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Sample records for mutation accumulation hypothesis

  1. Clonal mutations in primary human glial tumors: evidence in support of the mutator hypothesis

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    Sarkar Chitra

    2007-10-01

    Full Text Available Abstract Background A verifiable consequence of the mutator hypothesis is that even low grade neoplasms would accumulate a large number of mutations that do not influence the tumor phenotype (clonal mutations. In this study, we have attempted to quantify the number of clonal mutations in primary human gliomas of astrocytic cell origin. These alterations were identified in tumor tissue, microscopically confirmed to have over 70% neoplastic cells. Methods Random Amplified Polymorphic DNA (RAPD analysis was performed using a set of fifteen 10-mer primers of arbitrary but definite sequences in 17 WHO grade II astrocytomas (low grade diffuse astrocytoma or DA and 16 WHO grade IV astrocytomas (Glioblastoma Multiforme or GBM. The RAPD profile of the tumor tissue was compared with that of the leucocyte DNA of the same patient and alteration(s scored. A quantitative estimate of the overall genomic changes in these tumors was obtained by 2 different modes of calculation. Results The overall change in the tumors was estimated to be 4.24% in DA and 2.29% in GBM by one method and 11.96% and 6.03% in DA and GBM respectively by the other. The difference between high and lower grade tumors was statistically significant by both methods. Conclusion This study demonstrates the presence of extensive clonal mutations in gliomas, more in lower grade. This is consistent with our earlier work demonstrating that technique like RAPD analysis, unbiased for locus, is able to demonstrate more intra-tumor genetic heterogeneity in lower grade gliomas compared to higher grade. The results support the mutator hypothesis proposed by Loeb.

  2. Clonal mutations in primary human glial tumors: evidence in support of the mutator hypothesis

    International Nuclear Information System (INIS)

    Misra, Anjan; Chattopadhyay, Parthaprasad; Chosdol, Kunzang; Sarkar, Chitra; Mahapatra, Ashok K; Sinha, Subrata

    2007-01-01

    A verifiable consequence of the mutator hypothesis is that even low grade neoplasms would accumulate a large number of mutations that do not influence the tumor phenotype (clonal mutations). In this study, we have attempted to quantify the number of clonal mutations in primary human gliomas of astrocytic cell origin. These alterations were identified in tumor tissue, microscopically confirmed to have over 70% neoplastic cells. Random Amplified Polymorphic DNA (RAPD) analysis was performed using a set of fifteen 10-mer primers of arbitrary but definite sequences in 17 WHO grade II astrocytomas (low grade diffuse astrocytoma or DA) and 16 WHO grade IV astrocytomas (Glioblastoma Multiforme or GBM). The RAPD profile of the tumor tissue was compared with that of the leucocyte DNA of the same patient and alteration(s) scored. A quantitative estimate of the overall genomic changes in these tumors was obtained by 2 different modes of calculation. The overall change in the tumors was estimated to be 4.24% in DA and 2.29% in GBM by one method and 11.96% and 6.03% in DA and GBM respectively by the other. The difference between high and lower grade tumors was statistically significant by both methods. This study demonstrates the presence of extensive clonal mutations in gliomas, more in lower grade. This is consistent with our earlier work demonstrating that technique like RAPD analysis, unbiased for locus, is able to demonstrate more intra-tumor genetic heterogeneity in lower grade gliomas compared to higher grade. The results support the mutator hypothesis proposed by Loeb

  3. Deleterious mutation accumulation in organelle genomes.

    Science.gov (United States)

    Lynch, M; Blanchard, J L

    1998-01-01

    It is well established on theoretical grounds that the accumulation of mildly deleterious mutations in nonrecombining genomes is a major extinction risk in obligately asexual populations. Sexual populations can also incur mutational deterioration in genomic regions that experience little or no recombination, i.e., autosomal regions near centromeres, Y chromosomes, and organelle genomes. Our results suggest, for a wide array of genes (transfer RNAs, ribosomal RNAs, and proteins) in a diverse collection of species (animals, plants, and fungi), an almost universal increase in the fixation probabilities of mildly deleterious mutations arising in mitochondrial and chloroplast genomes relative to those arising in the recombining nuclear genome. This enhanced width of the selective sieve in organelle genomes does not appear to be a consequence of relaxed selection, but can be explained by the decline in the efficiency of selection that results from the reduction of effective population size induced by uniparental inheritance. Because of the very low mutation rates of organelle genomes (on the order of 10(-4) per genome per year), the reduction in fitness resulting from mutation accumulation in such genomes is a very long-term process, not likely to imperil many species on time scales of less than a million years, but perhaps playing some role in phylogenetic lineage sorting on time scales of 10 to 100 million years.

  4. Mutation Accumulation, Soft Selection and the Middle-Class Neighborhood

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    Moorad, Jacob A.; Hall, David W.

    2009-01-01

    The “middle-class neighborhood” is a breeding design intended to allow new mutations to accumulate by lessening the effects of purifying selection through the elimination of among-line fitness variation. We show that this design effectively applies soft selection to the experimental population, potentially causing biased estimates of mutational effects if social effects contribute to fitness. PMID:19448272

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

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    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.

  6. Accumulation of neutral mutations in growing cell colonies with competition.

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    Sorace, Ron; Komarova, Natalia L

    2012-12-07

    Neutral mutations play an important role in many biological processes including cancer initiation and progression, the generation of drug resistance in bacterial and viral diseases as well as cancers, and the development of organs in multicellular organisms. In this paper we study how neutral mutants are accumulated in nonlinearly growing colonies of cells subject to growth constraints such as crowding or lack of resources. We investigate different types of growth control which range from "division-controlled" to "death-controlled" growth (and various mixtures of both). In division-controlled growth, the burden of handling overcrowding lies with the process of cell-divisions, the divisions slow down as the carrying capacity is approached. In death-controlled growth, it is death rate that increases to slow down expansion. We show that division-controlled growth minimizes the number of accumulated mutations, and death-controlled growth corresponds to the maximum number of mutants. We check that these results hold in both deterministic and stochastic settings. We further develop a general (deterministic) theory of neutral mutations and achieve an analytical understanding of the mutant accumulation in colonies of a given size in the absence of back-mutations. The long-term dynamics of mutants in the presence of back-mutations is also addressed. In particular, with equal forward- and back-mutation rates, if division-controlled and a death-controlled types are competing for space and nutrients, cells obeying division-controlled growth will dominate the population. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Comparison of poliovirus recombinants: accumulation of point mutations provides further advantages.

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    Savolainen-Kopra, Carita; Samoilovich, Elena; Kahelin, Heidi; Hiekka, Anna-Kaisa; Hovi, Tapani; Roivainen, Merja

    2009-08-01

    The roles of recombination and accumulation of point mutations in the origin of new poliovirus (PV) characteristics have been hypothesized, but it is not known which are essential to evolution. We studied phenotypic differences between recombinant PV strains isolated from successive stool specimens of an oral PV vaccine recipient. The studied strains included three PV2/PV1 recombinants with increasing numbers of mutations in the VP1 gene, two of the three with an amino acid change I-->T in the DE-loop of VP1, their putative PV1 parent and strains Sabin 1 and 2. Growth of these viruses was examined in three cell lines: colorectal adenocarcinoma, neuroblastoma and HeLa. The main observation was a higher growth rate between 4 and 6 h post-infection of the two recombinants with the I-->T substitution. All recombinants grew at a higher rate than parental strains in the exponential phase of the replication cycle. In a temperature sensitivity test, the I-->T-substituted recombinants replicated equally well at an elevated temperature. Complete genome sequencing of the three recombinants revealed 12 (3), 19 (3) and 27 (3) nucleotide (amino acid) differences from Sabin. Mutations were located in regions defining attenuation, temperature sensitivity, antigenicity and the cis-acting replicating element. The recombination site was in the 5' end of 3D. In a competition assay, the most mutated recombinant beat parental Sabin in all three cell lines, strongly suggesting that this virus has an advantage. Two independent intertypic recombinants, PV3/PV1 and PV3/PV2, also showed similar growth advantages, but they also contained several point mutations. Thus, our data defend the hypothesis that accumulation of certain advantageous mutations plays a key role in gaining increased fitness.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    -strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene......-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait--the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very...

  9. Environmentally responsive genome-wide accumulation of de novo Arabidopsis thaliana mutations and epimutations

    KAUST Repository

    Jiang, Caifu

    2014-10-14

    Evolution is fueled by phenotypic diversity, which is in turn due to underlying heritable genetic (and potentially epigenetic) variation. While environmental factors are well known to influence the accumulation of novel variation in microorganisms and human cancer cells, the extent to which the natural environment influences the accumulation of novel variation in plants is relatively unknown. Here we use whole-genome and whole-methylome sequencing to test if a specific environmental stress (high-salinity soil) changes the frequency and molecular profile of accumulated mutations and epimutations (changes in cytosine methylation status) in mutation accumulation (MA) lineages of Arabidopsis thaliana. We first show that stressed lineages accumulate ∼100% more mutations, and that these mutations exhibit a distinctive molecular mutational spectrum (specific increases in relative frequency of transversion and insertion/deletion [indel] mutations). We next show that stressed lineages accumulate ∼45% more differentially methylated cytosine positions (DMPs) at CG sites (CG-DMPs) than controls, and also show that while many (∼75%) of these CG-DMPs are inherited, some can be lost in subsequent generations. Finally, we show that stress-associated CG-DMPs arise more frequently in genic than in nongenic regions of the genome. We suggest that commonly encountered natural environmental stresses can accelerate the accumulation and change the profiles of novel inherited variants in plants. Our findings are significant because stress exposure is common among plants in the wild, and they suggest that environmental factors may significantly alter the rates and patterns of incidence of the inherited novel variants that fuel plant evolution.

  10. Environmentally responsive genome-wide accumulation of de novo Arabidopsis thaliana mutations and epimutations

    KAUST Repository

    Jiang, Caifu; Mithani, Aziz; Belfield, Eric J.; Mott, Richard; Hurst, Laurence D.; Harberd, Nicholas P.

    2014-01-01

    Evolution is fueled by phenotypic diversity, which is in turn due to underlying heritable genetic (and potentially epigenetic) variation. While environmental factors are well known to influence the accumulation of novel variation in microorganisms and human cancer cells, the extent to which the natural environment influences the accumulation of novel variation in plants is relatively unknown. Here we use whole-genome and whole-methylome sequencing to test if a specific environmental stress (high-salinity soil) changes the frequency and molecular profile of accumulated mutations and epimutations (changes in cytosine methylation status) in mutation accumulation (MA) lineages of Arabidopsis thaliana. We first show that stressed lineages accumulate ∼100% more mutations, and that these mutations exhibit a distinctive molecular mutational spectrum (specific increases in relative frequency of transversion and insertion/deletion [indel] mutations). We next show that stressed lineages accumulate ∼45% more differentially methylated cytosine positions (DMPs) at CG sites (CG-DMPs) than controls, and also show that while many (∼75%) of these CG-DMPs are inherited, some can be lost in subsequent generations. Finally, we show that stress-associated CG-DMPs arise more frequently in genic than in nongenic regions of the genome. We suggest that commonly encountered natural environmental stresses can accelerate the accumulation and change the profiles of novel inherited variants in plants. Our findings are significant because stress exposure is common among plants in the wild, and they suggest that environmental factors may significantly alter the rates and patterns of incidence of the inherited novel variants that fuel plant evolution.

  11. HFE gene mutation is a risk factor for tissue iron accumulation in hemodialysis patients.

    Science.gov (United States)

    Turkmen, Ercan; Yildirim, Tolga; Yilmaz, Rahmi; Hazirolan, Tuncay; Eldem, Gonca; Yilmaz, Engin; Aybal Kutlugun, Aysun; Altindal, Mahmut; Altun, Bulent

    2017-07-01

    HFE gene mutations are responsible from iron overload in general population. Studies in hemodialysis patients investigated the effect of presence of HFE gene mutations on serum ferritin and transferrin saturation (TSAT) with conflicting results. However effect of HFE mutations on iron overload in hemodialysis patients was not previously extensively studied. 36 hemodialysis patients (age 51.3 ± 15.6, (18/18) male/female) and 44 healthy control subjects included in this cross sectional study. Hemoglobin, ferritin, TSAT in the preceding 2 years were recorded. Iron and erythropoietin (EPO) administered during this period were calculated. Iron accumulation in heart and liver was detected by MRI. Relationship between HFE gene mutation, hemoglobin, iron parameters and EPO doses, and tissue iron accumulation were determined. Iron overload was detected in nine (25%) patients. Hemoglobin, iron parameters, weekly EPO doses, and monthly iron doses of patients with and without iron overload were similar. There was no difference between control group and hemodialysis patients with respect to the prevalence of HFE gene mutations. Iron overload was detected in five of eight patients who had HFE gene mutations, but iron overload was present in 4 of 28 patients who had no mutations (P = 0.01). Hemoglobin, iron parameters, erythropoietin, and iron doses were similar in patients with and without gene mutations. HFE gene mutations remained the main determinant of iron overload after multivariate logistic regression analysis (P = 0.02; OR, 11.6). Serum iron parameters were not adequate to detect iron overload and HFE gene mutation was found to be an important risk factor for iron accumulation. © 2017 International Society for Hemodialysis.

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

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    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.

  13. Mutation accumulation and fitness effects in hybridogenetic populations: a comparison to sexual and asexual systems

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    Bagheri Homayoun C

    2007-05-01

    Full Text Available Abstract Background Female only unisexual vertebrates that reproduce by hybridogenesis show an unusual genetic composition. They are of hybrid origin but show no recombination between the genomes of their parental species. Instead, the paternal genome is discarded from the germline prior to meiosis, and gametes (eggs only contain solely unrecombined maternal genomes. Hence hybridogens only transmit maternally inherited mutations. Hybridity is restored each generation by backcrossing with males of the sexual parental species whose genome was eliminated. In contrast, recombining sexual species propagate an intermixed pool of mutations derived from the maternal and paternal parts of the genome. If mutation rates are lower in female gametes than males, it raises the possibility for lower mutation accumulation in a hybridogenetic population, and consequently, higher population fitness than its sexual counterpart. Results We show through Monte-Carlo simulations that at higher male to female mutation ratios, and sufficiently large population sizes, hybridogenetic populations can carry a lower mutation load than sexual species. This effect is more pronounced with synergistic forms of epistasis. Mutations accumulate faster on the sexual part of the genome, and with the purifying effects of epistasis, it makes it more difficult for mutations to be transmitted on the clonal part of the genome. In smaller populations, the same mechanism reduces the speed of Muller's Ratchet and the number of fixed mutations compared to similar asexual species. Conclusion Since mutation accumulation can be less pronounced in hybridogenetic populations, the question arises why hybridogenetic organisms are so scarce compared to sexual species. In considering this, it is likely that comparison of population fitnesses is not sufficient. Despite competition with the sexual parental species, hybrid populations are dependent on the maintenance of – and contact with – their

  14. Mutational analysis of PVX TGBp3 links subcellular accumulation and protein turnover

    International Nuclear Information System (INIS)

    Ju, H.-J.; Ye, C.-M.; Verchot-Lubicz, Jeanmarie

    2008-01-01

    Potato virus X (PVX) TGBp3 is required for virus cell-to-cell transport, has an N-terminal transmembrane domain, and a C-terminal cytosolic domain. In the absence of virus infection TGBp3:GFP is seen in the cortical and perinuclear ER. In PVX infected cells the TGBp3:GFP fusion is also seen in the nucleoplasm indicating that events during PVX infection trigger entry into the nucleus. Mutational analysis failed to identify a nuclear targeting domain. Mutations inhibiting TGBp3 association with the ER and inhibiting virus movement did not block TGBp3:GFP in the nucleoplasm. A mutation disrupting the N-terminal transmembrane domain of TGBp3 caused the fusion to accumulate in the nucleus indicating that nuclear import is regulated by ER interactions. Tunicamycin, an ER-stress inducing chemical, caused lower levels of GFP and TGBp3:GFP to accumulate in virus infected protoplasts. MG115 and MG132 were used to demonstrate that wild-type and mutant TGBp3:GFP fusions were degraded by the 26S proteasome. These observations are consistent with an ER-associated protein degradation (ERAD) pathway suggesting that PVX TGBp3, similar to aberrant ER proteins, is translocate to the cytoplasm for degradation. Nuclear accumulation of mutant and wild-type TGBp3:GFP is independent of other PVX proteins and may be another feature of an ERAD pathway

  15. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.

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    Deschauer, M; Gaul, C; Behrmann, C; Prokisch, H; Zierz, S; Haack, T B

    2012-11-01

    Mutations in C19orf12 have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three C19orf12-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that C19orf12 defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.

  16. Recurrent loss of sex is associated with accumulation of deleterious mutations in Oenothera.

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    Hollister, Jesse D; Greiner, Stephan; Wang, Wei; Wang, Jun; Zhang, Yong; Wong, Gane Ka-Shu; Wright, Stephen I; Johnson, Marc T J

    2015-04-01

    Sexual reproduction is nearly universal among eukaryotes. Theory predicts that the rarity of asexual eukaryotic species is in part caused by accumulation of deleterious mutations and heightened extinction risk associated with suppressed recombination and segregation in asexual species. We tested this prediction with a large data set of 62 transcriptomes from 29 species in the plant genus Oenothera, spanning ten independent transitions between sexual and a functionally asexual genetic system called permanent translocation heterozygosity. Illumina short-read sequencing and de novo transcript assembly yielded an average of 16.4 Mb of sequence per individual. Here, we show that functionally asexual species accumulate more deleterious mutations than sexual species using both population genomic and phylogenetic analysis. At an individual level, asexual species exhibited 1.8 × higher heterozygosity than sexual species. Within species, we detected a higher proportion of nonsynonymous polymorphism relative to synonymous variation within asexual compared with sexual species, indicating reduced efficacy of purifying selection. Asexual species also exhibited a greater proportion of transcripts with premature stop codons. The increased proportion of nonsynonymous mutations was also positively correlated with divergence time between sexual and asexual species, consistent with Muller's ratchet. Between species, we detected repeated increases in the ratio of nonsynonymous to synonymous divergence in asexual species compared with sexually reproducing sister taxa, indicating increased accumulation of deleterious mutations. These results confirm that an important advantage of sex is that it facilitates selection against deleterious alleles, which might help to explain the dearth of extant asexual species. © The Author 2014. 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.

  17. Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis.

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    Marchesi, Vincent T

    2016-02-01

    Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes. © FASEB.

  18. The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.

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    Kang, Jing-Qiong; Shen, Wangzhen; Zhou, Chengwen; Xu, Dong; Macdonald, Robert L

    2015-07-01

    Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far-reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases.

  19. Antagonistic pleiotropy and mutation accumulation contribute to age-related decline in stress response.

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    Everman, Elizabeth R; Morgan, Theodore J

    2018-02-01

    As organisms age, the effectiveness of natural selection weakens, leading to age-related decline in fitness-related traits. The evolution of age-related changes associated with senescence is likely influenced by mutation accumulation (MA) and antagonistic pleiotropy (AP). MA predicts that age-related decline in fitness components is driven by age-specific sets of alleles, nonnegative genetic correlations within trait across age, and an increase in the coefficient of genetic variance. AP predicts that age-related decline in a trait is driven by alleles with positive effects on fitness in young individuals and negative effects in old individuals, and is expected to lead to negative genetic correlations within traits across age. We build on these predictions using an association mapping approach to investigate the change in additive effects of SNPs across age and among traits for multiple stress-response fitness-related traits, including cold stress with and without acclimation and starvation resistance. We found support for both MA and AP theories of aging in the age-related decline in stress tolerance. Our study demonstrates that the evolution of age-related decline in stress tolerance is driven by a combination of alleles that have age-specific additive effects, consistent with MA, as well as nonindependent and antagonistic genetic architectures characteristic of AP. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

  20. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

    Science.gov (United States)

    Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam

    2018-01-01

    Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. PMID:29488881

  1. Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons.

    Science.gov (United States)

    Schapansky, Jason; Khasnavis, Saurabh; DeAndrade, Mark P; Nardozzi, Jonathan D; Falkson, Samuel R; Boyd, Justin D; Sanderson, John B; Bartels, Tim; Melrose, Heather L; LaVoie, Matthew J

    2018-03-01

    Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

    Science.gov (United States)

    Ye, Qi; Kim, Jonghan

    2016-06-01

    Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn.

  3. Fitness decline under osmotic stress in Caenorhabditis elegans populations subjected to spontaneous mutation accumulation at varying population sizes.

    Science.gov (United States)

    Katju, Vaishali; Packard, Lucille B; Keightley, Peter D

    2018-04-01

    The consequences of mutations for population fitness depends on their individual selection coefficients and the effective population size. An earlier study of Caenorhabditis elegans spontaneous mutation accumulation lines evolved for 409 generations at three population sizes found that N e   = 1 populations declined significantly in fitness whereas the fitness of larger populations (N e   = 5, 50) was indistinguishable from the ancestral control under benign conditions. To test if larger MA populations harbor a load of cryptic deleterious mutations that are obscured under benign laboratory conditions, we measured fitness under osmotic stress via exposure to hypersaline conditions. The fitness of N e   = 1 lines exhibited a further decline under osmotic stress compared to benign conditions. However, the fitness of larger populations remained indistinguishable from that of the ancestral control. The average effects of deleterious mutations in N e   = 1 lines were estimated to be 22% for productivity and 14% for survivorship, exceeding values previously detected under benign conditions. Our results suggest that fitness decline is due to large effect mutations that are rapidly removed via selection even in small populations, with implications for conservation practices. Genetic stochasticity may not be as potent and immediate a threat to the persistence of small populations as other demographic and environmental stochastic factors. © 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.

  4. ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function.

    Science.gov (United States)

    Suh, Jaehong; Choi, Se Hoon; Romano, Donna M; Gannon, Moira A; Lesinski, Andrea N; Kim, Doo Yeon; Tanzi, Rudolph E

    2013-10-16

    The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by α-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated α-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished α-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis.

    Science.gov (United States)

    Frisch, Amos; Colombo, Roberto; Michaelovsky, Elena; Karpati, Mazal; Goldman, Boleslaw; Peleg, Leah

    2004-03-01

    The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

  6. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells

    Science.gov (United States)

    Bagley, Pamela J.; Selhub, Jacob

    1998-01-01

    A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) (5-methyltetrahydrofolate:(acceptor) oxidoreductase, EC 1.7.99.5), a key regulatory enzyme in one-carbon metabolism, results in a thermolabile variant of the MTHFR enzyme with reduced activity in vitro. In the present study we used a chromatographic method for folate analysis to test the hypothesis that this mutation would be associated with altered distribution of red blood cell (RBC) folates. An alteration was found as manifested by the presence of formylated tetrahydrofolate polyglutamates in addition to methylated derivatives in the RBCs from homozygous mutant individuals. 5-Methyltetrahydrofolate polyglutamates were the only folate form found in RBCs from individuals with the wild-type genotype. Existence of formylated folates in RBCs only from individuals with the thermolabile MTHFR is consistent with the hypothesis that there is in vivo impairment in the activity of the thermolabile variant of MTHFR and that this impairment results in an altered distribution of RBC folates. PMID:9789068

  7. Mutation of a Rice Gene Encoding a Phenylalanine Biosynthetic Enzyme Results in Accumulation of Phenylalanine and Tryptophan[W

    Science.gov (United States)

    Yamada, Tetsuya; Matsuda, Fumio; Kasai, Koji; Fukuoka, Shuichi; Kitamura, Keisuke; Tozawa, Yuzuru; Miyagawa, Hisashi; Wakasa, Kyo

    2008-01-01

    Two distinct biosynthetic pathways for Phe in plants have been proposed: conversion of prephenate to Phe via phenylpyruvate or arogenate. The reactions catalyzed by prephenate dehydratase (PDT) and arogenate dehydratase (ADT) contribute to these respective pathways. The Mtr1 mutant of rice (Oryza sativa) manifests accumulation of Phe, Trp, and several phenylpropanoids, suggesting a link between the synthesis of Phe and Trp. Here, we show that the Mtr1 mutant gene (mtr1-D) encodes a form of rice PDT with a point mutation in the putative allosteric regulatory region of the protein. Transformed callus lines expressing mtr1-D exhibited all the characteristics of Mtr1 callus tissue. Biochemical analysis revealed that rice PDT possesses both PDT and ADT activities, with a preference for arogenate as substrate, suggesting that it functions primarily as an ADT. The wild-type enzyme is feedback regulated by Phe, whereas the mutant enzyme showed a reduced feedback sensitivity, resulting in Phe accumulation. In addition, these observations indicate that rice PDT is critical for regulating the size of the Phe pool in plant cells. Feeding external Phe to wild-type callus tissue and seedlings resulted in Trp accumulation, demonstrating a connection between Phe accumulation and Trp pool size. PMID:18487352

  8. Mutation of the Glucosinolate Biosynthesis Enzyme Cytochrome P450 83A1 Monooxygenase Increases Camalexin Accumulation and Powdery Mildew Resistance.

    Science.gov (United States)

    Liu, Simu; Bartnikas, Lisa M; Volko, Sigrid M; Ausubel, Frederick M; Tang, Dingzhong

    2016-01-01

    Small secondary metabolites, including glucosinolates and the major phytoalexin camalexin, play important roles in immunity in Arabidopsis thaliana. We isolated an Arabidopsis mutant with increased resistance to the powdery mildew fungus Golovinomyces cichoracearum and identified a mutation in the gene encoding cytochrome P450 83A1 monooxygenase (CYP83A1), which functions in glucosinolate biosynthesis. The cyp83a1-3 mutant exhibited enhanced defense responses to G. cichoracearum and double mutant analysis showed that this enhanced resistance requires NPR1, EDS1, and PAD4, but not SID2 or EDS5. In cyp83a1-3 mutants, the expression of genes related to camalexin synthesis increased upon G. cichoracearum infection. Significantly, the cyp83a1-3 mutant also accumulated higher levels of camalexin. Decreasing camalexin levels by mutation of the camalexin synthetase gene PAD3 or the camalexin synthesis regulator AtWRKY33 compromised the powdery mildew resistance in these mutants. Consistent with these observations, overexpression of PAD3 increased camalexin levels and enhanced resistance to G. cichoracearum. Taken together, our data indicate that accumulation of higher levels of camalexin contributes to increased resistance to powdery mildew.

  9. Mutation of the glucosinolate biosynthesis enzyme cytochrome P450 83A1 monooxygenase increases camalexin accumulation and powdery mildew resistance

    Directory of Open Access Journals (Sweden)

    Simu eLiu

    2016-03-01

    Full Text Available Small secondary metabolites, including glucosinolates and the major phytoalexin camalexin, play important roles in immunity in Arabidopsis thaliana. We isolated an Arabidopsis mutant with increased resistance to the powdery mildew fungus Golovinomyces cichoracearum and identified a mutation in the gene encoding cytochrome P450 83A1 monooxygenase (CYP83A1, which functions in glucosinolate biosynthesis. The cyp83a1-3 mutant exhibited enhanced defense responses to G. cichoracearum and double mutant analysis showed that this enhanced resistance requires NPR1, EDS1, and PAD4, but not SID2 or EDS5. In cyp83a1-3 mutants, the expression of genes related to camalexin synthesis increased upon G. cichoracearum infection. Significantly, the cyp83a1-3 mutant also accumulated higher levels of camalexin. Decreasing camalexin levels by mutation of the camalexin synthetase gene PAD3 or the camalexin synthesis regulator AtWRKY33 compromised the powdery mildew resistance in these mutants. Consistent with these observations, overexpression of PAD3 increased camalexin levels and enhanced resistance to G. cichoracearum. Taken together, our data indicate that accumulation of higher levels of camalexin contributes to increased resistance to powdery mildew.

  10. NEW HYPOTHESIS AND ELECTROPHYSICS NATURE OF ADDITIONAL MECHANISMS OF ORIGIN, ACCUMULATION AND DIVISION OF ELECTRIC CHARGES IN THE ATMOSPHERIC CLOUDS OF EARTH

    Directory of Open Access Journals (Sweden)

    M. I. Baranov

    2018-02-01

    Full Text Available Purpose. Development of new hypothesis about the possible additional mechanisms of origin, accumulation and division of electric charges in atmospheric clouds, containing shallow dispersible drops of water, shallow particulate dielectric matters and crystals of ice. Methodology. Electrophysics bases of technique of high voltage, theoretical bases of the electrical engineering, theoretical electrophysics, theory of the electromagnetic field, technique of the high electric and magnetic fields. Results. Pulled out and grounded new scientific supposition, related to possible existence in earthly troposphere of additional mechanisms of origin, accumulation and division of electric charges in the atmospheric clouds of Earth, being based on electrization in the warm ascending currents of air of shallow round particulate dielectric matters, getting in an air atmosphere from a terrene and from the smoke extras of industrial enterprises. By a calculation a way it is shown that the offered additional electrophysics mechanisms are able to provide achievement in the atmospheric clouds of such values of volume closeness of charges, total electric charge and tension of the electrostatic field stocked in them inwardly and on the external border of storm clouds which correspond modern experimental information from an area atmospheric electricity. The calculation estimations of levels of electric potential and stocked electric energy executed on the basis of the offered hypothesis in storm clouds specify on possibility of receipt in them of ever higher electric potentials and large supplies of electric energy. The obtained results are supplemented by the known approaches of forming and development in earthly troposphere of the electric charged atmospheric clouds, being based on electrization in the warm ascending streams of air the masses of shallow round aquatic drops. Originality. First on the basis of the well-known theses of technique and electrophysics of

  11. More about the Viking hypothesis of origin of the delta32 mutation in the CCR5 gene conferring resistance to HIV-1 infection.

