutants that add new insights into the heterogeneity of genomic insertions at exon 12. More ongoing larger studies are warranted to elucidate the molecular pathogenesis of AML that arises in this part of the world. Furthermore, we believe that in light of its high prevalence worldwide, inclusion of NPM1 mutation detection assay in diagnostic evaluations of AML may improve the efficacy of routine genetic characterization and allow assignment of patients to better-defined risk categories.

  13. Mutations in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-10-01

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

  14. The Reliability and Validity of the English and Spanish Strengths and Weaknesses of ADHD and Normal Behavior Rating Scales in a Preschool Sample: Continuum Measures of Hyperactivity and Inattention

    Science.gov (United States)

    Lakes, Kimberley D.; Swanson, James M.; Riggs, Matt

    2012-01-01

    Objective: To evaluate the reliability and validity of the English and Spanish versions of the Strengths and Weaknesses of ADHD-symptom and Normal-behavior (SWAN) rating scale. Method: Parents of preschoolers completed both a SWAN and the well-established Strengths and Difficulties Questionnaire (SDQ) on two separate occasions over a span of 3…

  15. Mutations in the thyrotropin receptor signal transduction pathway in the hyperfunctioning thyroid nodules from multinodular goiters: a study in the Turkish population.

    Science.gov (United States)

    Gozu, Hulya; Avsar, Melike; Bircan, Rifat; Sahin, Serap; Deyneli, Oguzhan; Cirakoglu, Beyazit; Akalin, Sema

    2005-10-01

    Many studies have been carried out to determine G(s) alpha and TSHR mutations in autonomously functioning thyroid nodules. Variable prevalences for somatic constitutively activating TSHR mutations in hot nodules have been reported. Moreover, the increased prevalence of toxic multinodular goiters in iodine-deficient regions is well known. In Turkey, a country with high incidence rates of goiter due to iodine deficiency, the frequency of mutations in the thyrotropin receptor signal transduction pathway has not been evaluated up to now. In the present study, a part of the genes of the TSHR, G(s)alpha and the catalytic subunit of the PKA were checked for activating mutations. Thirty-five patients who underwent thyroidectomy for multinodular goiters were examined. Genomic DNAs were extracted from 58 hyperactive nodular specimens and surrounding normal thyroid tissues. Mutation screening was done by single-strand conformational polymorphism (SSCP) analysis. In those cases where a mutation was detected, the localization of the mutation was determined by automatic DNA sequencing. No G(s)alpha or PKA mutations were detected, whereas ten mutations (17%) were identified in the TSHR gene. All mutations were somatic and heterozygotic. In conclusion, the frequency of mutations in the cAMP signal transduction pathway was found to be lower than expected in the Turkish population most likely because of the use of SSCP as a screening method and sequencing only a part of TSHR exon 10.

  16. Volatility of Mutator Phenotypes at Single Cell Resolution.

    Directory of Open Access Journals (Sweden)

    Scott R Kennedy

    2015-04-01

    Full Text Available Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.

  17. Ascorbate/menadione-induced oxidative stress kills cancer cells that express normal or mutated forms of the oncogenic protein Bcr-Abl. An in vitro and in vivo mechanistic study.

    Science.gov (United States)

    Beck, Raphaël; Pedrosa, Rozangela Curi; Dejeans, Nicolas; Glorieux, Christophe; Levêque, Philippe; Gallez, Bernard; Taper, Henryk; Eeckhoudt, Stéphane; Knoops, Laurent; Calderon, Pedro Buc; Verrax, Julien

    2011-10-01

    Numerous studies suggest that generation of oxidative stress could be useful in cancer treatment. In this study, we evaluated, in vitro and in vivo, the antitumor potential of oxidative stress induced by ascorbate/menadione (asc/men). This combination of a reducing agent (ascorbate) and a redox active quinone (menadione) generates redox cycling leading to formation of reactive oxygen species (ROS). Asc/men was tested in several cell types including K562 cells (a stable human-derived leukemia cell line), freshly isolated leukocytes from patients with chronic myeloid leukemia, BaF3 cells (a murine pro-B cell line) transfected with Bcr-Abl and peripheral blood leukocytes derived from healthy donors. Although these latter cells were resistant to asc/men, survival of all the other cell lines was markedly reduced, including the BaF3 cells expressing either wild-type or mutated Bcr-Abl. In a standard in vivo model of subcutaneous tumor transplantation, asc/men provoked a significant delay in the proliferation of K562 and BaF3 cells expressing the T315I mutated form of Bcr-Abl. No effect of asc/men was observed when these latter cells were injected into blood of mice most probably because of the high antioxidant potential of red blood cells, as shown by in vitro experiments. We postulate that cancer cells are more sensitive to asc/men than healthy cells because of their lack of antioxidant enzymes, mainly catalase. The mechanism underlying this cytotoxicity involves the oxidative cleavage of Hsp90 with a subsequent loss of its chaperone function thus leading to degradation of wild-type and mutated Bcr-Abl protein.

  18. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.

    Science.gov (United States)

    Barnes, Aileen M; Carter, Erin M; Cabral, Wayne A; Weis, MaryAnn; Chang, Weizhong; Makareeva, Elena; Leikin, Sergey; Rotimi, Charles N; Eyre, David R; Raggio, Cathleen L; Marini, Joan C

    2010-02-11

    Osteogenesis imperfecta is a heritable disorder that causes bone fragility. Mutations in type I collagen result in autosomal dominant osteogenesis imperfecta, whereas mutations in either of two components of the collagen prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and prolyl 3-hydroxylase 1 [P3H1]) cause autosomal recessive osteogenesis imperfecta with rhizomelia (shortening of proximal segments of upper and lower limbs) and delayed collagen folding. We identified two siblings who had recessive osteogenesis imperfecta without rhizomelia. They had a homozygous start-codon mutation in the peptidyl-prolyl isomerase B gene (PPIB), which results in a lack of cyclophilin B (CyPB), the third component of the complex. The proband's collagen had normal collagen folding and normal prolyl 3-hydroxylation, suggesting that CyPB is not the exclusive peptidyl-prolyl cis-trans isomerase that catalyzes the rate-limiting step in collagen folding, as is currently thought. 2010 Massachusetts Medical Society

  19. Effects of low dose rate γ-rays on cell proliferation and survival in exponentially growing and plateau phase cultures of normal rat kidney cells

    International Nuclear Information System (INIS)

    Tsuboi, A.

    1982-01-01

    The effects of 60 Co γ-rays on cell clonogenicity and cell proliferation were examined in NRK cells in exponential and plateau growth phases during and after irradiation at various dose rates. The typical dese rate effect for the survival responses was observed between acute irradiation and continuous irradiation at dose rates of 9.6-44 rads/h. Similar dose rate effect for the perturbation of the proliferation was observed in exponentially growing cells during irradiation. Some differences were found in survival when the cells were exposed to γ-rays at 9.6 rads/h or at 13.7 rads/h. The survival curves of exponential phase cells irradiated at these dose rates showed a shape different from that observed in plateau phase cells. Namely, a steady state of survival appeared around an accumulated dose of 1000 rads (dose-rate of 9.6 rads/h) and an accumulated dose of 1500 rads (dose-rate of 13.7 rads/h) in the exponential phase cells, while such a steady state of survival was not detected in plateau phase cells after similar conditions of irradiation. Moreover, the extrapolation number of the survival curve was much larger at the lower dose rate in exponential phase cells, in contrast to a value of the unity oberved in plateau phase cells, The radiosensitivity of plateau phase cells was somewhat lower compared to exponential phase cells over the range of accumulated doses at the dose rates used. These differences in cellular responses to the radiation between the two phases could be explained by changes in cell proliferation, the redistribution of the cell cycle compartments and the repair capacity of cellular damage during irradiation. (author)

  20. Insulin's acute effects on glomerular filtration rate correlate with insulin sensitivity whereas insulin's acute effects on proximal tubular sodium reabsorption correlate with salt sensitivity in normal subjects

    NARCIS (Netherlands)

    ter Maaten, JC; Bakker, SJL; Serne, EH; ter Wee, PM; Gans, ROB

    1999-01-01

    Background. Insulin induces increasing distal tubular sodium reabsorption. Opposite effects of insulin to offset insulin-induced sodium retention are supposedly increases in glomerular filtration rate (GFR) and decreases in proximal tubular sodium reabsorption. Defects in these opposing effects

  1. Salivary protein concentration, flow rate, buffer capacity and pH estimation: A comparative study among young and elderly subjects, both normal and with gingivitis and periodontitis.

    Science.gov (United States)

    Shaila, Mulki; Pai, G Prakash; Shetty, Pushparaj

    2013-01-01

    To evaluate the salivary protein concentration in gingivitis and periodontitis patients and compare the parameters like salivary total protein, salivary albumin, salivary flow rate, pH, buffer capacity and flow rate in both young and elderly patients with simple methods. One hundred and twenty subjects were grouped based on their age as young and elderly. Each group was subgrouped (20 subjects) as controls, gingivitis and periodontitis. Unstimulated whole saliva was collected from patients and flow rate was noted down during collection of the sample. Salivary protein estimation was done using the Biuret method and salivary albumin was assessed using the Bromocresol green method. pH was estimated with a pHmeter and buffering capacity was analyzed with the titration method. Student's t-test, Fisher's test (ANOVA) and Tukey HSD (ANOVA) tests were used for statistical analysis. A very highly significant rise in the salivary total protein and albumin concentration was noted in gingivitis and periodontitis subjects of both young and elderly. An overall decrease in salivary flow rate was observed among the elderly, and also the salivary flow rate of women was significantly lower than that of men. Significant associations between salivary total protein and albumin in gingivitis and periodontitis were found with simple biochemical tests. A decrease in salivary flow rate among elderly and among women was noted.

  2. Photoreactivation of conversion and de novo suppressor mutation in Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Bockrath, R C; Plamer, J E [Indiana Univ., Indianapolis (USA). Dept. of Microbiology

    1977-04-01

    Studies of mutagenesis and photoreactivation in various E.coli strains have shown that conversion mutation of a mutant containing an amber suppressor to one containing an ochre suppressor is sensitive to photoreactivation. Direct photoreactivation by photoreactivating light (PRL) after uv mutagenesis reduced mutation frequencies by a factor of about 2 for each minute of exposure during the first 5 to 8 min of exposure for cells with normal repair capacity. Conversion and potential de novo suppressor mutations were about equally sensitive. For conversion, the sensitivities to PRL were identical in the repair-normal and excisions-repair-deficient strains. For de novo suppressor mutation, the rate of mutation frequency reduction by PRL in the repair-deficient strain was about one-half that in the other strains. The results suggest that ultraviolet radiation produces both de novo suppressor mutation and conversion at the sup(E,B) locus by photoreversible pyrimidine dimers in the DNA. The causative dimers could be Thy()Cyt dimers in the transcribed strand or the non-transcribed strand, respectively.

  3. SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.

    Science.gov (United States)

    Krieger, Michael; Roos, Andreas; Stendel, Claudia; Claeys, Kristl G; Sonmez, Fatma Mujgan; Baudis, Michael; Bauer, Peter; Bornemann, Antje; de Goede, Christian; Dufke, Andreas; Finkel, Richard S; Goebel, Hans H; Häussler, Martin; Kingston, Helen; Kirschner, Janbernd; Medne, Livija; Muschke, Petra; Rivier, François; Rudnik-Schöneborn, Sabine; Spengler, Sabrina; Inzana, Francesca; Stanzial, Franco; Benedicenti, Francesco; Synofzik, Matthis; Lia Taratuto, Ana; Pirra, Laura; Tay, Stacey Kiat-Hong; Topaloglu, Haluk; Uyanik, Gökhan; Wand, Dorothea; Williams, Denise; Zerres, Klaus; Weis, Joachim; Senderek, Jan

    2013-12-01

    Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be

  4. Heart-specific expression of laminopathic mutations in transgenic zebrafish.

    Science.gov (United States)

    Verma, Ajay D; Parnaik, Veena K

    2017-07-01

    Lamins are key determinants of nuclear organization and function in the metazoan nucleus. Mutations in human lamin A cause a spectrum of genetic diseases that affect cardiac muscle and skeletal muscle as well as other tissues. A few laminopathies have been modeled using the mouse. As zebrafish is a well established model for the study of cardiac development and disease, we have investigated the effects of heart-specific lamin A mutations in transgenic zebrafish. We have developed transgenic lines of zebrafish expressing conserved lamin A mutations that cause cardiac dysfunction in humans. Expression of zlamin A mutations Q291P and M368K in the heart was driven by the zebrafish cardiac troponin T2 promoter. Homozygous mutant embryos displayed nuclear abnormalities in cardiomyocyte nuclei. Expression analysis showed the upregulation of genes involved in heart regeneration in transgenic mutant embryos and a cell proliferation marker was increased in adult heart tissue. At the physiological level, there was deviation of up to 20% from normal heart rate in transgenic embryos expressing mutant lamins. Adult homozygous zebrafish were fertile and did not show signs of early mortality. Our results suggest that transgenic zebrafish models of heart-specific laminopathies show cardiac regeneration and moderate deviations in heart rate during embryonic development. © 2017 International Federation for Cell Biology.

  5. A twin study of Attention-Deficit/Hyperactivity Disorder Dimensions rated by the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN) Scale

    NARCIS (Netherlands)

    Hay, D.A.; Bennett, K.S.; Levy, J.; Sergeant, J.A.; Swanson, J.

    2007-01-01

    Background: When symptom rating scales are used in the general population, there is severe skewness, with many individuals having no symptoms. While this has major implications for genetic designs that require extremely discordant and concordant (EDAC) siblings, little is known of the genetics of

  6. Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Gram, Jeppe; Høegh-Andersen, Pernille

    2005-01-01

    of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found...

  7. The Blood Disappearance Rate of 1{sup 98A}u-Colloid and Changes of Hepatic Blood Flow During Position Change in Normal Persons and in Patients with Various Hepatic Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Bo Yeon [Capital Armed Force General Hospital, Seoul (Korea, Republic of); Hong, Kee Suk; Koh, Chang Soon; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1977-03-15

    To evaluate the diagnostic significance of the blood disappearance rate of {sup 198}Au-colloid and to evaluate the change of hepatic blood flow during position change from supine to erect, we measured the half time of blood disappearance rate of {sup 198}Au-colloid using external counting method in 94 normal persons and in 77 patients with various hepatic diseases. The results obtained were as follows: 1) In normal control, the mean blood disappearance half time of {sup 198}Au-colloid in supine position was 2.7+-0.4 minutes. There was no significant difference of hepatic blood flow in age and sex. 2) In acute hepatitis, chronic hepatitis and hepatic cirrhosis, the mean blood disappearance half times in supine position were 3.0+-0.45, 3.5+-0.74, 7.2+-3.6 minutes respectively. The hepatic blood flow of the patients with chronic hepatitis and hepatic cirrhosis were significantly decreased than that of normal control. 3) In the normal control and acute hepatitis, the decreases of the hepatic blood flow during the position change from supine to erect were 27.7% and 22.6% respectively.