    Science.gov (United States)

    Lucotte, Gérard; Dieterlen, Florent

    2003-11-01

    The chemokine receptor CCR5 constitutes the major coreceptor for the HIV-1, because a mutant allele of the CCR5 gene named delta32 was shown to provide to homozygotes a strong resistance against infection. In the present study the frequency of the delta32 allele was collected in 36 European populations and in Cyprus, and the highest allele frequencies were found in Nordic countries. We constructed an allele map of delta32 frequencies in Europe; the map is in accordance to the Vikings hypothesis of the origin of the mutation and his dissemination during the eighth to the tenth centuries.

  12. Ubiquinone accumulates in the mitochondria of yeast mutated in the ubiquinone binding protein, Qcr8p

    International Nuclear Information System (INIS)

    Hagerman, Ruth A.; Waring, Natashya J.; Willis, Richard A.; Hagerman, Ann E.

    2006-01-01

    In Saccharomyces cerevisiae, the trans-membrane helix of Qcr8p, the ubiquinone binding protein of complex III, contributes to the Q binding site. In wild-type cells, residue 62 of the helix is non-polar (proline). Substitution of proline 62 with a polar, uncharged residue does not impair the ability of the cells to respire, complex III assembly is unaffected, ubiquinone occupancy of the Q binding site is unchanged, and mitochondrial ubiquinone levels are in the wild-type range. Substitution with a +1 charged residue is associated with partial respiratory competence, impaired complex III assembly, and loss of cytochrome b. Although ubiquinone occupancy of the Q binding site is similar to wild-type, total mitochondrial ubiquinone doubled in these mutants. Mutants with a +2 charged substitution at position 62 are unable to respire. These results suggest that the accumulation of ubiquinone in the mitochondria may be a compensatory mechanism for impaired electron transport at cytochrome b

  13. Deep sequencing shows that oocytes are not prone to accumulate mtDNA heteroplasmic mutations during ovarian ageing.

    Science.gov (United States)

    Boucret, L; Bris, C; Seegers, V; Goudenège, D; Desquiret-Dumas, V; Domin-Bernhard, M; Ferré-L'Hotellier, V; Bouet, P E; Descamps, P; Reynier, P; Procaccio, V; May-Panloup, P

    2017-10-01

    Does ovarian ageing increase the number of heteroplasmic mitochondrial DNA (mtDNA) point mutations in oocytes? Our results suggest that oocytes are not subject to the accumulation of mtDNA point mutations during ovarian ageing. Ageing is associated with the alteration of mtDNA integrity in various tissues. Primary oocytes, present in the ovary since embryonic life, may accumulate mtDNA mutations during the process of ovarian ageing. This was an observational study of 53 immature oocyte-cumulus complexes retrieved from 35 women undergoing IVF at the University Hospital of Angers, France, from March 2013 to March 2014. The women were classified in two groups, one including 19 women showing signs of ovarian ageing objectified by a diminished ovarian reserve (DOR), and the other, including 16 women with a normal ovarian reserve (NOR), which served as a control group. mtDNA was extracted from isolated oocytes, and from their corresponding cumulus cells (CCs) considered as a somatic cell compartment. The average mtDNA content of each sample was assessed by using a quantitative real-time PCR technique. Deep sequencing was performed using the Ion Torrent Proton for Next-Generation Sequencing. Signal processing and base calling were done by the embedded pre-processing pipeline and the variants were analyzed using an in-house workflow. The distribution of the different variants between DOR and NOR patients, on one hand, and oocyte and CCs, on the other, was analyzed with the generalized mixed linear model to take into account the cluster of cells belonging to a given mother. There were no significant differences between the numbers of mtDNA variants between the DOR and the NOR patients, either in the oocytes (P = 0.867) or in the surrounding CCs (P = 0.154). There were also no differences in terms of variants with potential functional consequences. De-novo mtDNA variants were found in 28% of the oocytes and in 66% of the CCs with the mean number of variants being

  14. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa.

    Science.gov (United States)

    Sigaloff, Kim C E; Hamers, Raph L; Wallis, Carole L; Kityo, Cissy; Siwale, Margaret; Ive, Prudence; Botes, Mariette E; Mandaliya, Kishor; Wellington, Maureen; Osibogun, Akin; Stevens, Wendy S; van Vugt, Michèle; de Wit, Tobias F Rinke

    2011-09-01

    This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (≥2 TAMs or Q151M or K65R/K70E). Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA <1000 copies per milliliter occurred in 46.9% of CIF only patients versus 12.4% of patients with targeted VL (P < 0.001). NRTI cross-resistance was observed in 48.0% of 183 specimens available for genotypic analysis, comprising ≥2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross-resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Africa.

  15. 'SEEDY' (Simulation of Evolutionary and Epidemiological Dynamics: An R Package to Follow Accumulation of Within-Host Mutation in Pathogens.

    Directory of Open Access Journals (Sweden)

    Colin J Worby

    Full Text Available Genome sequencing is an increasingly common component of infectious disease outbreak investigations. However, the relationship between pathogen transmission and observed genetic data is complex, and dependent on several uncertain factors. As such, simulation of pathogen dynamics is an important tool for interpreting observed genomic data in an infectious disease outbreak setting, in order to test hypotheses and to explore the range of outcomes consistent with a given set of parameters. We introduce 'seedy', an R package for the simulation of evolutionary and epidemiological dynamics (http://cran.r-project.org/web/packages/seedy/. Our software implements stochastic models for the accumulation of mutations within hosts, as well as individual-level disease transmission. By allowing variables such as the transmission bottleneck size, within-host effective population size and population mixing rates to be specified by the user, our package offers a flexible framework to investigate evolutionary dynamics during disease outbreaks. Furthermore, our software provides theoretical pairwise genetic distance distributions to provide a likelihood of person-to-person transmission based on genomic observations, and using this framework, implements transmission route assessment for genomic data collected during an outbreak. Our open source software provides an accessible platform for users to explore pathogen evolution and outbreak dynamics via simulation, and offers tools to assess observed genomic data in this context.

  16. A new look at an old virus: patterns of mutation accumulation in the human H1N1 influenza virus since 1918

    Directory of Open Access Journals (Sweden)

    Carter Robert W

    2012-10-01

    Full Text Available Abstract Background The H1N1 influenza A virus has been circulating in the human population for over 95 years, first manifesting itself in the pandemic of 1917–1918. Initial mortality was extremely high, but dropped exponentially over time. Influenza viruses have high mutation rates, and H1N1 has undergone significant genetic changes since 1918. The exact nature of H1N1 mutation accumulation over time has not been fully explored. Methods We have made a comprehensive historical analysis of mutational changes within H1N1 by examining over 4100 fully-sequenced H1N1 genomes. This has allowed us to examine the genetic changes arising within H1N1 from 1918 to the present. Results We document multiple extinction events, including the previously known extinction of the human H1N1 lineage in the 1950s, and an apparent second extinction of the human H1N1 lineage in 2009. These extinctions appear to be due to a continuous accumulation of mutations. At the time of its disappearance in 2009, the human H1N1 lineage had accumulated over 1400 point mutations (more than 10% of the genome, including approximately 330 non-synonymous changes (7.4% of all codons. The accumulation of both point mutations and non-synonymous amino acid changes occurred at constant rates (μ = 14.4 and 2.4 new mutations/year, respectively, and mutations accumulated uniformly across the entire influenza genome. We observed a continuous erosion over time of codon-specificity in H1N1, including a shift away from host (human, swine, and bird [duck] codon preference patterns. Conclusions While there have been numerous adaptations within the H1N1 genome, most of the genetic changes we document here appear to be non-adaptive, and much of the change appears to be degenerative. We suggest H1N1 has been undergoing natural genetic attenuation, and that significant attenuation may even occur during a single pandemic. This process may play a role in natural pandemic cessation and has apparently

  17. Coulomb Failure Stress Accumulation in Nepal After the 2015 Mw 7.8 Gorkha Earthquake: Testing Earthquake Triggering Hypothesis and Evaluating Seismic Hazards

    Science.gov (United States)

    Xiong, N.; Niu, F.

    2017-12-01

    A Mw 7.8 earthquake struck Gorkha, Nepal, on April 5, 2015, resulting in more than 8000 deaths and 3.5 million homeless. The earthquake initiated 70km west of Kathmandu and propagated eastward, rupturing an area of approximately 150km by 60km in size. However, the earthquake failed to fully rupture the locked fault beneath the Himalaya, suggesting that the region south of Kathmandu and west of the current rupture are still locked and a much more powerful earthquake might occur in future. Therefore, the seismic hazard of the unruptured region is of great concern. In this study, we investigated the Coulomb failure stress (CFS) accumulation on the unruptured fault transferred by the Gorkha earthquake and some nearby historical great earthquakes. First, we calculated the co-seismic CFS changes of the Gorkha earthquake on the nodal planes of 16 large aftershocks to quantitatively examine whether they were brought closer to failure by the mainshock. It is shown that at least 12 of the 16 aftershocks were encouraged by an increase of CFS of 0.1-3 MPa. The correspondence between the distribution of off-fault aftershocks and the increased CFS pattern also validates the applicability of the earthquake triggering hypothesis in the thrust regime of Nepal. With the validation as confidence, we calculated the co-seismic CFS change on the locked region imparted by the Gorkha earthquake and historical great earthquakes. A newly proposed ramp-flat-ramp-flat fault geometry model was employed, and the source parameters of historical earthquakes were computed with the empirical scaling relationship. A broad region south of the Kathmandu and west of the current rupture were shown to be positively stressed with CFS change roughly ranging between 0.01 and 0.5 MPa. The maximum of CFS increase (>1MPa) was found in the updip segment south of the current rupture, implying a high seismic hazard. Since the locked region may be additionally stressed by the post-seismic relaxation of the lower

  18. Mutations that alter a conserved element upstream of the potato virus X triple block and coat protein genes affect subgenomic RNA accumulation.

    Science.gov (United States)

    Kim, K H; Hemenway, C

    1997-05-26

    The putative subgenomic RNA (sgRNA) promoter regions upstream of the potato virus X (PVX) triple block and coat protein (CP) genes contain sequences common to other potexviruses. The importance of these sequences to PVX sgRNA accumulation was determined by inoculation of Nicotiana tabacum NT1 cell suspension protoplasts with transcripts derived from wild-type and modified PVX cDNA clones. Analyses of RNA accumulation by S1 nuclease digestion and primer extension indicated that a conserved octanucleotide sequence element and the spacing between this element and the start-site for sgRNA synthesis are critical for accumulation of the two major sgRNA species. The impact of mutations on CP sgRNA levels was also reflected in the accumulation of CP. In contrast, genomic minus- and plus-strand RNA accumulation were not significantly affected by mutations in these regions. Studies involving inoculation of tobacco plants with the modified transcripts suggested that the conserved octanucleotide element functions in sgRNA accumulation and some other aspect of the infection process.

  19. The (not so) immortal strand hypothesis.

    Science.gov (United States)

    Tomasetti, Cristian; Bozic, Ivana

    2015-03-01

    Non-random segregation of DNA strands during stem cell replication has been proposed as a mechanism to minimize accumulated genetic errors in stem cells of rapidly dividing tissues. According to this hypothesis, an "immortal" DNA strand is passed to the stem cell daughter and not the more differentiated cell, keeping the stem cell lineage replication error-free. After it was introduced, experimental evidence both in favor and against the hypothesis has been presented. Using a novel methodology that utilizes cancer sequencing data we are able to estimate the rate of accumulation of mutations in healthy stem cells of the colon, blood and head and neck tissues. We find that in these tissues mutations in stem cells accumulate at rates strikingly similar to those expected without the protection from the immortal strand mechanism. Utilizing an approach that is fundamentally different from previous efforts to confirm or refute the immortal strand hypothesis, we provide evidence against non-random segregation of DNA during stem cell replication. Our results strongly suggest that parental DNA is passed randomly to stem cell daughters and provides new insight into the mechanism of DNA replication in stem cells. Copyright © 2015. Published by Elsevier B.V.

  20. Role of Mitochondrial DNA Mutations in Cellular Vulnerability to Mitochondria-Specific Environmental Toxins

    National Research Council Canada - National Science Library

    Hirsch, Etienne C

    2005-01-01

    .... To test such a hypothesis in Parkinson's disease we proposed to: 1) develop an animal model with accumulated mtDNA mutations in catecholaminergic neurons by creating a transgenic mouse containing a tyrosine hydroxylase (TH...

  1. A nonsense mutation in the beta-carotene oxygenase 2 (BCO2 gene is tightly associated with accumulation of carotenoids in adipose tissue in sheep (Ovis aries

    Directory of Open Access Journals (Sweden)

    Boman Inger A

    2010-02-01

    Full Text Available Abstract Background Sheep carcasses with yellow fat are sporadically observed at Norwegian slaughter houses. This phenomenon is known to be inherited as a recessive trait, and is caused by accumulation of carotenoids in adipose tissue. Two enzymes are known to be important in carotenoid degradation in mammals, and are therefore potential candidate genes for this trait. These are beta-carotene 15,15'-monooxygenase 1 (BCMO1 and the beta-carotene oxygenase 2 (BCO2. Results In the present study the coding region of the BCMO1 and the BCO2 gene were sequenced in yellow fat individuals and compared to the corresponding sequences from control animals with white fat. In the yellow fat individuals a nonsense mutation was found in BCO2 nucleotide position 196 (c.196C>T, introducing a stop codon in amino acid position 66. The full length protein consists of 575 amino acids. In spite of a very low frequency of this mutation in the Norwegian AI-ram population, 16 out of 18 yellow fat lambs were found to be homozygous for this mutation. Conclusion In the present study a nonsense mutation (c.196C>T in the beta-carotene oxygenase 2 (BCO2 gene is found to strongly associate with the yellow fat phenotype in sheep. The existence of individuals lacking this mutation, but still demonstrating yellow fat, suggests that additional mutations may cause a similar phenotype in this population. The results demonstrate a quantitatively important role for BCO2 in carotenoid degradation, which might indicate a broad enzyme specificity for carotenoids. Animals homozygous for the mutation are not reported to suffer from any negative health or development traits, pointing towards a minor role of BCO2 in vitamin A formation. Genotyping AI rams for c.196C>T can now be actively used in selection against the yellow fat trait.

  2. Plum pox virus accumulates mutations in different genome parts during a long-term maintenance in Prunus host plants and passage in Nicotiana benthamiana.

    Science.gov (United States)

    Vozárová, Z; Kamencayová, M; Glasa, M; Subr, Z

    2013-01-01

    Plum pox virus (PPV) isolates of the strain PPV-M prevalently infect peaches under natural conditions in Middle Europe. Comparison of complete genome sequences obtained from subisolates of a PPV-M isolate maintained experimentally over a 6-year period in different Prunus host species and passaged in Nicotiana benthamiana was performed with the aim to highlight the mutations potentially connected with the virus-host adaptation. The results showed that the lowest number of non-silent mutations was accumulated in PPV-M maintained in peach (original host species), approximately two times higher diversity was recorded in plum, apricot and N. benthamiana, indicating the genetic determination of the PPV host preference. The sequence variability of Prunus subisolates was distributed more or less evenly along the PPV genome and no amino acid motif could be outlined as responsible for the host adaptation. In N. benthamiana the mutations were accumulated notably in the P1 and P3 genes indicating their non-essentiality in the infection of this experimental host plant.

  3. Effects of Point Mutations in the Major Capsid Protein of Beet Western Yellows Virus on Capsid Formation, Virus Accumulation, and Aphid Transmission

    Science.gov (United States)

    Brault, V.; Bergdoll, M.; Mutterer, J.; Prasad, V.; Pfeffer, S.; Erdinger, M.; Richards, K. E.; Ziegler-Graff, V.

    2003-01-01

    Point mutations were introduced into the major capsid protein (P3) of cloned infectious cDNA of the polerovirus beet western yellows virus (BWYV) by manipulation of cloned infectious cDNA. Seven mutations targeted sites on the S domain predicted to lie on the capsid surface. An eighth mutation eliminated two arginine residues in the R domain, which is thought to extend into the capsid interior. The effects of the mutations on virus capsid formation, virus accumulation in protoplasts and plants, and aphid transmission were tested. All of the mutants replicated in protoplasts. The S-domain mutant W166R failed to protect viral RNA from RNase attack, suggesting that this particular mutation interfered with stable capsid formation. The R-domain mutant R7A/R8A protected ∼90% of the viral RNA strand from RNase, suggesting that lower positive-charge density in the mutant capsid interior interfered with stable packaging of the complete strand into virions. Neither of these mutants systemically infected plants. The six remaining mutants properly packaged viral RNA and could invade Nicotiana clevelandii systemically following agroinfection. Mutant Q121E/N122D was poorly transmitted by aphids, implicating one or both targeted residues in virus-vector interactions. Successful transmission of mutant D172N was accompanied either by reversion to the wild type or by appearance of a second-site mutation, N137D. This finding indicates that D172 is also important for transmission but that the D172N transmission defect can be compensated for by a “reverse” substitution at another site. The results have been used to evaluate possible structural models for the BWYV capsid. PMID:12584348

  4. Mutation of the regulatory phosphorylation site of tobacco nitrate reductase results in constitutive activation of the enzyme in vivo and nitrite accumulation.

    Science.gov (United States)

    Lillo, Cathrine; Lea, Unni S; Leydecker, Marie-Thérèse; Meyer, Christian

    2003-09-01

    In wild-type Nicotiana plumbaginifolia and other higher plants, nitrate reductase (NR) is rapidly inactivated/activated in response to dark/light transitions. Inactivation of NR is believed to be caused by phosphorylation at a special conserved regulatory Ser residue, Ser 521, and interactions with divalent cations and inhibitory 14-3-3 proteins. A transgenic N. plumbaginifolia line (S(521)) was constructed where the Ser 521 had been changed by site-directed mutagenesis into Asp. This mutation resulted in complete abolishment of inactivation in response to light/dark transitions or other treatments known to inactivate NR. During prolonged darkness, NR in wild-type plants is in the inactivated form, whereas NR in the S(521) line is always in the active form. Differences in degradation rate between NR from S(521) and lines with non-mutated NR were not found. Kinetic constants like Km values for NADH and NO3(-) were not changed, but a slightly different pH profile was observed for mutated NR as opposed to non-mutated NR. Under optimal growth conditions, the phenotype of the S(521) plants was not different from the wild type (WT). However, when plants were irrigated with high nitrate concentration, 150 mM, the transgenic plants accumulated nitrite in darkness, and young leaves showed chlorosis.

  5. Mutations that alter a repeated ACCA element located at the 5' end of the Potato virus X genome affect RNA accumulation.

    Science.gov (United States)

    Park, Mi-Ri; Kwon, Sun-Jung; Choi, Hong-Soo; Hemenway, Cynthia L; Kim, Kook-Hyung

    2008-08-15

    The repeated ACCA or AC-rich sequence and structural (SL1) elements in the 5' non-translated region (NTR) of the Potato virus X (PVX) RNA play vital roles in the PVX life cycle by controlling translation, RNA replication, movement, and assembly. It has already been shown that the repeated ACCA or AC-rich sequence affect both gRNA and sgRNA accumulation, while not affecting minus-strand RNA accumulation, and are also required for host protein binding. The functional significance of the repeated ACCA sequence elements in the 5' NTR region was investigated by analyzing the effects of deletion and site-directed mutations on PVX replication in Nicotiana benthamiana plants and NT1 protoplasts. Substitution (ACCA into AAAA or UUUU) mutations introduced in the first (nt 10-13) element in the 5' NTR of the PVX RNA significantly affected viral replication, while mutations introduced in the second (nt 17-20) and third (nt 20-23) elements did not. The fourth (nt 29-32) ACCA element weakly affected virus replication, whereas mutations in the fifth (nt 38-41) significantly reduced virus replication due to the structure disruption of SL1 by AAAA and/or UUUU substitutions. Further characterization of the first ACCA element indicated that duplication of ACCA at nt 10-13 (nt 10-17, ACCAACCA) caused severe symptom development as compared to that of wild type, while deletion of the single element (nt 10-13), DeltaACCA) or tripling of this element caused reduced symptom development. Single- and double-nucleotide substitutions introduced into the first ACCA element revealed the importance of CC located at nt positions 11 and 12. Altogether, these results indicate that the first ACCA element is important for PVX replication.

  6. Effect of CCS on the accumulation of FALS SOD1 mutant-containing aggregates and on mitochondrial translocation of SOD1 mutants: implication of a free radical hypothesis.

    Science.gov (United States)

    Kim, Ha Kun; Chung, Youn Wook; Chock, P Boon; Yim, Moon B

    2011-05-15

    Missense mutations of SOD1 are linked to familial amyotrophic lateral sclerosis (FALS) through a yet-to-be identified toxic-gain-of-function. One of the proposed mechanisms involves enhanced aggregate formation. However, a recent study showed that dual transgenic mice overexpressing both G93A and CCS copper chaperone (G93A/CCS) exhibit no SOD1-positive aggregates yet show accelerated FALS symptoms with enhanced mitochondrial pathology compared to G93A mice. Using a dicistronic mRNA to simultaneously generate hSOD1 mutants, G93A, A4V and G85R, and hCCS in AAV293 cells, we revealed: (i) CCS is degraded primarily via a macroautophagy pathway. It forms a stable heterodimer with inactive G85R, and via its novel copper chaperone-independent molecular chaperone activity facilitates G85R degradation via a macroautophagy-mediated pathway. For active G93A and A4V, CCS catalyzes their maturation to form active and soluble homodimers. (ii) CCS reduces, under non-oxidative conditions, yet facilitates in the presence of H(2)O(2), mitochondrial translocation of inactive SOD1 mutants. These results, together with previous reports showing FALS SOD1 mutants enhanced free radical-generating activity, provide a mechanistic explanation for the observations with G93A/CCS dual transgenic mice and suggest that free radical generation by FALS SOD1, enhanced by CCS, may, in part, be responsible for the FALS SOD1 mutant-linked aggregation, mitochondrial translocation, and degradation. Published by Elsevier Inc.

  7. Impaired Malate and Fumarate Accumulation Due to the Mutation of the Tonoplast Dicarboxylate Transporter Has Little Effects on Stomatal Behavior.

    Science.gov (United States)

    Medeiros, David B; Barros, Kallyne A; Barros, Jessica Aline S; Omena-Garcia, Rebeca P; Arrivault, Stéphanie; Sanglard, Lílian M V P; Detmann, Kelly C; Silva, Willian Batista; Daloso, Danilo M; DaMatta, Fábio M; Nunes-Nesi, Adriano; Fernie, Alisdair R; Araújo, Wagner L

    2017-11-01

    Malate is a central metabolite involved in a multiplicity of plant metabolic pathways, being associated with mitochondrial metabolism and playing significant roles in stomatal movements. Vacuolar malate transport has been characterized at the molecular level and is performed by at least one carrier protein and two channels in Arabidopsis ( Arabidopsis thaliana ) vacuoles. The absence of the Arabidopsis tonoplast Dicarboxylate Transporter (tDT) in the tdt knockout mutant was associated previously with an impaired accumulation of malate and fumarate in leaves. Here, we investigated the consequences of this lower accumulation on stomatal behavior and photosynthetic capacity as well as its putative metabolic impacts. Neither the stomatal conductance nor the kinetic responses to dark, light, or high CO 2 were highly affected in tdt plants. In addition, we did not observe any impact on stomatal aperture following incubation with abscisic acid, malate, or citrate. Furthermore, an effect on photosynthetic capacity was not observed in the mutant lines. However, leaf mitochondrial metabolism was affected in the tdt plants. Levels of the intermediates of the tricarboxylic acid cycle were altered, and increases in both light and dark respiration were observed. We conclude that manipulation of the tonoplastic organic acid transporter impacted mitochondrial metabolism, while the overall stomatal and photosynthetic capacity were unaffected. © 2017 American Society of Plant Biologists. All Rights Reserved.

  8. Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa.

    Science.gov (United States)

    Goodall, Ruth L; Dunn, David T; Nkurunziza, Peter; Mugarura, Lincoln; Pattery, Theresa; Munderi, Paula; Kityo, Cissy; Gilks, Charles; Kaleebu, Pontiano; Pillay, Deenan; Gupta, Ravindra K

    2017-05-01

    Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting. A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics). At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P  =   0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P  =   0.18). Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

  9. [Genome loses all 5-methylcytosine a life span. How is this connected with accumulation of mutations during aging?].

    Science.gov (United States)

    Mazin, A L

    1993-01-01

    The 5-methylcytosine (5mC) content in liver DNA has been determined for rats of different age. The rate of the 5mC loss from DNA is maximal in pre- and neonatal rats, 1.28% of reduction of the 5mC content per day, then it decreases to 0.33% and becomes minimal and constant in adult rats, 0.028% per day. During pregnancy and the first 15 days of postnatal development rat genome loses 49% of all 5mC. Within the next 45 days 15% of 5mC disappears, and during maximal rat life span, about four years, 39% of the genomic 5mC may be lost. Thus, it has been found for the first time that the animal genome loses practically all 5mC residues during the life span. Analysis of the literature data shows that for embryos the rate of the 5mC loss from DNA proves to be higher than that for adult animals by 96 times for mice, 69-for rats and 28-for cows. The rate of embryonal DNA hypomethylation may be inversely proportional to the pregnancy duration of species. In adult animals the rate inversely correlates with their maximal life span and accounts for the 5mC loss from DNA of a mouse by 0.028%, of a rat by 0.024%, of a hamster by 0.007%, of a cow by 0.004% and of a human being by 0.0005% per day. During the entire ontogenesis, the genome of a mouse loses 93% of all 5mC residues, that of a rat-101% and of a cow-88%. The age-dependent loss of 5mC from DNA is also typical for cell lines aging in vitro. It is constant, as a rule, and correlates with the number of cell population doublings (PD). The removal of all 5mC from DNA corresponds to 70-130 PD for human, 40-60 PD-for hamster and 6 PD- for mouse cells. In immortal lines the level of DNA methylation is stable or grows with age. A possible mechanism of an age-related 5mC loss from DNA is discussed. DNA hypomethylation may result from 5mC deamination directly at the moment of replicative DNA methylation and subsequent reparation of the G.T mispairs which leads to accumulation of the 5mC-->T+C substitutions in the genome with each

  10. Mutational meltdown in laboratory yeast populations

    NARCIS (Netherlands)

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

    2001-01-01

    In small or repeatedly bottlenecked populations, mutations are expected to accumulate by genetic drift, causing fitness declines. In mutational meltdown models, such fitness declines further reduce population size, thus accelerating additional mutation accumulation and leading to extinction. Because

  11. Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect.

    Science.gov (United States)

    Barashkov, Nikolay A; Dzhemileva, Lilya U; Fedorova, Sardana A; Teryutin, Fedor M; Posukh, Olga L; Fedotova, Elvira E; Lobov, Simeon L; Khusnutdinova, Elza K

    2011-09-01

    Hereditary forms of hearing impairment (HI) caused by GJB2 (Cx26) mutations are the frequent sensory disorders registered among newborns in various human populations. In this study, we present data on the molecular, audiological and population features of autosomal recessive deafness 1A (DFNB1A) associated with the donor splicing site IVS1+1G>A mutation of GJB2 gene in Yakut population isolate of the Sakha Republic (Yakutia) located in Eastern Siberia (Russian Federation). The Yakut population exhibits high frequency of some Mendelian disorders, which are rare in other populations worldwide. Mutational analysis of GJB2 gene in 86 unrelated Yakut patients with congenital HI without other clinical features has been performed. In this study, we registered a large cohort of Yakut patients homozygous for the IVS1+1G>A mutation (70 unrelated deaf subjects in total). Detailed audiological analysis of 40 deaf subjects with genotype IVS1+1G>A/IVS1+1G>A revealed significant association of this genotype with mostly symmetrical bilateral severe to profound HI (85% severe-to-profound HI versus 15% mild-to-moderate HI, PA mutation (11.7%) has been found in Yakut population. Reconstruction of 140 haplotypes with IVS1+1G>A mutation demonstrates the common origin of all mutant chromosomes found in Yakuts. The age of mutation was estimated to be approximately 800 years. These findings characterize Eastern Siberia as the region with the most extensive accumulation of the IVS1+1G>A mutation in the world as a result of founder effect.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  13. Sexual selection on spontaneous mutations strengthens the between-sex genetic correlation for fitness.

    Science.gov (United States)

    Allen, Scott L; McGuigan, Katrina; Connallon, Tim; Blows, Mark W; Chenoweth, Stephen F

    2017-10-01

    A proposed benefit to sexual selection is that it promotes purging of deleterious mutations from populations. For this benefit to be realized, sexual selection, which is usually stronger on males, must purge mutations deleterious to both sexes. Here, we experimentally test the hypothesis that sexual selection on males purges deleterious mutations that affect both male and female fitness. We measured male and female fitness in two panels of spontaneous mutation-accumulation lines of the fly, Drosophila serrata, each established from a common ancestor. One panel of mutation accumulation lines limited both natural and sexual selection (LS lines), whereas the other panel limited natural selection, but allowed sexual selection to operate (SS lines). Although mutation accumulation caused a significant reduction in male and female fitness in both the LS and SS lines, sexual selection had no detectable effect on the extent of the fitness reduction. Similarly, despite evidence of mutational variance for fitness in males and females of both treatments, sexual selection had no significant impact on the amount of mutational genetic variance for fitness. However, sexual selection did reshape the between-sex correlation for fitness: significantly strengthening it in the SS lines. After 25 generations, the between-sex correlation for fitness was positive but considerably less than one in the LS lines, suggesting that, although most mutations had sexually concordant fitness effects, sex-limited, and/or sex-biased mutations contributed substantially to the mutational variance. In the SS lines this correlation was strong and could not be distinguished from unity. Individual-based simulations that mimick the experimental setup reveal two conditions that may drive our results: (1) a modest-to-large fraction of mutations have sex-limited (or highly sex-biased) fitness effects, and (2) the average fitness effect of sex-limited mutations is larger than the average fitness effect of

  14. 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.

  15. Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage.

    Science.gov (United States)

    Quek, Hazel; Luff, John; Cheung, KaGeen; Kozlov, Sergei; Gatei, Magtouf; Lee, C Soon; Bellingham, Mark C; Noakes, Peter G; Lim, Yi Chieh; Barnett, Nigel L; Dingwall, Steven; Wolvetang, Ernst; Mashimo, Tomoji; Roberts, Tara L; Lavin, Martin F

    2017-04-01

    Mutations in the ataxia-telangiectasia (A-T)-mutated ( ATM ) gene give rise to the human genetic disorder A-T, characterized by immunodeficiency, cancer predisposition, and neurodegeneration. Whereas a series of animal models recapitulate much of the A-T phenotype, they fail to present with ataxia or neurodegeneration. We describe here the generation of an Atm missense mutant [amino acid change of leucine (L) to proline (P) at position 2262 (L2262P)] rat by intracytoplasmic injection (ICSI) of mutant sperm into oocytes. Atm -mutant rats ( Atm L2262P/L2262P ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with Atm +/+ Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors. Closer examination revealed the presence of both dsDNA and ssDNA in the cytoplasm of cells in the hippocampus, cerebellum, and spinal cord of Atm L2262P/L2262P rats. Significantly increased levels of IFN-β and IL-1β in all 3 tissues were indicative of DNA damage induction of the type 1 IFN response. This was further supported by NF-κB activation, as evidenced by p65 phosphorylation (P65) and translocation to the nucleus in the spinal cord and parahippocampus. Other evidence of neuroinflammation in the brain and spinal cord was the loss of motor neurons and the presence of increased activation of microglia. These data provide support for a proinflammatory phenotype that is manifested in the Atm mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T. © Society for Leukocyte Biology.

  16. THE FRACTAL MARKET HYPOTHESIS

    OpenAIRE

    FELICIA RAMONA BIRAU

    2012-01-01

    In this article, the concept of capital market is analysed using Fractal Market Hypothesis which is a modern, complex and unconventional alternative to classical finance methods. Fractal Market Hypothesis is in sharp opposition to Efficient Market Hypothesis and it explores the application of chaos theory and fractal geometry to finance. Fractal Market Hypothesis is based on certain assumption. Thus, it is emphasized that investors did not react immediately to the information they receive and...

  17. Variability: A Pernicious Hypothesis.

    Science.gov (United States)

    Noddings, Nel

    1992-01-01

    The hypothesis of greater male variability in test results is discussed in its historical context, and reasons feminists have objected to the hypothesis are considered. The hypothesis acquires political importance if it is considered that variability results from biological, rather than cultural, differences. (SLD)

  18. Mutations and epimutations in the origin of cancer

    Energy Technology Data Exchange (ETDEWEB)

    Peltomaeki, Paeivi, E-mail: Paivi.Peltomaki@Helsinki.Fi

    2012-02-15

    Cancer is traditionally viewed as a disease of abnormal cell proliferation controlled by a series of mutations. Mutations typically affect oncogenes or tumor suppressor genes thereby conferring growth advantage. Genomic instability facilitates mutation accumulation. Recent findings demonstrate that activation of oncogenes and inactivation of tumor suppressor genes, as well as genomic instability, can be achieved by epigenetic mechanisms as well. Unlike genetic mutations, epimutations do not change the base sequence of DNA and are potentially reversible. Similar to genetic mutations, epimutations are associated with specific patterns of gene expression that are heritable through cell divisions. Knudson's hypothesis postulates that inactivation of tumor suppressor genes requires two hits, with the first hit occurring either in somatic cells (sporadic cancer) or in the germline (hereditary cancer) and the second one always being somatic. Studies on hereditary and sporadic forms of colorectal carcinoma have made it evident that, apart from genetic mutations, epimutations may serve as either hit or both. Furthermore, recent next-generation sequencing studies show that epigenetic genes, such as those encoding histone modifying enzymes and subunits for chromatin remodeling systems, are themselves frequent targets of somatic mutations in cancer and can act like tumor suppressor genes or oncogenes. This review discusses genetic vs. epigenetic origin of cancer, including cancer susceptibility, in light of recent discoveries. Situations in which mutations and epimutations occur to serve analogous purposes are highlighted.

  19. THE FRACTAL MARKET HYPOTHESIS

    Directory of Open Access Journals (Sweden)

    FELICIA RAMONA BIRAU

    2012-05-01

    Full Text Available In this article, the concept of capital market is analysed using Fractal Market Hypothesis which is a modern, complex and unconventional alternative to classical finance methods. Fractal Market Hypothesis is in sharp opposition to Efficient Market Hypothesis and it explores the application of chaos theory and fractal geometry to finance. Fractal Market Hypothesis is based on certain assumption. Thus, it is emphasized that investors did not react immediately to the information they receive and of course, the manner in which they interpret that information may be different. Also, Fractal Market Hypothesis refers to the way that liquidity and investment horizons influence the behaviour of financial investors.

  20. Mismatch or cumulative stress : Toward an integrated hypothesis of programming effects

    NARCIS (Netherlands)

    Nederhof, Esther; Schmidt, Mathias V.

    2012-01-01

    This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the

  1. Ancestral trees for modeling stem cell lineages genetically rather than functionally: understanding mutation accumulation and distinguishing the restrictive cancer stem cell propagation theory and the unrestricted cell propagation theory of human tumorigenesis.

    Science.gov (United States)

    Shibata, Darryl K; Kern, Scott E

    2008-01-01

    Cancer stem cells either could be rare or common in tumors, constituting the major distinction between the two fundamentally opposed theoretical models of tumor progression: A newer and restrictive stem cell propagation model, in which the stem cells are a small and special minority of the tumor cells, and a standard older model, an unrestricted cell proliferation theory, in which many or most tumor cells are capable of indefinite generations of cell division. Stem cells of tumors are difficult to quantitate using functional assays, and the validity of the most common assays is seriously questioned. Nonetheless, stem cells are an essential component of any tumorigenesis model. Alternative approaches to studying tumor stem cells should be explored. Cell populations can be conceived of as having a genealogy, a relationship of cells to their ancestral lineage, from the zygote to the adult cells or neoplasms. Models using ancestral trees thus offer an anatomic and genetic means to "observe" stem cells independent of artificial conditions. Ancestral trees broaden our attention backward along a lineage, to the zygote stage, and thereby add insight into how the mutations of tumors accumulate. It is possible that a large fraction of mutations in a tumor originate from normal, endogenous, replication errors (nearly all being passenger mutations) occurring prior to the emergence of the first transformed cell. Trees can be constructed from experimental measurements - molecular clocks - of real human tissues and tumors. Detailed analysis of single-cell methylation patterns, heritable yet slightly plastic, now can provide this information in the necessary depth. Trees based on observations of molecular clocks may help us to distinguish between competing theories regarding the proliferative properties among cells of actual human tumors, to observe subtle and difficult phenomena such as the extinction of stem lineages, and to address the origins and rates of mutations in various

  2. The (not so) Immortal Strand Hypothesis

    OpenAIRE

    Tomasetti, Cristian; Bozic, Ivana

    2015-01-01

    Background: Non-random segregation of DNA strands during stem cell replication has been proposed as a mechanism to minimize accumulated genetic errors in stem cells of rapidly dividing tissues. According to this hypothesis, an “immortal” DNA strand is passed to the stem cell daughter and not the more differentiated cell, keeping the stem cell lineage replication error-free. After it was introduced, experimental evidence both in favor and against the hypothesis has been presented. Principal...

  3. Campylobacter jejuni CsrA complements an Escherichia coli csrA mutation for the regulation of biofilm formation, motility and cellular morphology but not glycogen accumulation

    Science.gov (United States)

    2012-01-01

    Background Although Campylobacter jejuni is consistently ranked as one of the leading causes of bacterial diarrhea worldwide, the mechanisms by which C. jejuni causes disease and how they are regulated have yet to be clearly defined. The global regulator, CsrA, has been well characterized in several bacterial genera and is known to regulate a number of independent pathways via a post transcriptional mechanism, but remains relatively uncharacterized in the genus Campylobacter. Previously, we reported data illustrating the requirement for CsrA in several virulence related phenotypes of C. jejuni strain 81–176, indicating that the Csr pathway is important for Campylobacter pathogenesis. Results We compared the Escherichia coli and C. jejuni orthologs of CsrA and characterized the ability of the C. jejuni CsrA protein to functionally complement an E. coli csrA mutant. Phylogenetic comparison of E. coli CsrA to orthologs from several pathogenic bacteria demonstrated variability in C. jejuni CsrA relative to the known RNA binding domains of E. coli CsrA and in several amino acids reported to be involved in E. coli CsrA-mediated gene regulation. When expressed in an E. coli csrA mutant, C. jejuni CsrA succeeded in recovering defects in motility, biofilm formation, and cellular morphology; however, it failed to return excess glycogen accumulation to wild type levels. Conclusions These findings suggest that C. jejuni CsrA is capable of efficiently binding some E. coli CsrA binding sites, but not others, and provide insight into the biochemistry of C. jejuni CsrA. PMID:23051923

  4. Physiopathological Hypothesis of Cellulite

    Science.gov (United States)

    de Godoy, José Maria Pereira; de Godoy, Maria de Fátima Guerreiro

    2009-01-01

    A series of questions are asked concerning this condition including as regards to its name, the consensus about the histopathological findings, physiological hypothesis and treatment of the disease. We established a hypothesis for cellulite and confirmed that the clinical response is compatible with this hypothesis. Hence this novel approach brings a modern physiological concept with physiopathologic basis and clinical proof of the hypothesis. We emphasize that the choice of patient, correct diagnosis of cellulite and the technique employed are fundamental to success. PMID:19756187

  5. Life Origination Hydrate Hypothesis (LOH-Hypothesis

    Directory of Open Access Journals (Sweden)

    Victor Ostrovskii

    2012-01-01

    Full Text Available The paper develops the Life Origination Hydrate Hypothesis (LOH-hypothesis, according to which living-matter simplest elements (LMSEs, which are N-bases, riboses, nucleosides, nucleotides, DNA- and RNA-like molecules, amino-acids, and proto-cells repeatedly originated on the basis of thermodynamically controlled, natural, and inevitable processes governed by universal physical and chemical laws from CH4, niters, and phosphates under the Earth's surface or seabed within the crystal cavities of the honeycomb methane-hydrate structure at low temperatures; the chemical processes passed slowly through all successive chemical steps in the direction that is determined by a gradual decrease in the Gibbs free energy of reacting systems. The hypothesis formulation method is based on the thermodynamic directedness of natural movement and consists ofan attempt to mentally backtrack on the progression of nature and thus reveal principal milestones alongits route. The changes in Gibbs free energy are estimated for different steps of the living-matter origination process; special attention is paid to the processes of proto-cell formation. Just the occurrence of the gas-hydrate periodic honeycomb matrix filled with LMSEs almost completely in its final state accounts for size limitation in the DNA functional groups and the nonrandom location of N-bases in the DNA chains. The slowness of the low-temperature chemical transformations and their “thermodynamic front” guide the gross process of living matter origination and its successive steps. It is shown that the hypothesis is thermodynamically justified and testable and that many observed natural phenomena count in its favor.

  6. Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in the HFE Gene

    Directory of Open Access Journals (Sweden)

    Marcin Luszczyk

    2017-01-01

    Full Text Available Iron overload resulting from the mutation of genes involved in iron metabolism or excess dietary intake has been reported to negatively influence human physical performance. The aim of this study was to test the hypothesis that adolescents bearing a hemochromatosis gene (HFE mutation in contrast to adults with the same mutation will not experience iron accumulation and their aerobic capacity will be similar to that of age-matched controls. Thirteen boys participated in the study. Seven of them are carriers of H63D mutation in the HFE gene and six were wild type. Fitness levels were assessed using the cardiopulmonary exercise test. In addition, iron status and inflammatory markers were determined. We observed that cardiovascular fitness was significantly lower in the group bearing the HFE mutation compared to the control group. Moreover, the HFE mutation group achieved lower maximal power output compared to the control group. There were no differences in blood ferritin concentrations between the two groups which indicates similar amounts of stored iron. Obtained data do not confirm our hypothesis. On the contrary, it was demonstrated that HFE mutation is associated with a lower level of aerobic capacity, even in the absence of iron accumulation.

  7. Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in the HFE Gene.

    Science.gov (United States)

    Luszczyk, Marcin; Kaczorowska-Hac, Barbara; Milosz, Ewa; Adamkiewicz-Drozynska, Elzbieta; Ziemann, Ewa; Laskowski, Radoslaw; Flis, Damian; Rokicka-Hebel, Magdalena; Antosiewicz, Jedrzej

    2017-01-01

    Iron overload resulting from the mutation of genes involved in iron metabolism or excess dietary intake has been reported to negatively influence human physical performance. The aim of this study was to test the hypothesis that adolescents bearing a hemochromatosis gene (HFE) mutation in contrast to adults with the same mutation will not experience iron accumulation and their aerobic capacity will be similar to that of age-matched controls. Thirteen boys participated in the study. Seven of them are carriers of H63D mutation in the HFE gene and six were wild type. Fitness levels were assessed using the cardiopulmonary exercise test. In addition, iron status and inflammatory markers were determined. We observed that cardiovascular fitness was significantly lower in the group bearing the HFE mutation compared to the control group. Moreover, the HFE mutation group achieved lower maximal power output compared to the control group. There were no differences in blood ferritin concentrations between the two groups which indicates similar amounts of stored iron. Obtained data do not confirm our hypothesis. On the contrary, it was demonstrated that HFE mutation is associated with a lower level of aerobic capacity, even in the absence of iron accumulation.

  8. Hypothesis analysis methods, hypothesis analysis devices, and articles of manufacture

    Science.gov (United States)

    Sanfilippo, Antonio P [Richland, WA; Cowell, Andrew J [Kennewick, WA; Gregory, Michelle L [Richland, WA; Baddeley, Robert L [Richland, WA; Paulson, Patrick R [Pasco, WA; Tratz, Stephen C [Richland, WA; Hohimer, Ryan E [West Richland, WA

    2012-03-20

    Hypothesis analysis methods, hypothesis analysis devices, and articles of manufacture are described according to some aspects. In one aspect, a hypothesis analysis method includes providing a hypothesis, providing an indicator which at least one of supports and refutes the hypothesis, using the indicator, associating evidence with the hypothesis, weighting the association of the evidence with the hypothesis, and using the weighting, providing information regarding the accuracy of the hypothesis.

  9. On the Keyhole Hypothesis

    DEFF Research Database (Denmark)

    Mikkelsen, Kaare B.; Kidmose, Preben; Hansen, Lars Kai

    2017-01-01

    simultaneously recorded scalp EEG. A cross-validation procedure was employed to ensure unbiased estimates. We present several pieces of evidence in support of the keyhole hypothesis: There is a high mutual information between data acquired at scalp electrodes and through the ear-EEG "keyhole," furthermore we......We propose and test the keyhole hypothesis that measurements from low dimensional EEG, such as ear-EEG reflect a broadly distributed set of neural processes. We formulate the keyhole hypothesis in information theoretical terms. The experimental investigation is based on legacy data consisting of 10...

  10. The Qualitative Expectations Hypothesis

    DEFF Research Database (Denmark)

    Frydman, Roman; Johansen, Søren; Rahbek, Anders

    2017-01-01

    We introduce the Qualitative Expectations Hypothesis (QEH) as a new approach to modeling macroeconomic and financial outcomes. Building on John Muth's seminal insight underpinning the Rational Expectations Hypothesis (REH), QEH represents the market's forecasts to be consistent with the predictions...... of an economistís model. However, by assuming that outcomes lie within stochastic intervals, QEH, unlike REH, recognizes the ambiguity faced by an economist and market participants alike. Moreover, QEH leaves the model open to ambiguity by not specifying a mechanism determining specific values that outcomes take...

  11. The Qualitative Expectations Hypothesis

    DEFF Research Database (Denmark)

    Frydman, Roman; Johansen, Søren; Rahbek, Anders

    We introduce the Qualitative Expectations Hypothesis (QEH) as a new approach to modeling macroeconomic and financial outcomes. Building on John Muth's seminal insight underpinning the Rational Expectations Hypothesis (REH), QEH represents the market's forecasts to be consistent with the predictions...... of an economist's model. However, by assuming that outcomes lie within stochastic intervals, QEH, unlike REH, recognizes the ambiguity faced by an economist and market participants alike. Moreover, QEH leaves the model open to ambiguity by not specifying a mechanism determining specific values that outcomes take...

  12. Revisiting the Dutch hypothesis

    NARCIS (Netherlands)

    Postma, Dirkje S.; Weiss, Scott T.; van den Berge, Maarten; Kerstjens, Huib A. M.; Koppelman, Gerard H.

    The Dutch hypothesis was first articulated in 1961, when many novel and advanced scientific techniques were not available, such as genomics techniques for pinpointing genes, gene expression, lipid and protein profiles, and the microbiome. In addition, computed tomographic scans and advanced analysis

  13. The Lehman Sisters Hypothesis

    NARCIS (Netherlands)

    I.P. van Staveren (Irene)

    2014-01-01

    markdownabstract__Abstract__ This article explores the Lehman Sisters Hypothesis. It reviews empirical literature about gender differences in behavioral, experimental, and neuro-economics as well as in other fields of behavioral research. It discusses gender differences along three dimensions of

  14. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  15. Bayesian Hypothesis Testing

    Energy Technology Data Exchange (ETDEWEB)

    Andrews, Stephen A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Sigeti, David E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-11-15

    These are a set of slides about Bayesian hypothesis testing, where many hypotheses are tested. The conclusions are the following: The value of the Bayes factor obtained when using the median of the posterior marginal is almost the minimum value of the Bayes factor. The value of τ2 which minimizes the Bayes factor is a reasonable choice for this parameter. This allows a likelihood ratio to be computed with is the least favorable to H0.

  16. The Drift Burst Hypothesis

    OpenAIRE

    Christensen, Kim; Oomen, Roel; Renò, Roberto

    2016-01-01

    The Drift Burst Hypothesis postulates the existence of short-lived locally explosive trends in the price paths of financial assets. The recent US equity and Treasury flash crashes can be viewed as two high profile manifestations of such dynamics, but we argue that drift bursts of varying magnitude are an expected and regular occurrence in financial markets that can arise through established mechanisms such as feedback trading. At a theoretical level, we show how to build drift bursts into the...

  17. Hypothesis in research

    Directory of Open Access Journals (Sweden)

    Eudaldo Enrique Espinoza Freire

    2018-01-01

    Full Text Available It is intended with this work to have a material with the fundamental contents, which enable the university professor to formulate the hypothesis, for the development of an investigation, taking into account the problem to be solved. For its elaboration, the search of information in primary documents was carried out, such as thesis of degree and reports of research results, selected on the basis of its relevance with the analyzed subject, current and reliability, secondary documents, as scientific articles published in journals of recognized prestige, the selection was made with the same terms as in the previous documents. It presents a conceptualization of the updated hypothesis, its characterization and an analysis of the structure of the hypothesis in which the determination of the variables is deepened. The involvement of the university professor in the teaching-research process currently faces some difficulties, which are manifested, among other aspects, in an unstable balance between teaching and research, which leads to a separation between them.

  18. Aminoglycoside antibiotics and autism: a speculative hypothesis

    Directory of Open Access Journals (Sweden)

    Manev Hari

    2001-10-01

    Full Text Available Abstract Background Recently, it has been suspected that there is a relationship between therapy with some antibiotics and the onset of autism; but even more curious, some children benefited transiently from a subsequent treatment with a different antibiotic. Here, we speculate how aminoglycoside antibiotics might be associated with autism. Presentation We hypothesize that aminoglycoside antibiotics could a trigger the autism syndrome in susceptible infants by causing the stop codon readthrough, i.e., a misreading of the genetic code of a hypothetical critical gene, and/or b improve autism symptoms by correcting the premature stop codon mutation in a hypothetical polymorphic gene linked to autism. Testing Investigate, retrospectively, whether a link exists between aminoglycoside use (which is not extensive in children and the onset of autism symptoms (hypothesis "a", or between amino glycoside use and improvement of these symptoms (hypothesis "b". Whereas a prospective study to test hypothesis "a" is not ethically justifiable, a study could be designed to test hypothesis "b". Implications It should be stressed that at this stage no direct evidence supports our speculative hypothesis and that its main purpose is to initiate development of new ideas that, eventually, would improve our understanding of the pathobiology of autism.

  19. The oxidative hypothesis of senescence

    Directory of Open Access Journals (Sweden)

    Gilca M

    2007-01-01

    Full Text Available The oxidative hypothesis of senescence, since its origin in 1956, has garnered significant evidence and growing support among scientists for the notion that free radicals play an important role in ageing, either as "damaging" molecules or as signaling molecules. Age-increasing oxidative injuries induced by free radicals, higher susceptibility to oxidative stress in short-lived organisms, genetic manipulations that alter both oxidative resistance and longevity and the anti-ageing effect of caloric restriction and intermittent fasting are a few examples of accepted scientific facts that support the oxidative theory of senescence. Though not completely understood due to the complex "network" of redox regulatory systems, the implication of oxidative stress in the ageing process is now well documented. Moreover, it is compatible with other current ageing theories (e.g., those implicating the mitochondrial damage/mitochondrial-lysosomal axis, stress-induced premature senescence, biological "garbage" accumulation, etc. This review is intended to summarize and critically discuss the redox mechanisms involved during the ageing process: sources of oxidant agents in ageing (mitochondrial -electron transport chain, nitric oxide synthase reaction- and non-mitochondrial- Fenton reaction, microsomal cytochrome P450 enzymes, peroxisomal β -oxidation and respiratory burst of phagocytic cells, antioxidant changes in ageing (enzymatic- superoxide dismutase, glutathione-reductase, glutathion peroxidase, catalase- and non-enzymatic glutathione, ascorbate, urate, bilirubine, melatonin, tocopherols, carotenoids, ubiquinol, alteration of oxidative damage repairing mechanisms and the role of free radicals as signaling molecules in ageing.

  20. [Dilemma of null hypothesis in ecological hypothesis's experiment test.

    Science.gov (United States)

    Li, Ji

    2016-06-01

    Experimental test is one of the major test methods of ecological hypothesis, though there are many arguments due to null hypothesis. Quinn and Dunham (1983) analyzed the hypothesis deduction model from Platt (1964) and thus stated that there is no null hypothesis in ecology that can be strictly tested by experiments. Fisher's falsificationism and Neyman-Pearson (N-P)'s non-decisivity inhibit statistical null hypothesis from being strictly tested. Moreover, since the null hypothesis H 0 (α=1, β=0) and alternative hypothesis H 1 '(α'=1, β'=0) in ecological progresses are diffe-rent from classic physics, the ecological null hypothesis can neither be strictly tested experimentally. These dilemmas of null hypothesis could be relieved via the reduction of P value, careful selection of null hypothesis, non-centralization of non-null hypothesis, and two-tailed test. However, the statistical null hypothesis significance testing (NHST) should not to be equivalent to the causality logistical test in ecological hypothesis. Hence, the findings and conclusions about methodological studies and experimental tests based on NHST are not always logically reliable.

  1. Accumulation of multiple mutations in linezolid-resistant Staphylococcus epidermidis causing bloodstream infections; in silico analysis of L3 amino acid substitutions that might confer high-level linezolid resistance.

    Science.gov (United States)

    Ikonomidis, Alexandros; Grapsa, Anastasia; Pavlioglou, Charikleia; Demiri, Antonia; Batarli, Alexandra; Panopoulou, Maria

    2016-12-01

    Fifty-six Staphylococcus epidermidis clinical isolates, showing high-level linezolid resistance and causing bacteremia in critically ill patients, were studied. All isolates belonged to ST22 clone and carried the T2504A and C2534T mutations in gene coding for 23SrRNA as well as the C189A, G208A, C209T and G384C missense mutations in L3 protein which resulted in Asp159Tyr, Gly152Asp and Leu94Val substitutions. Other silent mutations were also detected in genes coding for ribosomal proteins L3 and L22. In silico analysis of missense mutations showed that although L3 protein retained the sequence of secondary motifs, the tertiary structure was influenced. The observed alteration in L3 protein folding provides an indication on the putative role of L3-coding gene mutations in high-level linezolid resistance. Furthermore, linezolid pressure in health care settings where linezolid consumption is of high rates might lead to the selection of resistant mutants possessing L3 mutations that might confer high-level linezolid resistance.

  2. Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate.

    Science.gov (United States)

    Choi, Sung Won; Ryu, Ok Hee; Choi, Sun Jin; Song, In Sun; Bleyer, Anthony J; Hart, Thomas C

    2005-10-01

    As a consequence of uromodulin gene mutations, individuals develop precocious hyperuricemia, gout, and progressive renal failure. In vitro studies suggest that pathologic accumulation of uromodulin/Tamm-Horsfall glycoprotein (THP) occurs in the endoplasmic reticulum (ER), but the pathophysiology of renal damage is unclear. It was hypothesized that programmed cell death triggered by accumulation of misfolded THP in the ER causes progressive renal disease. Stably transfected human embryonic kidney 293 cells and immortalized thick ascending limb of Henle's loop cells with wild-type and mutated uromodulin cDNA were evaluated to test this hypothesis. Immunocytochemistry, ELISA, and deglycosylation studies indicated that accumulation of mutant THP occurred in the ER. FACS analyses showed a significant increase in early apoptosis signal in human embryonic kidney 293 and thick ascending limb of Henle's loop cells that were transfected with mutant uromodulin constructs. Colchicine and sodium 4-phenylbutyrate treatment increased secretion of THP from the ER to the cell membrane and into the culture media and significantly improved cell viability. These findings indicate that intracellular accumulation of THP facilitates apoptosis and that this may provide the pathologic mechanism responsible for the progressive renal damage associated with uromodulin gene mutations. Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases.

  3. The Bergschrund Hypothesis Revisited

    Science.gov (United States)

    Sanders, J. W.; Cuffey, K. M.; MacGregor, K. R.

    2009-12-01

    After Willard Johnson descended into the Lyell Glacier bergschrund nearly 140 years ago, he proposed that the presence of the bergschrund modulated daily air temperature fluctuations and enhanced freeze-thaw processes. He posited that glaciers, through their ability to birth bergschrunds, are thus able to induce rapid cirque headwall retreat. In subsequent years, many researchers challenged the bergschrund hypothesis on grounds that freeze-thaw events did not occur at depth in bergschrunds. We propose a modified version of Johnson’s original hypothesis: that bergschrunds maintain subfreezing temperatures at values that encourage rock fracture via ice lensing because they act as a cold air trap in areas that would otherwise be held near zero by temperate glacial ice. In support of this claim we investigated three sections of the bergschrund at the West Washmawapta Glacier, British Columbia, Canada, which sits in an east-facing cirque. During our bergschrund reconnaissance we installed temperature sensors at multiple elevations, light sensors at depth in 2 of the 3 locations and painted two 1 m2 sections of the headwall. We first emphasize bergschrunds are not wanting for ice: verglas covers significant fractions of the headwall and icicles dangle from the base of bödens or overhanging rocks. If temperature, rather than water availability, is the limiting factor governing ice-lensing rates, our temperature records demonstrate that the bergschrund provides a suitable environment for considerable rock fracture. At the three sites (north, west, and south walls), the average temperature at depth from 9/3/2006 to 8/6/2007 was -3.6, -3.6, and -2.0 °C, respectively. During spring, when we observed vast amounts of snow melt trickle in to the bergschrund, temperatures averaged -3.7, -3.8, and -2.2 °C, respectively. Winter temperatures are even lower: -8.5, -7.3, and -2.4 °C, respectively. Values during the following year were similar. During the fall, diurnal

  4. Hypothesis of K+-Recycling Defect Is Not a Primary Deafness Mechanism for Cx26 (GJB2 Deficiency

    Directory of Open Access Journals (Sweden)

    Hong-Bo Zhao

    2017-05-01

    Full Text Available K+-recycling defect is a long-standing hypothesis for deafness mechanism of Connexin26 (Cx26, GJB2 mutations, which cause the most common hereditary deafness and are responsible for >50% of nonsyndromic hearing loss. The hypothesis states that Cx26 deficiency may disrupt inner ear gap junctions and compromise sinking and recycling of expelled K+ ions after hair cell excitation, causing accumulation of K+-ions in the extracellular space around hair cells producing K+-toxicity, which eventually induces hair cell degeneration and hearing loss. However, this hypothesis has never been directly evidenced, even though it has been widely referred to. Recently, more and more experiments demonstrate that this hypothesis may not be a deafness mechanism underlying Cx26 deficiency. In this review article, we summarized recent advances on the K+-recycling and mechanisms underlying Cx26 deficiency induced hearing loss. The mechanisms underlying K+-sinking, which is the first step for K+-recycling in the cochlea, and Cx26 deficiency induced cochlear developmental disorders, which are responsible for Cx26 deficiency induced congenital deafness and associated with disruption of permeability of inner ear gap junctional channels to miRNAs, are also summarized and discussed.

  5. 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.

  6. 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.