  8. Malware Normalization

    OpenAIRE

    Christodorescu, Mihai; Kinder, Johannes; Jha, Somesh; Katzenbeisser, Stefan; Veith, Helmut

    2005-01-01

    Malware is code designed for a malicious purpose, such as obtaining root privilege on a host. A malware detector identifies malware and thus prevents it from adversely affecting a host. In order to evade detection by malware detectors, malware writers use various obfuscation techniques to transform their malware. There is strong evidence that commercial malware detectors are susceptible to these evasion tactics. In this paper, we describe the design and implementation of a malware normalizer ...

  9. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Yu Chaowen

    2011-12-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: PKD1 (16p13.3 and PKD2 (4q21. Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of PKD1 gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both PKD1 and PKD2 genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC. Methods Both PKD1 and PKD2 genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources. Results A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65. About 69% (20/29 of the mutations are first reported with a recurrent mutation rate of 31%. Conclusions Mutation study of PKD1 and PKD2 genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.

  10. Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts

    International Nuclear Information System (INIS)

    Kukat, Alexandra; Edgar, Daniel; Bratic, Ivana; Maiti, Priyanka; Trifunovic, Aleksandra

    2011-01-01

    Highlights: → Increased mtDNA mutations in MEFs lead to high level of spontaneous immortalization. → This process is independent of endogenous ROS production. → Aerobic glycolysis significantly contributes to spontaneous immortalization of MEFs. -- Abstract: An increase in mtDNA mutation load leads to a loss of critical cells in different tissues thereby contributing to the physiological process of organismal ageing. Additionally, the accumulation of senescent cells that display changes in metabolic function might act in an active way to further disrupt the normal tissue function. We believe that this could be the important link missing in our understanding of the molecular mechanisms of premature ageing in the mtDNA mutator mice. We tested proliferation capacity of mtDNA mutator cells in vitro. When cultured in physiological levels of oxygen (3%) their proliferation capacity is somewhat lower than wild-type cells. Surprisingly, in conditions of increased oxidative stress (20% O 2 ) mtDNA mutator mouse embryonic fibroblasts exhibit continuous proliferation due to spontaneous immortalization, whereas the same conditions promote senescence in wild-type cells. We believe that an increase in aerobic glycolysis observed in mtDNA mutator mice is a major mechanism behind this process. We propose that glycolysis promotes proliferation and allows a fast turnover of metabolites, but also leads to energy crisis due to lower ATP production rate. This could lead to compromised replication and/or repair and therefore, in rare cases, might lead to mutations in tumor suppressor genes and spontaneous immortalization.

  11. Fisetin-Rich Extracts of Rhus verniciflua Stokes Improve Blood Flow Rates in Mice Fed Both Normal and High-Fat Diets.

    Science.gov (United States)

    Im, Won Kyun; Park, Hyun Jung; Lee, Kwang Soo; Lee, Jung Hoon; Kim, Young Dong; Kim, Kyeong-Hee; Park, Sang-Jae; Hong, Seokmann; Jeon, Sung Ho

    2016-02-01

    Although it has been previously reported that Rhus verniciflua Stokes (RVS) possesses in vitro anti-inflammatory activity, the precise in vivo mechanisms of RVS extracts and a main active component called fisetin have not been well elucidated. In this study, using newly developed protocols, we prepared urushiol-free but fisetin-enriched RVS extracts and investigated their effects on the vascular immune system. We found that the water-soluble fractions of detoxified RVS with the flavonoid fisetin can inhibit lipopolysaccharide-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2). Furthermore, RVS can reduce inducible nitric oxide synthase and COX2 gene expression levels, which are responsible for NO and PGE2 production, respectively, in RAW264.7 macrophage cells. Because inflammation is linked to the activation of the coagulation system, we hypothesized that RVS and its active component fisetin possess anticoagulatory activities. As expected, we found that both RVS and fisetin could inhibit the coagulation of human peripheral blood cells. Moreover, in vivo RVS treatment could return the retarded blood flow elicited by a high-fat diet (HFD) back to the normal level in mice. In addition, RVS treatment has significantly reduced body weight gained by HFD in mice. Taken together, the fisetin-rich RVS extracts have potential antiplatelet and antiobesity activities and could be used as a functional food ingredient to improve blood circulation.

  12. Approach of the value of an annuity when non-central moments of the capitalization factor are known: an R application with interest rates following normal and beta distributions

    Directory of Open Access Journals (Sweden)

    Salvador Cruz Rambaud

    2015-07-01

    Full Text Available This paper proposes an expression of the value of an annuity with payments of 1 unit each when the interest rate is random. In order to attain this objective, we proceed on the assumption that the non-central moments of the capitalization factor are known. Specifically, to calculate the value of these annuities, we propose two different expressions. First, we suppose that the random interest rate is normally distributed; then, we assume that it follows the beta distribution. A practical application of these two methodologies is also implemented using the R statistical software.

  13. Differentiating inflamed and normal lungs by the apparent reaction rate constants of lactate dehydrogenase probed by hyperpolarized (13)C labeled pyruvate.

    Science.gov (United States)

    Xu, He N; Kadlececk, Stephen; Shaghaghi, Hoora; Zhao, Huaqing; Profka, Harilla; Pourfathi, Mehrdad; Rizi, Rahim; Li, Lin Z

    2016-02-01

    Clinically translatable hyperpolarized (HP) (13)C-NMR can probe in vivo enzymatic reactions, e.g., lactate dehydrogenase (LDH)-catalyzed reaction by injecting HP (13)C-pyruvate into the subject, which is converted to (13)C labeled lactate by the enzyme. Parameters such as (13)C-lactate signals and lactate-to-pyruvate signal ratio are commonly used for analyzing the HP (13)C-NMR data. However, the biochemical/biological meaning of these parameters remains either unclear or dependent on experimental settings. It is preferable to quantify the reaction rate constants with a clearer physical meaning. Here we report the extraction of the kinetic parameters of the LDH reaction from HP (13)C-NMR data and investigate if they can be potential predictors of lung inflammation. Male Sprague-Dawley rats (12 controls, 14 treated) were used. One dose of bleomycin (2.5 U/kg) was administered intratracheally to the treatment group. The lungs were removed, perfused, and observed by the HP-NMR technique, where a HyperSense dynamic nuclear polarization system was used to generate the HP (13)C-pyruvate for injecting into the lungs. A 20 mm (1)H/(13)C dual-tuned coil in a 9.4-T Varian vertical bore NMR spectrometer was employed to acquire the (13)C spectral data every 1 s over a time period of 300 s using a non-selective, 15-degree radiofrequency pulse. The apparent rate constants of the LDH reaction and their ratio were quantified by applying ratiometric fitting analysis to the time series data of (13)C labeled pyruvate and lactate. The apparent forward rate constant kp =(3.67±3.31)×10(-4) s(-1), reverse rate constant kl =(4.95±2.90)×10(-2) s(-1), rate constant ratio kp /kl =(7.53±5.75)×10(-3) for the control lungs; kp =(11.71±4.35)×10(-4) s(-1), kl =(9.89±3.89)×10(-2) s(-1), and kp /kl =(12.39±4.18)×10(-3) for the inflamed lungs at the 7(th) day post treatment. Wilcoxon rank-sum test showed that the medians of these kinetic parameters of the 7-day cohort were significantly

  14. Do apolipoprotein E genotype and educational attainment predict the rate of cognitive decline in normal aging? A 12-year follow-up of the Maastricht Aging Study.

    Science.gov (United States)

    Van Gerven, Pascal W M; Van Boxtel, Martin P J; Ausems, Eleonora E B; Bekers, Otto; Jolles, Jelle

    2012-07-01

    We investigated suspected longitudinal interaction effects of apolipoprotein E (APOE) genotype and educational attainment on cognitive decline in normal aging. Our sample consisted of 571 healthy, nondemented adults aged between 49 and 82 years. Linear mixed-models analyses were performed with four measurement time points: baseline, 3-year, 6-year, and 12-year follow-up. Covariates included age at baseline, sex, and self-perceived physical and mental health. Dependent measures were global cognitive functioning (Mini-Mental State Examination; Folstein, Folstein, & McHugh, 1975), Stroop performance (Stroop Color-Word Test; Van der Elst, Van Boxtel, Van Breukelen, & Jolles, 2006a), set-shifting performance (Concept Shifting Test; Van der Elst, Van Boxtel, Van Breukelen, & Jolles, 2006b), cognitive speed (Letter-Digit Substitution Test; Van der Elst, Van Boxtel, Van Breukelen, & Jolles, 2006c), verbal learning (Verbal Learning Test: Sum of five trials; Van der Elst, Van Boxtel, Van Breukelen, & Jolles, 2005), and long-term memory (Verbal Learning Test: Delayed recall). We found only faint evidence that older, high-educated carriers of the APOE-ε4 allele (irrespective of zygosity) show a more pronounced decline than younger, low-educated carriers and noncarriers (irrespective of educational attainment). Moreover, this outcome was confined to concept-shifting performance and was especially observable between 6- and 12-year follow-ups. No protective effects of higher education were found on any of the six cognitive measures. We conclude that the combination of APOE-ε4 allele and high educational attainment may be a risk factor for accelerated cognitive decline in older age, as has been reported before, but only to a very limited extent. Moreover, we conclude that, within the cognitive reserve framework, education does not have significant protective power against age-related cognitive decline.

  15. Normal accidents

    International Nuclear Information System (INIS)

    Perrow, C.

    1989-01-01

    The author has chosen numerous concrete examples to illustrate the hazardousness inherent in high-risk technologies. Starting with the TMI reactor accident in 1979, he shows that it is not only the nuclear energy sector that bears the risk of 'normal accidents', but also quite a number of other technologies and industrial sectors, or research fields. The author refers to the petrochemical industry, shipping, air traffic, large dams, mining activities, and genetic engineering, showing that due to the complexity of the systems and their manifold, rapidly interacting processes, accidents happen that cannot be thoroughly calculated, and hence are unavoidable. (orig./HP) [de

  16. Dissolution rates of unirradiated UO2, UO2 doped with 233U, and spent fuel under normal atmospheric conditions and under reducing conditions using an isotope dilution method

    International Nuclear Information System (INIS)

    Ollila, Kaija; Albinsson, Yngve; Oversby, Virginia; Cowper, Mark

    2003-10-01

    The experimental results given in this report allow us to draw the following conclusions. 1) Tests using unirradiated fuel pellet materials from two different manufacturers gave very different dissolution rates under air atmosphere testing. Tests for fragments of pellets from different pellets made by the same manufacturer gave good agreement. This indicates that details of the manufacturing process have a large effect on the behavior of unirradiated UO 2 in dissolution experiments. Care must be taken in interpreting differences in results obtained in different laboratories because the results may be affected by manufacturing effects. 2) Long-term tests under air atmosphere have begun to show the effects of precipitation. Further testing will be needed before the samples reach steady state. 3) Testing of unirradiated UO 2 in systems containing an iron strip to produce reducing conditions gave [U] less than detection limits ( 235 U added as spike was recovered, indicating that 90% of the spike had precipitated onto the solid sample or the iron strip. 9) Tests of UO 2 pellet materials containing 233 U to provide an alpha decay activity similar to that expected for spent fuel 3000 and 10,000 years after disposal showed that the pellet materials behaved as expected under air atmosphere conditions, showing that the manufacturing method was successful. 10) Early testing of the 233 U-doped materials under reducing conditions showed relatively rapid (30 minute) dissolution of small amounts of U at the start of the puff test procedure. Results of analyses of an acidified fraction of the same solutions after 1 or 2 weeks holding indicate that the solutions were inhomogeneous, indicating the presence of colloidal material or small grains of solid. 11) Samples from the 233 U-doped tests initially indicated dissolution of solid during the first week of testing, with some indication of more rapid dissolution of the material with the higher doping. 12) The second cycle of testing

  17. CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.

    Directory of Open Access Journals (Sweden)

    Yi-Hung Carol Tan

    2010-01-01

    Full Text Available Non-small cell lung cancer (NSCLC is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET, and functionality in NSCLC.Using archival formalin-fixed paraffin embedded (FFPE extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH for the c-CBL locus (22%, n = 8/37 and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively transfected in NSCLC cell lines, there was increased cell viability and cell motility.Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis.

  18. BRAF mutations in conjunctival melanoma

    DEFF Research Database (Denmark)

    Larsen, Ann-Cathrine; Dahl, Christina; Dahmcke, Christina M.

    2016-01-01

    with atypia. BRAF mutations were identified in 39 of 111 (35%) cases. The rate ratio of BRAF-mutated versus BRAF-wild-type melanoma did not change over time. BRAF mutations were associated with T1 stage (p = 0.007), young age (p = 0.001), male gender (p = 0.02), sun-exposed location (p = 0.01), mixed....../non-pigmented tumour colour (p = 0.02) and nevus origin (p = 0.005), but did not associate with prognosis. BRAF status in conjunctival melanoma and paired premalignant lesions corresponded in 19 of 20 cases. Immunohistochemistry detected BRAF V600E mutations with a sensitivity of 0.94 and a specificity of 1...

  19. Mutation in cultured mammalian cells

    International Nuclear Information System (INIS)

    Nakamura, N.; Okada, S.

    1982-01-01

    Mammalian cell cultures were exposed to gamma-rays at various dose rates. Dose-rate effects were observed in cultured somatic cells of the mouse for cell killing and mutations resistant to 6-thioguanine (TGsup(r)) and to methotrexate (MTXsup(r)). Linear quadratic model may be applied to cell killing and TGsup(r) mutations in some cases but can not explain the whole data. Results at low doses with far low dose-rate were not predictable from data at high doses with acute or chronic irradiation. Radioprotective effects of dimethyl sulfoxide were seen only after acute exposure but not after chronic one, suggesting that damages by indirect action of radiations may be potentially reparable by cells. TGsup(r) mutations seem to contain gross structural changes whereas MTXsup(r) ones may have smaller alterations. (Namekawa, K.)