  7. Is the Aluminum Hypothesis Dead?

    Science.gov (United States)

    2014-01-01

    The Aluminum Hypothesis, the idea that aluminum exposure is involved in the etiology of Alzheimer disease, dates back to a 1965 demonstration that aluminum causes neurofibrillary tangles in the brains of rabbits. Initially the focus of intensive research, the Aluminum Hypothesis has gradually been abandoned by most researchers. Yet, despite this current indifference, the Aluminum Hypothesis continues to attract the attention of a small group of scientists and aluminum continues to be viewed with concern by some of the public. This review article discusses reasons that mainstream science has largely abandoned the Aluminum Hypothesis and explores a possible reason for some in the general public continuing to view aluminum with mistrust. PMID:24806729

  8. Characterization of a mutation commonly associated with persistent stuttering: evidence for a founder mutation

    Science.gov (United States)

    Fedyna, Alison; Drayna, Dennis; Kang, Changsoo

    2010-01-01

    Stuttering is a disorder which affects the fluency of speech. It has been shown to have high heritability, and has recently been linked to mutations in the GNPTAB gene. One such mutation, Glu1200Lys, has been repeatedly observed in unrelated families and individual cases. Eight unrelated individuals carrying this mutation were analyzed in an effort to distinguish whether these arise from repeated mutation at the same site, or whether they represent a founder mutation with a single origin. Results show that all 12 chromosomes carrying this mutation share a common haplotype in this region, indicating it is a founder mutation. Further analysis estimated the age of this allele to be ~572 generations. Construction of a cladogram tracing the mutation through our study sample also supports the founder mutation hypothesis. PMID:20944643

  9. Hypothesis Designs for Three-Hypothesis Test Problems

    OpenAIRE

    Yan Li; Xiaolong Pu

    2010-01-01

    As a helpful guide for applications, the alternative hypotheses of the three-hypothesis test problems are designed under the required error probabilities and average sample number in this paper. The asymptotic formulas and the proposed numerical quadrature formulas are adopted, respectively, to obtain the hypothesis designs and the corresponding sequential test schemes under the Koopman-Darmois distributions. The example of the normal mean test shows that our methods are qu...

  10. Tests of the lunar hypothesis

    Science.gov (United States)

    Taylor, S. R.

    1984-01-01

    The concept that the Moon was fissioned from the Earth after core separation is the most readily testable hypothesis of lunar origin, since direct comparisons of lunar and terrestrial compositions can be made. Differences found in such comparisons introduce so many ad hoc adjustments to the fission hypothesis that it becomes untestable. Further constraints may be obtained from attempting to date the volatile-refractory element fractionation. The combination of chemical and isotopic problems suggests that the fission hypothesis is no longer viable, and separate terrestrial and lunar accretion from a population of fractionated precursor planetesimals provides a more reasonable explanation.

  11. Evaluating the Stage Learning Hypothesis.

    Science.gov (United States)

    Thomas, Hoben

    1980-01-01

    A procedure for evaluating the Genevan stage learning hypothesis is illustrated by analyzing Inhelder, Sinclair, and Bovet's guided learning experiments (in "Learning and the Development of Cognition." Cambridge: Harvard University Press, 1974). (Author/MP)

  12. The Purchasing Power Parity Hypothesis:

    African Journals Online (AJOL)

    2011-10-02

    Oct 2, 2011 ... reject the unit root hypothesis in real exchange rates may simply be due to the shortness ..... Violations of Purchasing Power Parity and Their Implications for Efficient ... Official Intervention in the Foreign Exchange Market:.

  13. The atomic hypothesis: physical consequences

    International Nuclear Information System (INIS)

    Rivas, Martin

    2008-01-01

    The hypothesis that matter is made of some ultimate and indivisible objects, together with the restricted relativity principle, establishes a constraint on the kind of variables we are allowed to use for the variational description of elementary particles. We consider that the atomic hypothesis not only states the indivisibility of elementary particles, but also that these ultimate objects, if not annihilated, cannot be modified by any interaction so that all allowed states of an elementary particle are only kinematical modifications of any one of them. Therefore, an elementary particle cannot have excited states. In this way, the kinematical group of spacetime symmetries not only defines the symmetries of the system, but also the variables in terms of which the mathematical description of the elementary particles can be expressed in either the classical or the quantum mechanical description. When considering the interaction of two Dirac particles, the atomic hypothesis restricts the interaction Lagrangian to a kind of minimal coupling interaction

  14. Multiple sclerosis: a geographical hypothesis.

    Science.gov (United States)

    Carlyle, I P

    1997-12-01

    Multiple sclerosis remains a rare neurological disease of unknown aetiology, with a unique distribution, both geographically and historically. Rare in equatorial regions, it becomes increasingly common in higher latitudes; historically, it was first clinically recognized in the early nineteenth century. A hypothesis, based on geographical reasoning, is here proposed: that the disease is the result of a specific vitamin deficiency. Different individuals suffer the deficiency in separate and often unique ways. Evidence to support the hypothesis exists in cultural considerations, in the global distribution of the disease, and in its historical prevalence.

  15. Discussion of the Porter hypothesis

    International Nuclear Information System (INIS)

    1999-11-01

    In the reaction to the long-range vision of RMNO, published in 1996, The Dutch government posed the question whether a far-going and progressive modernization policy will lead to competitive advantages of high-quality products on partly new markets. Such a question is connected to the so-called Porter hypothesis: 'By stimulating innovation, strict environmental regulations can actually enhance competitiveness', from which statement it can be concluded that environment and economy can work together quite well. A literature study has been carried out in order to determine under which conditions that hypothesis is endorsed in the scientific literature and policy documents. Recommendations are given for further studies. refs

  16. The thrifty phenotype hypothesis revisited

    DEFF Research Database (Denmark)

    Vaag, A A; Grunnet, L G; Arora, G P

    2012-01-01

    Twenty years ago, Hales and Barker along with their co-workers published some of their pioneering papers proposing the 'thrifty phenotype hypothesis' in Diabetologia (4;35:595-601 and 3;36:62-67). Their postulate that fetal programming could represent an important player in the origin of type 2...... of the underlying molecular mechanisms. Type 2 diabetes is a multiple-organ disease, and developmental programming, with its idea of organ plasticity, is a plausible hypothesis for a common basis for the widespread organ dysfunctions in type 2 diabetes and the metabolic syndrome. Only two among the 45 known type 2...

  17. Mutation, somatic mutation and diseases of man

    International Nuclear Information System (INIS)

    Burnet, F.M.

    1976-01-01

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

  18. The Trojan Female Technique for pest control: a candidate mitochondrial mutation confers low male fertility across diverse nuclear backgrounds in Drosophila melanogaster.

    Science.gov (United States)

    Dowling, Damian K; Tompkins, Daniel M; Gemmell, Neil J

    2015-10-01

    Pest species represent a major ongoing threat to global biodiversity. Effective management approaches are required that regulate pest numbers, while minimizing collateral damage to nontarget species. The Trojan Female Technique (TFT) was recently proposed as a prospective approach to biological pest control. The TFT draws on the evolutionary hypothesis that maternally inherited mitochondrial genomes are prone to the accumulation of male, but not female, harming mutations. These mutations could be harnessed to provide trans-generational fertility-based control of pest species. A candidate TFT mutation was recently described in the fruit fly, Drosophila melanogaster, which confers male-only sterility in the specific isogenic nuclear background in which it is maintained. However, applicability of the TFT relies on mitochondrial mutations whose male-sterilizing effects are general across nuclear genomic contexts. We test this assumption, expressing the candidate TFT-mutation bearing haplotype alongside a range of nuclear backgrounds and comparing its fertility in males, relative to that of control haplotypes. We document consistently lower fertility for males harbouring the TFT mutation, in both competitive and noncompetitive mating contexts, across all nuclear backgrounds screened. This indicates that TFT mutations conferring reduced male fertility can segregate within populations and could be harnessed to facilitate this novel form of pest control.

  19. Questioning the social intelligence hypothesis.

    Science.gov (United States)

    Holekamp, Kay E

    2007-02-01

    The social intelligence hypothesis posits that complex cognition and enlarged "executive brains" evolved in response to challenges that are associated with social complexity. This hypothesis has been well supported, but some recent data are inconsistent with its predictions. It is becoming increasingly clear that multiple selective agents, and non-selective constraints, must have acted to shape cognitive abilities in humans and other animals. The task now is to develop a larger theoretical framework that takes into account both inter-specific differences and similarities in cognition. This new framework should facilitate consideration of how selection pressures that are associated with sociality interact with those that are imposed by non-social forms of environmental complexity, and how both types of functional demands interact with phylogenetic and developmental constraints.

  20. Whiplash and the compensation hypothesis.

    Science.gov (United States)

    Spearing, Natalie M; Connelly, Luke B

    2011-12-01

    Review article. To explain why the evidence that compensation-related factors lead to worse health outcomes is not compelling, either in general, or in the specific case of whiplash. There is a common view that compensation-related factors lead to worse health outcomes ("the compensation hypothesis"), despite the presence of important, and unresolved sources of bias. The empirical evidence on this question has ramifications for the design of compensation schemes. Using studies on whiplash, this article outlines the methodological problems that impede attempts to confirm or refute the compensation hypothesis. Compensation studies are prone to measurement bias, reverse causation bias, and selection bias. Errors in measurement are largely due to the latent nature of whiplash injuries and health itself, a lack of clarity over the unit of measurement (specific factors, or "compensation"), and a lack of appreciation for the heterogeneous qualities of compensation-related factors and schemes. There has been a failure to acknowledge and empirically address reverse causation bias, or the likelihood that poor health influences the decision to pursue compensation: it is unclear if compensation is a cause or a consequence of poor health, or both. Finally, unresolved selection bias (and hence, confounding) is evident in longitudinal studies and natural experiments. In both cases, between-group differences have not been addressed convincingly. The nature of the relationship between compensation-related factors and health is unclear. Current approaches to testing the compensation hypothesis are prone to several important sources of bias, which compromise the validity of their results. Methods that explicitly test the hypothesis and establish whether or not a causal relationship exists between compensation factors and prolonged whiplash symptoms are needed in future studies.

  1. Simple non-invasive assessment of advanced glycation endproduct accumulation

    NARCIS (Netherlands)

    Meerwaldt, R; Graaff, R; Links, TP; Jager, JJ; Alderson, NL; Thorpe, [No Value; Baynes, JW; Gans, ROB; Smit, AJ

    Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a

  2. Roles of Mitochondrial DNA Mutations in Stem Cell Ageing

    Directory of Open Access Journals (Sweden)

    Tianhong Su

    2018-03-01

    Full Text Available Mitochondrial DNA (mtDNA mutations accumulate in somatic stem cells during ageing and cause mitochondrial dysfunction. In this review, we summarize the studies that link mtDNA mutations to stem cell ageing. We discuss the age-related behaviours of the somatic mtDNA mutations in stem cell populations and how they potentially contribute to stem cell ageing by altering mitochondrial properties in humans and in mtDNA-mutator mice. We also draw attention to the diverse fates of the mtDNA mutations with different origins during ageing, with potential selective pressures on the germline inherited but not the somatic mtDNA mutations.

  3. 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

  4. Advanced accumulator for PWR

    International Nuclear Information System (INIS)

    Ichimura, Taiki; Chikahata, Hideyuki

    1997-01-01

    Advanced accumulators have been incorporated into the APWR design in order to simplify the safety system configuration and to improve reliability. The advanced accumulators refill the reactor vessel with a large discharge flow rate in a large LOCA, then switch to a small flow rate to continue safety injection for core reflooding. The functions of the conventional accumulator and the low head safety injection pump are integrated into this advanced accumulator. Injection performance tests simulating LOCA conditions and visualization tests for new designs have been carried out. This paper describes the APWR ECCS configuration, the advanced accumulator design and some of the injection performance and visualization test results. It was verified that the flow resistance of the advanced accumulator is independent of the model scale. The similarity law and performance data of the advanced accumulator for applying APWR was established. (author)

  5. A Molecular–Structure Hypothesis

    Directory of Open Access Journals (Sweden)

    Jan C. A. Boeyens

    2010-11-01

    Full Text Available The self-similar symmetry that occurs between atomic nuclei, biological growth structures, the solar system, globular clusters and spiral galaxies suggests that a similar pattern should characterize atomic and molecular structures. This possibility is explored in terms of the current molecular structure-hypothesis and its extension into four-dimensional space-time. It is concluded that a quantum molecule only has structure in four dimensions and that classical (Newtonian structure, which occurs in three dimensions, cannot be simulated by quantum-chemical computation.

  6. Antiaging therapy: a prospective hypothesis

    Directory of Open Access Journals (Sweden)

    Shahidi Bonjar MR

    2015-01-01

    Full Text Available Mohammad Rashid Shahidi Bonjar,1 Leyla Shahidi Bonjar2 1School of Dentistry, Kerman University of Medical Sciences, Kerman Iran; 2Department of Pharmacology, College of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran Abstract: This hypothesis proposes a new prospective approach to slow the aging process in older humans. The hypothesis could lead to developing new treatments for age-related illnesses and help humans to live longer. This hypothesis has no previous documentation in scientific media and has no protocol. Scientists have presented evidence that systemic aging is influenced by peculiar molecules in the blood. Researchers at Albert Einstein College of Medicine, New York, and Harvard University in Cambridge discovered elevated titer of aging-related molecules (ARMs in blood, which trigger cascade of aging process in mice; they also indicated that the process can be reduced or even reversed. By inhibiting the production of ARMs, they could reduce age-related cognitive and physical declines. The present hypothesis offers a new approach to translate these findings into medical treatment: extracorporeal adjustment of ARMs would lead to slower rates of aging. A prospective “antiaging blood filtration column” (AABFC is a nanotechnological device that would fulfill the central role in this approach. An AABFC would set a near-youth homeostatic titer of ARMs in the blood. In this regard, the AABFC immobilizes ARMs from the blood while blood passes through the column. The AABFC harbors antibodies against ARMs. ARM antibodies would be conjugated irreversibly to ARMs on contact surfaces of the reaction platforms inside the AABFC till near-youth homeostasis is attained. The treatment is performed with the aid of a blood-circulating pump. Similar to a renal dialysis machine, blood would circulate from the body to the AABFC and from there back to the body in a closed circuit until ARMs were sufficiently depleted from the blood. The

  7. Is PMI the Hypothesis or the Null Hypothesis?

    Science.gov (United States)

    Tarone, Aaron M; Sanford, Michelle R

    2017-09-01

    Over the past several decades, there have been several strident exchanges regarding whether forensic entomologists estimate the postmortem interval (PMI), minimum PMI, or something else. During that time, there has been a proliferation of terminology reflecting this concern regarding "what we do." This has been a frustrating conversation for some in the community because much of this debate appears to be centered on what assumptions are acknowledged directly and which are embedded within a list of assumptions (or ignored altogether) in the literature and in case reports. An additional component of the conversation centers on a concern that moving away from the use of certain terminology like PMI acknowledges limitations and problems that would make the application of entomology appear less useful in court-a problem for lawyers, but one that should not be problematic for scientists in the forensic entomology community, as uncertainty is part of science that should and can be presented effectively in the courtroom (e.g., population genetic concepts in forensics). Unfortunately, a consequence of the way this conversation is conducted is that even as all involved in the debate acknowledge the concerns of their colleagues, parties continue to talk past one another advocating their preferred terminology. Progress will not be made until the community recognizes that all of the terms under consideration take the form of null hypothesis statements and that thinking about "what we do" as a null hypothesis has useful legal and scientific ramifications that transcend arguments over the usage of preferred terminology. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. The Stoichiometric Divisome: A Hypothesis

    Directory of Open Access Journals (Sweden)

    Waldemar eVollmer

    2015-05-01

    Full Text Available Dividing Escherichia coli cells simultaneously constrict the inner membrane, peptidoglycan layer and outer membrane to synthesize the new poles of the daughter cells. For this, more than 30 proteins localize to mid-cell where they form a large, ring-like assembly, the divisome, facilitating division. Although the precise function of most divisome proteins is unknown, it became apparent in recent years that dynamic protein-protein interactions are essential for divisome assembly and function. However, little is known about the nature of the interactions involved and the stoichiometry of the proteins within the divisome. A recent study (Li et al., 2014 used ribosome profiling to measure the absolute protein synthesis rates in E. coli. Interestingly, they observed that most proteins which participate in known multiprotein complexes are synthesized proportional to their stoichiometry. Based on this principle we present a hypothesis for the stoichiometry of the core of the divisome, taking into account known protein-protein interactions. From this hypothesis we infer a possible mechanism for PG synthesis during division.

  9. DAMPs, ageing, and cancer: The 'DAMP Hypothesis'.

    Science.gov (United States)

    Huang, Jin; Xie, Yangchun; Sun, Xiaofang; Zeh, Herbert J; Kang, Rui; Lotze, Michael T; Tang, Daolin

    2015-11-01

    Ageing is a complex and multifactorial process characterized by the accumulation of many forms of damage at the molecular, cellular, and tissue level with advancing age. Ageing increases the risk of the onset of chronic inflammation-associated diseases such as cancer, diabetes, stroke, and neurodegenerative disease. In particular, ageing and cancer share some common origins and hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury, reprogrammed metabolism, and degradation system impairment (including within the ubiquitin-proteasome system and the autophagic machinery). Recent advances indicate that damage-associated molecular pattern molecules (DAMPs) such as high mobility group box 1, histones, S100, and heat shock proteins play location-dependent roles inside and outside the cell. These provide interaction platforms at molecular levels linked to common hallmarks of ageing and cancer. They can act as inducers, sensors, and mediators of stress through individual plasma membrane receptors, intracellular recognition receptors (e.g., advanced glycosylation end product-specific receptors, AIM2-like receptors, RIG-I-like receptors, and NOD1-like receptors, and toll-like receptors), or following endocytic uptake. Thus, the DAMP Hypothesis is novel and complements other theories that explain the features of ageing. DAMPs represent ideal biomarkers of ageing and provide an attractive target for interventions in ageing and age-associated diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Child Benefit Payments and Household Wealth Accumulation

    OpenAIRE

    Melvin Stephens Jr.; Takashi Unayama

    2014-01-01

    Using the life-cycle/permanent income hypothesis, we theoretically and empirically assess the impact of child benefit payments on household wealth accumulation. Consistent with the predictions of the model, we find that higher cumulative benefits received increase current assets, higher future benefit payments lower asset holding, and that these effects systematically vary over the life-cycle. We find different wealth responses to child benefit payments for liquidity constrained and unconstra...

  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. Microbial accumulation of uranium

    International Nuclear Information System (INIS)

    Zhang Wei; Dong Faqin; Dai Qunwei

    2005-01-01

    The mechanism of microbial accumulation of uranium and the effects of some factors (including pH, initial uranium concentration, pretreatment of bacteria, and so on) on microbial accumulation of uranium are discussed briefly. The research direction and application prospect are presented. (authors)

  13. Atopic dermatitis and the hygiene hypothesis revisited.

    Science.gov (United States)

    Flohr, Carsten; Yeo, Lindsey

    2011-01-01

    We published a systematic review on atopic dermatitis (AD) and the hygiene hypothesis in 2005. Since then, the body of literature has grown significantly. We therefore repeated our systematic review to examine the evidence from population-based studies for an association between AD risk and specific infections, childhood immunizations, the use of antibiotics and environmental exposures that lead to a change in microbial burden. Medline was searched from 1966 until June 2010 to identify relevant studies. We found an additional 49 papers suitable for inclusion. There is evidence to support an inverse relationship between AD and endotoxin, early day care, farm animal and dog exposure in early life. Cat exposure in the presence of skin barrier impairment is positively associated with AD. Helminth infection at least partially protects against AD. This is not the case for viral and bacterial infections, but consumption of unpasteurized farm milk seems protective. Routine childhood vaccinations have no effect on AD risk. The positive association between viral infections and AD found in some studies appears confounded by antibiotic prescription, which has been consistently associated with an increase in AD risk. There is convincing evidence for an inverse relationship between helminth infections and AD but no other pathogens. The protective effect seen with early day care, endotoxin, unpasteurized farm milk and animal exposure is likely to be due to a general increase in exposure to non-pathogenic microbes. This would also explain the risk increase associated with the use of broad-spectrum antibiotics. Future studies should assess skin barrier gene mutation carriage and phenotypic skin barrier impairment, as gene-environment interactions are likely to impact on AD risk. Copyright © 041_ S. Karger AG, Basel.

  14. Memory in astrocytes: a hypothesis

    Directory of Open Access Journals (Sweden)

    Caudle Robert M

    2006-01-01

    Full Text Available Abstract Background Recent work has indicated an increasingly complex role for astrocytes in the central nervous system. Astrocytes are now known to exchange information with neurons at synaptic junctions and to alter the information processing capabilities of the neurons. As an extension of this trend a hypothesis was proposed that astrocytes function to store information. To explore this idea the ion channels in biological membranes were compared to models known as cellular automata. These comparisons were made to test the hypothesis that ion channels in the membranes of astrocytes form a dynamic information storage device. Results Two dimensional cellular automata were found to behave similarly to ion channels in a membrane when they function at the boundary between order and chaos. The length of time information is stored in this class of cellular automata is exponentially related to the number of units. Therefore the length of time biological ion channels store information was plotted versus the estimated number of ion channels in the tissue. This analysis indicates that there is an exponential relationship between memory and the number of ion channels. Extrapolation of this relationship to the estimated number of ion channels in the astrocytes of a human brain indicates that memory can be stored in this system for an entire life span. Interestingly, this information is not affixed to any physical structure, but is stored as an organization of the activity of the ion channels. Further analysis of two dimensional cellular automata also demonstrates that these systems have both associative and temporal memory capabilities. Conclusion It is concluded that astrocytes may serve as a dynamic information sink for neurons. The memory in the astrocytes is stored by organizing the activity of ion channels and is not associated with a physical location such as a synapse. In order for this form of memory to be of significant duration it is necessary

  15. Robust and distributed hypothesis testing

    CERN Document Server

    Gül, Gökhan

    2017-01-01

    This book generalizes and extends the available theory in robust and decentralized hypothesis testing. In particular, it presents a robust test for modeling errors which is independent from the assumptions that a sufficiently large number of samples is available, and that the distance is the KL-divergence. Here, the distance can be chosen from a much general model, which includes the KL-divergence as a very special case. This is then extended by various means. A minimax robust test that is robust against both outliers as well as modeling errors is presented. Minimax robustness properties of the given tests are also explicitly proven for fixed sample size and sequential probability ratio tests. The theory of robust detection is extended to robust estimation and the theory of robust distributed detection is extended to classes of distributions, which are not necessarily stochastically bounded. It is shown that the quantization functions for the decision rules can also be chosen as non-monotone. Finally, the boo...

  16. The venom optimization hypothesis revisited.

    Science.gov (United States)

    Morgenstern, David; King, Glenn F

    2013-03-01

    Animal venoms are complex chemical mixtures that typically contain hundreds of proteins and non-proteinaceous compounds, resulting in a potent weapon for prey immobilization and predator deterrence. However, because venoms are protein-rich, they come with a high metabolic price tag. The metabolic cost of venom is sufficiently high to result in secondary loss of venom whenever its use becomes non-essential to survival of the animal. The high metabolic cost of venom leads to the prediction that venomous animals may have evolved strategies for minimizing venom expenditure. Indeed, various behaviors have been identified that appear consistent with frugality of venom use. This has led to formulation of the "venom optimization hypothesis" (Wigger et al. (2002) Toxicon 40, 749-752), also known as "venom metering", which postulates that venom is metabolically expensive and therefore used frugally through behavioral control. Here, we review the available data concerning economy of venom use by animals with either ancient or more recently evolved venom systems. We conclude that the convergent nature of the evidence in multiple taxa strongly suggests the existence of evolutionary pressures favoring frugal use of venom. However, there remains an unresolved dichotomy between this economy of venom use and the lavish biochemical complexity of venom, which includes a high degree of functional redundancy. We discuss the evidence for biochemical optimization of venom as a means of resolving this conundrum. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Alien abduction: a medical hypothesis.

    Science.gov (United States)

    Forrest, David V

    2008-01-01

    In response to a new psychological study of persons who believe they have been abducted by space aliens that found that sleep paralysis, a history of being hypnotized, and preoccupation with the paranormal and extraterrestrial were predisposing experiences, I noted that many of the frequently reported particulars of the abduction experience bear more than a passing resemblance to medical-surgical procedures and propose that experience with these may also be contributory. There is the altered state of consciousness, uniformly colored figures with prominent eyes, in a high-tech room under a round bright saucerlike object; there is nakedness, pain and a loss of control while the body's boundaries are being probed; and yet the figures are thought benevolent. No medical-surgical history was apparently taken in the above mentioned study, but psychological laboratory work evaluated false memory formation. I discuss problems in assessing intraoperative awareness and ways in which the medical hypothesis could be elaborated and tested. If physicians are causing this syndrome in a percentage of patients, we should know about it; and persons who feel they have been abducted should be encouraged to inform their surgeons and anesthesiologists without challenging their beliefs.

  18. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

    Science.gov (United States)

    Barage, Sagar H; Sonawane, Kailas D

    2015-08-01

    Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Kathleen Sprouffske

    2018-04-01

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

  20. Conjecture and hypothesis: The importance of reality checks

    Directory of Open Access Journals (Sweden)

    David Deamer

    2017-03-01

    Full Text Available In origins of life research, it is important to understand the difference between conjecture and hypothesis. This commentary explores the difference and recommends alternative hypotheses as a way to advance our understanding of how life can begin on the Earth and other habitable planets. As an example of how this approach can be used, two conditions have been proposed for sites conducive to the origin of life: hydrothermal vents in salty seawater, and fresh water hydrothermal fields associated with volcanic landmasses. These are considered as alternative hypotheses and the accumulating weight of evidence for each site is described and analyzed.

  1. Mutational specificity of SOS mutagenesis

    International Nuclear Information System (INIS)

    Kato, Takeshi

    1986-01-01

    In an approach to the isolation of mutants of E. coli unable to produce mutations by ultraviolet light, the author has found new umuC-mutants. Their properties could be explained by ''SOS hypothesis of Radman and Witkin'', which has now been justified by many investigators. Analysis of the umuC region of E. coli chromosome cloned in pSK 100 has led to the conclusion that two genes, umuD and umuC, having the capacity of mutation induction express in the same mechanism as that of SOS genes, which is known to be inhibited by LexA protein bonding to ''SOS box'' found at promotor region. Suppressor analysis for mutational specificity has revealed: (i) umuDC-independent mutagens, such as EMS and (oh) 4 Cy, induce selected base substitution alone; and (ii) umuDC-dependent mutagens, such as X-rays and gamma-rays, induce various types of base substitution simultaneously, although they have mutational specificity. In the umuDC-dependent processes of basechange mutagenesis, the spectra of base substitution were a mixture of base substitution reflecting the specific base damages induced by individual mutagens and nonspecific base substitution. In conclusion, base substitution plays the most important role in umuDC-dependent mutagenesis, although mutagenesis of umuDC proteins remains uncertain. (Namekawa, K.)

  2. [Secondary metabolites accumulating and geoherbs formation under enviromental stress].

    Science.gov (United States)

    Huang, Lu-Qi; Guo, Lan-Ping

    2007-02-01

    This paper analyzed how habitat affected the formation of geoherbs after summarizing the influences of environmental stress on plants growth, especially on theirs secondary metabolites accumulating, and introducing 4 kinds hypothesis about environmental stress affects plants. It was then pointed out that environmental stress may have advantage on the formation of geoherbs. The stress effect hypothesis on forming geoherbs was brought forward, and the ways and methods on study the geoherbs under environmental stress was discussed.

  3. How organisms do the right thing: The attractor hypothesis

    Science.gov (United States)

    Emlen, J.M.; Freeman, D.C.; Mills, A.; Graham, J.H.

    1998-01-01

    Neo-Darwinian theory is highly successful at explaining the emergence of adaptive traits over successive generations. However, there are reasons to doubt its efficacy in explaining the observed, impressively detailed adaptive responses of organisms to day-to-day changes in their surroundings. Also, the theory lacks a clear mechanism to account for both plasticity and canalization. In effect, there is a growing sentiment that the neo-Darwinian paradigm is incomplete, that something more than genetic structure, mutation, genetic drift, and the action of natural selection is required to explain organismal behavior. In this paper we extend the view of organisms as complex self-organizing entities by arguing that basic physical laws, coupled with the acquisitive nature of organisms, makes adaptation all but tautological. That is, much adaptation is an unavoidable emergent property of organisms' complexity and, to some a significant degree, occurs quite independently of genomic changes wrought by natural selection. For reasons that will become obvious, we refer to this assertion as the attractor hypothesis. The arguments also clarify the concept of "adaptation." Adaptation across generations, by natural selection, equates to the (game theoretic) maximization of fitness (the success with which one individual produces more individuals), while self-organizing based adaptation, within generations, equates to energetic efficiency and the matching of intake and biosynthesis to need. Finally, we discuss implications of the attractor hypothesis for a wide variety of genetical and physiological phenomena, including genetic architecture, directed mutation, genetic imprinting, paramutation, hormesis, plasticity, optimality theory, genotype-phenotype linkage and puncuated equilibrium, and present suggestions for tests of the hypothesis. ?? 1998 American Institute of Physics.

  4. 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.

  5. Plastids and Carotenoid Accumulation.

    Science.gov (United States)

    Li, Li; Yuan, Hui; Zeng, Yunliu; Xu, Qiang

    Plastids are ubiquitously present in plants and are the organelles for carotenoid biosynthesis and storage. Based on their morphology and function, plastids are classified into various types, i.e. proplastids, etioplasts, chloroplasts, amyloplasts, and chromoplasts. All plastids, except proplastids, can synthesize carotenoids. However, plastid types have a profound effect on carotenoid accumulation and stability. In this chapter, we discuss carotenoid biosynthesis and regulation in various plastids with a focus on carotenoids in chromoplasts. Plastid transition related to carotenoid biosynthesis and the different capacity of various plastids to sequester carotenoids and the associated effect on carotenoid stability are described in light of carotenoid accumulation in plants.

  6. Investigation of intercellular salicylic acid accumulation during compatible and incompatible Arabidopsis-pseudomonas syringae interactions using a fast neutron-generated mutant allele of EDS5 identified by genetic mapping and whole-genome sequencing.

    Directory of Open Access Journals (Sweden)

    Jessie L Carviel

    Full Text Available A whole-genome sequencing technique developed to identify fast neutron-induced deletion mutations revealed that iap1-1 is a new allele of EDS5 (eds5-5. RPS2-AvrRpt2-initiated effector-triggered immunity (ETI was compromised in iap1-1/eds5-5 with respect to in planta bacterial levels and the hypersensitive response, while intra- and intercellular free salicylic acid (SA accumulation was greatly reduced, suggesting that SA contributes as both an intracellular signaling molecule and an antimicrobial agent in the intercellular space during ETI. During the compatible interaction between wild-type Col-0 and virulent Pseudomonas syringae pv. tomato (Pst, little intercellular free SA accumulated, which led to the hypothesis that Pst suppresses intercellular SA accumulation. When Col-0 was inoculated with a coronatine-deficient strain of Pst, high levels of intercellular SA accumulation were observed, suggesting that Pst suppresses intercellular SA accumulation using its phytotoxin coronatine. This work suggests that accumulation of SA in the intercellular space is an important component of basal/PAMP-triggered immunity as well as ETI to pathogens that colonize the intercellular space.

  7. Validity of Linder Hypothesis in Bric Countries

    Directory of Open Access Journals (Sweden)

    Rana Atabay

    2016-03-01

    Full Text Available In this study, the theory of similarity in preferences (Linder hypothesis has been introduced and trade in BRIC countries has been examined whether the trade between these countries was valid for this hypothesis. Using the data for the period 1996 – 2010, the study applies to panel data analysis in order to provide evidence regarding the empirical validity of the Linder hypothesis for BRIC countries’ international trade. Empirical findings show that the trade between BRIC countries is in support of Linder hypothesis.

  8. 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)

  9. Accumulation by Conservation

    NARCIS (Netherlands)

    Büscher, Bram; Fletcher, Robert

    2015-01-01

    Following the financial crisis and its aftermath, it is clear that the inherent contradictions of capitalist accumulation have become even more intense and plunged the global economy into unprecedented turmoil and urgency. Governments, business leaders and other elite agents are frantically

  10. Accumulation by Conservation

    NARCIS (Netherlands)

    Büscher, Bram; Fletcher, Robert

    2014-01-01

    Following the financial crisis and its aftermath, it is clear that the inherent contradictions of capitalist accumulation have become even more intense and plunged the global economy into unprecedented turmoil and urgency. Governments, business leaders and other elite agents are frantically

  11. Creation / accumulation city

    NARCIS (Netherlands)

    Doevendans, C.H.; Schram, A.L.

    2005-01-01

    A distinction between basic archetypes of urban form was made by Bruno Fortier: the accumulation city as opposed to the creation city. These archetypes derive from archaeology - being based on the Roman and the Egyptian city - but are interpreted as morphological paradigms, as a set of assumptions

  12. Intraclutch variation in avian eggshell pigmentation: the anaemia hypothesis.

    Science.gov (United States)

    De Coster, Greet; De Neve, Liesbeth; Lens, Luc

    2012-10-01

    Many passerine species lay eggs that are speckled with dark protoporphyrin pigmentation. Because protoporphyrin is mainly derived from the blood, we here formulate and test a new hypothesis that links an increase in anaemia along the laying sequence to within-clutch variation in egg pigmentation. More intense pigmentation is expected if pigments accumulate during enhanced red blood cell production in response to anaemia. Reduced pigmentation is expected if pigments are derived from the degradation of red blood cells that circulate in smaller numbers due to blood loss. To test this hypothesis, we manipulated anaemia in great tit (Parus major) females by infesting the nests with hen fleas (Ceratophyllus gallinae) prior to egg laying. Polychromatophil (i.e., immature red blood cells) percentage, as a measure of blood cell production, was positively correlated with parasite load confirming that female great tits experienced stronger anaemia when infested with haematophagous parasites during egg laying. We found a positive relationship between spot darkness and laying order that weakened under high parasite load. This result suggests that anaemia in females due to blood-sucking parasites led to diminished protoporphyrin from disintegrated red blood cells and hence a decreased deposition of protoporphyrin. However, the overall increase in pigment darkness along the laying sequence suggests that pigments also accumulate by enhanced red blood cell production caused by anaemia due to egg production itself.

  13. The zinc dyshomeostasis hypothesis of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Travis J A Craddock

    Full Text Available Alzheimer's disease (AD is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ, intracellular neurofibrillary tangles (NFTs composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau, and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1 used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2 performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3 used metallomic imaging mass spectrometry (MIMS to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of

  14. The zinc dyshomeostasis hypothesis of Alzheimer's disease.

    Science.gov (United States)

    Craddock, Travis J A; Tuszynski, Jack A; Chopra, Deepak; Casey, Noel; Goldstein, Lee E; Hameroff, Stuart R; Tanzi, Rudolph E

    2012-01-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized

  15. Hypothesis Testing in the Real World

    Science.gov (United States)

    Miller, Jeff

    2017-01-01

    Critics of null hypothesis significance testing suggest that (a) its basic logic is invalid and (b) it addresses a question that is of no interest. In contrast to (a), I argue that the underlying logic of hypothesis testing is actually extremely straightforward and compelling. To substantiate that, I present examples showing that hypothesis…

  16. Error probabilities in default Bayesian hypothesis testing

    NARCIS (Netherlands)

    Gu, Xin; Hoijtink, Herbert; Mulder, J,

    2016-01-01

    This paper investigates the classical type I and type II error probabilities of default Bayes factors for a Bayesian t test. Default Bayes factors quantify the relative evidence between the null hypothesis and the unrestricted alternative hypothesis without needing to specify prior distributions for

  17. Reassessing the Trade-off Hypothesis

    DEFF Research Database (Denmark)

    Rosas, Guillermo; Manzetti, Luigi

    2015-01-01

    Do economic conditions drive voters to punish politicians that tolerate corruption? Previous scholarly work contends that citizens in young democracies support corrupt governments that are capable of promoting good economic outcomes, the so-called trade-off hypothesis. We test this hypothesis based...

  18. Mastery Learning and the Decreasing Variability Hypothesis.

    Science.gov (United States)

    Livingston, Jennifer A.; Gentile, J. Ronald

    1996-01-01

    This report results from studies that tested two variations of Bloom's decreasing variability hypothesis using performance on successive units of achievement in four graduate classrooms that used mastery learning procedures. Data do not support the decreasing variability hypothesis; rather, they show no change over time. (SM)

  19. Selenium accumulation by plants

    Science.gov (United States)

    White, Philip J.

    2016-01-01

    Background Selenium (Se) is an essential mineral element for animals and humans, which they acquire largely from plants. The Se concentration in edible plants is determined by the Se phytoavailability in soils. Selenium is not an essential element for plants, but excessive Se can be toxic. Thus, soil Se phytoavailability determines the ecology of plants. Most plants cannot grow on seleniferous soils. Most plants that grow on seleniferous soils accumulate 100 mg Se kg–1 dry matter. These plants are considered to be Se accumulators. Some species can even accumulate Se concentrations of 1000–15 000 mg Se kg–1 dry matter and are called Se hyperaccumulators. Scope This article provides an overview of Se uptake, translocation and metabolism in plants and highlights the possible genetic basis of differences in these between and within plant species. The review focuses initially on adaptations allowing plants to tolerate large Se concentrations in their tissues and the evolutionary origin of species that hyperaccumulate Se. It then describes the variation in tissue Se concentrations between and within angiosperm species and identifies genes encoding enzymes limiting the rates of incorporation of Se into organic compounds and chromosomal loci that might enable the development of crops with greater Se concentrations in their edible portions. Finally, it discusses transgenic approaches enabling plants to tolerate greater Se concentrations in the rhizosphere and in their tissues. Conclusions The trait of Se hyperaccumulation has evolved several times in separate angiosperm clades. The ability to tolerate large tissue Se concentrations is primarily related to the ability to divert Se away from the accumulation of selenocysteine and selenomethionine, which might be incorporated into non-functional proteins, through the synthesis of less toxic Se metabilites. There is potential to breed or select crops with greater Se concentrations in their edible tissues, which

  20. Accumulation of satellites

    International Nuclear Information System (INIS)

    Safronov, V.S.; Ruskol, E.L.

    1977-01-01

    Formation and evolution of circumplanetary satellite swarms are investigated. Characteristic times of various processes are estimated. The characteristic time for the accumulation of the bodies in the swarm was several orders of magnitude shorter than that of the planet, i.e. than the time of the replenishment of the material by the swarm (10 8 yr). The model of the accumulation of the swarm is constructed taking into account the increase of its mass due to trapping of heliocentrically moving particles and its decrease due to outfall of the inner part of the swarm onto the growing planet. The accumulation of circumplanetary bodies is also considered. The main features of the evolution of the swarm essentially depend on the size distribution of bodies in the swarm and in the zone of the planet and also on the degree of the concentration of the swarm mass toward the planet. If the sum of the exponents of the inverse power laws of these distributions is less than 7, the model of the transparent swarm developed in this paper should be preferred. When this sum is greater than 7, the model of opaque swarm suggested by A. Harris and W.M. Kaula is better. There is predominant trapping of small particles into the swarm due to their more frequent collisions. Optical thickness of the protoplanetary cloud in radial direction is estimated. It is shown that at the final stage of the planetary accumulation, the cloud was semitransparent in the region of terrestrial planets and volatile substances evaporated at collisions could be swept out from the outer parts of the satellite swarm by the solar wind

  1. Antiproton Accumulator (AA)

    CERN Multimedia

    Photographic Service

    1980-01-01

    The AA in its final stage of construction, before it disappeared from view under concrete shielding. Antiprotons were first injected, stochastically cooled and accumulated in July 1980. From 1981 on, the AA provided antiprotons for collisions with protons, first in the ISR, then in the SPS Collider. From 1983 on, it also sent antiprotons, via the PS, to the Low-Energy Antiproton Ring (LEAR). The AA was dismantled in 1997 and shipped to Japan.

  2. Selenium accumulation by plants.

    Science.gov (United States)

    White, Philip J

    2016-02-01

    Selenium (Se) is an essential mineral element for animals and humans, which they acquire largely from plants. The Se concentration in edible plants is determined by the Se phytoavailability in soils. Selenium is not an essential element for plants, but excessive Se can be toxic. Thus, soil Se phytoavailability determines the ecology of plants. Most plants cannot grow on seleniferous soils. Most plants that grow on seleniferous soils accumulate plant species have evolved tolerance to Se, and commonly accumulate tissue Se concentrations >100 mg Se kg(-1) dry matter. These plants are considered to be Se accumulators. Some species can even accumulate Se concentrations of 1000-15 000 mg Se kg(-1 )dry matter and are called Se hyperaccumulators. This article provides an overview of Se uptake, translocation and metabolism in plants and highlights the possible genetic basis of differences in these between and within plant species. The review focuses initially on adaptations allowing plants to tolerate large Se concentrations in their tissues and the evolutionary origin of species that hyperaccumulate Se. It then describes the variation in tissue Se concentrations between and within angiosperm species and identifies genes encoding enzymes limiting the rates of incorporation of Se into organic compounds and chromosomal loci that might enable the development of crops with greater Se concentrations in their edible portions. Finally, it discusses transgenic approaches enabling plants to tolerate greater Se concentrations in the rhizosphere and in their tissues. The trait of Se hyperaccumulation has evolved several times in separate angiosperm clades. The ability to tolerate large tissue Se concentrations is primarily related to the ability to divert Se away from the accumulation of selenocysteine and selenomethionine, which might be incorporated into non-functional proteins, through the synthesis of less toxic Se metabilites. There is potential to breed or select crops

  3. Iron accumulates in the lavage and explanted lungs of cystic fibrosis patients.

    Science.gov (United States)

    Abstract Oxidative stress participates in the pathophysiology of cystic fibrosis (CF). An underlying disruption in iron homeostasis can frequently be demonstrated in injuries and diseases associated with an oxidative stress. We tested the hypothesis that iron accumulation and ...

  4. The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, S.J.; Gladwin, A.J.; Dixon, M.J. [Univ. of Manchester (United Kingdom)

    1997-03-01

    Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mutations, which are spread throughout the gene, are presented. This brings the total reported to date to 35, which represents a detection rate of 60%. Of the mutations that have been reported to date, all but one result in the introduction of a premature-termination codon into the predicted protein, treacle. Moreover, the mutations are largely family specific, although a common 5-bp deletion in exon 24 (seven different families) and a recurrent splicing mutation in intron 3 (two different families) have been identified. This mutational spectrum supports the hypothesis that TCS results from haploin-sufficiency. 49 refs., 4 figs., 3 tabs.

  5. Implications of the Bohm-Aharonov hypothesis

    International Nuclear Information System (INIS)

    Ghirardi, G.C.; Rimini, A.; Weber, T.

    1976-01-01

    It is proved that the Bohm-Aharonov hypothesis concerning largerly separated subsystems of composite quantum systems implies that it is impossible to express the dynamical evolution in terms of the density operator

  6. Multi-agent sequential hypothesis testing

    KAUST Repository

    Kim, Kwang-Ki K.; Shamma, Jeff S.

    2014-01-01

    incorporate costs of taking private/public measurements, costs of time-difference and disagreement in actions of agents, and costs of false declaration/choices in the sequential hypothesis testing. The corresponding sequential decision processes have well

  7. Enhanced accumulation of U(VI) by Aspergillus oryzae mutant generated by dielectric barrier discharge air plasma

    International Nuclear Information System (INIS)

    Wencheng Song; North China Electric Power University, Beijing; Xiangxue Wang; Soochow University, Suzhou; Wen Tao; Hongqing Wang; Tasawar Hayat; Quaid-I-Azam University, Islamabad; Xiangke Wang; Soochow University, Suzhou; King Abdulaziz University, Jeddah

    2016-01-01

    Aspergillus oryzae was isolated from radionuclides' contaminated soils, and dielectric barrier discharge plasma was used to mutate A. oryzae to improve bioremediation capability of U(VI) pollution. The maximum accumulation capacities of U(VI) on mutated A.oryzae was 627.4 mg/g at T = 298 K and pH = 5.5, which was approximately twice than that of raw A.oryzae. XPS analysis indicated that U(VI) accumulation on mutated A. oryzae was largely attributable to nitrogen- and oxygen-containing functional groups on fungal mycelia. The mutated A. oryzae can be harnessed as bioremediation agents for radionuclides pollution. (author)

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

    Science.gov (United States)

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

    2015-07-01

    The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.

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

    Directory of Open Access Journals (Sweden)

    Toshihiko Kishimoto

    2015-07-01

    Full Text Available The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.

  10. Asynchronous accumulation of lettuce infectious yellows virus RNAs 1 and 2 and identification of an RNA 1 trans enhancer of RNA 2 accumulation.

    Science.gov (United States)

    Yeh, H H; Tian, T; Rubio, L; Crawford, B; Falk, B W

    2000-07-01

    Time course and mutational analyses were used to examine the accumulation in protoplasts of progeny RNAs of the bipartite Crinivirus, Lettuce infectious yellow virus (LIYV; family Closteroviridae). Hybridization analyses showed that simultaneous inoculation of LIYV RNAs 1 and 2 resulted in asynchronous accumulation of progeny LIYV RNAs. LIYV RNA 1 progeny genomic and subgenomic RNAs could be detected in protoplasts as early as 12 h postinoculation (p.i.) and accumulated to high levels by 24 h p.i. The LIYV RNA 1 open reading frame 2 (ORF 2) subgenomic RNA was the most abundant of all LIYV RNAs detected. In contrast, RNA 2 progeny were not readily detected until ca. 36 h p.i. Mutational analyses showed that in-frame stop codons introduced into five of seven RNA 2 ORFs did not affect accumulation of progeny LIYV RNA 1 or RNA 2, confirming that RNA 2 does not encode proteins necessary for LIYV RNA replication. Mutational analyses also supported that LIYV RNA 1 encodes proteins necessary for replication of LIYV RNAs 1 and 2. A mutation introduced into the LIYV RNA 1 region encoding the overlapping ORF 1B and ORF 2 was lethal. However, mutations introduced into only LIYV RNA 1 ORF 2 resulted in accumulation of progeny RNA 1 near or equal to wild-type RNA 1. In contrast, the RNA 1 ORF 2 mutants did not efficiently support the trans accumulation of LIYV RNA 2. Three distinct RNA 1 ORF 2 mutants were analyzed and all exhibited a similar phenotype for progeny LIYV RNA accumulation. These data suggest that the LIYV RNA 1 ORF 2 encodes a trans enhancer for RNA 2 accumulation.

  11. Failure of the statistical hypothesis for compound nucleus decay

    International Nuclear Information System (INIS)

    Chrien, R.E.

    1976-01-01

    In the past five years, conclusive evidence has accumulated that channel correlations are important in resonance reactions. Experiments showing the failure of the statistical hypothesis for compound nucleus decay are described. The emphasis is on the radiative neutron capture reaction, where much detailed work has been done. A short summary of the theory of the (n,γ) reaction is presented; it is demonstrated that this reaction is a sensitive probe of the wave functions for highly excited nuclear states. Various experimental techniques using reactor and accelerator-based neutron sources are presented. The experiments have shown that both resonant and non-resonant reactions can show single particle effects where the external part of configuration space is dominant. In the non-resonant case, hard sphere capture is important; on resonances, valence particle motion and the contributions of 1 and 3 quasi-particle doorway states make up a significant fraction of the radiative width

  12. Population-based statistical inference for temporal sequence of somatic mutations in cancer genomes.

    Science.gov (United States)

    Rhee, Je-Keun; Kim, Tae-Min

    2018-04-20

    It is well recognized that accumulation of somatic mutations in cancer genomes plays a role in carcinogenesis; however, the temporal sequence and evolutionary relationship of somatic mutations remain largely unknown. In this study, we built a population-based statistical framework to infer the temporal sequence of acquisition of somatic mutations. Using the model, we analyzed the mutation profiles of 1954 tumor specimens across eight tumor types. As a result, we identified tumor type-specific directed networks composed of 2-15 cancer-related genes (nodes) and their mutational orders (edges). The most common ancestors identified in pairwise comparison of somatic mutations were TP53 mutations in breast, head/neck, and lung cancers. The known relationship of KRAS to TP53 mutations in colorectal cancers was identified, as well as potential ancestors of TP53 mutation such as NOTCH1, EGFR, and PTEN mutations in head/neck, lung and endometrial cancers, respectively. We also identified apoptosis-related genes enriched with ancestor mutations in lung cancers and a relationship between APC hotspot mutations and TP53 mutations in colorectal cancers. While evolutionary analysis of cancers has focused on clonal versus subclonal mutations identified in individual genomes, our analysis aims to further discriminate ancestor versus descendant mutations in population-scale mutation profiles that may help select cancer drivers with clinical relevance.

  13. The Antiproton Accumulator (AA)

    CERN Multimedia

    1980-01-01

    Section 06 - 08*) of the AA where the dispersion (and hence the horizontal beam size) is large. One can distinguish (left to right): A vacuum-tank, two bending magnets (BST06 and BST07 in blue) with a quadrupole (QDN07, in red) in between, another vacuum-tank, a wide quadrupole (QFW08) and a further tank . The tanks are covered with heating tape for bake-out. The tank left of BST06 contained the stack core pickup for stochastic cooling (see 7906193, 7906190, 8005051), the two other tanks served mainly as vacuum chambers in the region where the beam was large. Peter Zettwoch works on BST06. *) see: H. Koziol, Antiproton Accumulator Parameter List, PS/AA/Note 84-2 (1984)

  14. Solids Accumulation Scouting Studies

    Energy Technology Data Exchange (ETDEWEB)

    Duignan, M. R.; Steeper, T. J.; Steimke, J. L.

    2012-09-26

    The objective of Solids Accumulation activities was to perform scaled testing to understand the behavior of remaining solids in a Double Shell Tank (DST), specifically AW-105, at Hanford during multiple fill, mix, and transfer operations. It is important to know if fissionable materials can concentrate when waste is transferred from staging tanks prior to feeding waste treatment plants. Specifically, there is a concern that large, dense particles containing plutonium could accumulate in poorly mixed regions of a blend tank heel for tanks that employ mixing jet pumps. At the request of the DOE Hanford Tank Operations Contractor, Washington River Protection Solutions, the Engineering Development Laboratory of the Savannah River National Laboratory performed a scouting study in a 1/22-scale model of a waste staging tank to investigate this concern and to develop measurement techniques that could be applied in a more extensive study at a larger scale. Simulated waste tank solids: Gibbsite, Zirconia, Sand, and Stainless Steel, with stainless steel particles representing the heavier particles, e.g., plutonium, and supernatant were charged to the test tank and rotating liquid jets were used to mix most of the solids while the simulant was pumped out. Subsequently, the volume and shape of the mounds of residual solids and the spatial concentration profiles for the surrogate for heavier particles were measured. Several techniques were developed and equipment designed to accomplish the measurements needed and they included: 1. Magnetic particle separator to remove simulant stainless steel solids. A device was designed and built to capture these solids, which represent the heavier solids during a waste transfer from a staging tank. 2. Photographic equipment to determine the volume of the solids mounds. The mounds were photographed as they were exposed at different tank waste levels to develop a composite of topographical areas. 3. Laser rangefinders to determine the volume of

  15. Multiple hypothesis tracking for the cyber domain

    Science.gov (United States)

    Schwoegler, Stefan; Blackman, Sam; Holsopple, Jared; Hirsch, Michael J.

    2011-09-01

    This paper discusses how methods used for conventional multiple hypothesis tracking (MHT) can be extended to domain-agnostic tracking of entities from non-kinematic constraints such as those imposed by cyber attacks in a potentially dense false alarm background. MHT is widely recognized as the premier method to avoid corrupting tracks with spurious data in the kinematic domain but it has not been extensively applied to other problem domains. The traditional approach is to tightly couple track maintenance (prediction, gating, filtering, probabilistic pruning, and target confirmation) with hypothesis management (clustering, incompatibility maintenance, hypothesis formation, and Nassociation pruning). However, by separating the domain specific track maintenance portion from the domain agnostic hypothesis management piece, we can begin to apply the wealth of knowledge gained from ground and air tracking solutions to the cyber (and other) domains. These realizations led to the creation of Raytheon's Multiple Hypothesis Extensible Tracking Architecture (MHETA). In this paper, we showcase MHETA for the cyber domain, plugging in a well established method, CUBRC's INFormation Engine for Real-time Decision making, (INFERD), for the association portion of the MHT. The result is a CyberMHT. We demonstrate the power of MHETA-INFERD using simulated data. Using metrics from both the tracking and cyber domains, we show that while no tracker is perfect, by applying MHETA-INFERD, advanced nonkinematic tracks can be captured in an automated way, perform better than non-MHT approaches, and decrease analyst response time to cyber threats.

  16. Do depressive episodes lead to accumulation of vulnerability in the elderly?

    NARCIS (Netherlands)

    Oldehinkel, AJ; van den Berg, MD; Bouhuys, AL; Ormel, J

    2003-01-01

    The vulnerability-accumulation (or scarring) hypothesis postulates that the experience of depression induces a lasting increase in vulnerability, and through this raises the risk of recurrence. We examined the validity of the vulnerability-accumulation model for depressive episodes in later life.

  17. 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.)

  18. Testing competing forms of the Milankovitch hypothesis

    DEFF Research Database (Denmark)

    Kaufmann, Robert K.; Juselius, Katarina

    2016-01-01

    We test competing forms of the Milankovitch hypothesis by estimating the coefficients and diagnostic statistics for a cointegrated vector autoregressive model that includes 10 climate variables and four exogenous variables for solar insolation. The estimates are consistent with the physical...... ice volume and solar insolation. The estimated adjustment dynamics show that solar insolation affects an array of climate variables other than ice volume, each at a unique rate. This implies that previous efforts to test the strong form of the Milankovitch hypothesis by examining the relationship...... that the latter is consistent with a weak form of the Milankovitch hypothesis and that it should be restated as follows: Internal climate dynamics impose perturbations on glacial cycles that are driven by solar insolation. Our results show that these perturbations are likely caused by slow adjustment between land...

  19. Rejecting the equilibrium-point hypothesis.

    Science.gov (United States)

    Gottlieb, G L

    1998-01-01

    The lambda version of the equilibrium-point (EP) hypothesis as developed by Feldman and colleagues has been widely used and cited with insufficient critical understanding. This article offers a small antidote to that lack. First, the hypothesis implicitly, unrealistically assumes identical transformations of lambda into muscle tension for antagonist muscles. Without that assumption, its definitions of command variables R, C, and lambda are incompatible and an EP is not defined exclusively by R nor is it unaffected by C. Second, the model assumes unrealistic and unphysiological parameters for the damping properties of the muscles and reflexes. Finally, the theory lacks rules for two of its three command variables. A theory of movement should offer insight into why we make movements the way we do and why we activate muscles in particular patterns. The EP hypothesis offers no unique ideas that are helpful in addressing either of these questions.

  20. The linear hypothesis and radiation carcinogenesis

    International Nuclear Information System (INIS)

    Roberts, P.B.

    1981-10-01

    An assumption central to most estimations of the carcinogenic potential of low levels of ionising radiation is that the risk always increases in direct proportion to the dose received. This assumption (the linear hypothesis) has been both strongly defended and attacked on several counts. It appears unlikely that conclusive, direct evidence on the validity of the hypothesis will be forthcoming. We review the major indirect arguments used in the debate. All of them are subject to objections that can seriously weaken their case. In the present situation, retention of the linear hypothesis as the basis of extrapolations from high to low dose levels can lead to excessive fears, over-regulation and unnecessarily expensive protection measures. To offset these possibilities, support is given to suggestions urging a cut-off dose, probably some fraction of natural background, below which risks can be deemed acceptable

  1. Rayleigh's hypothesis and the geometrical optics limit.

    Science.gov (United States)

    Elfouhaily, Tanos; Hahn, Thomas

    2006-09-22

    The Rayleigh hypothesis (RH) is often invoked in the theoretical and numerical treatment of rough surface scattering in order to decouple the analytical form of the scattered field. The hypothesis stipulates that the scattered field away from the surface can be extended down onto the rough surface even though it is formed by solely up-going waves. Traditionally this hypothesis is systematically used to derive the Volterra series under the small perturbation method which is equivalent to the low-frequency limit. In this Letter we demonstrate that the RH also carries the high-frequency or the geometrical optics limit, at least to first order. This finding has never been explicitly derived in the literature. Our result comforts the idea that the RH might be an exact solution under some constraints in the general case of random rough surfaces and not only in the case of small-slope deterministic periodic gratings.

  2. 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.

  3. 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

  4. The Antiproton Accumulator (AA)

    CERN Multimedia

    1980-01-01

    A section of the AA where the dispersion (and hence the horizontal beam size) is large. One can distinguish (left to right): A large vacuum-tank, a quadrupole (QDN09*), a bending magnet (BST08), another vacuum-tank, a wide quadrupole (QFW08) and (in the background) a further bending magnet (BST08). The tanks are covered with heating tape for bake-out. The tank left of QDN09 contained the kickers for stochastic pre-cooling (see 790621, 8002234, 8002637X), the other one served mainly as vacuum chamber in the region where the beam was large. Peter Zettwoch works on QFW08. * see: H. Koziol, Antiproton Accumulator Parameter List, PS/AA/Note 84-2 (1984) See under 7911303, 7911597X, 8004261 and 8202324. For photos of the AA in different phases of completion (between 1979 and 1982) see: 7911303, 7911597X, 8004261, 8004608X, 8005563X, 8005565X, 8006716X, 8006722X, 8010939X, 8010941X, 8202324, 8202658X, 8203628X .

  5. On the generalized gravi-magnetic hypothesis

    International Nuclear Information System (INIS)

    Massa, C.

    1989-01-01

    According to a generalization of the gravi-magnetic hypothesis (GMH) any neutral mass moving in a curvilinear path with respect to an inertial frame creates a magnetic field, dependent on the curvature radius of the path. A simple astrophysical consequence of the generalized GMH is suggested considering the special cases of binary pulsars and binary neutron stars

  6. Remarks about the hypothesis of limiting fragmentation

    International Nuclear Information System (INIS)

    Chou, T.T.; Yang, C.N.

    1987-01-01

    Remarks are made about the hypothesis of limiting fragmentation. In particular, the concept of favored and disfavored fragment distribution is introduced. Also, a sum rule is proved leading to a useful quantity called energy-fragmentation fraction. (author). 11 refs, 1 fig., 2 tabs

  7. Multiple hypothesis clustering in radar plot extraction

    NARCIS (Netherlands)

    Huizing, A.G.; Theil, A.; Dorp, Ph. van; Ligthart, L.P.

    1995-01-01

    False plots and plots with inaccurate range and Doppler estimates may severely degrade the performance of tracking algorithms in radar systems. This paper describes how a multiple hypothesis clustering technique can be applied to mitigate the problems involved in plot extraction. The measures of

  8. The (not so immortal strand hypothesis

    Directory of Open Access Journals (Sweden)

    Cristian Tomasetti

    2015-03-01

    Significance: Utilizing an approach that is fundamentally different from previous efforts to confirm or refute the immortal strand hypothesis, we provide evidence against non-random segregation of DNA during stem cell replication. Our results strongly suggest that parental DNA is passed randomly to stem cell daughters and provides new insight into the mechanism of DNA replication in stem cells.