  20. Standardisation of tracer and type of meal in the evaluation of gastric emptying and colon transit rates in normal Beagle dogs

    International Nuclear Information System (INIS)

    Dormehl, I.C.; Jordaan, J.H.; Jacobs, D.J.; Plessis, M. du; Pilloy, W.

    1984-01-01

    The transit of 111 In-labelled polymer beads of different particle sizes in the stomach and colon of five healthy Beagle dogs was monitored after intake of different kinds of meal by a gamma camera and data processor system. The various meals studied were a solid balanced type of dog food mixed with molk, pure milk, and finally a metal of raw meat. The polymer beads carried triethylenetetramine type functions which efficiently chelated 111 In +3 from an aqueous solution of InCl 3 . These labelled beads were well mixed into the food before being offered to the dogs. Gastric emptying curves from which half-times of emptying (Tsub(1/2)) could be obtained are presented and statistically compared. Good quality images with quantification of the colon transit rate also became possible. It appeared that standardisation of the tracer and of the metal is compulsory for relevant and reproducible results. (orig.)

  1. Standardisation of tracer and type of meal in the evaluation of gastric emptying and colon transit rates in normal Beagle dogs

    Energy Technology Data Exchange (ETDEWEB)

    Dormehl, I.C.; Jordaan, J.H.; Jacobs, D.J.; Plessis, M. du; Pilloy, W.

    1984-01-01

    The transit of /sup 111/In-labelled polymer beads of different particle sizes in the stomach and colon of five healthy Beagle dogs was monitored after intake of different kinds of meal by a gamma camera and data processor system. The various meals studied were a solid balanced type of dog food mixed with molk, pure milk, and finally a meal of raw meat. The polymer beads carried triethylenetetramine type functions which efficiently chelated /sup 111/In/sup +3/ from an aqueous solution of InCl/sub 3/. These labelled beads were well mixed into the food before being offered to the dogs. Gastric emptying curves from which half-times of emptying (Tsub(1/2)) could be obtained are presented and statistically compared. Good quality images with quantification of the colon transit rate also became possible. It appeared that standardisation of the tracer and of the metal is compulsory for relevant and reproducible results.

  2. Measurement of fission gas release, internal pressure and cladding creep rate in the fuel pins of PHWR bundle of normal discharge burnup

    Energy Technology Data Exchange (ETDEWEB)

    Viswanathan, U.K. [Post Irradiation Examination Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Sah, D.N., E-mail: dnsah@barc.gov.i [Post Irradiation Examination Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Rath, B.N.; Anantharaman, S. [Post Irradiation Examination Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India)

    2009-08-01

    Fuel pins of a Pressurised Heavy Water Reactor (PHWR) fuel bundle discharged from Narora Atomic Power Station unit no. 1 after attaining a fuel burnup of 7528 MWd/tU have been subjected to two types of studies, namely (i) puncture test to estimate extent of fission gas release and internal pressure in the fuel pin and (ii) localized heating of the irradiated fuel pin to measure the creep rate of the cladding in temperature range 800 deg. C - 900 deg. C. The fission gas release in the fuel pins from the outer ring of the bundle was found to be about 8%. However, only marginal release was found in fuel pins from the middle ring and the central fuel pin. The internal gas pressure in the outer fuel pin was measured to be 0.55 +- 0.05 MPa at room temperature. In-cell isothermal heating of a small portion of the outer fuel pins was carried out at 800 deg. C, 850 deg. C and 900 deg. C for 10 min and the increase in diameter of the fuel pin was measured after heat treatment. Creep rates of the cladding obtained from the measurement of the diameter change of the cladding due to heating at 800 deg. C, 850 deg. C and 900 deg. C were found respectively to be 2.4 x 10{sup -5} s{sup -1}, 24.6 x 10{sup -5} s{sup -1} and 45.6 x 10{sup -5} s{sup -1}.

  3. Cystic fibrosis transmembrane conductance regulator gene mutations: do they play a role in the aetiology of allergic bronchopulmonary aspergillosis?

    Science.gov (United States)

    Eaton, T E; Weiner Miller, P; Garrett, J E; Cutting, G R

    2002-05-01

    Previous work suggests that cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations may be implicated in the aetiology of allergic bronchopulmonary aspergilosis (ABPA). To compare the frequency of CF gene mutations in asthmatics with ABPA of varying severity with asthmatics who were skin prick test (SPT)-positive to Aspergillus fumigatus (Af) without evidence of ABPA and asthmatics SPT-negative to Af. Thirty-one Caucasian patients with ABPA were identified, together with asthmatics SPT positive to Af without evidence of ABPA (n = 23) and SPT negative to Af (n = 28). Genomic DNA was tested for 16 CF mutations accounting for approximately 85% of CF alleles in Caucasian New Zealanders. Four (12.9%) ABPA patients were found to be carriers of a CF mutation (DeltaF508 n = 3, R117H n = 1), one (4.3%) asthmatic SPT positive to Af without ABPA (DeltaF508), and one (3.6%) asthmatic SPT negative to Af (R117H). All patients with a CF mutation had normal sweat chloride (< 40 mM). There was no significant difference between the frequency of CF mutations in the ABPA patients and asthmatics without ABPA. However, the frequency of CF mutations in the ABPA patients was significantly different (P = 0.0125) to the expected carrier rate in the general population. These results lend further support to a possible link between CF mutations and ABPA.

  4. Effect of ST36 Acupuncture on Hyperventilation-Induced CO2 Reactivity of the Basilar and Middle Cerebral Arteries and Heart Rate Variability in Normal Subjects

    Directory of Open Access Journals (Sweden)

    Sang-Ho Hyun

    2014-01-01

    Full Text Available This study was conducted to verify the effect of acupuncture on cerebral haemodynamics to provide evidence for the use of acupuncture treatment as a complementary therapy for the high-risk stroke population. The effect of ST36 acupuncture treatment on the hyperventilation-induced CO2 reactivity of the basilar and middle cerebral arteries was studied in 10 healthy male volunteers (mean age, 25.2 ± 1.5 years using a transcranial Doppler sonography with an interval of 1 week between measurements, and a portable ECG monitoring system was used to obtain ECG data simultaneously. The CO2 reactivity of the basilar and middle cerebral arteries increased significantly after ST36 acupuncture treatment, whereas the mean arterial blood pressure and pulse rate did not change significantly. The high-frequency power significantly increased after ST36 acupuncture treatment, and the percentage increase of high-frequency power correlated significantly with the percentage increase in the CO2 reactivity of the contralateral middle cerebral artery. These data suggest that ST36 acupuncture treatment increases CO2 reactivity, indicating improvement of vasodilatory potential of the cerebral vasculature to compensate for fluctuations caused by changes in external conditions. The increase in parasympathetic tone by ST36 acupuncture treatment is responsible for this therapeutic effect.

  5. A mathematical model resolving normal human blood lymphocyte population X-ray survival curves into six components: radiosensitivity, death rate and size of two responding sub-populations

    International Nuclear Information System (INIS)

    Thomson, A.E.R.; Vaughan-Smith, S.; Peel, W.E.

    1982-01-01

    The analysis was based on observations of survival decrease as a function of dose (range 0-5 Gy (= 500 rad)) and time after irradiation in vitro. Since lymphocyte survival is also sensitive to culture conditions the effects of radiation were examined daily up to 3 days only, while survival of control cells remained ca. 90 per cent. The time-dependent changes were resolved as the death rates (first-order governed) of lethally-hit cells (apparent survivors), so rendering these distinguishable from the morphologically identical, true (ultimate) survivors. For 12 blood donors the estimated dose permitting 37 per cent ultimate survival (D 37 value) averaged 0.72 +- 0.18 (SD) Gy for the more radiosensitive lymphocyte fraction and 2.50 +- 0.67 Gy for the less radiosensitive, each fraction proving homogeneously radiosensitive and the latter identifying substantially in kind with T-type (E-rosetting lymphocytes). The half-life of lethally-hit members of either fraction varied widely among the donors (ranges, 25-104 hours and 11-40 hours, respectively). Survival curves reconstructed by summating the numerical estimates of the six parameters according to the theoretical model closely matched those observed experimentally (ranged in multiple correlation coefficient, 0.9709-0.9994) for all donors). This signified the absence of any additional, totally radioresistant cell fraction. (author)

  6. Reconstructing Normality

    DEFF Research Database (Denmark)

    Gildberg, Frederik Alkier; Bradley, Stephen K.; Fristed, Peter Billeskov

    2012-01-01

    Forensic psychiatry is an area of priority for the Danish Government. As the field expands, this calls for increased knowledge about mental health nursing practice, as this is part of the forensic psychiatry treatment offered. However, only sparse research exists in this area. The aim of this study...... was to investigate the characteristics of forensic mental health nursing staff interaction with forensic mental health inpatients and to explore how staff give meaning to these interactions. The project included 32 forensic mental health staff members, with over 307 hours of participant observations, 48 informal....... The intention is to establish a trusting relationship to form behaviour and perceptual-corrective care, which is characterized by staff's endeavours to change, halt, or support the patient's behaviour or perception in relation to staff's perception of normality. The intention is to support and teach the patient...

  7. Pursuing Normality

    DEFF Research Database (Denmark)

    Madsen, Louise Sofia; Handberg, Charlotte

    2018-01-01

    implying an influence on whether to participate in cancer survivorship care programs. Because of "pursuing normality," 8 of 9 participants opted out of cancer survivorship care programming due to prospects of "being cured" and perceptions of cancer survivorship care as "a continuation of the disease......BACKGROUND: The present study explored the reflections on cancer survivorship care of lymphoma survivors in active treatment. Lymphoma survivors have survivorship care needs, yet their participation in cancer survivorship care programs is still reported as low. OBJECTIVE: The aim of this study...... was to understand the reflections on cancer survivorship care of lymphoma survivors to aid the future planning of cancer survivorship care and overcome barriers to participation. METHODS: Data were generated in a hematological ward during 4 months of ethnographic fieldwork, including participant observation and 46...

  8. Sentinel and other mutational effects in offspring of cancer survivors

    International Nuclear Information System (INIS)

    Mulvihill, J.J.

    1990-01-01

    To date, no agent has been documented to cause germ cell mutation in human beings, with the possible exception of radiation causing abnormal meiotic chromosomes in testes. For studies in humans, mutation epidemiologists prefer the cohort approach, starting with an exposed population and looking for mutations that may be expressed in offspring as variants in health, chromosomes, proteins, or nucleic acids. Currently patients with cancer are the cohort exposed to the largest doses of potential mutagens, i.e., radiotherapy and drugs. In 12 large studies with over 825 patients and 1573 pregnancies, 46 (4%) of 1240 liveborns had a major birth defect, a rate comparable to that in the general population. One of these was a classic sentinel phenotype, i.e., a new sporadic case of a dominant mendelian syndrome. In collaboration with 5 U.S. cancer registries, we interviewed a retrospective cohort of 2383 patients diagnosed with cancer under age 20 years, from 1945 through 1975. Records were sought to verify major genetic disease, defined as a cytogenetic or single gene disorder or 1 of 15 isolated birth defects. In 2308 offspring of survivors, 5 had a chromosomal syndrome, 11 had a single gene disorder, and 62 had at least one major malformation. Among 4722 offspring of sibling controls, the respective numbers were 7, 12, and 127, nonsignificant differences. 7% of the parents of the offspring with possibly new mutations received potentially mutagenic therapy, compared with 12% of parents of normal children. Since pregnancy in or by cancer survivors is still a rare event, future efforts to document germ cell mutation may be best studied through international cooperation coupled with diverse laboratory measures of mutation

  9. Rare beneficial mutations can halt Muller's ratchet

    Science.gov (United States)

    Balick, Daniel; Goyal, Sidhartha; Jerison, Elizabeth; Neher, Richard; Shraiman, Boris; Desai, Michael

    2012-02-01

    In viral, bacterial, and other asexual populations, the vast majority of non-neutral mutations are deleterious. This motivates the application of models without beneficial mutations. Here we show that the presence of surprisingly few compensatory mutations halts fitness decay in these models. Production of deleterious mutations is balanced by purifying selection, stabilizing the fitness distribution. However, stochastic vanishing of fitness classes can lead to slow fitness decay (i.e. Muller's ratchet). For weakly deleterious mutations, production overwhelms purification, rapidly decreasing population fitness. We show that when beneficial mutations are introduced, a stable steady state emerges in the form of a dynamic mutation-selection balance. We argue this state is generic for all mutation rates and population sizes, and is reached as an end state as genomes become saturated by either beneficial or deleterious mutations. Assuming all mutations have the same magnitude selective effect, we calculate the fraction of beneficial mutations necessary to maintain the dynamic balance. This may explain the unexpected maintenance of asexual genomes, as in mitochondria, in the presence of selection. This will affect in the statistics of genetic diversity in these populations.

  10. [Observation and analysis on mutation of routine STR locus].

    Science.gov (United States)

    Li, Qiu-yang; Feng, Wei-jun; Yang, Qin-gen

    2005-05-01

    To observe and analyze the characteristic of mutation at STR locus. 27 mutant genes observed in 1211 paternity testing cases were checked by PAGE-silver stained and PowerPlex 16 System Kit and validated by sequencing. Mutant genes locate on 15 loci. The pattern of mutation was accord with stepwise mutation model. The mutation ratio of male-to-female was 8:1 and correlated to the age of father. Mutation rate is correlated to the geometric mean of the number of homogeneous repeats of locus. The higher the mean, the higher the mutation rate. These loci are not so appropriate for use in paternity testing.

  11. SQSTM1 Mutations and Glaucoma.

    Directory of Open Access Journals (Sweden)

    Todd E Scheetz

    Full Text Available Glaucoma is the most common cause of irreversible blindness worldwide. One subset of glaucoma, normal tension glaucoma (NTG occurs in the absence of high intraocular pressure. Mutations in two genes, optineurin (OPTN and TANK binding kinase 1 (TBK1, cause familial NTG and have known roles in the catabolic cellular process autophagy. TKB1 encodes a kinase that phosphorylates OPTN, an autophagy receptor, which ultimately activates autophagy. The sequestosome (SQSTM1 gene also encodes an autophagy receptor and also is a target of TBK1 phosphorylation. Consequently, we hypothesized that mutations in SQSTM1 may also cause NTG. We tested this hypothesis by searching for glaucoma-causing mutations in a cohort of NTG patients (n = 308 and matched controls (n = 157 using Sanger sequencing. An additional 1098 population control samples were also analyzed using whole exome sequencing. A total of 17 non-synonymous mutations were detected which were not significantly skewed between cases and controls when analyzed separately, or as a group (p > 0.05. These data suggest that SQSTM1 mutations are not a common cause of NTG.

  12. Fate of induced mutations in higher plants with special emphasis on sexually reproducing species

    International Nuclear Information System (INIS)

    Cornu, Andre

    1978-01-01

    A mutation induced in a plant somatic cell has to overcome quite many difficulties before being isolated and utilized as a marker in a mutated line. If induced in a meristem, three conditions must be fulfilled for the mutation to be transmitted to the subsequent generation: it must be compatible with normal cell multiplication, it must be located in a cell mass that will provide an inflorescence, and it must be in the sporogenetic layer (t2). Under these conditions, or if it is induced in a gamete or in a zygote, the mutation enters a first cycle of sexual reproduction. Meiosis and the subsequent haploid phase constitute severe screening steps for many chromosome aberrations. Studies on Petunia performed by means of marker genes show that male and female gametic viabilities are drastically impaired by deletions. However, a deficient chromosome can be transmitted when the losss of information is compensated for by homologous information as, for example, diploid gametes from tetraploids or disomic gametes resulting from non-disjunction. If partial or complete sterility, whether sporo- or gametophytic, is avoided, then the mutation can be transmitted to the next generation in heterozygous state. When becoming homozygous, the mutation may have effects such that its use can be most difficult. This is the case when this mutation causes rather early lethality or severe sterility. Thus, in higher plants, one faces several cases of powerful and efficient selection against mutations. On the basis of experiments carried out on Petunia, the per locus mutation rate of practical interest ranges between I and 5/10000M 1 plants. Practical conclusions are drawn about which organ should be treated, which mutagen at what dose should be used according to the scope of the research undertaken [fr

  13. Phosphomimetic mutation of cysteine string protein-α increases the rate of regulated exocytosis by modulating fusion pore dynamics in PC12 cells.

    Directory of Open Access Journals (Sweden)

    Ning Chiang

    Full Text Available BACKGROUND: Cysteine string protein-α (CSPα is a chaperone to ensure protein folding. Loss of CSPα function associates with many neurological diseases. However, its function in modulating regulated exocytosis remains elusive. Although cspα-knockouts exhibit impaired synaptic transmission, overexpression of CSPα in neuroendocrine cells inhibits secretion. These seemingly conflicting results lead to a hypothesis that CSPα may undergo a modification that switches its function in regulating neurotransmitter and hormone secretion. Previous studies implied that CSPα undergoes phosphorylation at Ser10 that may influence exocytosis by altering fusion pore dynamics. However, direct evidence is missing up to date. METHODOLOGY/PRINCIPAL FINDINGS: Using amperometry, we investigated how phosphorylation at Ser10 of CSPα (CSPα-Ser10 modulates regulated exocytosis and if this modulation involves regulating a specific kinetic step of fusion pore dynamics. The real-time exocytosis of single vesicles was detected in PC12 cells overexpressing control vector, wild-type CSPα (WT, the CSPα phosphodeficient mutant (S10A, or the CSPα phosphomimetic mutants (S10D and S10E. The shapes of amperometric signals were used to distinguish the full-fusion events (i.e., prespike feet followed by spikes and the kiss-and-run events (i.e., square-shaped flickers. We found that the secretion rate was significantly increased in cells overexpressing S10D or S10E compared to WT or S10A. Further analysis showed that overexpression of S10D or S10E prolonged fusion pore lifetime compared to WT or S10A. The fraction of kiss-and-run events was significantly lower but the frequency of full-fusion events was higher in cells overexpressing S10D or S10E compared to WT or S10A. Advanced kinetic analysis suggests that overexpression of S10D or S10E may stabilize open fusion pores mainly by inhibiting them from closing. CONCLUSIONS/SIGNIFICANCE: CSPα may modulate fusion pore dynamics

  14. A molecular biological study on the identification of the molecular species of DNA polymerases for repairing radiation-damaged DNA and the factors modifying the mutation rate

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Koichi; Inoue, Shuji [National Inst. of Health and Nutrition, Tokyo (Japan)

    1997-02-01

    Aiming at prevention and treatment of radiation damages, the authors have been investigating DNA damages by X-ray and its repairing mechanism, however, the molecular species of DNA polymerase which mediate the repairing could not been identified by biochemical methods using various inhibitors because of their low specificity. Therefore, in this study, anti-sense oligonucleotides for DNA polymerase {alpha}, {delta} and {epsilon} were obtained by chemical synthesis and transduced into human fibroblast cell, NB1RGB by three methods; endocytotic method, electroporation method and lipofection method. For the first method, the addition of those peptides into the cell culture at 5 {mu}M inhibited the polymerase activity by up to 30% and it was economically difficult to use at higher concentrations than it. For the electroporation method, different conditions were tested in the respects of initial potential, time constant and buffer, but the uptake of thimidine was scarcely decreased in the surviving cells, suggesting that the surviving rate would be short in the cells electroporated with those anti-sense peptides. For the lipofection method, among several cationic lipids tested, lipofectamine significantly enlarged the decrease of thymidine uptake by anti-sense {delta}, however it was considered that its application to DNA repairing is difficult because lipofectamine is strongly cytotoxic. Therefore, construction of a vector which allows to express anti-sense RNA in those cells is undertaken. (M.N.)

  15. A molecular biological study on the identification of the molecular species of DNA polymerases for repairing radiation-damaged DNA and the factors modifying the mutation rate

    International Nuclear Information System (INIS)

    Yamada, Koichi; Inoue, Shuji

    1997-01-01

    Aiming at prevention and treatment of radiation damages, the authors have been investigating DNA damages by X-ray and its repairing mechanism, however, the molecular species of DNA polymerase which mediate the repairing could not been identified by biochemical methods using various inhibitors because of their low specificity. Therefore, in this study, anti-sense oligonucleotides for DNA polymerase α, δ and ε were obtained by chemical synthesis and transduced into human fibroblast cell, NB1RGB by three methods; endocytotic method, electroporation method and lipofection method. For the first method, the addition of those peptides into the cell culture at 5 μM inhibited the polymerase activity by up to 30% and it was economically difficult to use at higher concentrations than it. For the electroporation method, different conditions were tested in the respects of initial potential, time constant and buffer, but the uptake of thimidine was scarcely decreased in the surviving cells, suggesting that the surviving rate would be short in the cells electroporated with those anti-sense peptides. For the lipofection method, among several cationic lipids tested, lipofectamine significantly enlarged the decrease of thymidine uptake by anti-sense δ, however it was considered that its application to DNA repairing is difficult because lipofectamine is strongly cytotoxic. Therefore, construction of a vector which allows to express anti-sense RNA in those cells is undertaken. (M.N.)

  16. Impact of the reg1 mutation glycocen accumulation and glucose consumption rates in Saccharomyces cerevisiae cells based on a macrokinetic model

    Directory of Open Access Journals (Sweden)

    Rocha-Leão M.H.M.

    2003-01-01

    Full Text Available In S. cerevisiae, catabolite repression controls glycogen accumulation and glucose consumption. Glycogen is responsible for stress resistance, and its accumulation in derepression conditions results in a yeast with good quality. In yeast cells, catabolite repression also named glucose effect takes place at the transcriptional levels, decreasing enzyme respiration and causing the cells to enter a fermentative metabolism, low cell mass yield and yeast with poor quality. Since glucose is always present in molasses the glucose effect occurs in industrial media. A quantitative characterization of cell growth, substrate consumption and glycogen formation was undertaken based on an unstructured macrokinetic model for a reg1/hex2 mutant, capable of the respiration while growing on glucose, and its isogenic repressible strain (REG1/HEX2. The results show that the estimated value to maximum specific glycogen accumulation rate (muG,MAX is eight times greater in the reg1/hex2 mutant than its isogenic strain, and the glucose affinity constant (K SS is fifth times greater in reg1/hex2 mutant than in its isogenic strain with less glucose uptake by the former channeling glucose into cell mass growth and glycogen accumulation simultaneously. This approach may be one more tool to improve the glucose removal in yeast production. Thus, disruption of the REG1/HEX2 gene may constitute an important strategy for producing commercial yeast.

  17. Assessment of Adaptive Rate Response Provided by Accelerometer, Minute Ventilation and Dual Sensor Compared with Normal Sinus Rhythm During Exercise: A Self-controlled Study in Chronotropically Competent Subjects

    Directory of Open Access Journals (Sweden)

    Yuanyuan Cao

    2015-01-01

    Full Text Available Background: Dual sensor (DS for rate adaption was supposed to be more physiological. To evaluate its superiority, the DS (accelerometer [ACC] and minute ventilation [MV] and normal sinus rate response were compared in a self-controlled way during exercise treadmill testing. Methods: This self-controlled study was performed in atrioventricular block patients with normal sinus function who met the indications of pacemaker implant. Twenty-one patients came to the 1-month follow-up visit. Patients performed a treadmill test 1-month post implant while programmed in DDDR and sensor passive mode. For these patients, sensor response factors were left at default settings (ACC = 8, MV = 3 and sensor indicated rates (SIRs for DS, ACC and MV sensor were retrieved from the pacemaker memories, along with measured sinus node (SN rates from the beginning to 1-minute after the end of the treadmill test, and compared among study groups. Repeated measures analysis of variance and profile analysis, as well as variance analysis of randomized block designs, were used for statistical analysis. Results: Fifteen patients (15/21 were determined to be chronotropically competent. The mean differences between DS SIRs and intrinsic sinus rates during treadmill testing were smaller than those for ACC and MV sensor (mean difference between SIR and SN rate: ACC vs. SN, MV vs. SN, DS vs. SN, respectively, 34.84, 17.60, 16.15 beats/min, though no sensors could mimic sinus rates under the default settings for sensor response factor (ACC vs. SN P-adjusted < 0.001; MV vs. SN P-adjusted = 0.002; DS vs. SN P-adjusted = 0.005. However, both in the range of 1 st minute and first 3 minutes of exercise, only the DS SIR profile did not differ from sinus rates (P-adjusted = 0.09, 0.90, respectively. Conclusions: The DS under default settings provides more physiological rate response during physical activity than the corresponding single sensors (ACC or MV sensor. Further study is needed to

  18. Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

    Science.gov (United States)

    Franken, Romy; den Hartog, Alexander W; Radonic, Teodora; Micha, Dimitra; Maugeri, Alessandra; van Dijk, Fleur S; Meijers-Heijboer, Hanne E; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Groenink, Maarten; Mulder, Barbara J M; Zwinderman, Aeilko H; de Waard, Vivian; Pals, Gerard

    2015-04-01

    It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups. In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive losartan 100 mg or no losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal fibrillin-1, or (2) dominant negative, normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan, 1.3±1.5 mm/3 years, n=59 versus losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However, losartan reduced only aortic root dilatation rate in haploinsufficient patients (no losartan, 1.8±1.5 mm/3 years, n=21 versus losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no losartan, 1.2±1.7 mm/3 years, n=38 versus losartan 0.8±1.3 mm/3 years, n=41; P=0.197). Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations. http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423. © 2015 American Heart Association, Inc.

  19. Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I.

    Science.gov (United States)

    Chen, Kaitian; Zhan, Yuan; Wu, Xuan; Zong, Ling; Jiang, Hongyan

    2018-01-01

    Waardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. Complete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. The two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. These previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Clinical significance of the BRAFV600E mutation in Asian patients with colorectal cancer.

    Science.gov (United States)

    Cheng, Hou-Hsuan; Lin, Jen-Kou; Chen, Wei-Shone; Jiang, Jeng-Kai; Yang, Shung-Haur; Chang, Shih-Ching

    2018-06-04

    To investigate the clinicopathological features and prognostic significance of the BRAFV600E mutation in Asian patients with colorectal cancer. We retrospectively reviewed the medical records of 1969 patients with colorectal cancer admitted to Taipei Veterans General Hospital for surgical treatment between 2000 and 2013. The measured endpoint was overall survival after surgery. The prognostic value of the BRAFV600E mutation was analyzed using the log-rank test and Cox regression analysis. The BRAFV600E mutation was detected in 106 (5.4%) patients and associated with female gender, abnormal cancer antigen (CA)19-9 at diagnosis, microsatellite status, right-sided primary tumors, mucinous histology, poor differentiation, and lymphovascular invasion. Metastatic patterns were more common in non-regional lymph node metastasis (20.8 vs. 7.4%, p = 0.06) and peritoneal seeding (41. vs. 21.2%, p = 0.04). Mutations were not prognostic in the overall survival of the entire study group but only in specific patients: age < 65, normal carcinoembryonic antigen at diagnosis, and stage IV disease. The BRAFV600E mutation was associated with distinct clinicopathological features and metastatic patterns. The overall survival rate was lower in selected colorectal patients with the BRAFV600E mutation.

  1. Factor V Leiden mutation in pregnancy.

    Science.gov (United States)

    Cohen, Susan Murphy

    2004-01-01

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

  2. Repair-resistant mutation in Neurospora

    International Nuclear Information System (INIS)

    Stadler, D.; Macleod, H.; Loo, M.