  9. A Developmental Study of the Infrahumanization Hypothesis

    Science.gov (United States)

    Martin, John; Bennett, Mark; Murray, Wayne S.

    2008-01-01

    Intergroup attitudes in children were examined based on Leyen's "infrahumanization hypothesis". This suggests that some uniquely human emotions, such as shame and guilt (secondary emotions), are reserved for the in-group, whilst other emotions that are not uniquely human and shared with animals, such as anger and pleasure (primary…

  10. Morbidity and Infant Development: A Hypothesis.

    Science.gov (United States)

    Pollitt, Ernesto

    1983-01-01

    Results of a study conducted in 14 villages of Sui Lin Township, Taiwan, suggest the hypothesis that, under conditions of extreme economic impoverishment and among children within populations where energy protein malnutrition is endemic, there is an inverse relationship between incidence of morbidity in infancy and measures of motor and mental…

  11. Diagnostic Hypothesis Generation and Human Judgment

    Science.gov (United States)

    Thomas, Rick P.; Dougherty, Michael R.; Sprenger, Amber M.; Harbison, J. Isaiah

    2008-01-01

    Diagnostic hypothesis-generation processes are ubiquitous in human reasoning. For example, clinicians generate disease hypotheses to explain symptoms and help guide treatment, auditors generate hypotheses for identifying sources of accounting errors, and laypeople generate hypotheses to explain patterns of information (i.e., data) in the…

  12. Multi-hypothesis distributed stereo video coding

    DEFF Research Database (Denmark)

    Salmistraro, Matteo; Zamarin, Marco; Forchhammer, Søren

    2013-01-01

    for stereo sequences, exploiting an interpolated intra-view SI and two inter-view SIs. The quality of the SI has a major impact on the DVC Rate-Distortion (RD) performance. As the inter-view SIs individually present lower RD performance compared with the intra-view SI, we propose multi-hypothesis decoding...

  13. [Resonance hypothesis of heart rate variability origin].

    Science.gov (United States)

    Sheĭkh-Zade, Iu R; Mukhambetaliev, G Kh; Cherednik, I L

    2009-09-01

    A hypothesis is advanced of the heart rate variability being subjected to beat-to-beat regulation of cardiac cycle duration in order to ensure the resonance interaction between respiratory and own fluctuation of the arterial system volume for minimization of power expenses of cardiorespiratory system. Myogenic, parasympathetic and sympathetic machanisms of heart rate variability are described.

  14. In Defense of Chi's Ontological Incompatibility Hypothesis

    Science.gov (United States)

    Slotta, James D.

    2011-01-01

    This article responds to an article by A. Gupta, D. Hammer, and E. F. Redish (2010) that asserts that M. T. H. Chi's (1992, 2005) hypothesis of an "ontological commitment" in conceptual development is fundamentally flawed. In this article, I argue that Chi's theoretical perspective is still very much intact and that the critique offered by Gupta…

  15. Vacuum counterexamples to the cosmic censorship hypothesis

    International Nuclear Information System (INIS)

    Miller, B.D.

    1981-01-01

    In cylindrically symmetric vacuum spacetimes it is possible to specify nonsingular initial conditions such that timelike singularities will (necessarily) evolve from these conditions. Examples are given; the spacetimes are somewhat analogous to one of the spherically symmetric counterexamples to the cosmic censorship hypothesis

  16. Batteries and accumulators in France

    International Nuclear Information System (INIS)

    2012-12-01

    The present report gives an overview of the batteries and accumulators market in France in 2011 based on the data reported through ADEME's Register of Batteries and accumulators. In 2001, the French Environmental Agency, known as ADEME, implemented a follow-up of the batteries and accumulators market, creating the Observatory of batteries and accumulators (B and A). In 2010, ADEME created the National Register of producers of Batteries and Accumulators in the context of the implementation of the order issued on November 18, 2009. This is one of the four enforcement orders for the decree 2009-1139 issued on September 22, 2009, concerning batteries and accumulators put on the market and the disposal of waste batteries and accumulators, and which transposes the EU-Directive 2006/66/CE into French law. This Register follows the former Observatory for batteries and accumulators. This Register aims to record the producers on French territory and to collect the B and A producers and recycling companies' annual reporting: the regulation indeed requires that all B and A producers and recycling companies report annually on the Register the quantities of batteries and accumulators they put on the market, collect and treat. Based on this data analysis, ADEME issues an annual report allowing both the follow-up of the batteries and accumulators market in France and communication regarding the achievement of the collection and recovery objectives set by EU regulation. This booklet presents the situation in France in 2011

  17. A novel hypothesis splitting method implementation for multi-hypothesis filters

    DEFF Research Database (Denmark)

    Bayramoglu, Enis; Ravn, Ole; Andersen, Nils Axel

    2013-01-01

    The paper presents a multi-hypothesis filter library featuring a novel method for splitting Gaussians into ones with smaller variances. The library is written in C++ for high performance and the source code is open and free1. The multi-hypothesis filters commonly approximate the distribution tran...

  18. The Income Inequality Hypothesis Revisited : Assessing the Hypothesis Using Four Methodological Approaches

    NARCIS (Netherlands)

    Kragten, N.; Rözer, J.

    The income inequality hypothesis states that income inequality has a negative effect on individual’s health, partially because it reduces social trust. This article aims to critically assess the income inequality hypothesis by comparing several analytical strategies, namely OLS regression,

  19. Einstein's Revolutionary Light-Quantum Hypothesis

    Science.gov (United States)

    Stuewer, Roger H.

    2005-05-01

    The paper in which Albert Einstein proposed his light-quantum hypothesis was the only one of his great papers of 1905 that he himself termed ``revolutionary.'' Contrary to widespread belief, Einstein did not propose his light-quantum hypothesis ``to explain the photoelectric effect.'' Instead, he based his argument for light quanta on the statistical interpretation of the second law of thermodynamics, with the photoelectric effect being only one of three phenomena that he offered as possible experimental support for it. I will discuss Einstein's light-quantum hypothesis of 1905 and his introduction of the wave-particle duality in 1909 and then turn to the reception of his work on light quanta by his contemporaries. We will examine the reasons that prominent physicists advanced to reject Einstein's light-quantum hypothesis in succeeding years. Those physicists included Robert A. Millikan, even though he provided convincing experimental proof of the validity of Einstein's equation of the photoelectric effect in 1915. The turning point came after Arthur Holly Compton discovered the Compton effect in late 1922, but even then Compton's discovery was contested both on experimental and on theoretical grounds. Niels Bohr, in particular, had never accepted the reality of light quanta and now, in 1924, proposed a theory, the Bohr-Kramers-Slater theory, which assumed that energy and momentum were conserved only statistically in microscopic interactions. Only after that theory was disproved experimentally in 1925 was Einstein's revolutionary light-quantum hypothesis generally accepted by physicists---a full two decades after Einstein had proposed it.

  20. A Dopamine Hypothesis of Autism Spectrum Disorder.

    Science.gov (United States)

    Pavăl, Denis

    2017-01-01

    Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by social deficits and stereotyped behaviors. While several theories have emerged, the pathogenesis of ASD remains unknown. Although studies report dopamine signaling abnormalities in autistic patients, a coherent dopamine hypothesis which could link neurobiology to behavior in ASD is currently lacking. In this paper, we present such a hypothesis by proposing that autistic behavior arises from dysfunctions in the midbrain dopaminergic system. We hypothesize that a dysfunction of the mesocorticolimbic circuit leads to social deficits, while a dysfunction of the nigrostriatal circuit leads to stereotyped behaviors. Furthermore, we discuss 2 key predictions of our hypothesis, with emphasis on clinical and therapeutic aspects. First, we argue that dopaminergic dysfunctions in the same circuits should associate with autistic-like behavior in nonautistic subjects. Concerning this, we discuss the case of PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections) which displays behaviors similar to those of ASD, presumed to arise from dopaminergic dysfunctions. Second, we argue that providing dopamine modulators to autistic subjects should lead to a behavioral improvement. Regarding this, we present clinical studies of dopamine antagonists which seem to have improving effects on autistic behavior. Furthermore, we explore the means of testing our hypothesis by using neuroreceptor imaging, which could provide comprehensive evidence for dopamine signaling dysfunctions in autistic subjects. Lastly, we discuss the limitations of our hypothesis. Along these lines, we aim to provide a dopaminergic model of ASD which might lead to a better understanding of the ASD pathogenesis. © 2017 S. Karger AG, Basel.

  1. Role of heterozygous APC mutation in niche succession and initiation of colorectal cancer--a computational study.

    Directory of Open Access Journals (Sweden)

    Roschen Sasikumar

    Full Text Available Mutations in the adenomatous polyposis coli (APC gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC(+/- stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking.

  2. Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.

    Directory of Open Access Journals (Sweden)

    Yasushi Ogawa

    2014-05-01

    Full Text Available When two mutations, one dominant pathogenic and the other "confining" nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.

  3. Common Variable Immunodeficiency Caused by FANC Mutations.

    Science.gov (United States)

    Sekinaka, Yujin; Mitsuiki, Noriko; Imai, Kohsuke; Yabe, Miharu; Yabe, Hiromasa; Mitsui-Sekinaka, Kanako; Honma, Kenichi; Takagi, Masatoshi; Arai, Ayako; Yoshida, Kenichi; Okuno, Yusuke; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Muramatsu, Hideki; Kojima, Seiji; Hira, Asuka; Takata, Minoru; Ohara, Osamu; Ogawa, Seishi; Morio, Tomohiro; Nonoyama, Shigeaki

    2017-07-01

    Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4 + T cells were skewed toward CD45RO + memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

  4. Mutation of Blakeslea trispora in lycopene production by ion beams

    International Nuclear Information System (INIS)

    Zhang Ning; Yu Long; Shen Yiling

    2008-01-01

    In this paper the mutation of lycopene producing strain, B. trispora(-) by use of low energy N + ion implantation, was studied. Experimental results show that higher mutation rate and wider mutation spectrum have been obtained after B. trispora (-) being implanted and four lycopene high yielding strains B. trispora (-) BH3-701 et al have been screened out. It has been found that the average production of lycopene increases by 50% compared with that of original strain after five passages in shaking flasks. The highest yield strain BH3-701 can accumulate lycopene in the later stage and increase production efficiency greatly. (authors)

  5. 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

  6. Mutation dynamics and fitness effects followed in single cells.

    Science.gov (United States)

    Robert, Lydia; Ollion, Jean; Robert, Jerome; Song, Xiaohu; Matic, Ivan; Elez, Marina

    2018-03-16

    Mutations have been investigated for more than a century but remain difficult to observe directly in single cells, which limits the characterization of their dynamics and fitness effects. By combining microfluidics, time-lapse imaging, and a fluorescent tag of the mismatch repair system in Escherichia coli , we visualized the emergence of mutations in single cells, revealing Poissonian dynamics. Concomitantly, we tracked the growth and life span of single cells, accumulating ~20,000 mutations genome-wide over hundreds of generations. This analysis revealed that 1% of mutations were lethal; nonlethal mutations displayed a heavy-tailed distribution of fitness effects and were dominated by quasi-neutral mutations with an average cost of 0.3%. Our approach has enabled the investigation of single-cell individuality in mutation rate, mutation fitness costs, and mutation interactions. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  7. From bad to good: Fitness reversals and the ascent of deleterious mutations.

    Directory of Open Access Journals (Sweden)

    Matthew C Cowperthwaite

    2006-10-01

    Full Text Available Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10(-5 of all mutations.

  8. Tests of the Giant Impact Hypothesis

    Science.gov (United States)

    Jones, J. H.

    1998-01-01

    The giant impact hypothesis has gained popularity as a means of explaining a volatile-depleted Moon that still has a chemical affinity to the Earth. As Taylor's Axiom decrees, the best models of lunar origin are testable, but this is difficult with the giant impact model. The energy associated with the impact would be sufficient to totally melt and partially vaporize the Earth. And this means that there should he no geological vestige of Barber times. Accordingly, it is important to devise tests that may be used to evaluate the giant impact hypothesis. Three such tests are discussed here. None of these is supportive of the giant impact model, but neither do they disprove it.

  9. The discovered preference hypothesis - an empirical test

    DEFF Research Database (Denmark)

    Lundhede, Thomas; Ladenburg, Jacob; Olsen, Søren Bøye

    Using stated preference methods for valuation of non-market goods is known to be vulnerable to a range of biases. Some authors claim that these so-called anomalies in effect render the methods useless for the purpose. However, the Discovered Preference Hypothesis, as put forth by Plott [31], offers...... an nterpretation and explanation of biases which entails that the stated preference methods need not to be completely written off. In this paper we conduct a test for the validity and relevance of the DPH interpretation of biases. In a choice experiment concerning preferences for protection of Danish nature areas...... as respondents evaluate more and more choice sets. This finding supports the Discovered Preference Hypothesis interpretation and explanation of starting point bias....

  10. The Hypothesis-Driven Physical Examination.

    Science.gov (United States)

    Garibaldi, Brian T; Olson, Andrew P J

    2018-05-01

    The physical examination remains a vital part of the clinical encounter. However, physical examination skills have declined in recent years, in part because of decreased time at the bedside. Many clinicians question the relevance of physical examinations in the age of technology. A hypothesis-driven approach to teaching and practicing the physical examination emphasizes the performance of maneuvers that can alter the likelihood of disease. Likelihood ratios are diagnostic weights that allow clinicians to estimate the post-probability of disease. This hypothesis-driven approach to the physical examination increases its value and efficiency, while preserving its cultural role in the patient-physician relationship. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. MOLIERE: Automatic Biomedical Hypothesis Generation System.

    Science.gov (United States)

    Sybrandt, Justin; Shtutman, Michael; Safro, Ilya

    2017-08-01

    Hypothesis generation is becoming a crucial time-saving technique which allows biomedical researchers to quickly discover implicit connections between important concepts. Typically, these systems operate on domain-specific fractions of public medical data. MOLIERE, in contrast, utilizes information from over 24.5 million documents. At the heart of our approach lies a multi-modal and multi-relational network of biomedical objects extracted from several heterogeneous datasets from the National Center for Biotechnology Information (NCBI). These objects include but are not limited to scientific papers, keywords, genes, proteins, diseases, and diagnoses. We model hypotheses using Latent Dirichlet Allocation applied on abstracts found near shortest paths discovered within this network, and demonstrate the effectiveness of MOLIERE by performing hypothesis generation on historical data. Our network, implementation, and resulting data are all publicly available for the broad scientific community.

  12. The Method of Hypothesis in Plato's Philosophy

    Directory of Open Access Journals (Sweden)

    Malihe Aboie Mehrizi

    2016-09-01

    Full Text Available The article deals with the examination of method of hypothesis in Plato's philosophy. This method, respectively, will be examined in three dialogues of Meno, Phaedon and Republic in which it is explicitly indicated. It will be shown the process of change of Plato’s attitude towards the position and usage of the method of hypothesis in his realm of philosophy. In Meno, considering the geometry, Plato attempts to introduce a method that can be used in the realm of philosophy. But, ultimately in Republic, Plato’s special attention to the method and its importance in the philosophical investigations, leads him to revise it. Here, finally Plato introduces the particular method of philosophy, i.e., the dialectic

  13. Debates—Hypothesis testing in hydrology: Introduction

    Science.gov (United States)

    Blöschl, Günter

    2017-03-01

    This paper introduces the papers in the "Debates—Hypothesis testing in hydrology" series. The four articles in the series discuss whether and how the process of testing hypotheses leads to progress in hydrology. Repeated experiments with controlled boundary conditions are rarely feasible in hydrology. Research is therefore not easily aligned with the classical scientific method of testing hypotheses. Hypotheses in hydrology are often enshrined in computer models which are tested against observed data. Testability may be limited due to model complexity and data uncertainty. All four articles suggest that hypothesis testing has contributed to progress in hydrology and is needed in the future. However, the procedure is usually not as systematic as the philosophy of science suggests. A greater emphasis on a creative reasoning process on the basis of clues and explorative analyses is therefore needed.

  14. Multi-agent sequential hypothesis testing

    KAUST Repository

    Kim, Kwang-Ki K.

    2014-12-15

    This paper considers multi-agent sequential hypothesis testing and presents a framework for strategic learning in sequential games with explicit consideration of both temporal and spatial coordination. The associated Bayes risk functions explicitly incorporate costs of taking private/public measurements, costs of time-difference and disagreement in actions of agents, and costs of false declaration/choices in the sequential hypothesis testing. The corresponding sequential decision processes have well-defined value functions with respect to (a) the belief states for the case of conditional independent private noisy measurements that are also assumed to be independent identically distributed over time, and (b) the information states for the case of correlated private noisy measurements. A sequential investment game of strategic coordination and delay is also discussed as an application of the proposed strategic learning rules.

  15. Hypothesis testing of scientific Monte Carlo calculations

    Science.gov (United States)

    Wallerberger, Markus; Gull, Emanuel

    2017-11-01

    The steadily increasing size of scientific Monte Carlo simulations and the desire for robust, correct, and reproducible results necessitates rigorous testing procedures for scientific simulations in order to detect numerical problems and programming bugs. However, the testing paradigms developed for deterministic algorithms have proven to be ill suited for stochastic algorithms. In this paper we demonstrate explicitly how the technique of statistical hypothesis testing, which is in wide use in other fields of science, can be used to devise automatic and reliable tests for Monte Carlo methods, and we show that these tests are able to detect some of the common problems encountered in stochastic scientific simulations. We argue that hypothesis testing should become part of the standard testing toolkit for scientific simulations.

  16. Reverse hypothesis machine learning a practitioner's perspective

    CERN Document Server

    Kulkarni, Parag

    2017-01-01

    This book introduces a paradigm of reverse hypothesis machines (RHM), focusing on knowledge innovation and machine learning. Knowledge- acquisition -based learning is constrained by large volumes of data and is time consuming. Hence Knowledge innovation based learning is the need of time. Since under-learning results in cognitive inabilities and over-learning compromises freedom, there is need for optimal machine learning. All existing learning techniques rely on mapping input and output and establishing mathematical relationships between them. Though methods change the paradigm remains the same—the forward hypothesis machine paradigm, which tries to minimize uncertainty. The RHM, on the other hand, makes use of uncertainty for creative learning. The approach uses limited data to help identify new and surprising solutions. It focuses on improving learnability, unlike traditional approaches, which focus on accuracy. The book is useful as a reference book for machine learning researchers and professionals as ...

  17. Exploring heterogeneous market hypothesis using realized volatility

    Science.gov (United States)

    Chin, Wen Cheong; Isa, Zaidi; Mohd Nor, Abu Hassan Shaari

    2013-04-01

    This study investigates the heterogeneous market hypothesis using high frequency data. The cascaded heterogeneous trading activities with different time durations are modelled by the heterogeneous autoregressive framework. The empirical study indicated the presence of long memory behaviour and predictability elements in the financial time series which supported heterogeneous market hypothesis. Besides the common sum-of-square intraday realized volatility, we also advocated two power variation realized volatilities in forecast evaluation and risk measurement in order to overcome the possible abrupt jumps during the credit crisis. Finally, the empirical results are used in determining the market risk using the value-at-risk approach. The findings of this study have implications for informationally market efficiency analysis, portfolio strategies and risk managements.

  18. Water Taxation and the Double Dividend Hypothesis

    OpenAIRE

    Nicholas Kilimani

    2014-01-01

    The double dividend hypothesis contends that environmental taxes have the potential to yield multiple benefits for the economy. However, empirical evidence of the potential impacts of environmental taxation in developing countries is still limited. This paper seeks to contribute to the literature by exploring the impact of a water tax in a developing country context, with Uganda as a case study. Policy makers in Uganda are exploring ways of raising revenue by taxing environmental goods such a...

  19. [Working memory, phonological awareness and spelling hypothesis].

    Science.gov (United States)

    Gindri, Gigiane; Keske-Soares, Márcia; Mota, Helena Bolli

    2007-01-01

    Working memory, phonological awareness and spelling hypothesis. To verify the relationship between working memory, phonological awareness and spelling hypothesis in pre-school children and first graders. Participants of this study were 90 students, belonging to state schools, who presented typical linguistic development. Forty students were preschoolers, with the average age of six and 50 students were first graders, with the average age of seven. Participants were submitted to an evaluation of the working memory abilities based on the Working Memory Model (Baddeley, 2000), involving phonological loop. Phonological loop was evaluated using the Auditory Sequential Test, subtest 5 of Illinois Test of Psycholinguistic Abilities (ITPA), Brazilian version (Bogossian & Santos, 1977), and the Meaningless Words Memory Test (Kessler, 1997). Phonological awareness abilities were investigated using the Phonological Awareness: Instrument of Sequential Assessment (CONFIAS - Moojen et al., 2003), involving syllabic and phonemic awareness tasks. Writing was characterized according to Ferreiro & Teberosky (1999). Preschoolers presented the ability of repeating sequences of 4.80 digits and 4.30 syllables. Regarding phonological awareness, the performance in the syllabic level was of 19.68 and in the phonemic level was of 8.58. Most of the preschoolers demonstrated to have a pre-syllabic writing hypothesis. First graders repeated, in average, sequences of 5.06 digits and 4.56 syllables. These children presented a phonological awareness of 31.12 in the syllabic level and of 16.18 in the phonemic level, and demonstrated to have an alphabetic writing hypothesis. The performance of working memory, phonological awareness and spelling level are inter-related, as well as being related to chronological age, development and scholarity.

  20. Privacy on Hypothesis Testing in Smart Grids

    OpenAIRE

    Li, Zuxing; Oechtering, Tobias

    2015-01-01

    In this paper, we study the problem of privacy information leakage in a smart grid. The privacy risk is assumed to be caused by an unauthorized binary hypothesis testing of the consumer's behaviour based on the smart meter readings of energy supplies from the energy provider. Another energy supplies are produced by an alternative energy source. A controller equipped with an energy storage device manages the energy inflows to satisfy the energy demand of the consumer. We study the optimal ener...

  1. Box-particle probability hypothesis density filtering

    OpenAIRE

    Schikora, M.; Gning, A.; Mihaylova, L.; Cremers, D.; Koch, W.

    2014-01-01

    This paper develops a novel approach for multitarget tracking, called box-particle probability hypothesis density filter (box-PHD filter). The approach is able to track multiple targets and estimates the unknown number of targets. Furthermore, it is capable of dealing with three sources of uncertainty: stochastic, set-theoretic, and data association uncertainty. The box-PHD filter reduces the number of particles significantly, which improves the runtime considerably. The small number of box-p...

  2. Quantum effects and hypothesis of cosmic censorship

    International Nuclear Information System (INIS)

    Parnovskij, S.L.

    1989-01-01

    It is shown that filamentary characteristics with linear mass of less than 10 25 g/cm distort slightly the space-time at distances, exceeding Planck ones. Their formation doesn't change vacuum energy and doesn't lead to strong quantum radiation. Therefore, the problem of their occurrence can be considered within the framework of classical collapse. Quantum effects can be ignored when considering the problem of validity of cosmic censorship hypothesis

  3. A test of the orthographic recoding hypothesis

    Science.gov (United States)

    Gaygen, Daniel E.

    2003-04-01

    The Orthographic Recoding Hypothesis [D. E. Gaygen and P. A. Luce, Percept. Psychophys. 60, 465-483 (1998)] was tested. According to this hypothesis, listeners recognize spoken words heard for the first time by mapping them onto stored representations of the orthographic forms of the words. Listeners have a stable orthographic representation of words, but no phonological representation, when those words have been read frequently but never heard or spoken. Such may be the case for low frequency words such as jargon. Three experiments using visually and auditorily presented nonword stimuli tested this hypothesis. The first two experiments were explicit tests of memory (old-new tests) for words presented visually. In the first experiment, the recognition of auditorily presented nonwords was facilitated when they previously appeared on a visually presented list. The second experiment was similar, but included a concurrent articulation task during a visual word list presentation, thus preventing covert rehearsal of the nonwords. The results were similar to the first experiment. The third experiment was an indirect test of memory (auditory lexical decision task) for visually presented nonwords. Auditorily presented nonwords were identified as nonwords significantly more slowly if they had previously appeared on the visually presented list accompanied by a concurrent articulation task.

  4. Consumer health information seeking as hypothesis testing.

    Science.gov (United States)

    Keselman, Alla; Browne, Allen C; Kaufman, David R

    2008-01-01

    Despite the proliferation of consumer health sites, lay individuals often experience difficulty finding health information online. The present study attempts to understand users' information seeking difficulties by drawing on a hypothesis testing explanatory framework. It also addresses the role of user competencies and their interaction with internet resources. Twenty participants were interviewed about their understanding of a hypothetical scenario about a family member suffering from stable angina and then searched MedlinePlus consumer health information portal for information on the problem presented in the scenario. Participants' understanding of heart disease was analyzed via semantic analysis. Thematic coding was used to describe information seeking trajectories in terms of three key strategies: verification of the primary hypothesis, narrowing search within the general hypothesis area and bottom-up search. Compared to an expert model, participants' understanding of heart disease involved different key concepts, which were also differently grouped and defined. This understanding provided the framework for search-guiding hypotheses and results interpretation. Incorrect or imprecise domain knowledge led individuals to search for information on irrelevant sites, often seeking out data to confirm their incorrect initial hypotheses. Online search skills enhanced search efficiency, but did not eliminate these difficulties. Regardless of their web experience and general search skills, lay individuals may experience difficulty with health information searches. These difficulties may be related to formulating and evaluating hypotheses that are rooted in their domain knowledge. Informatics can provide support at the levels of health information portals, individual websites, and consumer education tools.

  5. Statistical method on nonrandom clustering with application to somatic mutations in cancer

    Directory of Open Access Journals (Sweden)

    Rejto Paul A

    2010-01-01

    Full Text Available Abstract Background Human cancer is caused by the accumulation of tumor-specific mutations in oncogenes and tumor suppressors that confer a selective growth advantage to cells. As a consequence of genomic instability and high levels of proliferation, many passenger mutations that do not contribute to the cancer phenotype arise alongside mutations that drive oncogenesis. While several approaches have been developed to separate driver mutations from passengers, few approaches can specifically identify activating driver mutations in oncogenes, which are more amenable for pharmacological intervention. Results We propose a new statistical method for detecting activating mutations in cancer by identifying nonrandom clusters of amino acid mutations in protein sequences. A probability model is derived using order statistics assuming that the location of amino acid mutations on a protein follows a uniform distribution. Our statistical measure is the differences between pair-wise order statistics, which is equivalent to the size of an amino acid mutation cluster, and the probabilities are derived from exact and approximate distributions of the statistical measure. Using data in the Catalog of Somatic Mutations in Cancer (COSMIC database, we have demonstrated that our method detects well-known clusters of activating mutations in KRAS, BRAF, PI3K, and β-catenin. The method can also identify new cancer targets as well as gain-of-function mutations in tumor suppressors. Conclusions Our proposed method is useful to discover activating driver mutations in cancer by identifying nonrandom clusters of somatic amino acid mutations in protein sequences.

  6. Bladder-type hydropneumatic accumulators

    International Nuclear Information System (INIS)

    Anigas, F.

    1985-01-01

    Hydropneumatic pressure accumulators allow liquids to be stored under pressure, their operating principle being based on the inherent compressibility of elements in a liquid and gaseous state. A wide range of fluids can be covered by means of the appropriate choice of the material for the body and bladder. Their main applications are: energy accumulation, safety reserve, suspension. (author)

  7. 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.

  8. Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis.

    Science.gov (United States)

    Mawson, Anthony

    2013-07-15

    Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners). Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects.

  9. Seeing via miniature eye movements: A dynamic hypothesis for vision

    Directory of Open Access Journals (Sweden)

    Ehud eAhissar

    2012-11-01

    Full Text Available During natural viewing, the eyes are never still. Even during fixation, miniature movements of the eyes move the retinal image across tens of foveal photoreceptors. Most theories of vision implicitly assume that the visual system ignores these movements and somehow overcomes the resulting smearing. However, evidence has accumulated to indicate that fixational eye movements cannot be ignored by the visual system if fine spatial details are to be resolved. We argue that the only way the visual system can achieve its high resolution given its fixational movements is by seeing via these movements. Seeing via eye movements also eliminates the instability of the image, which would be induced by them otherwise. Here we present a hypothesis for vision, in which coarse details are spatially-encoded in gaze-related coordinates, and fine spatial details are temporally-encoded in relative retinal coordinates. The temporal encoding presented here achieves its highest resolution by encoding along the elongated axes of simple cell receptive fields and not across these axes as suggested by spatial models of vision. According to our hypothesis, fine details of shape are encoded by inter-receptor temporal phases, texture by instantaneous intra-burst rates of individual receptors, and motion by inter-burst temporal frequencies. We further describe the ability of the visual system to readout the encoded information and recode it internally. We show how reading out of retinal signals can be facilitated by neuronal phase-locked loops (NPLLs, which lock to the retinal jitter; this locking enables recoding of motion information and temporal framing of shape and texture processing. A possible implementation of this locking-and-recoding process by specific thalamocortical loops is suggested. Overall it is suggested that high-acuity vision is based primarily on temporal mechanisms of the sort presented here and low-acuity vision is based primarily on spatial mechanisms.

  10. 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.