    1987-01-01

    Chronic UV treatment produces severalfold fewer mutations in Neurospora conidia than does the same total dose of acute UV. Experiments were designed to determine the conditions required for chronic UV mutagenesis. Measurement of the coincidence frequency for two independent mutations revealed the existence of a subset of cells which are mutable by chronic UV. Analysis of forward mutation at the mtr locus showed that the genetic alterations produced by chronic UV were virtually all point mutants, even though the assay system could detect alterations or deletions extending into neighboring genes. A significant fraction of the mutants produced by acute UV were multigenic deletions. The size of the dose-rate effect (acute UV mutation frequency divided by chronic UV mutation frequency) was compared for several different mutation assay systems. Forward mutations (recessive lethals and mtr) gave values ranging from four to nine. For events which were restricted to specific molecular sites (specific reversions and nonsense suppressor mutations), there was a wider range of dose-rate ratios. This suggests that chronic UV mutation may be restricted to certain molecular sequences or configurations

  3. Role of specific DNA mutations in the peripheral blood of colorectal cancer patients for the assessment of tumor stage and residual disease following tumor resection

    Science.gov (United States)

    Norcic, Gregor; Jelenc, Franc; Cerkovnik, Petra; Stegel, Vida; Novakovic, Srdjan

    2016-01-01

    In the present study, the detection of tumor-specific KRAS proto-oncogene, GTPase (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations in the peripheral blood of colorectal cancer (CRC) patients at all stages and adenomas was used for the estimation of disease stage prior to surgery and for residual disease following surgery. A total of 65 CRC patients were enrolled. The primary tumor tested positive for the specific mutations (KRAS mutations in codons 12, 13, 61, 117 or 146 and BRAF mutations in codon 600) in 35 patients. In all these patients, the specimen of normal bowel resected with the tumor was also tested for the presence of the same mutations in order to exclude the germ-line mutations. Only patients who tested positive for the specific mutation in the primary tumor were included in further analysis for the presence of tumor-specific mutation in the peripheral blood. No statistically significant differences were found between the detection rates of tumor mutations in the blood and different tumor stages (P=0.491). However, statistically significant differences in the proportions of patients with detected tumor-specific DNA mutations in the peripheral blood were found when comparing the groups of patients with R0 and R2 resections (P=0.038). Tumor-specific DNA mutations in the peripheral blood were more frequently detected in the patients with an incomplete surgical clearance of the tumor due to macroscopic residual disease (R2 resections). Therefore, the study concludes that the follow-up of somatic KRAS- and BRAF-mutated DNA in the peripheral blood of CRC patients may be useful in assessing the surgical clearance of the disease. PMID:27900004

  4. Molecular methods for the detection of mutations.

    Science.gov (United States)

    Monteiro, C; Marcelino, L A; Conde, A R; Saraiva, C; Giphart-Gassler, M; De Nooij-van Dalen, A G; Van Buuren-van Seggelen, V; Van der Keur, M; May, C A; Cole, J; Lehmann, A R; Steinsgrimsdottir, H; Beare, D; Capulas, E; Armour, J A

    2000-01-01

    We report the results of a collaborative study aimed at developing reliable, direct assays for mutation in human cells. The project used common lymphoblastoid cell lines, both with and without mutagen treatment, as a shared resource to validate the development of new molecular methods for the detection of low-level mutations in the presence of a large excess of normal alleles. As the "gold standard, " hprt mutation frequencies were also measured on the same samples. The methods under development included i) the restriction site mutation (RSM) assay, in which mutations lead to the destruction of a restriction site; ii) minisatellite length-change mutation, in which mutations lead to alleles containing new numbers of tandem repeat units; iii) loss of heterozygosity for HLA epitopes, in which antibodies can be used to direct selection for mutant cells; iv) multiple fluorescence-based long linker arm nucleotides assay (mf-LLA) technology, for the detection of substitutional mutations; v) detection of alterations in the TP53 locus using a (CA) array as the target for the screening; and vi) PCR analysis of lymphocytes for the presence of the BCL2 t(14:18) translocation. The relative merits of these molecular methods are discussed, and a comparison made with more "traditional" methods.

  5. TFAP2B mutation and dental anomalies.

    Science.gov (United States)

    Tanasubsinn, Natchaya; Sittiwangkul, Rekwan; Pongprot, Yupada; Kawasaki, Katsushige; Ohazama, Atsushi; Sastraruji, Thanapat; Kaewgahya, Massupa; Kantaputra, Piranit Nik

    2017-08-01

    Mutations inTFAP2B has been reported in patients with isolated patent ductus arteriosus (PDA) and Char syndrome. We performed mutation analysis of TFAP2B in 43 patients with isolated PDA, 7 patients with PDA with other congenital heart defects and 286 patients with isolated tooth agenesis with or without other dental anomalies. The heterozygous c.1006G>A mutation was identified in 20 individuals. Those mutation carriers consisted of 1 patient with term PDA (1/43), 16 patients with isolated tooth agenesis with or without other dental anomalies (16/286; 5.6%), 1 patient with PDA and severe valvular aortic stenosis and tooth agenesis (1/4) and 2 normal controls (2/100; 1%). The mutation is predicted to cause an amino-acid substitution p.Val336Ile in the TFAP2B protein. Tfap2b expression during early mouse tooth development supports the association of TFAP2B mutation and dental anomalies. It is hypothesized that this incidence might have been the result of founder effect. Here we report for the first time that TFAP2B mutation is associated with tooth agenesis, microdontia, supernumerary tooth and root maldevelopment. In addition, we also found that TFAP2B mutations, the common causes of PDA in Caucasian, are not the common cause of PDA in Thai population.

  6. 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.

  7. A combination of high dose rate (10X FFF/2400 MU/min/10 MV X-rays) and total low dose (0.5 Gy) induces a higher rate of apoptosis in melanoma cells in vitro and superior preservation of normal melanocytes.

    Science.gov (United States)

    Sarojini, Sreeja; Pecora, Andrew; Milinovikj, Natasha; Barbiere, Joseph; Gupta, Saakshi; Hussain, Zeenathual M; Tuna, Mehmet; Jiang, Jennifer; Adrianzen, Laura; Jun, Jaewook; Catello, Laurice; Sanchez, Diana; Agarwal, Neha; Jeong, Stephanie; Jin, Youngjin; Remache, Yvonne; Goy, Andre; Ndlovu, Alois; Ingenito, Anthony; Suh, K Stephen

    2015-10-01

    The aim of this study was to determine the apoptotic effects, toxicity, and radiosensitization of total low dose irradiation delivered at a high dose rate in vitro to melanoma cells, normal human epidermal melanocytes (HEM), or normal human dermal fibroblasts (HDF) and to study the effect of mitochondrial inhibition in combination with radiation to enhance apoptosis in melanoma cells. Cells irradiated using 10X flattening filter-free (FFF) 10 MV X-rays at a dose rate of 400 or 2400 MU/min and a total dose of 0.25-8 Gy were analyzed by cell/colony counting, MitoTracker, MTT, and DNA-damage assays, as well as by quantitative real-time reverse transcriptase PCR in the presence or absence of mitochondrial respiration inhibitors. A dose rate of 2400 MU/min killed on average five-fold more melanoma cells than a dose rate 400 MU/min at a total dose of 0.5 Gy and preserved 80% survival of HEM and 90% survival of HDF. Increased apoptosis at the 2400 MU/min dose rate is mediated by greater DNA damage, reduced cell proliferation, upregulation of apoptotic genes, and downregulation of cell cycle genes. HEM and HDF were relatively unharmed at 2400 MU/min. Radiation induced upregulation of mitochondrial respiration in both normal and cancer cells, and blocking the respiration with inhibitors enhanced apoptosis only in melanoma cells. A high dose rate with a low total dose (2400 MU/min, 0.5 Gy/10X FFF 10 MV X-rays) enhances radiosensitivity of melanoma cells while reducing radiotoxicity toward HEM and HDF. Selective cytotoxicity of melanoma cells is increased by blocking mitochondrial respiration.

  8. Difference in the craniocaudal gradient of the maximum pixel value change rate between chronic obstructive pulmonary disease patients and normal subjects using sub-mGy dynamic chest radiography with a flat panel detector system.

    Science.gov (United States)

    Yamada, Yoshitake; Ueyama, Masako; Abe, Takehiko; Araki, Tetsuro; Abe, Takayuki; Nishino, Mizuki; Jinzaki, Masahiro; Hatabu, Hiroto; Kudoh, Shoji

    2017-07-01

    To compare the craniocaudal gradients of the maximum pixel value change rate (MPCR) during tidal breathing between chronic obstructive pulmonary disease (COPD) patients and normal subjects using dynamic chest radiography. This prospective study was approved by the institutional review board and all participants provided written informed consent. Forty-three COPD patients (mean age, 71.6±8.7 years) and 47 normal subjects (non-smoker healthy volunteers) (mean age, 54.8±9.8 years) underwent sequential chest radiographs during tidal breathing in a standing position using dynamic chest radiography with a flat panel detector system. We evaluated the craniocaudal gradient of MPCR. The results were analyzed using an unpaired t-test and the Tukey-Kramer method. The craniocaudal gradients of MPCR in COPD patients were significantly lower than those in normal subjects (right inspiratory phase, 75.5±48.1 vs. 108.9±42.0s -1 cm -1 , P<0.001; right expiratory phase, 66.4±40.6 vs. 89.8±31.6s -1 cm -1 , P=0.003; left inspiratory phase, 75.5±48.2 vs. 108.2±47.2s -1 cm -1 , P=0.002; left expiratory phase, 60.9±38.2 vs. 84.3±29.5s -1 cm -1 , P=0.002). No significant differences in height, weight, or BMI were observed between COPD and normal groups. In the sub-analysis, the gradients in severe COPD patients (global initiative for chronic obstructive lung disease [GOLD] 3 or 4, n=26) were significantly lower than those in mild COPD patients (GOLD 1 or 2, n=17) for both right and left inspiratory/expiratory phases (all P≤0.005). A decrease of the craniocaudal gradient of MPCR was observed in COPD patients. The craniocaudal gradient was lower in severe COPD patients than in mild COPD patients. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  9. Variability induced by spaceflight environment on high oil and normal maize lines

    International Nuclear Information System (INIS)

    Xu Xiaowei; Xu Li; Dong Xin; Jin Weiwei; Chen Shaojiang

    2011-01-01

    High oil inbred line BY815 and two normal inbred lines 1145 and F349 treated with spaceflight were used for variability analysis. Results showed that the mutation rate of BY815 was 21.61% in SP 1 , while the mutation rates of 1145 and F349 were 2.57% and 3.13% respectively. Only six mutants were found from these three materials in SP 2 , of which two mutants, HT-3 from BY815 exhibiting albino leaf color and HT-5 from 1145 exhibiting stripe-like spots leaves, were worthy of further study. Genetic analysis of the two mutants showed that the segregation ratio of normal and mutant phenotypes was 3 : 1, which was in accordance with Mendel's single gene inheritance law. Cytological observation of all the six mutants showed no chromosome abnormalities. By using SSR (simple sequence repeat) method, 130 pairs of primers were employed and only one mutant originated from inbred line 1145 showed polymorphic and the mutated loci rate of the genome in this mutant was 8.46%. (authors)

  10. The Normal Fetal Pancreas.

    Science.gov (United States)

    Kivilevitch, Zvi; Achiron, Reuven; Perlman, Sharon; Gilboa, Yinon

    2017-10-01

    The aim of the study was to assess the sonographic feasibility of measuring the fetal pancreas and its normal development throughout pregnancy. We conducted a cross-sectional prospective study between 19 and 36 weeks' gestation. The study included singleton pregnancies with normal pregnancy follow-up. The pancreas circumference was measured. The first 90 cases were tested to assess feasibility. Two hundred ninety-seven fetuses of nondiabetic mothers were recruited during a 3-year period. The overall satisfactory visualization rate was 61.6%. The intraobserver and interobserver variability had high interclass correlation coefficients of of 0.964 and 0.967, respectively. A cubic polynomial regression described best the correlation of pancreas circumference with gestational age (r = 0.744; P pancreas circumference percentiles for each week of gestation were calculated. During the study period, we detected 2 cases with overgrowth syndrome and 1 case with an annular pancreas. In this study, we assessed the feasibility of sonography for measuring the fetal pancreas and established a normal reference range for the fetal pancreas circumference throughout pregnancy. This database can be helpful when investigating fetomaternal disorders that can involve its normal development. © 2017 by the American Institute of Ultrasound in Medicine.

  11. Sequential acquisition of mutations in myelodysplastic syndromes.

    Science.gov (United States)

    Makishima, Hideki

    2017-01-01

    Recent progress in next-generation sequencing technologies allows us to discover frequent mutations throughout the coding regions of myelodysplastic syndromes (MDS), potentially providing us with virtually a complete spectrum of driver mutations in this disease. As shown by many study groups these days, such driver mutations are acquired in a gene-specific fashion. For instance, DDX41 mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A and TET2 mutations are detected as age-related clonal hematopoiesis and are believed to be a risk factor for hematological neoplasms. In MDS, mutations of genes such as NRAS and FLT3, designated as Type-1 genes, may be significantly associated with leukemic evolution. Another type (Type-2) of genes, including RUNX1 and GATA2, are related to progression from low-risk to high-risk MDS. Overall, various driver mutations are sequentially acquired in MDS, at a specific time, in either germline cells, normal hematopoietic cells, or clonal MDS cells.

  12. The Oenothera plastome mutator: effect of UV irradiation and nitroso-methyl urea on mutation frequencies

    International Nuclear Information System (INIS)

    Sears, B.B.; Sokalski, M.B.

    1991-01-01

    Oenothera plants homozygous for a recessive plastome mutator allele (pm) showed spontaneous mutation frequencies for plastome genes that are 200-fold higher than spontaneous levels. Mutations occurred at high frequencies in plants grown in the field, in a glasshouse, or as leaf tip cultures under fluorescent light, indicating that the plastome mutator activity is UV-independent. However, the chlorotic sectors became visible at an earlier stage of development when seedlings were irradiated, compared to seedlings that were not exposed to UV. These results imply that the rate of sorting-out was increased by the irradiation treatment, possibly due to a decrease in the effective number of multiplication-competent plastids, or a reduction in the extent of cytoplasmic mixing. Nitroso-methyl urea treatment of seeds had a dramatic effect on mutation frequency in both wild-type and plastome mutator samples. When the background mutation rates were low, the combination of the plastome mutator nucleus and the chemical mutagenesis treatment resulted in a synergistic effect, suggesting that the plastome mutator may involve a cpDNA repair pathway. (author)

  13. Deletion mutations of bacteriophage

    International Nuclear Information System (INIS)

    Ryo, Yeikou

    1975-01-01

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

  14. Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'

    DEFF Research Database (Denmark)

    Svenstrup, Kirsten; Giraud, Geneviève; Boespflug-Tanguy, Odile

    2010-01-01

    with the 'rumpshaker mutation.' PATIENTS: A family with HSP caused by the 'rumpshaker mutation.' RESULTS: The patients showed nystagmus during infancy and had early onset of HSP. They had normal cognition, and cerebral MRI showed relatively unspecific white matter abnormalities on T2 sequences without clear...

  15. Novel Mitochondrial Homoplasmic T4216C Mutation in Iranian Patients with Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    M Heidari

    2010-06-01

    Full Text Available Introduction: The mitochondrial defects in Friedreich ataxia (FRDA have been reported in many researches. Friedreich ataxia is an autosomal recessive neurodegenerative disorder caused by decreased expression of the Frataxin protein. Frataxin deficiency leads to excessive free radical production and dysfunction of respiratory chain complexes. Mitochondrial DNA (mtDNA could be considered as a candidate modifier factor for FRDA disease. It prompted us to focus on the mtDNA and monitor the nucleotide changes of genome which are probably the cause of respiratory chain defects and reduced ATP generation. Methods: We searched the mitochondrial NADH dehydroganase I (ND1 gene by PCR-TTGE and DNA fragments showing abnormal banding patterns were sequenced for the identification of exact mutations. Results: In 20 patients, we detected 3 mtDNA mutations which is novel in Friedreich ataxia. T4216C mutation results in conversion of Tyrosine to Histidine in 313 amino acid locations in ND1 and bioinformatics studies show that ND1 protein loses sixth intramembrane α chain. Conclusion: Our results showed that ND1 gene mutations in FRDA samples are higher than normal controls (P<0.001. It is possible that mutations in mtDNA could constitute a predisposing factor in combination with environmental risk factors that could affect the age of onset and rate of disease progression.

  16. Search for gene mutations affecting protein structure in children of A-bomb survivors, 2

    International Nuclear Information System (INIS)

    Satoh, Chiyoko; Fujita, Mikio; Goriki, Kazuaki; Asakawa, Jun-ichi; Takahashi, Norio; Hamilton, H.B.; Hazama, Ryuji; Neel, J.V.

    1984-01-01

    Children who were born between May 1, 1946 and April 1, 1971 to survivor(s) exposed to A-bombing within 2,000 m from the hypocenter in Hiroshima and Nagasaki were selected as exposed group; their sex- and age-matched children born to survivor(s) who were exposed at 2,500 m or farther were selected as control group. When these children were in junior high school, mutation of protein structure was examined by using electrophoresis and by determining red cell enzymes with decreased activity and heat-unstable red cell enzymes. Electrophoretic study revealed a ''rare type of protein mutation'' in 635 of 12,242 individuals in the exposed group and in 448 of 10,154 individuals in the control group. The number of locuses in all proteins examined was calculated. The number of locuses per protein was corrected using the rate of parents' mutation type, and relative number of locuses were obtained. As a result, there was no difference in the mutation frequency per locus and generation between the exposed and control groups. Among children having red cell enzymes with decreased activity, mutant in triose phosphate isomerase was detected in one child in the exposed group, in whom electrophoretic pattern was normal and red cell enzymes were stable to heat. Heat-unstable red cell enzymes were seen in 9 children and their parents. However, family survey revealed genetic mutation in all instances irrespective of A-bombing. (Namekawa, K.)

  17. RET gene mutations and polymorphisms in medullary thyroid ...

    Indian Academy of Sciences (India)

    51 clinically diagnosed MTC patients, 39 family members of patients and 50 normal individuals. The method of .... Documentation system (Amersham Pharmacia Biotech,. Uppsala ... direct nucleotide sequencing to identify the mutations, using.

  18. Normal Pressure Hydrocephalus (NPH)

    Science.gov (United States)

    ... local chapter Join our online community Normal Pressure Hydrocephalus (NPH) Normal pressure hydrocephalus is a brain disorder ... Symptoms Diagnosis Causes & risks Treatments About Normal Pressure Hydrocephalus Normal pressure hydrocephalus occurs when excess cerebrospinal fluid ...

  19. Genomic mutation study for long-term cells induced by carbon ions

    International Nuclear Information System (INIS)

    Wang, X.; Furusawa, Y.; Suzuki, M.; Hirayama, R.; Matsumoto, Y.; Qin, Y.

    2007-01-01

    Complete text of publication follows. Objective: Densely ionizing (high LET) radiation can increase the relative biological effectiveness of cell and tissue. Astronauts in the space exploration have the potential exposure of chronic low-dose radiations in the field of low-flux galactic cosmic rays (GCR) and the subsequent biological effects have become one of the major concerns of space science. Furthermore, Heavy ions also are used new radiation therapy owing increased lethal effectiveness of high LET radiation. During radiation therapy, normal tissues also are exposed to ionizing radiation. Radiation can induce genomic mutation and instability in descendants of irradiated cells. Induction of genomic instability can represent one of the initiating steps leading to malignant transformation. Higher frequencies of mutation can be expected to provide higher rates of carcinogenicity with human exposure. Therefore, the study of radiation induced genomic mutation and instability is relevant to the estimates of the risk of secondary malignancies associated with radiation therapy and the carcinogenic effects of space environmental radiation. The hypoxanthine-guanine phosphoribosyltransferase (hprt) locus has been the most commonly used as a target gene for mutation detection studies. In this study, we investigated the generation expression dependence of mutation induction on HPRT locus in CHO cells irradiated with carbon ions. Methods: Chinese hamster ovary (CHO) cells were irradiated with graded doses of carbon ions (290MeV/u, LET:13kev/um) accelerated with Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences(NIRS). The survival effect of cells plated immediately after irradiation was measured with cell colony formation assay. After irradiation, cells were continues reseeding and cultures for lone-term proliferation. Cell samples were collected at 6, 12, 18, 24, 30, 37 and 44 days post irradiation. Mutation induction of cell

  20. Comparison of the image quality of digital radiography system and film screen system - Radiologist' rating of the visibility of normal anatomic - Structures in chest PA, Skull radiograph and K. U. B

    International Nuclear Information System (INIS)

    Song, Kounn Sik; Kim, Young Goo; Lee, Jong Beum; Kim, Kun Sang

    1987-01-01

    Digital image acquisition and display is widely used in computed tomography, ultrasonography, digital subtraction angiography, nuclear medicine and magnetic resonance image. But most of the radiological examinations performed in radiology department are made by using conventional system. The development of the digital radiography system is essential if totally digitized radiology department is desired. The advantages of digitizing the radiographic information are usually discussed in terms of PACS (picture archiving and communication system), furthermore there are many other advantages such as contrast modification, spatial filtering subtraction and superimposition of the images through the image processing by computer. Currently several approaches are under development or in clinical use, the most promising approach is the use of imaging plate composed of photostimulate phosphors such as barium fluorohalide crystal read with a He-Ne laser to produce digital radiographic images. Another promising approach is scan projection radiography. The authors performed the clinical study of comparing the image qualities of digital radiography system using scanning laser luminescence (FCR) and conventional film-screen system in chest PA, skull radiography and K. U. B. in terms of the visibility of the normal anatomic structure rating those (qualities) on a scale of 0 to 3 and obtained the following results. Normal contrast digital images are comparable to conventional film-screen images, but the images of high frequency enhancement is far superior to conventional film-screen especially in peripherally located structures such as skin, subcutaneous fat, musculoskeletal systems, nasal bone, inner and outer table of the skull including the diploic space, paranasal sinuses, nasopharynx and larynx, trachea and main bronchi, mediastinal structures, retrocardiac and subphrenic vascular markings. Another promising aspects of digital radiography system is its wide exposure latitude and

  1. Evaluation of {sup 123}I-orthoiodohippurate single kidney clearance rate by renal sequential scintigraphy in a large cohort of likely normal subjects aged between 0 and 18 years

    Energy Technology Data Exchange (ETDEWEB)

    Imperiale, Alessio; Olianti, Catia; Comis, Giannetto; Cava, Giuseppe la [University of Florence, Nuclear Medicine Unit, Department of Clinical Pathophysiology, Florence (Italy)

    2006-12-15

    Age-related values of{sup 123}I-orthoiodohippurate (OIH) single kidney clearance rate (Cl) were estimated in a large cohort of likely normal children aged between 0 and 18 years. Among 4,111 children examined in the past 10 years, 917 were selected with the following inclusion criteria: (a) mild ultrasonographic hydronephrosis with right differential renal function (DRF) <53% and >47% (498 pts), (b) known or suspected urinary tract infection with normal ultrasound, serum creatinine and DMSA and DRF <53% and >47% (419 pts).{sup 123}I-OIH-Cl was assessed using a validated gamma camera method. Children were divided into 21 age classes: from 0 to 2 years, eight 3-month classes; from 2 to 14 years, twelve 1-year classes; from 14 to 18 years, one 4-year class. Cl, plotted against age, was fitted using an increasing function (y = a - be - cx). Mean{sup 123}I-OIH-Cl of 1,834 kidneys was 306{+-}22 ml/min/1.73 m{sup 2} BSA. Mean{sup 123}I-OIH-Cl of the right and left kidneys was 307{+-}23 and 305{+-}22 ml/min/1.73 m{sup 2} BSA, respectively (p<0.002). The best-fitting{sup 123}I-OIH-Cl growing function was: Cl=311-230e-0.69 x Age (months).{sup 123}I-OIH-Cl improved progressively starting from birth, reaching 96% and 98% of the mature value at 1 and 1.5 years, respectively.{sup 123}I-OIH-Cl at birth (age=0) was 81 ml/min/1.73 m{sup 2} BSA. After 18.6 days of life, the renal function had doubled its starting value, and it reached a plateau of 311 ml/min/1.73 m{sup 2} BSA at 2 years. This work represents a systematic evaluation of ERPF by a gamma camera method in a large cohort of selected likely normal paediatric subjects. (orig.)

  2. Effects of chronic low level radiation in the population residing in the high level natural radiation area in Kerala, India: employing heritable DNA mutation studies.

    Science.gov (United States)

    Ahmad, Shazia; Koya, P K M; Seshadri, M

    2013-03-18

    To study the effect of chronic low level radiation, 4040 meiosis were screened at eight microsatellite and five minisatellite (2485 and 1555 meiosis respectively) marker loci in people residing in high and normal level natural radiation areas of Kerala. Variants in the repeat length of allele were considered as mutants. Mutation rates (expressed as the number of mutations observed in the total number of meiosis) were 6.4×10(-3) (16/2485) and 2.6×10(-3) (4/1555) at microsatellite and minisatellite respectively. The germline microsatellite mutation frequency of father was 1.78 times higher at 7.52×10(-3) (8/1064) compared to 4.22×10(-3) (6/1421) of mother (P=0.292, Fisher's Exact two-sided test). The paternal and maternal mutation rates at minisatellite loci were more or less similar at 2.78×10(-3) (2/719) and 2.39×10(-3) (2/836), respectively (P=1.0, Fisher's Exact two-sided test). Higher but statistically non-significant microsatellite mutation frequency was observed in HLNRA compared to NLNRA (7.25×10(-3) vs 3.64×10(-3); P=0.547). The apparent increase in the mutation rate of microsatellite loci with the increase in radiation dose was also not statistically significant. All the four minisatellite mutation observed were from HLNRA (1198 meiosis) and no mutation was observed among 357 meiosis screened from NLNRA families. All the markers used in the present study were in the non-coding region and hence mutations in these regions may not cause adverse health effects, but the study is important in understanding the effect of chronic low level radiation. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Frequency of factor V Leiden mutation

    International Nuclear Information System (INIS)

    Nasiruddin; Ali, W.; Rehman, Z.; Anwar, M.; Ayyub, M.; Ali, W.; Ahmed, S.

    2005-01-01

    Objective: To determine the frequency of factor V Leiden mutation. Design: Observational study. Patients and Methods: Two hundred subjects each of apparently healthy and unrelated Punjabi and Pathan origins were included in the study. Peripheral blood samples were collected in EDTA and DNA extracted by phenol- chloroform extraction method. DNA analysis was done by PCR for restriction fragment length polymorphism. The product was digested overnight with Mn/1 and electrophoresed on acrylamide gel to detect 67 and 153 base pair fragments of factor V Leiden against 37, 67 and 116 base pair fragments of normal factor V. Results: In the 400 subjects studied, only 5 cases of heterozygotes for factor V Leiden were detected. The overall carrier rate was 1.3% (95% CI 0.2-2.2%). The carrier rate in Punjabis and Pathans was 1 % and 1.5% respectively. Conclusion: This study confirms that the prevalence of factor V Leiden is low in Asians and Africans as compared to the European population. (author)

  4. Mutation at the Human D1S80 Minisatellite Locus

    Directory of Open Access Journals (Sweden)

    Kuppareddi Balamurugan

    2012-01-01

    Full Text Available Little is known about the general biology of minisatellites. The purpose of this study is to examine repeat mutations from the D1S80 minisatellite locus by sequence analysis to elucidate the mutational process at this locus. This is a highly polymorphic minisatellite locus, located in the subtelomeric region of chromosome 1. We have analyzed 90,000 human germline transmission events and found seven (7 mutations at this locus. The D1S80 alleles of the parentage trio, the child, mother, and the alleged father were sequenced and the origin of the mutation was determined. Using American Association of Blood Banks (AABB guidelines, we found a male mutation rate of 1.04×10-4 and a female mutation rate of 5.18×10-5 with an overall mutation rate of approximately 7.77×10-5. Also, in this study, we found that the identified mutations are in close proximity to the center of the repeat array rather than at the ends of the repeat array. Several studies have examined the mutational mechanisms of the minisatellites according to infinite allele model (IAM and the one-step stepwise mutation model (SMM. In this study, we found that this locus fits into the one-step mutation model (SMM mechanism in six out of seven instances similar to STR loci.

  5. GPR143 mutations in Chinese patients with ocular albinism type 1.

    Science.gov (United States)

    Jia, Xiuhua; Yuan, Jin; Jia, Xiaoyun; Ling, Shiqi; Li, Shiqiang; Guo, Xiangming

    2017-05-01

    The aim of the present study was to evaluate mutations of the G protein-coupled receptor 143 (GPR143) gene for ocular albinism type 1 (OA1) in Chinese patients. For the current study, 8 patients with OA1 were selected from the database of ocular genetic diseases. Genomic DNA of OA1 was prepared from venous leukocytes collected from the patients. Cycle sequencing was used to analyze the exons and adjacent introns of GPR143. The variation detected was analyzed by bidirectional DNA sequencing and further evaluated in 96 controls using heteroduplex‑single strand conformational polymorphism analysis. Additionally, slit lamp photography of anterior segment, fundus photography and optical coherence tomography (OCT) were performed to identify the clinical features of OA1. In five patients with OA1, 5 GPR143 gene mutations were identified and four of them there were novel mutations. The screening rate is 62.5%, including c.333G>A (p.W111X), c.353G>A (p.G118E) (known mutation), C.658+2T>G (splice mutation), c.215_216insCGCTGC (p.71‑72insAA) and c.17T>C (p. L6P). These mutations were absent in the 96 normal controls. Only one patient with OA1 in the present study was female. Patients with OA1 often have congenital nystagmus, refractive error, severe decline of visual acuity (from 0.1 to 0.4) and foveal hypoplasia. Different degrees of pigment loss were evident in the patients' iris and retina, whereas macular structure was not identified in the OCT examination. The findings of the present study expanded the gene mutation spectrum of GPR143 and investigated the clinical phenotype of patients with OA1 in the Chinese population. Additional evidence for clinical diagnosis was provided along with differential diagnosis and genetic counseling.