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

    Science.gov (United States)

    Carvajal-Rodríguez, Antonio

    2012-07-01

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

  12. Updating the lamellar hypothesis of hippocampal organization

    Directory of Open Access Journals (Sweden)

    Robert S Sloviter

    2012-12-01

    Full Text Available In 1971, Andersen and colleagues proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a trisynaptic circuit lying within transverse hippocampal slices or lamellae [Andersen, Bliss, and Skrede. 1971. Lamellar organization of hippocampal pathways. Exp Brain Res 13, 222-238]. In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs. The lamellar hypothesis derives primary support from the lamellar distribution of dentate granule cell axons (the mossy fibers, which innervate dentate hilar neurons and area CA3 pyramidal cells and interneurons within the confines of a thin transverse hippocampal segment. Following the initial formulation of the lamellar hypothesis, anatomical studies revealed that unlike granule cells, hilar mossy cells, CA3 pyramidal cells, and Layer II entorhinal cells all form axonal projections that are more divergent along the longitudinal axis than the clearly lamellar mossy fiber pathway. The existence of pathways with translamellar distribution patterns has been interpreted, incorrectly in our view, as justifying outright rejection of the lamellar hypothesis [Amaral and Witter. 1989. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571-591]. We suggest that the functional implications of longitudinally-projecting axons depend not on whether they exist, but on what they do. The observation that focal granule cell layer discharges normally inhibit, rather than excite, distant granule cells suggests that longitudinal axons in the dentate gyrus may mediate "lateral" inhibition and define lamellar function, rather than undermine it. In this review, we attempt a reconsideration of the evidence that most directly impacts the physiological concept of hippocampal lamellar

  13. Hypothesis Testing as an Act of Rationality

    Science.gov (United States)

    Nearing, Grey

    2017-04-01

    Statistical hypothesis testing is ad hoc in two ways. First, setting probabilistic rejection criteria is, as Neyman (1957) put it, an act of will rather than an act of rationality. Second, physical theories like conservation laws do not inherently admit probabilistic predictions, and so we must use what are called epistemic bridge principles to connect model predictions with the actual methods of hypothesis testing. In practice, these bridge principles are likelihood functions, error functions, or performance metrics. I propose that the reason we are faced with these problems is because we have historically failed to account for a fundamental component of basic logic - namely the portion of logic that explains how epistemic states evolve in the presence of empirical data. This component of Cox' (1946) calculitic logic is called information theory (Knuth, 2005), and adding information theory our hypothetico-deductive account of science yields straightforward solutions to both of the above problems. This also yields a straightforward method for dealing with Popper's (1963) problem of verisimilitude by facilitating a quantitative approach to measuring process isomorphism. In practice, this involves data assimilation. Finally, information theory allows us to reliably bound measures of epistemic uncertainty, thereby avoiding the problem of Bayesian incoherency under misspecified priors (Grünwald, 2006). I therefore propose solutions to four of the fundamental problems inherent in both hypothetico-deductive and/or Bayesian hypothesis testing. - Neyman (1957) Inductive Behavior as a Basic Concept of Philosophy of Science. - Cox (1946) Probability, Frequency and Reasonable Expectation. - Knuth (2005) Lattice Duality: The Origin of Probability and Entropy. - Grünwald (2006). Bayesian Inconsistency under Misspecification. - Popper (1963) Conjectures and Refutations: The Growth of Scientific Knowledge.

  14. The conscious access hypothesis: Explaining the consciousness.

    Science.gov (United States)

    Prakash, Ravi

    2008-01-01

    The phenomenon of conscious awareness or consciousness is complicated but fascinating. Although this concept has intrigued the mankind since antiquity, exploration of consciousness from scientific perspectives is not very old. Among myriad of theories regarding nature, functions and mechanism of consciousness, off late, cognitive theories have received wider acceptance. One of the most exciting hypotheses in recent times has been the "conscious access hypotheses" based on the "global workspace model of consciousness". It underscores an important property of consciousness, the global access of information in cerebral cortex. Present article reviews the "conscious access hypothesis" in terms of its theoretical underpinnings as well as experimental supports it has received.

  15. Interstellar colonization and the zoo hypothesis

    International Nuclear Information System (INIS)

    Jones, E.M.

    1978-01-01

    Michael Hart and others have pointed out that current estimates of the number of technological civilizations arisen in the Galaxy since its formation is in fundamental conflict with the expectation that such a civilization could colonize and utilize the entire Galaxy in 10 to 20 million years. This dilemma can be called Hart's paradox. Resolution of the paradox requires that one or more of the following are true: we are the Galaxy's first technical civilization; interstellar travel is immensely impractical or simply impossible; technological civilizations are very short-lived; or we inhabit a wildnerness preserve. The latter is the zoo hypothesis

  16. RANDOM WALK HYPOTHESIS IN FINANCIAL MARKETS

    Directory of Open Access Journals (Sweden)

    Nicolae-Marius JULA

    2017-05-01

    Full Text Available Random walk hypothesis states that the stock market prices do not follow a predictable trajectory, but are simply random. If you are trying to predict a random set of data, one should test for randomness, because, despite the power and complexity of the used models, the results cannot be trustworthy. There are several methods for testing these hypotheses and the use of computational power provided by the R environment makes the work of the researcher easier and with a cost-effective approach. The increasing power of computing and the continuous development of econometric tests should give the potential investors new tools in selecting commodities and investing in efficient markets.

  17. Confluence Model or Resource Dilution Hypothesis?

    DEFF Research Database (Denmark)

    Jæger, Mads

    have a negative effect on educational attainment most studies cannot distinguish empirically between the CM and the RDH. In this paper, I use the different theoretical predictions in the CM and the RDH on the role of cognitive ability as a partial or complete mediator of the sibship size effect......Studies on family background often explain the negative effect of sibship size on educational attainment by one of two theories: the Confluence Model (CM) or the Resource Dilution Hypothesis (RDH). However, as both theories – for substantively different reasons – predict that sibship size should...

  18. Set theory and the continuum hypothesis

    CERN Document Server

    Cohen, Paul J

    2008-01-01

    This exploration of a notorious mathematical problem is the work of the man who discovered the solution. The independence of the continuum hypothesis is the focus of this study by Paul J. Cohen. It presents not only an accessible technical explanation of the author's landmark proof but also a fine introduction to mathematical logic. An emeritus professor of mathematics at Stanford University, Dr. Cohen won two of the most prestigious awards in mathematics: in 1964, he was awarded the American Mathematical Society's Bôcher Prize for analysis; and in 1966, he received the Fields Medal for Logic.

  19. Statistical hypothesis testing with SAS and R

    CERN Document Server

    Taeger, Dirk

    2014-01-01

    A comprehensive guide to statistical hypothesis testing with examples in SAS and R When analyzing datasets the following questions often arise:Is there a short hand procedure for a statistical test available in SAS or R?If so, how do I use it?If not, how do I program the test myself? This book answers these questions and provides an overview of the most commonstatistical test problems in a comprehensive way, making it easy to find and performan appropriate statistical test. A general summary of statistical test theory is presented, along with a basicdescription for each test, including the

  20. Strain accumulation in quasicrystalline solids

    International Nuclear Information System (INIS)

    Nori, F.; Ronchetti, M.; Elser, V.

    1988-01-01

    We study the relaxation of 2D quasicrystalline elastic networks when their constituent bonds are perturbed homogeneously. Whereas ideal, quasiperiodic networks are stable against such perturbations, we find significant accumulations of strain in a class of disordered networks generated by a growth process. The grown networks are characterized by root mean square phason fluctuations which grow linearly with system size. The strain accumulation we observe in these networks also grows linearly with system size. Finally, we find a dependence of strain accumulation on cooling rate

  1. Gypsum accumulation on carbonate stone

    Science.gov (United States)

    McGee, E.S.; Mossotti, V.G.

    1992-01-01

    The accumulation of gypsum on carbonate stone has been investigated through exposure of fresh samples of limestone and marble at monitored sites, through examination of alteration crusts from old buildings and through laboratory experiments. Several factors contribute to gypsum accumulation on carbonate stone. Marble or limestone that is sheltered from direct washing by rain in an urban environment with elevated pollution levels is likely to accumulate a gypsum crust. Crust development may be enhanced if the stone is porous or has an irregular surface area. Gypsum crusts are a surficial alteration feature; gypsum crystals form at the pore opening-air interface, where evaporation is greatest.

  2. Testing the activitystat hypothesis: a randomised controlled trial protocol.

    Science.gov (United States)

    Gomersall, Sjaan; Maher, Carol; Norton, Kevin; Dollman, Jim; Tomkinson, Grant; Esterman, Adrian; English, Coralie; Lewis, Nicole; Olds, Tim

    2012-10-08

    The activitystat hypothesis proposes that when physical activity or energy expenditure is increased or decreased in one domain, there will be a compensatory change in another domain to maintain an overall, stable level of physical activity or energy expenditure. To date, there has been no experimental study primarily designed to test the activitystat hypothesis in adults. The aim of this trial is to determine the effect of two different imposed exercise loads on total daily energy expenditure and physical activity levels. This study will be a randomised, multi-arm, parallel controlled trial. Insufficiently active adults (as determined by the Active Australia survey) aged 18-60 years old will be recruited for this study (n=146). Participants must also satisfy the Sports Medicine Australia Pre-Exercise Screening System and must weigh less than 150 kg. Participants will be randomly assigned to one of three groups using a computer-generated allocation sequence. Participants in the Moderate exercise group will receive an additional 150 minutes of moderate to vigorous physical activity per week for six weeks, and those in the Extensive exercise group will receive an additional 300 minutes of moderate to vigorous physical activity per week for six weeks. Exercise targets will be accumulated through both group and individual exercise sessions monitored by heart rate telemetry. Control participants will not be given any instructions regarding lifestyle. The primary outcome measures are activity energy expenditure (doubly labeled water) and physical activity (accelerometry). Secondary measures will include resting metabolic rate via indirect calorimetry, use of time, maximal oxygen consumption and several anthropometric and physiological measures. Outcome measures will be conducted at baseline (zero weeks), mid- and end-intervention (three and six weeks) with three (12 weeks) and six month (24 week) follow-up. All assessors will be blinded to group allocation. This protocol

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

    Science.gov (United States)

    Fox, Edward J; Loeb, Lawrence A

    2010-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Nathaniel P Sharp

    2016-03-01

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

  5. Hypothesis-driven physical examination curriculum.

    Science.gov (United States)

    Allen, Sharon; Olson, Andrew; Menk, Jeremiah; Nixon, James

    2017-12-01

    Medical students traditionally learn physical examination skills as a rote list of manoeuvres. Alternatives like hypothesis-driven physical examination (HDPE) may promote students' understanding of the contribution of physical examination to diagnostic reasoning. We sought to determine whether first-year medical students can effectively learn to perform a physical examination using an HDPE approach, and then tailor the examination to specific clinical scenarios. Medical students traditionally learn physical examination skills as a rote list of manoeuvres CONTEXT: First-year medical students at the University of Minnesota were taught both traditional and HDPE approaches during a required 17-week clinical skills course in their first semester. The end-of-course evaluation assessed HDPE skills: students were assigned one of two cardiopulmonary cases. Each case included two diagnostic hypotheses. During an interaction with a standardised patient, students were asked to select physical examination manoeuvres in order to make a final diagnosis. Items were weighted and selection order was recorded. First-year students with minimal pathophysiology performed well. All students selected the correct diagnosis. Importantly, students varied the order when selecting examination manoeuvres depending on the diagnoses under consideration, demonstrating early clinical decision-making skills. An early introduction to HDPE may reinforce physical examination skills for hypothesis generation and testing, and can foster early clinical decision-making skills. This has important implications for further research in physical examination instruction. © 2016 John Wiley & Sons Ltd and The Association for the Study of Medical Education.

  6. A default Bayesian hypothesis test for mediation.

    Science.gov (United States)

    Nuijten, Michèle B; Wetzels, Ruud; Matzke, Dora; Dolan, Conor V; Wagenmakers, Eric-Jan

    2015-03-01

    In order to quantify the relationship between multiple variables, researchers often carry out a mediation analysis. In such an analysis, a mediator (e.g., knowledge of a healthy diet) transmits the effect from an independent variable (e.g., classroom instruction on a healthy diet) to a dependent variable (e.g., consumption of fruits and vegetables). Almost all mediation analyses in psychology use frequentist estimation and hypothesis-testing techniques. A recent exception is Yuan and MacKinnon (Psychological Methods, 14, 301-322, 2009), who outlined a Bayesian parameter estimation procedure for mediation analysis. Here we complete the Bayesian alternative to frequentist mediation analysis by specifying a default Bayesian hypothesis test based on the Jeffreys-Zellner-Siow approach. We further extend this default Bayesian test by allowing a comparison to directional or one-sided alternatives, using Markov chain Monte Carlo techniques implemented in JAGS. All Bayesian tests are implemented in the R package BayesMed (Nuijten, Wetzels, Matzke, Dolan, & Wagenmakers, 2014).

  7. Gaussian Hypothesis Testing and Quantum Illumination.

    Science.gov (United States)

    Wilde, Mark M; Tomamichel, Marco; Lloyd, Seth; Berta, Mario

    2017-09-22

    Quantum hypothesis testing is one of the most basic tasks in quantum information theory and has fundamental links with quantum communication and estimation theory. In this paper, we establish a formula that characterizes the decay rate of the minimal type-II error probability in a quantum hypothesis test of two Gaussian states given a fixed constraint on the type-I error probability. This formula is a direct function of the mean vectors and covariance matrices of the quantum Gaussian states in question. We give an application to quantum illumination, which is the task of determining whether there is a low-reflectivity object embedded in a target region with a bright thermal-noise bath. For the asymmetric-error setting, we find that a quantum illumination transmitter can achieve an error probability exponent stronger than a coherent-state transmitter of the same mean photon number, and furthermore, that it requires far fewer trials to do so. This occurs when the background thermal noise is either low or bright, which means that a quantum advantage is even easier to witness than in the symmetric-error setting because it occurs for a larger range of parameters. Going forward from here, we expect our formula to have applications in settings well beyond those considered in this paper, especially to quantum communication tasks involving quantum Gaussian channels.

  8. Inoculation stress hypothesis of environmental enrichment.

    Science.gov (United States)

    Crofton, Elizabeth J; Zhang, Yafang; Green, Thomas A

    2015-02-01

    One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Athlete's Heart: Is the Morganroth Hypothesis Obsolete?

    Science.gov (United States)

    Haykowsky, Mark J; Samuel, T Jake; Nelson, Michael D; La Gerche, Andre

    2018-05-01

    In 1975, Morganroth and colleagues reported that the increased left ventricular (LV) mass in highly trained endurance athletes versus nonathletes was primarily due to increased end-diastolic volume while the increased LV mass in resistance trained athletes was solely due to an increased LV wall thickness. Based on the divergent remodelling patterns observed, Morganroth and colleagues hypothesised that the increased "volume" load during endurance exercise may be similar to that which occurs in patients with mitral or aortic regurgitation while the "pressure" load associated with performing a Valsalva manoeuvre (VM) during resistance exercise may mimic the stress imposed on the heart by systemic hypertension or aortic stenosis. Despite widespread acceptance of the four-decade old Morganroth hypothesis in sports cardiology, some investigators have questioned whether such a divergent "athlete's heart" phenotype exists. Given this uncertainty, the purpose of this brief review is to re-evaluate the Morganroth hypothesis regarding: i) the acute effects of resistance exercise performed with a brief VM on LV wall stress, and the patterns of LV remodelling in resistance-trained athletes; ii) the acute effects of endurance exercise on biventricular wall stress, and the time course and pattern of LV and right ventricular (RV) remodelling with endurance training; and iii) the value of comparing "loading" conditions between athletes and patients with cardiac pathology. Copyright © 2018. Published by Elsevier B.V.

  10. The Debt Overhang Hypothesis: Evidence from Pakistan

    Directory of Open Access Journals (Sweden)

    Shah Muhammad Imran

    2016-04-01

    Full Text Available This study investigates the debt overhang hypothesis for Pakistan in the period 1960-2007. The study examines empirically the dynamic behaviour of GDP, debt services, the employed labour force and investment using the time series concepts of unit roots, cointegration, error correlation and causality. Our findings suggest that debt-servicing has a negative impact on the productivity of both labour and capital, and that in turn has adversely affected economic growth. By severely constraining the ability of the country to service debt, this lends support to the debt-overhang hypothesis in Pakistan. The long run relation between debt services and economic growth implies that future increases in output will drain away in form of high debt service payments to lender country as external debt acts like a tax on output. More specifically, foreign creditors will benefit more from the rise in productivity than will domestic producers and labour. This suggests that domestic labour and capital are the ultimate losers from this heavy debt burden.

  11. Roots and Route of the Artification Hypothesis

    Directory of Open Access Journals (Sweden)

    Ellen Dissanayake

    2017-08-01

    Full Text Available Over four decades, my ideas about the arts in human evolution have themselves evolved, from an original notion of art as a human behaviour of “making special” to a full-fledged hypothesis of artification. A summary of the gradual developmental path (or route of the hypothesis, based on ethological principles and concepts, is given, and an argument presented in which artification is described as an exaptation whose roots lie in adaptive features of ancestral mother–infant interaction that contributed to infant survival and maternal reproductive success. I show how the interaction displays features of a ritualised behavior whose operations (formalization, repetition, exaggeration, and elaboration can be regarded as characteristic elements of human ritual ceremonies as well as of art (including song, dance, performance, literary language, altered surroundings, and other examples of making ordinary sounds, movement, language, environments, objects, and bodies extraordinary. Participation in these behaviours in ritual practices served adaptive ends in early Homo by coordinating brain and body states, and thereby emotionally bonding members of a group in common cause as well as reducing existential anxiety in individuals. A final section situates artification within contemporary philosophical and popular ideas of art, claiming that artifying is not a synonym for or definition of art but foundational to any evolutionary discussion of artistic/aesthetic behaviour.

  12. Hypothesis: does ochratoxin A cause testicular cancer?

    Science.gov (United States)

    Schwartz, Gary G

    2002-02-01

    Little is known about the etiology of testicular cancer, which is the most common cancer among young men. Epidemiologic data point to a carcinogenic exposure in early life or in utero, but the nature of the exposure is unknown. We hypothesize that the mycotoxin, ochratoxin A, is a cause of testicular cancer. Ochratoxin A is a naturally occurring contaminant of cereals, pigmeat, and other foods and is a known genotoxic carcinogen in animals. The major features of the descriptive epidemiology of testicular cancer (a high incidence in northern Europe, increasing incidence over time, and associations with high socioeconomic status, and with poor semen quality) are all associated with exposure to ochratoxin A. Exposure of animals to ochratoxin A via the diet or via in utero transfer induces adducts in testicular DNA. We hypothesize that consumption of foods contaminated with ochratoxin A during pregnancy and/or childhood induces lesions in testicular DNA and that puberty promotes these lesions to testicular cancer. We tested the ochratoxin A hypothesis using ecologic data on the per-capita consumption of cereals, coffee, and pigmeat, the principal dietary sources of ochratoxin A. Incidence rates for testicular cancer in 20 countries were significantly correlated with the per-capita consumption of coffee and pigmeat (r = 0.49 and 0.54, p = 0.03 and 0.01). The ochratoxin A hypothesis offers a coherent explanation for much of the descriptive epidemiology of testicular cancer and suggests new avenues for analytic research.

  13. Urbanization and the more-individuals hypothesis.

    Science.gov (United States)

    Chiari, Claudia; Dinetti, Marco; Licciardello, Cinzia; Licitra, Gaetano; Pautasso, Marco

    2010-03-01

    1. Urbanization is a landscape process affecting biodiversity world-wide. Despite many urban-rural studies of bird assemblages, it is still unclear whether more species-rich communities have more individuals, regardless of the level of urbanization. The more-individuals hypothesis assumes that species-rich communities have larger populations, thus reducing the chance of local extinctions. 2. Using newly collated avian distribution data for 1 km(2) grid cells across Florence, Italy, we show a significantly positive relationship between species richness and assemblage abundance for the whole urban area. This richness-abundance relationship persists for the 1 km(2) grid cells with less than 50% of urbanized territory, as well as for the remaining grid cells, with no significant difference in the slope of the relationship. These results support the more-individuals hypothesis as an explanation of patterns in species richness, also in human modified and fragmented habitats. 3. However, the intercept of the species richness-abundance relationship is significantly lower for highly urbanized grid cells. Our study confirms that urban communities have lower species richness but counters the common notion that assemblages in densely urbanized ecosystems have more individuals. In Florence, highly inhabited areas show fewer species and lower assemblage abundance. 4. Urbanized ecosystems are an ongoing large-scale natural experiment which can be used to test ecological theories empirically.

  14. The Younger Dryas impact hypothesis: A requiem

    Science.gov (United States)

    Pinter, Nicholas; Scott, Andrew C.; Daulton, Tyrone L.; Podoll, Andrew; Koeberl, Christian; Anderson, R. Scott; Ishman, Scott E.

    2011-06-01

    The Younger Dryas (YD) impact hypothesis is a recent theory that suggests that a cometary or meteoritic body or bodies hit and/or exploded over North America 12,900 years ago, causing the YD climate episode, extinction of Pleistocene megafauna, demise of the Clovis archeological culture, and a range of other effects. Since gaining widespread attention in 2007, substantial research has focused on testing the 12 main signatures presented as evidence of a catastrophic extraterrestrial event 12,900 years ago. Here we present a review of the impact hypothesis, including its evolution and current variants, and of efforts to test and corroborate the hypothesis. The physical evidence interpreted as signatures of an impact event can be separated into two groups. The first group consists of evidence that has been largely rejected by the scientific community and is no longer in widespread discussion, including: particle tracks in archeological chert; magnetic nodules in Pleistocene bones; impact origin of the Carolina Bays; and elevated concentrations of radioactivity, iridium, and fullerenes enriched in 3He. The second group consists of evidence that has been active in recent research and discussions: carbon spheres and elongates, magnetic grains and magnetic spherules, byproducts of catastrophic wildfire, and nanodiamonds. Over time, however, these signatures have also seen contrary evidence rather than support. Recent studies have shown that carbon spheres and elongates do not represent extraterrestrial carbon nor impact-induced megafires, but are indistinguishable from fungal sclerotia and arthropod fecal material that are a small but common component of many terrestrial deposits. Magnetic grains and spherules are heterogeneously distributed in sediments, but reported measurements of unique peaks in concentrations at the YD onset have yet to be reproduced. The magnetic grains are certainly just iron-rich detrital grains, whereas reported YD magnetic spherules are

  15. Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

    Directory of Open Access Journals (Sweden)

    Takayuki Mito

    Full Text Available Mitochondrial DNA (mtDNA mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0 mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

  16. Choice Rules and Accumulator Networks

    Science.gov (United States)

    2015-01-01

    This article presents a preference accumulation model that can be used to implement a number of different multi-attribute heuristic choice rules, including the lexicographic rule, the majority of confirming dimensions (tallying) rule and the equal weights rule. The proposed model differs from existing accumulators in terms of attribute representation: Leakage and competition, typically applied only to preference accumulation, are also assumed to be involved in processing attribute values. This allows the model to perform a range of sophisticated attribute-wise comparisons, including comparisons that compute relative rank. The ability of a preference accumulation model composed of leaky competitive networks to mimic symbolic models of heuristic choice suggests that these 2 approaches are not incompatible, and that a unitary cognitive model of preferential choice, based on insights from both these approaches, may be feasible. PMID:28670592

  17. Mutational Analysis of Merkel Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-17

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

  18. Mutational Analysis of Merkel Cell Carcinoma

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  19. Approaches to informed consent for hypothesis-testing and hypothesis-generating clinical genomics research.

    Science.gov (United States)

    Facio, Flavia M; Sapp, Julie C; Linn, Amy; Biesecker, Leslie G

    2012-10-10

    Massively-parallel sequencing (MPS) technologies create challenges for informed consent of research participants given the enormous scale of the data and the wide range of potential results. We propose that the consent process in these studies be based on whether they use MPS to test a hypothesis or to generate hypotheses. To demonstrate the differences in these approaches to informed consent, we describe the consent processes for two MPS studies. The purpose of our hypothesis-testing study is to elucidate the etiology of rare phenotypes using MPS. The purpose of our hypothesis-generating study is to test the feasibility of using MPS to generate clinical hypotheses, and to approach the return of results as an experimental manipulation. Issues to consider in both designs include: volume and nature of the potential results, primary versus secondary results, return of individual results, duty to warn, length of interaction, target population, and privacy and confidentiality. The categorization of MPS studies as hypothesis-testing versus hypothesis-generating can help to clarify the issue of so-called incidental or secondary results for the consent process, and aid the communication of the research goals to study participants.

  20. Deleterious effects of neuronal accumulation of glycogen in flies and mice

    OpenAIRE

    Duran, Jordi; Tevy, María Florencia; Garcia-Rocha, Mar; Calbó, Joaquim; Milán, Marco; Guinovart, Joan J

    2012-01-01

    Under physiological conditions, most neurons keep glycogen synthase (GS) in an inactive form and do not show detectable levels of glycogen. Nevertheless, aberrant glycogen accumulation in neurons is a hallmark of patients suffering from Lafora disease or other polyglucosan disorders. Although these diseases are associated with mutations in genes involved in glycogen metabolism, the role of glycogen accumulation remains elusive. Here, we generated mouse and fly models expressing an active form...

  1. Learning-Related Changes in Adolescents' Neural Networks during Hypothesis-Generating and Hypothesis-Understanding Training

    Science.gov (United States)

    Lee, Jun-Ki; Kwon, Yongju

    2012-01-01

    Fourteen science high school students participated in this study, which investigated neural-network plasticity associated with hypothesis-generating and hypothesis-understanding in learning. The students were divided into two groups and participated in either hypothesis-generating or hypothesis-understanding type learning programs, which were…

  2. Genetic Mutations in Cancer

    Science.gov (United States)

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

  3. AIP mutations and gigantism.

    Science.gov (United States)

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

    2017-06-01

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

  4. An endocannabinoid hypothesis of drug reward and drug addiction.

    Science.gov (United States)

    Onaivi, Emmanuel S

    2008-10-01

    Pharmacologic treatment of drug and alcohol dependency has largely been disappointing, and new therapeutic targets and hypotheses are needed. There is accumulating evidence indicating a central role for the previously unknown but ubiquitous endocannabinoid physiological control system (EPCS) in the regulation of the rewarding effects of abused substances. Thus an endocannabinoid hypothesis of drug reward is postulated. Endocannabinoids mediate retrograde signaling in neuronal tissues and are involved in the regulation of synaptic transmission to suppress neurotransmitter release by the presynaptic cannabinoid receptors (CB-Rs). This powerful modulatory action on synaptic transmission has significant functional implications and interactions with the effects of abused substances. Our data, along with those from other investigators, provide strong new evidence for a role for EPCS modulation in the effects of drugs of abuse, and specifically for involvement of cannabinoid receptors in the neural basis of addiction. Cannabinoids and endocannabinoids appear to be involved in adding to the rewarding effects of addictive substances, including, nicotine, opiates, alcohol, cocaine, and BDZs. The results suggest that the EPCS may be an important natural regulatory mechanism for drug reward and a target for the treatment of addictive disorders.

  5. Cation dyshomeostasis and cardiomyocyte necrosis: the Fleckenstein hypothesis revisited

    Science.gov (United States)

    Borkowski, Brian J.; Cheema, Yaser; Shahbaz, Atta U.; Bhattacharya, Syamal K.; Weber, Karl T.

    2011-01-01

    An ongoing loss of cardiomyocytes to apoptotic and necrotic cell death pathways contributes to the progressive nature of heart failure. The pathophysiological origins of necrotic cell loss relate to the neurohormonal activation that accompanies acute and chronic stressor states and which includes effector hormones of the adrenergic nervous system. Fifty years ago, Albrecht Fleckenstein and coworkers hypothesized the hyperadrenergic state, which accompanies such stressors, causes cardiomyocyte necrosis based on catecholamine-initiated excessive intracellular Ca2+ accumulation (EICA), and mitochondrial Ca2+ overloading in particular, in which the ensuing dysfunction and structural degeneration of these organelles leads to necrosis. In recent years, two downstream factors have been identified which, together with EICA, constitute a signal–transducer–effector pathway: (i) mitochondria-based induction of oxidative stress, in which the rate of reactive oxygen metabolite generation exceeds their rate of detoxification by endogenous antioxidant defences; and (ii) the opening of the mitochondrial inner membrane permeability transition pore (mPTP) followed by organellar swelling and degeneration. The pathogenesis of stress-related cardiomyopathy syndromes is likely related to this pathway. Other factors which can account for cytotoxicity in stressor states include: hypokalaemia; ionized hypocalcaemia and hypomagnesaemia with resultant elevations in parathyroid hormone serving as a potent mediator of EICA; and hypozincaemia with hyposelenaemia, which compromise antioxidant defences. Herein, we revisit the Fleckenstein hypothesis of EICA in leading to cardiomyocyte necrosis and the central role played by mitochondria. PMID:21398641

  6. New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis

    Directory of Open Access Journals (Sweden)

    Albert C. Yang

    2017-08-01

    Full Text Available Schizophrenia has been primarily associated with dopamine dysfunction, and treatments have been developed that target the dopamine pathway in the central nervous system. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid (GABA signaling, which may lead to aberrant functioning of interneurons that manifest as cognitive, behavioral, and social dysfunction through altered functioning of a broad range of macro- and microcircuits. The interactions between neurotransmitters can be modeled as nodes and edges by using graph theory, and oxidative balance, immune, and glutamatergic systems may represent multiple nodes interlocking at a central hub; imbalance within any of these nodes might affect the entire system. Therefore, this review attempts to address novel treatment targets beyond the dopamine hypothesis, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines. Furthermore, we outline that these treatment targets can be possibly integrated with novel treatment strategies aimed at different symptoms or phases of the illness. We anticipate that reversing anomalous activity in these novel treatment targets or combinations between these strategies might be beneficial in the treatment of schizophrenia.