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

    International Nuclear Information System (INIS)

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

    2003-01-01

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

  7. Radiation-induced mutations in mammals

    International Nuclear Information System (INIS)

    Ehling, U.H.

    1993-01-01

    The aims of the proposed project are to provide a better basis for extrapolation of animal data to man. Genetic endpoint, strain and species comparisons are made, which will provide critical experimental data regarding strategies in extrapolating laboratory animal data to man. Experiments were conducted to systematically compare the spontaneous and radiation-induced mutation rates for recessive specific-locus, dominant cataract and enzyme activity alleles in the mouse as well as a comparison of the mutation rate in the mouse and hamster for dominant cataract and enzyme activity alleles. The comparison of the radiation-dose response for recessive specific-locus and dominant cataract mutations are extended. Selected mutations are characterized at the genetic, biochemical and molecular levels. (R.P.) 5 refs., 3 tabs

  8. The directed mutation controversy and neo-Darwinism.

    Science.gov (United States)

    Lenski, R E; Mittler, J E

    1993-01-08

    According to neo-Darwinian theory, random mutation produces genetic differences among organisms whereas natural selection tends to increase the frequency of advantageous alleles. However, several recent papers claim that certain mutations in bacteria and yeast occur at much higher rates specifically when the mutant phenotypes are advantageous. Various molecular models have been proposed that might explain these directed mutations, but the models have not been confirmed. Critics contend that studies purporting to demonstrate directed mutation lack certain controls and fail to account adequately for population dynamics. Further experiments that address these criticisms do not support the existence of directed mutations.

  9. Mutator/hypermutable fetal/juvenile metakaryotic stem cells and human colorectal carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Lohith G. Kini

    2013-10-01

    Full Text Available Adult age-specific colorectal cancer incidence rates increase exponentially from maturity, reach a maximum, then decline in extreme old age. Armitage and Doll (1957 postulated that the exponential increase resulted from n mutations occurring throughout adult life in normal cells at risk that initiated the growth of a preneoplastic colony in which subsequent m mutations promoted one of the preneoplastic cells at risk to form a lethal neoplasia. We have reported cytologic evidence that these cells at risk are fetal/juvenile organogenic, then preneoplastic metakaryotic stem cells. Metakaryotic cells display stem-like behaviors of both symmetric and asymmetric nuclear divisions and peculiarities such as bell shaped nuclei and amitotic nuclear fission that distinguish them from embryonic, eukaryotic stem cells. Analyses of mutant colony sizes and numbers in adult lung epithelia supported the inferences that the metakaryotic organogenic stem cells are constitutively mutator/hypermutable and that their contributions to cancer initiation are limited to the fetal/juvenile period. We have amended the two-stage model of Armitage and Doll and incorporated these several inferences in a computer program CancerFit v.5.0. We compared the expectations of the amended model to adult (15-104 yr age-specific colon cancer rates for European American males born 1890-99 and observed remarkable concordance. When estimates of normal colonic fetal/juvenile APC and OAT gene mutation rates (~2-5 x 10-5 per stem cell doubling and preneoplastic colonic gene loss rates (~ 8 x 10-3 were applied, the model was in accordance only for the values of n = 2 and m = 4 or 5.

  10. Darwinism for the Genomic Age: Connecting Mutation to Diversification

    OpenAIRE

    Hua, Xia; Bromham, Lindell

    2017-01-01

    A growing body of evidence suggests that rates of diversification of biological lineages are correlated with differences in genome-wide mutation rate. Given that most research into differential patterns of diversification rate have focused on species traits or ecological parameters, a connection to the biochemical processes of genome change is an unexpected observation. While the empirical evidence for a significant association between mutation rate and diversification rate is mounting, there...

  11. Radiation mutation breeding

    International Nuclear Information System (INIS)

    Song, Hi Sup; Kim, Jae Sung; Kim, Jin Kyu; Shin, In Chul; Lim, Young Taek

    1998-04-01

    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected

  12. Radiation mutation breeding

    Energy Technology Data Exchange (ETDEWEB)

    Song, Hi Sup; Kim, Jae Sung; Kim, Jin Kyu; Shin, In Chul; Lim, Young Taek

    1998-04-01

    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected.

  13. On the validity of the Middlesex Hospital Questionnaire: a comparison of diagnostic self-ratings in psychiatric out-patients, general practice patients, and 'normals' based on the Hebrew version.

    Science.gov (United States)

    Dasberg, H; Shalif, I

    1978-09-01

    The short clinical diagnostic self-rating scale for psycho-neurotic patients (The Middlesex Hospital Questionnaire) was translated into everyday Hebrew and tested on 216 subjects for: (1) concurrent validity with clinical diagnoses; (2) discriminatory validity on a psychoneurotic gradient of psychiatric out-patients, general practice patients, and normal controls; (3) validity of subscales and discrete items using matrices of Spearman rank correlation coefficients; (4) construct validity using Guttman's smallest space analysis based on coefficients of similarity. The Hebrew MHQ was found to retain its validity and to be easily applicable in waiting-room situations. It is a useful method for generating and substantiating hypotheses on psychosomatic and psychosocial interrelationships. The MHQ seems to enable the expression of the 'neurotic load' of a general practice subpopulation as a centile on a scale, thereby corroborating previous epidemiological findings on the high prevalence of neurotic illness in general practice. There is reason to believe that the MHQ is a valid instrument for the analysis of symptom profiles of subjects involved in future drug trials.

  14. Normalization: A Preprocessing Stage

    OpenAIRE

    Patro, S. Gopal Krishna; Sahu, Kishore Kumar

    2015-01-01

    As we know that the normalization is a pre-processing stage of any type problem statement. Especially normalization takes important role in the field of soft computing, cloud computing etc. for manipulation of data like scale down or scale up the range of data before it becomes used for further stage. There are so many normalization techniques are there namely Min-Max normalization, Z-score normalization and Decimal scaling normalization. So by referring these normalization techniques we are ...

  15. Better plants through mutations

    International Nuclear Information System (INIS)

    1988-01-01

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

  16. Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.

    Science.gov (United States)

    Ichikawa, Shoji; Guigonis, Vincent; Imel, Erik A; Courouble, Mélanie; Heissat, Sophie; Henley, John D; Sorenson, Andrea H; Petit, Barbara; Lienhardt, Anne; Econs, Michael J

    2007-05-01

    Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes. Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient. Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA. A 5-year-old French boy with HHS and his family members participated. The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC. The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.

  17. Laser desorption mass spectrometry for point mutation detection

    Energy Technology Data Exchange (ETDEWEB)

    Taranenko, N.I.; Chung, C.N.; Zhu, Y.F. [Oak Ridge National Lab., TN (United States)] [and others

    1996-10-01

    A point mutation can be associated with the pathogenesis of inherited or acquired diseases. Laser desorption mass spectrometry coupled with allele specific polymerase chain reaction (PCR) was first used for point mutation detection. G551D is one of several mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene present in 1-3% of the mutant CFTR alleles in most European populations. In this work, two different approaches were pursued to detect G551D point mutation in the cystic fibrosis gene. The strategy is to amplify the desired region of DNA template by PCR using two primers that overlap one base at the site of the point mutation and which vary in size. If the two primers based on the normal sequence match the target DNA sequence, a normal PCR product will be produced. However, if the alternately sized primers that match the mutant sequence recognize the target DNA, an abnormal PCR product will be produced. Thus, the mass spectrometer can be used to identify patients that are homozygous normal, heterozygous for a mutation or homozygous abnormal at a mutation site. Another approach to identify similar mutations is the use of sequence specific restriction enzymes which respond to changes in the DNA sequence. Mass spectrometry is used to detect the length of the restriction fragments generated by digestion of a PCR generated target fragment. 21 refs., 10 figs., 2 tabs.

  18. Laser desorption mass spectrometry for point mutation detection

    Energy Technology Data Exchange (ETDEWEB)

    Taranenko, N.I.; Chung, C.N.; Zhu, Y.F. [Oak Ridge National Lab., TN (United States)] [and others

    1996-12-31

    A point mutation can be associated with the pathogenesis of inherited or acquired diseases. Laser desorption mass spectrometry coupled with allele specific polymerase chain reaction (PCR) was first used for point mutation detection. G551D is one of several mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene present in 1-3% of the mutant CFTR alleles in most European populations. In this work, two different approaches were pursued to detect G551D point mutation in the cystic fibrosis gene. The strategy is to amplify the desired region of DNA template by PCR using two primers that overlap one base at the site of the point mutation and which vary in size. If the two primers based on the normal sequence match the target DNA sequence, a normal PCR product will be produced. However, if the alternately sized primers that match the mutant sequence recognize the target DNA, an abnormal PCR product will be produced. Thus, the mass spectrometer can be used to identify patients that are homozygous normal, heterozygous for a mutation or homozygous abnormal at a mutation site. Another approach to identify similar mutations is the use of sequence specific restriction enzymes which respond to changes in the DNA sequence. Mass spectrometry is used to detect the length of the restriction fragments by digestion of a PCR generated target fragment. 21 refs., 10 figs., 2 tabs.

  19. Mutation and DNA replication in Escherichia coli treated with low concentrations of N-methyl-N'-nitro-N-nitrosoguanidine

    International Nuclear Information System (INIS)

    Jimenez-Sanchez, A.; Cerda-Olmedo, E.

    1975-01-01

    N-Methyl-N'-nitro-N-nitrosoguanidine (nitrosoguanidine) causes an unexpectedly high frequency of closely linked double mutants because of its specificity for chromosome regions in replication. Low nitrosoguanidine concentrations (I μg/ml) in liquid cultures allow replication at the normal rate and are mutagenic. It was expected that mutations would be spread over the chromosome as it replicated, but a high frequency of closely linked double mutants was found. If a thymine auxotroph is grown in the presence of 5-bromodeoxyuridine (BUdR) and nitrosoguanidine and then exposed to 313-nm radiation (which destroys BUdR-substituted DNA), the mutation frequency is much higher among survivors than among non-irradiated cells. It is concluded that nitrosoguanidine inhibits DNA replication in a small fraction of the population and that mutations are induced in that same fraction. Nitrosoguanidine treatment leads to a high frequency of closely linked double mutants under all known conditions

  20. WHO-defined ‘myelodysplastic syndrome with isolated del(5q)' in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations

    Science.gov (United States)

    Patnaik, M M; Lasho, T L; Finke, C M; Gangat, N; Caramazza, D; Holtan, S G; Pardanani, A; Knudson, R A; Ketterling, R P; Chen, D; Hoyer, J D; Hanson, C A; Tefferi, A

    2010-01-01

    The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with ‘myelodysplastic syndrome with isolated del(5q)' (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age ⩾70 years (P=0.01), transfusion need at diagnosis (P=0.04) and dysgranulopoiesis (P=0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or ⩾2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations. PMID:20485371

  1. Spectrum of small mutations in the dystrophin coding region

    Energy Technology Data Exchange (ETDEWEB)

    Prior, T.W.; Bartolo, C.; Pearl, D.K. [Ohio State Univ., Columbus, OH (United States)] [and others

    1995-07-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5` and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened {approximately} 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3` of exon 55. The extent of protein truncation caused by the 3` mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications. 71 refs., 2 figs., 2 tabs.

  2. New mutations affecting induced mutagenesis in yeast.

    Science.gov (United States)

    Lawrence, C W; Krauss, B R; Christensen, R B

    1985-01-01

    Previously isolated mutations in baker's yeast, Saccharomyces cerevisiae, that impair induced mutagenesis were all identified with the aid of tests that either exclusively or predominantly detect base-pair substitutions. To avoid this bias, we have screened 11 366 potentially mutant clones for UV-induced reversion of the frameshift allele, his4-38, and have identified 10 mutants that give much reduced yields of revertants. Complementation and recombination tests show that 6 of these carry mutations at the previously known REV1, REV1 and REV3 loci, while the remaining 4 define 3 new genes, REV4 (2 mutations), REV5 and REV6. The rev4 mutations are readily suppressed in many genetic backgrounds and, like the rev5 mutation, impart only a limited deficiency for induced mutagenesis: it is likely, therefore that the REV4+ and REV5+ gene functions are only remotely concerned with this process. The rev6 mutants have a more general deficiency, however, as well as marked sensitivity to UV and an increased spontaneous mutation rate, properties that suggest the REV6 gene is directly involved in mutation induction. The REV5 gene is located about 1 cM proximal to CYC1 on chromosome X.

  3. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

    Science.gov (United States)

    Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

    2013-10-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. Copyright © 2013 Wiley Periodicals, Inc.

  4. Mutation and premating isolation

    Science.gov (United States)

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

    2002-01-01

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

  5. Early evaluation of cerebral metabolic rate of glucose (CMRglu) with {sup 18}F-FDG PET/CT and clinical assessment in idiopathic normal pressure hydrocephalus (INPH) patients before and after ventricular shunt placement: preliminary experience

    Energy Technology Data Exchange (ETDEWEB)

    Calcagni, Maria Lucia; Lavalle, Mariadea; Leccisotti, Lucia; Giordano, Alessandro [Universita Cattolica del Sacro Cuore, Institute of Nuclear Medicine, Rome (Italy); Mangiola, Annunziato; De Bonis, Pasquale; Anile, Carmelo [Universita Cattolica del Sacro Cuore, Institute of Neurosurgery, Rome (Italy); Indovina, Luca [Universita Cattolica del Sacro Cuore, Institute of Physics, Rome (Italy); Marra, Camillo [Universita Cattolica del Sacro Cuore, Institute of Neurology, Rome (Italy); Pelliccioni, Armando [Istituto Nazionale per l' Assicurazione contro gli Infortuni sul Lavoro (INAIL), Rome (Italy)

    2012-02-15

    We evaluated the relationships between the cerebral metabolic rate of glucose (CMRglu) measured by dynamic {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and the clinical and neuropsychological assessment before and after the surgical procedure in idiopathic normal pressure hydrocephalus (INPH) patients. Eleven selected INPH patients underwent clinical assessment (modified Rankin scale, Krauss scale, Larsson categorization system and Stein-Langfitt scale), cognitive evaluation (Mini-Mental State Examination, MMSE) and dynamic {sup 18}F-FDG PET/CT scan 3 days before and 1 week after ventricular shunt placement. After shunting, the global CMRglu significantly increased (2.95 {+-} 0.44 vs 4.38 {+-} 0.68, p = 10{sup -7}) in all INPH patients with a mean percentage value of 48.7%. After shunting, no significant change was found in the Evans ratio whereas a significant decrease in all clinical scale scores was observed. Only a slight reduction in the MMSE was found. After shunting, a significant correlation between the global CMRglu value and clinical assessment was found (R {sup 2} = 0.75, p = 0.024); indeed all clinical scale scores varied (decreasing) and the CMRglu value also varied (increasing) in all INPH patients. Our preliminary data show that changes in the CMRglu are promptly reversible after surgery and that there is a relationship between the early metabolic changes and clinical symptoms, independently from the simultaneous changes in the ventricular size. The remarkable and prompt improvement in the global CMRglu and in symptoms may also have important implications for the current concept of ''neuronal plasticity'' and for the cells' reactivity in order to recover their metabolic function. (orig.)

  6. iPhone 4s photoplethysmography: which light color yields the most accurate heart rate and normalized pulse volume using the iPhysioMeter Application in the presence of motion artifact?

    Directory of Open Access Journals (Sweden)

    Kenta Matsumura

    Full Text Available Recent progress in information and communication technologies has made it possible to measure heart rate (HR and normalized pulse volume (NPV, which are important physiological indices, using only a smartphone. This has been achieved with reflection mode photoplethysmography (PPG, by using a smartphone's embedded flash as a light source and the camera as a light sensor. Despite its widespread use, the method of PPG is susceptible to motion artifacts as physical displacements influence photon propagation phenomena and, thereby, the effective optical path length. Further, it is known that the wavelength of light used for PPG influences the photon penetration depth and we therefore hypothesized that influences of motion artifact could be wavelength-dependant. To test this hypothesis, we made measurements in 12 healthy volunteers of HR and NPV derived from reflection mode plethysmograms recorded simultaneously at three different spectral regions (red, green and blue at the same physical location with a smartphone. We then assessed the accuracy of the HR and NPV measurements under the influence of motion artifacts. The analyses revealed that the accuracy of HR was acceptably high with all three wavelengths (all rs > 0.996, fixed biases: -0.12 to 0.10 beats per minute, proportional biases: r =  -0.29 to 0.03, but that of NPV was the best with green light (r = 0.791, fixed biases: -0.01 arbitrary units, proportional bias: r = 0.11. Moreover, the signal-to-noise ratio obtained with green and blue light PPG was higher than that of red light PPG. These findings suggest that green is the most suitable color for measuring HR and NPV from the reflection mode photoplethysmogram under motion artifact conditions. We conclude that the use of green light PPG could be of particular benefit in ambulatory monitoring where motion artifacts are a significant issue.

  7. Early evaluation of cerebral metabolic rate of glucose (CMRglu) with 18F-FDG PET/CT and clinical assessment in idiopathic normal pressure hydrocephalus (INPH) patients before and after ventricular shunt placement: preliminary experience

    International Nuclear Information System (INIS)

    Calcagni, Maria Lucia; Lavalle, Mariadea; Leccisotti, Lucia; Giordano, Alessandro; Mangiola, Annunziato; De Bonis, Pasquale; Anile, Carmelo; Indovina, Luca; Marra, Camillo; Pelliccioni, Armando

    2012-01-01

    We evaluated the relationships between the cerebral metabolic rate of glucose (CMRglu) measured by dynamic 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and the clinical and neuropsychological assessment before and after the surgical procedure in idiopathic normal pressure hydrocephalus (INPH) patients. Eleven selected INPH patients underwent clinical assessment (modified Rankin scale, Krauss scale, Larsson categorization system and Stein-Langfitt scale), cognitive evaluation (Mini-Mental State Examination, MMSE) and dynamic 18 F-FDG PET/CT scan 3 days before and 1 week after ventricular shunt placement. After shunting, the global CMRglu significantly increased (2.95 ± 0.44 vs 4.38 ± 0.68, p = 10 -7 ) in all INPH patients with a mean percentage value of 48.7%. After shunting, no significant change was found in the Evans ratio whereas a significant decrease in all clinical scale scores was observed. Only a slight reduction in the MMSE was found. After shunting, a significant correlation between the global CMRglu value and clinical assessment was found (R 2 = 0.75, p = 0.024); indeed all clinical scale scores varied (decreasing) and the CMRglu value also varied (increasing) in all INPH patients. Our preliminary data show that changes in the CMRglu are promptly reversible after surgery and that there is a relationship between the early metabolic changes and clinical symptoms, independently from the simultaneous changes in the ventricular size. The remarkable and prompt improvement in the global CMRglu and in symptoms may also have important implications for the current concept of ''neuronal plasticity'' and for the cells' reactivity in order to recover their metabolic function. (orig.)

  8. Mutation directional selection sheds light on prion pathogenesis

    International Nuclear Information System (INIS)

    Shen, Liang; Ji, Hong-Fang

    2011-01-01

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

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

    Science.gov (United States)

    Jain, Kavita; James, Ananthu

    2017-11-21

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

  10. Predicting Agency Rating Migrations with Spread Implied Ratings

    OpenAIRE

    Jianming Kou; Dr Simone Varotto

    2005-01-01

    Investors traditionally rely on credit ratings to price debt instruments. However, rating agencies are known to be prudent in their approach to rating revisions, which results in delayed ratings adjustments to mutating credit conditions. For a large set of eurobonds we derive credit spread implied ratings and compare them with the ratings issued by rating agencies. Our results indicate that spread implied ratings often anticipate future movement of agency ratings and hence could help track cr...

  11. Direct Measurements of Human Colon Crypt Stem Cell Niche Genetic Fidelity: The Role of Chance in Non-Darwinian Mutation Selection

    Directory of Open Access Journals (Sweden)

    Haeyoun eKang

    2013-10-01

    Full Text Available Perfect human stem cell genetic fidelity would prevent aging and cancer. However, perfection would be difficult to achieve, and aging is universal and cancers common. A hypothesis is that because mutations are inevitable over a human lifetime, downstream mechanisms have evolved to manage the deleterious effects of beneficial and lethal mutations. In the colon, a crypt stem cell architecture reduces the number of mitotic cells at risk for mutation accumulation, and multiple niche stem cells ensure that a lethal mutation within any single stem cell does not lead to crypt death. In addition, the architecture of the colon crypt stem cell niche may harness probability or chance to randomly discard many beneficial mutations that might lead to cancer. An analysis of somatic chromosome copy number alterations (CNAs reveals a lack of perfect fidelity in individual normal human crypts, with age-related increases and higher frequencies in ulcerative colitis, a proliferative, inflammatory disease. The age-related increase in somatic CNAs appears consistent with relatively normal replication error and cell division rates. Surprisingly, and similar to point mutations in cancer genomes, the types of crypt mutations were more consistent with random fixation rather than selection. In theory, a simple non-Darwinian way to nullify selection is to reduce the size of the reproducing population. Fates are more determined by chance rather than selection in very small populations, and therefore selection may be minimized within small crypt niches. The desired effect is that many beneficial mutations that might lead to cancer are randomly lost by drift rather than fixed by selection. The subdivision of the colon into multiple very small stem cell niches may trade Darwinian evolution for non-Darwinian somatic cell evolution, capitulating to aging but reducing cancer risks.

  12. Novel Mutations in the PC Gene in Patients with Type B Pyruvate Carboxylase Deficiency

    DEFF Research Database (Denmark)

    Ostergaard, Elsebet; Duno, Morten; Møller, Lisbeth Birk

    2013-01-01

    We have investigated seven patients with the type B form of pyruvate carboxylase (PC) deficiency. Mutation analysis revealed eight mutations, all novel. In a patient with exon skipping on cDNA analysis, we identified a homozygous mutation located in a potential branch point sequence, the first...... possible branch point mutation in PC. Two patients were homozygous for missense mutations (with normal protein amounts on western blot analysis), and two patients were homozygous for nonsense mutations. In addition, a duplication of one base pair was found in a patient who also harboured a splice site...... mutation. Another splice site mutation led to the activation of a cryptic splice site, shown by cDNA analysis.All patients reported until now with at least one missense mutation have had the milder type A form of PC deficiency. We thus report for the first time two patients with homozygous missense...

  13. Effect of space mutation of photosynthetic characteristics of soybean varieties

    International Nuclear Information System (INIS)

    Liu Xinlei; Ma Yansong; Luan Xiaoyan; Man Weiqun; Xu Dechun; Meng Lifen; Fu Lixin; Zhao Xiao'nan; Liu Qi

    2012-01-01

    In order to elucidate the response of the photosynthetic traits of soybean to space mutation, three soybean varieties (lines) of Heinong 48, Heinong 44 and Ha 2291-Y were carried by artificial satellite in 2006 and the net photo synthetic rate (Pn), stomatal conductance (Cond), intercellular CO 2 concentration (Ci) and stomatal resistance (Rs) from SP 1 to SP 4 generation were determined. The results showed that space mutation affected photosynthesis traits of soy bean. The photosynthetic rate of soybean varieties by space mutation occurred different levels of genetic variation and the positive mutation rate were higher. Coefficient of variation among generations were SP 2 >SP 3 >SP 4 >CK. Results suggest that space mutation can effectively create soybean materials with higher photosynthetic rate. (authors)

  14. Effect of space mutation on photosynthetic characteristics of soybean varieties

    International Nuclear Information System (INIS)

    Liu Xinlei; Ma Yansong; Luan Xiaoyan; Man Weiqun; Xu Dechun; Meng Lifen; Fu Lixin; Zhao Xiaonan; Liu Qi

    2011-01-01

    In order to elucidate the response of the photosynthetic traits of soybean to space mutation, three soybean varieties (lines) of Heinong 48, Heinong 44 and Ha 2291-Y were carried by artificial satellite in 2006 and the net photosynthetic rate (Pn), stomatal conductance (Cond), intercellular CO 2 concentration (Ci) and stomatal resistance (Rs) from SP 1 to SP 4 generation were determined. The results showed that space mutation affected photosynthesis traits of soybean. The photosynthetic rate of soybean varieties by space mutation occurred different levels of genetic variation and the positive mutation rate were higher. Coefficient of variation among generations were SP 2 > SP 3 > SP 4 > CK. Results suggest that space mutation can effectively create soybean materials with higher photosynthetic rate. (authors)

  15. The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome.

    Science.gov (United States)

    Garrity, Deborah M; Childs, Sarah; Fishman, Mark C

    2002-10-01

    Holt-Oram syndrome is one of the autosomal dominant human "heart-hand" disorders, with a combination of upper limb malformations and cardiac defects. Holt-Oram syndrome is caused by mutations in the TBX5 gene, a member of a large family of T-box transcription factors that play important roles in cell-type specification and morphogenesis. In a screen for mutations affecting zebrafish cardiac function, we isolated the recessive lethal mutant heartstrings, which lacks pectoral fins and exhibits severe cardiac dysfunction, beginning with a slow heart rate and progressing to a stretched, non-functional heart. We mapped and cloned the heartstrings mutation and find it to encode the zebrafish ortholog of the TBX5 gene. The heartstrings mutation causes premature termination at amino acid 316. Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. The total absence of any fin bud differentiation distinguishes heartstrings from most other mutations that affect zebrafish fin development, suggesting that Tbx5 functions very early in the pectoral fin induction pathway. Moderate reduction of Tbx5 by morpholino causes fin malformations, revealing an additional early requirement for Tbx5 in coordinating the axes of fin outgrowth. The heart of heartstrings mutant embryos appears to form and function normally through the early heart tube stage, manifesting only a slight bradycardia compared with wild-type siblings. However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. Relative to mammals, fish require lower levels of Tbx5 to produce malformed appendages and display whole-heart rather than atrial-predominant cardiac defects. However, the syndromic deficiencies of tbx5 mutation are remarkably well retained between fish and mammals.

  16. EGFR Mutation Status in Uighur Lung Adenocarcinoma Patients

    Directory of Open Access Journals (Sweden)

    Li SHAN

    2013-02-01

    Full Text Available Background and objective Epidermal growth factor receptor (EGFR, a transmembrane protein, is a member of the tyrosine kinase family. Gefitinib, an EGFR tyrosine-kinase inhibitors, has shown a high response rate in the treatment of lung cancer in patients with EGFR mutation. However, significant differences in EGFR mutations exist among different ethnic groups. The aim of this study is to investigate the prevalence of EGFR mutations in Uighur lung adenocarcinoma patients by using a rapid and sensitive detection method and to analyze EGFR mutation differences compared with Han lung adenocarcinoma patients. Methods We examined lung adenocarcinoma tissues from 138 patients, including 68 Uighur lung adenocarcinoma patients and 70 Han lung adenocarcinoma patients, for EGFR mutations in exons 18, 19, 20, and 21 by using the amplification refractory mutation system (ARMS PCR method. The mutation differences between Uighur and Han lung adenocarcinoma were compared by using the chi-square test method. Results EGFR mutations were detected in 43 (31.2% of the 138 lung adenocarcinoma patients. EGFR mutations were detected in 11 (16.2% of the 68 Uighur lung adenocarcinoma patients and in 32 (45.7% of the 70 Han lung adenocarcinoma patients. Significant differences were observed in the EGFR mutations between Uighur lung adenocarcinoma patients and Han lung adenocarcinoma patients (P<0.001. Conclusion Our results indicate that the EGFR mutation in Uighur lung adenocarcinoma patients (16.2% is significantly lower than that in Han lung adenocarcinoma patients (45.7%.

  17. Inference of directional selection and mutation parameters assuming equilibrium.

    Science.gov (United States)

    Vogl, Claus; Bergman, Juraj

    2015-12-01

    In a classical study, Wright (1931) proposed a model for the evolution of a biallelic locus under the influence of mutation, directional selection and drift. He derived the equilibrium distribution of the allelic proportion conditional on the scaled mutation rate, the mutation bias and the scaled strength of directional selection. The equilibrium distribution can be used for inference of these parameters with genome-wide datasets of "site frequency spectra" (SFS). Assuming that the scaled mutation rate is low, Wright's model can be approximated by a boundary-mutation model, where mutations are introduced into the population exclusively from sites fixed for the preferred or unpreferred allelic states. With the boundary-mutation model, inference can be partitioned: (i) the shape of the SFS distribution within the polymorphic region is determined by random drift and directional selection, but not by the