  7. Hypothesis: solid tumours behave as systemic metabolic dictators.

    Science.gov (United States)

    Lee, Yang-Ming; Chang, Wei-Chun; Ma, Wen-Lung

    2016-06-01

    Current knowledge regarding mechanisms of carcinogenesis in human beings centres around the accumulation of genetic instability, amplified cellular signalling, disturbed cellular energy metabolism and microenvironmental regulation governed by complicated cell-cell interactions. In this article, we provide an alternative view of cancer biology. We propose that cancer behaves as a systemic dictator that interacts with tissues throughout the body to control their metabolism and eventually homeostasis. The mechanism of development of this endocrine organ-like tumour (EOLT) tissue might be the driving force for cancer progression. Here, we review the literature that led to the development of this hypothesis. The EOLT phenotype can be defined as a tumour that alters systemic homeostasis. The literature indicates that the EOLT phenotype is present throughout cancer progression. The feedback mechanism that governs the interaction between tumours and various organs is unknown. We believe that investigating the mechanism of EOLT development may advance the current knowledge of regulation within the tumour macroenvironment and consequently lead to new diagnostic methods and therapy. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Mutation breeding in peas

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-02-01

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

  9. Mutation breeding in peas

    International Nuclear Information System (INIS)

    Jaranowski, J.; Micke, A.

    1985-01-01

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

  10. Natural selection against a circadian clock gene mutation in mice.

    Science.gov (United States)

    Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S I; Hau, Michaela

    2016-01-19

    Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.

  11. Alternatives to the linear risk hypothesis

    International Nuclear Information System (INIS)

    Craig, A.G.

    1976-01-01

    A theoretical argument is presented which suggests that in using the linear hypothesis for all values of LET the low dose risk is overestimated for low LET but that it is underestimated for very high LET. The argument is based upon the idea that cell lesions which do not lead to cell death may in fact lead to a malignant cell. Expressions for the Surviving Fraction and the Cancer Risk based on this argument are given. An advantage of this very general approach is that is expresses cell survival and cancer risk entirely in terms of the cell lesions and avoids the rather contentious argument as to how the average number of lesions should be related to the dose. (U.K.)

  12. Large numbers hypothesis. II - Electromagnetic radiation

    Science.gov (United States)

    Adams, P. J.

    1983-01-01

    This paper develops the theory of electromagnetic radiation in the units covariant formalism incorporating Dirac's large numbers hypothesis (LNH). A direct field-to-particle technique is used to obtain the photon propagation equation which explicitly involves the photon replication rate. This replication rate is fixed uniquely by requiring that the form of a free-photon distribution function be preserved, as required by the 2.7 K cosmic radiation. One finds that with this particular photon replication rate the units covariant formalism developed in Paper I actually predicts that the ratio of photon number to proton number in the universe varies as t to the 1/4, precisely in accord with LNH. The cosmological red-shift law is also derived and it is shown to differ considerably from the standard form of (nu)(R) - const.

  13. Artistic talent in dyslexia--a hypothesis.

    Science.gov (United States)

    Chakravarty, Ambar

    2009-10-01

    The present article hints at a curious neurocognitive phenomenon of development of artistic talents in some children with dyslexia. The article also takes note of the phenomenon of creating in the midst of language disability as observed in the lives of such creative people like Leonardo da Vinci and Albert Einstein who were most probably affected with developmental learning disorders. It has been hypothesised that a developmental delay in the dominant hemisphere most likely 'disinhibits' the non-dominant parietal lobe to unmask talents, artistic or otherwise, in some such individuals. The present hypothesis follows the phenomenon of paradoxical functional facilitation described earlier. It has been suggested that children with learning disorders be encouraged to develop such hidden talents to full capacity, rather than be subjected to overemphasising on the correction of the disturbed coded symbol operations, in remedial training.

  14. Tissue misrepair hypothesis for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Kondo, Sohei

    1991-01-01

    Dose-response curves for chronic leukemia in A-bomb survivors and liver tumors in patients given Thorotrast (colloidal thorium dioxide) show large threshold effects. The existence of these threshold effects can be explained by the following hypothesis. A high dose of radiation causes a persistent wound in a cellrenewable tissue. Disorder of the injured cell society partly frees the component cells from territorial restraints on their proliferation, enabling them to continue development of their cellular functions toward advanced autonomy. This progression might be achieved by continued epigenetic and genetic changes as a result of occasional errors in the otherwise concerted healing action of various endogeneous factors recruited for tissue repair. Carcinogenesis is not simply a single-cell problem but a cell-society problem. Therefore, it is not warranted to estimate risk at low doses by linear extrapolation from cancer data at high doses without knowledge of the mechanism of radiation carcinogenesis. (author) 57 refs

  15. Statistical hypothesis tests of some micrometeorological observations

    International Nuclear Information System (INIS)

    SethuRaman, S.; Tichler, J.

    1977-01-01

    Chi-square goodness-of-fit is used to test the hypothesis that the medium scale of turbulence in the atmospheric surface layer is normally distributed. Coefficients of skewness and excess are computed from the data. If the data are not normal, these coefficients are used in Edgeworth's asymptotic expansion of Gram-Charlier series to determine an altrnate probability density function. The observed data are then compared with the modified probability densities and the new chi-square values computed.Seventy percent of the data analyzed was either normal or approximatley normal. The coefficient of skewness g 1 has a good correlation with the chi-square values. Events with vertical-barg 1 vertical-bar 1 vertical-bar<0.43 were approximately normal. Intermittency associated with the formation and breaking of internal gravity waves in surface-based inversions over water is thought to be the reason for the non-normality

  16. The hexagon hypothesis: Six disruptive scenarios.

    Science.gov (United States)

    Burtles, Jim

    2015-01-01

    This paper aims to bring a simple but effective and comprehensive approach to the development, delivery and monitoring of business continuity solutions. To ensure that the arguments and principles apply across the board, the paper sticks to basic underlying concepts rather than sophisticated interpretations. First, the paper explores what exactly people are defending themselves against. Secondly, the paper looks at how defences should be set up. Disruptive events tend to unfold in phases, each of which invites a particular style of protection, ranging from risk management through to business continuity to insurance cover. Their impact upon any business operation will fall into one of six basic scenarios. The hexagon hypothesis suggests that everyone should be prepared to deal with each of these six disruptive scenarios and it provides them with a useful benchmark for business continuity.

  17. Novae, supernovae, and the island universe hypothesis

    International Nuclear Information System (INIS)

    Van Den Bergh, S.

    1988-01-01

    Arguments in Curtis's (1917) paper related to the island universe hypothesis and the existence of novae in spiral nebulae are considered. It is noted that the maximum magnitude versus rate-of-decline relation for novae may be the best tool presently available for the calibration of the extragalactic distance scale. Light curve observations of six novae are used to determine a distance of 18.6 + or - 3.5 MPc to the Virgo cluster. Results suggest that Type Ia supernovae cannot easily be used as standard candles, and that Type II supernovae are unsuitable as distance indicators. Factors other than precursor mass are probably responsible for determining the ultimate fate of evolving stars. 83 references

  18. Extra dimensions hypothesis in high energy physics

    Directory of Open Access Journals (Sweden)

    Volobuev Igor

    2017-01-01

    Full Text Available We discuss the history of the extra dimensions hypothesis and the physics and phenomenology of models with large extra dimensions with an emphasis on the Randall- Sundrum (RS model with two branes. We argue that the Standard Model extension based on the RS model with two branes is phenomenologically acceptable only if the inter-brane distance is stabilized. Within such an extension of the Standard Model, we study the influence of the infinite Kaluza-Klein (KK towers of the bulk fields on collider processes. In particular, we discuss the modification of the scalar sector of the theory, the Higgs-radion mixing due to the coupling of the Higgs boson to the radion and its KK tower, and the experimental restrictions on the mass of the radion-dominated states.

  19. Multiple model cardinalized probability hypothesis density filter

    Science.gov (United States)

    Georgescu, Ramona; Willett, Peter

    2011-09-01

    The Probability Hypothesis Density (PHD) filter propagates the first-moment approximation to the multi-target Bayesian posterior distribution while the Cardinalized PHD (CPHD) filter propagates both the posterior likelihood of (an unlabeled) target state and the posterior probability mass function of the number of targets. Extensions of the PHD filter to the multiple model (MM) framework have been published and were implemented either with a Sequential Monte Carlo or a Gaussian Mixture approach. In this work, we introduce the multiple model version of the more elaborate CPHD filter. We present the derivation of the prediction and update steps of the MMCPHD particularized for the case of two target motion models and proceed to show that in the case of a single model, the new MMCPHD equations reduce to the original CPHD equations.

  20. Mutations in FUS cause FALS and SALS in French and French Canadian populations.

    Science.gov (United States)

    Belzil, V V; Valdmanis, P N; Dion, P A; Daoud, H; Kabashi, E; Noreau, A; Gauthier, J; Hince, P; Desjarlais, A; Bouchard, J-P; Lacomblez, L; Salachas, F; Pradat, P-F; Camu, W; Meininger, V; Dupré, N; Rouleau, G A

    2009-10-13

    The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

  1. On the immunostimulatory hypothesis of cancer

    Directory of Open Access Journals (Sweden)

    Juan Bruzzo

    2011-12-01

    Full Text Available There is a rather generalized belief that the worst possible outcome for the application of immunological therapies against cancer is a null effect on tumor growth. However, a significant body of evidence summarized in the immunostimulatory hypothesis of cancer suggests that, upon certain circumstances, the growth of incipient and established tumors can be accelerated rather than inhibited by the immune response supposedly mounted to limit tumor growth. In order to provide more compelling evidence of this proposition, we have explored the growth behavior characteristics of twelve murine tumors -most of them of spontaneous origin- arisen in the colony of our laboratory, in putatively immunized and control mice. Using classical immunization procedures, 8 out of 12 tumors were actually stimulated in "immunized" mice while the remaining 4 were neither inhibited nor stimulated. Further, even these apparently non-antigenic tumors could reveal some antigenicity if more stringent than classical immunization procedures were used. This possibility was suggested by the results obtained with one of these four apparently non-antigenic tumors: the LB lymphoma. In effect, upon these stringent immunization pretreatments, LB was slightly inhibited or stimulated, depending on the titer of the immune reaction mounted against the tumor, with higher titers rendering inhibition and lower titers rendering tumor stimulation. All the above results are consistent with the immunostimulatory hypothesis that entails the important therapeutic implications -contrary to the orthodoxy- that, anti-tumor vaccines may run a real risk of doing harm if the vaccine-induced immunity is too weak to move the reaction into the inhibitory part of the immune response curve and that, a slight and prolonged immunodepression -rather than an immunostimulation- might interfere with the progression of some tumors and thus be an aid to cytotoxic therapies.

  2. The Stress Acceleration Hypothesis of Nightmares

    Directory of Open Access Journals (Sweden)

    Tore Nielsen

    2017-06-01

    Full Text Available Adverse childhood experiences can deleteriously affect future physical and mental health, increasing risk for many illnesses, including psychiatric problems, sleep disorders, and, according to the present hypothesis, idiopathic nightmares. Much like post-traumatic nightmares, which are triggered by trauma and lead to recurrent emotional dreaming about the trauma, idiopathic nightmares are hypothesized to originate in early adverse experiences that lead in later life to the expression of early memories and emotions in dream content. Accordingly, the objectives of this paper are to (1 review existing literature on sleep, dreaming and nightmares in relation to early adverse experiences, drawing upon both empirical studies of dreaming and nightmares and books and chapters by recognized nightmare experts and (2 propose a new approach to explaining nightmares that is based upon the Stress Acceleration Hypothesis of mental illness. The latter stipulates that susceptibility to mental illness is increased by adversity occurring during a developmentally sensitive window for emotional maturation—the infantile amnesia period—that ends around age 3½. Early adversity accelerates the neural and behavioral maturation of emotional systems governing the expression, learning, and extinction of fear memories and may afford short-term adaptive value. But it also engenders long-term dysfunctional consequences including an increased risk for nightmares. Two mechanisms are proposed: (1 disruption of infantile amnesia allows normally forgotten early childhood memories to influence later emotions, cognitions and behavior, including the common expression of threats in nightmares; (2 alterations of normal emotion regulation processes of both waking and sleep lead to increased fear sensitivity and less effective fear extinction. These changes influence an affect network previously hypothesized to regulate fear extinction during REM sleep, disruption of which leads to

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

    Directory of Open Access Journals (Sweden)

    Kathleen E Stevens

    2011-08-01

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

  4. Nonsense mutations in the human β-globin gene affect mRNA metabolism

    International Nuclear Information System (INIS)

    Baserga, S.J.; Benz, E.J. Jr.

    1988-01-01

    A number of premature translation termination mutations (nonsense mutations) have been described in the human α- and β-globin genes. Studies on mRNA isolated from patients with β 0 -thalassemia have shown that for both the β-17 and the β-39 mutations less than normal levels of β-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human β-globin mRNA). In vitro studies using the cloned β-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. The authors have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, they have studied the effect of five nonsense mutations and two missense mutations on the expression of human β-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation

  5. Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis.

    Science.gov (United States)

    Taymans, Jean-Marc; Nkiliza, Aurore; Chartier-Harlin, Marie-Christine

    2015-08-01

    Protein translation is one of the most fundamental and exquisitely controlled processes in biology, and is energetically demanding. The deregulation of this process is deleterious to cells, as demonstrated by several diseases caused by mutations in protein translation machinery. Emerging evidence now points to a role for protein translation in the pathogenesis of Parkinson's disease (PD); a debilitating neurodegenerative movement disorder. In this paper, we propose a hypothesis that protein translation machinery, PD-associated proteins and PD pathology are connected in a functional network linking cell survival to protein translation control. This hypothesis is a potential game changer in the field of the molecular pathogenesis of PD, with implications for the development of PD diagnostics and disease-modifying therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. The role of mutation in the new cancer paradigm

    Directory of Open Access Journals (Sweden)

    Prehn Richmond T

    2005-04-01

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

  7. 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.

  8. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo.

    Science.gov (United States)

    Rockenstein, Edward; Nuber, Silke; Overk, Cassia R; Ubhi, Kiren; Mante, Michael; Patrick, Christina; Adame, Anthony; Trejo-Morales, Margarita; Gerez, Juan; Picotti, Paola; Jensen, Poul H; Campioni, Silvia; Riek, Roland; Winkler, Jürgen; Gage, Fred H; Winner, Beate; Masliah, Eliezer

    2014-05-01

    In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the

  9. Induced Plant Accumulation of Lithium

    Directory of Open Access Journals (Sweden)

    Laurence Kavanagh

    2018-02-01

    Full Text Available Lithium’s (Li value has grown exponentially since the development of Li-ion batteries. It is usually accessed in one of two ways: hard rock mineral mining or extraction from mineral-rich brines. Both methods are expensive and require a rich source of Li. This paper examines the potential of agro-mining as an environmentally friendly, economically viable process for extracting Li from low grade ore. Agro-mining exploits an ability found in few plant species, to accumulate substantial amounts of metals in the above ground parts of the plant. Phyto-mined metals are then retrieved from the incinerated plants. Although the actual amount of metal collected from a crop may be low, the process has been shown to be profitable. We have investigated the suitability of several plant species including: Brassica napus and Helianthus annuus, as Li-accumulators under controlled conditions. Large plant trials were carried out with/without chelating agents to encourage Li accumulation. The question we sought to answer was, can any of the plant species investigated accumulate Li at levels high enough to justify using them to agro-mine Li. Results show maximum accumulated levels of >4000 mg/kg Li in some species. Our data suggests that agro-mining of Li is a potentially viable process.

  10. 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.

  11. 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.

  12. Himalayan Strain Accumulation 100 ka Timescales

    Science.gov (United States)

    Cannon, J. M.; Murphy, M. A.; Liu, Y.

    2015-12-01

    Crustal scale fault systems and tectonostratigraphic units in the Himalaya can be traced for 2500 km along strike. However regional studies have shown that there is variability in the location and rate of strain accumulation which appears to be driven by Main Himalayan Thrust (MHT) geometry and convergence obliquity. GPS illuminates the modern interseismic strain rate and the historical record of great earthquakes elucidates variations in strain accumulation over 103 years. To connect these patterns with the 106 year structural and thermochronometric geologic record we examine normalized river channel steepness (ksn), a proxy for rock uplift rate, which develops over 104 - 105 years. Here we present a ksn map of the Himalaya and compare it with bedrock geology, precipitation, the historic earthquake record, GPS, seismicity, and seismotectonic models. Our map shows significant along strike changes in the magnitude of channel steepness, the areal extent of swaths of high ksn channels, and their location with respect to the range front. Differences include the juxtaposition of two narrow (30 - 40 km) range parallel belts of high ksn in west Nepal and Bhutan coincident with MHT duplexes and belts of microseismcity, with a single broad (70 km) swath of high ksn and microseismicity in central and eastern Nepal. Separating west and central Nepal a band of low ksn crosses the range coincident with the West Nepal Fault (WNF) and the lowest rate of microseismicity in Nepal. To the west the orogen is obliquely convergent and has less high ksn channels, while the orthogonally convergent region to the east contains the highest concentration of oversteepened channels in the Himalaya supporting the idea that the WNF is a strain partitioning boundary. The syntaxes are characterized by locally high channel steepness surrounded by low to moderate ksn channels consistent with the hypothesis that rapid exhumation within the syntaxes is sustained by an influx of lower crust.

  13. A novel splicing mutation in the V2 vasopressin receptor

    DEFF Research Database (Denmark)

    Kamperis, Konstantinos; Siggaard, C; Herlin, Troels

    2000-01-01

    as clinical investigations comprising a fluid deprivation test and a 1-deamino-8-D-arginine-vasopressin (dDAVP) infusion test in the study subject and his mother. We found a highly unusual, novel, de novo 1447A-->C point mutation (gDNA), involving the invariable splice acceptor of the second intron...... of the gene in both the affected male (hemizygous) and his mother (heterozygous). This mutation is likely to cause aberrant splicing of the terminal intron of the gene, leading to a non-functional AVP receptor. The clinical studies were consistent with such a hypothesis, as the affected subject had a severe...

  14. The Matter-Gravity Entanglement Hypothesis

    Science.gov (United States)

    Kay, Bernard S.

    2018-03-01

    I outline some of my work and results (some dating back to 1998, some more recent) on my matter-gravity entanglement hypothesis, according to which the entropy of a closed quantum gravitational system is equal to the system's matter-gravity entanglement entropy. The main arguments presented are: (1) that this hypothesis is capable of resolving what I call the second-law puzzle, i.e. the puzzle as to how the entropy increase of a closed system can be reconciled with the asssumption of unitary time-evolution; (2) that the black hole information loss puzzle may be regarded as a special case of this second law puzzle and that therefore the same resolution applies to it; (3) that the black hole thermal atmosphere puzzle (which I recall) can be resolved by adopting a radically different-from-usual description of quantum black hole equilibrium states, according to which they are total pure states, entangled between matter and gravity in such a way that the partial states of matter and gravity are each approximately thermal equilibrium states (at the Hawking temperature); (4) that the Susskind-Horowitz-Polchinski string-theoretic understanding of black hole entropy as the logarithm of the degeneracy of a long string (which is the weak string coupling limit of a black hole) cannot be quite correct but should be replaced by a modified understanding according to which it is the entanglement entropy between a long string and its stringy atmosphere, when in a total pure equilibrium state in a suitable box, which (in line with (3)) goes over, at strong-coupling, to a black hole in equilibrium with its thermal atmosphere. The modified understanding in (4) is based on a general result, which I also describe, which concerns the likely state of a quantum system when it is weakly coupled to an energy-bath and the total state is a random pure state with a given energy. This result generalizes Goldstein et al.'s `canonical typicality' result to systems which are not necessarily small.

  15. The Matter-Gravity Entanglement Hypothesis

    Science.gov (United States)

    Kay, Bernard S.

    2018-05-01

    I outline some of my work and results (some dating back to 1998, some more recent) on my matter-gravity entanglement hypothesis, according to which the entropy of a closed quantum gravitational system is equal to the system's matter-gravity entanglement entropy. The main arguments presented are: (1) that this hypothesis is capable of resolving what I call the second-law puzzle, i.e. the puzzle as to how the entropy increase of a closed system can be reconciled with the asssumption of unitary time-evolution; (2) that the black hole information loss puzzle may be regarded as a special case of this second law puzzle and that therefore the same resolution applies to it; (3) that the black hole thermal atmosphere puzzle (which I recall) can be resolved by adopting a radically different-from-usual description of quantum black hole equilibrium states, according to which they are total pure states, entangled between matter and gravity in such a way that the partial states of matter and gravity are each approximately thermal equilibrium states (at the Hawking temperature); (4) that the Susskind-Horowitz-Polchinski string-theoretic understanding of black hole entropy as the logarithm of the degeneracy of a long string (which is the weak string coupling limit of a black hole) cannot be quite correct but should be replaced by a modified understanding according to which it is the entanglement entropy between a long string and its stringy atmosphere, when in a total pure equilibrium state in a suitable box, which (in line with (3)) goes over, at strong-coupling, to a black hole in equilibrium with its thermal atmosphere. The modified understanding in (4) is based on a general result, which I also describe, which concerns the likely state of a quantum system when it is weakly coupled to an energy-bath and the total state is a random pure state with a given energy. This result generalizes Goldstein et al.'s `canonical typicality' result to systems which are not necessarily small.

  16. Asthma and gender impact accumulation of T cell subtypes

    Directory of Open Access Journals (Sweden)

    Peters Stephen P

    2010-07-01

    Full Text Available Abstract Background The "Th2 hypothesis for asthma" asserts that an increased ratio of Th2:Th1 cytokine production plays an important pathogenic role in asthma. Although widely embraced, the hypothesis has been challenged by various empirical observations and has been described as overly simplistic. We sought to establish whether CD3+CD28-mediated and antigen-independent accumulation of type 1 and type 2 T cells differs significantly between nonasthmatic and asthmatic populations. Methods An ex vivo system was used to characterize the regulation of IFN-γ-producing (type 1 and IL-13-producing (type 2 T cell accumulation in response to CD3+CD28 and IL-2 stimulation by flow cytometry. Results IL-13-producing T cells increased in greater numbers in response to antigen-independent stimulation in peripheral blood lymphocytes from female atopic asthmatic subjects compared with male asthmatics and both male and female atopic non-asthmatic subjects. IFN-γ+ T cells increased in greater numbers in response to either antigen-independent or CD3+CD28-mediated stimulation in peripheral blood lymphocytes from atopic asthmatic subjects compared to non-asthmatic subjects, regardless of gender. Conclusions We demonstrate that T cells from asthmatics are programmed for increased accumulation of both type 2 and type 1 T cells. Gender had a profound effect on the regulation of type 2 T cells, thus providing a mechanism for the higher frequency of adult asthma in females.

  17. Mitochondrial mutations in subjects with psychiatric disorders.

    Directory of Open Access Journals (Sweden)

    Adolfo Sequeira

    Full Text Available A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C. Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

  18. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

    NARCIS (Netherlands)

    Pearson, E.R.; Pruhova, S.; Tack, C.J.J.; Johansen, A.; Castleden, H.A.; Lumb, P.J.; Wierzbicki, A.S.; Clark, P.M.; Lebl, J.; Pedersen, O.; Ellard, S.; Hansen, T.; Hattersley, A.T.

    2005-01-01

    AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and

  19. No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Andalib, Sasan; Talebi, Mahnaz; Sakhinia, Ebrahim

    2017-01-01

    Leber's Hereditary Optic Neuropathy (LHON) shares features with Multiple Sclerosis (MS). Both diseases develop optic lesions. Frequent secondary LHON mutations in MS patients may explain the optic damage. Here, we tested the hypothesis that secondary LHON mutations are associated with optic...

  20. Pathophysiological consequences and benefits of HFE mutations: 20 years of research

    Science.gov (United States)

    Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

    2017-01-01

    Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

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

    Science.gov (United States)

    Stanley, Craig E; Kulathinal, Rob J

    2016-11-08

    neurodevelopmental and neurodegenerative diseases. The well-known correlation between neurological spectrum disorders in children and paternal age may simply be a direct result of aging fathers accumulating mutations across these large neurodevelopmental genes. The large mutational target hypothesis can also explain the rapid evolution of other functional systems covering a large genomic fraction such as male fertility and its preferential association with hybrid male sterility among closely related taxa. Overall, a focus on mutational potential may increase our power in understanding the genetic basis of complex phenotypes such as behavior while filling a general gap in understanding their evolution.

  2. Hypothesis test for synchronization: twin surrogates revisited.

    Science.gov (United States)

    Romano, M Carmen; Thiel, Marco; Kurths, Jürgen; Mergenthaler, Konstantin; Engbert, Ralf

    2009-03-01

    The method of twin surrogates has been introduced to test for phase synchronization of complex systems in the case of passive experiments. In this paper we derive new analytical expressions for the number of twins depending on the size of the neighborhood, as well as on the length of the trajectory. This allows us to determine the optimal parameters for the generation of twin surrogates. Furthermore, we determine the quality of the twin surrogates with respect to several linear and nonlinear statistics depending on the parameters of the method. In the second part of the paper we perform a hypothesis test for phase synchronization in the case of experimental data from fixational eye movements. These miniature eye movements have been shown to play a central role in neural information processing underlying the perception of static visual scenes. The high number of data sets (21 subjects and 30 trials per person) allows us to compare the generated twin surrogates with the "natural" surrogates that correspond to the different trials. We show that the generated twin surrogates reproduce very well all linear and nonlinear characteristics of the underlying experimental system. The synchronization analysis of fixational eye movements by means of twin surrogates reveals that the synchronization between the left and right eye is significant, indicating that either the centers in the brain stem generating fixational eye movements are closely linked, or, alternatively that there is only one center controlling both eyes.

  3. Marginal contrasts and the Contrastivist Hypothesis

    Directory of Open Access Journals (Sweden)

    Daniel Currie Hall

    2016-12-01

    Full Text Available The Contrastivist Hypothesis (CH; Hall 2007; Dresher 2009 holds that the only features that can be phonologically active in any language are those that serve to distinguish phonemes, which presupposes that phonemic status is categorical. Many researchers, however, demonstrate the existence of gradient relations. For instance, Hall (2009 quantifies these using the information-theoretic measure of entropy (unpredictability of distribution and shows that a pair of sounds may have an entropy between 0 (totally predictable and 1 (totally unpredictable. We argue that the existence of such intermediate degrees of contrastiveness does not make the CH untenable, but rather offers insight into contrastive hierarchies. The existence of a continuum does not preclude categorical distinctions: a categorical line can be drawn between zero entropy (entirely predictable, and thus by the CH phonologically inactive and non-zero entropy (at least partially contrastive, and thus potentially phonologically active. But this does not mean that intermediate degrees of surface contrastiveness are entirely irrelevant to the CH; rather, we argue, they can shed light on how deeply ingrained a phonemic distinction is in the phonological system. As an example, we provide a case study from Pulaar [ATR] harmony, which has previously been claimed to be problematic for the CH.

  4. The Stem Cell Hypothesis of Aging

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2010-04-01

    Full Text Available BACKGROUND: There is probably no single way to age. Indeed, so far there is no single accepted explanation or mechanisms of aging (although more than 300 theories have been proposed. There is an overall decline in tissue regenerative potential with age, and the question arises as to whether this is due to the intrinsic aging of stem cells or rather to the impairment of stem cell function in the aged tissue environment. CONTENT: Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16INK4a may also induce an unwanted consequence: a decline in the replicative function of certain stem cells types with advancing age. This decrease regenerative capacity appears to pointing to the stem cell hypothesis of aging. SUMMARY: Recent evidence suggested that we grow old partly because of our stem cells grow old as a result of mechanisms that suppress the development of cancer over a lifetime. We believe that a further, more precise mechanistic understanding of this process will be required before this knowledge can be translated into human anti-aging therapies. KEYWORDS: stem cells, senescence, telomere, DNA damage, epigenetic, aging.

  5. Confabulation: Developing the 'emotion dysregulation' hypothesis.

    Science.gov (United States)

    Turnbull, Oliver H; Salas, Christian E

    2017-02-01

    Confabulations offer unique opportunities for establishing the neurobiological basis of delusional thinking. As regards causal factors, a review of the confabulation literature suggests that neither amnesia nor executive impairment can be the sole (or perhaps even the primary) cause of all delusional beliefs - though they may act in concert with other factors. A key perspective in the modern literature is that many delusions have an emotionally positive or 'wishful' element, that may serve to modulate or manage emotional experience. Some authors have referred to this perspective as the 'emotion dysregulation' hypothesis. In this article we review the theoretical underpinnings of this approach, and develop the idea by suggesting that the positive aspects of confabulatory states may have a role in perpetuating the imbalance between cognitive control and emotion. We draw on existing evidence from fields outside neuropsychology, to argue for three main causal factors: that positive emotions are related to more global or schematic forms of cognitive processing; that positive emotions influence the accuracy of memory recollection; and that positive emotions make people more susceptible to false memories. These findings suggest that the emotions that we want to feel (or do not want to feel) can influence the way we reconstruct past experiences and generate a sense of self - a proposition that bears on a unified theory of delusional belief states. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  6. Evolutionary hypothesis for Chiari type I malformation.

    Science.gov (United States)

    Fernandes, Yvens Barbosa; Ramina, Ricardo; Campos-Herrera, Cynthia Resende; Borges, Guilherme

    2013-10-01

    Chiari I malformation (CM-I) is classically defined as a cerebellar tonsillar herniation (≥5 mm) through the foramen magnum. A decreased posterior fossa volume, mainly due to basioccipital hypoplasia and sometimes platybasia, leads to posterior fossa overcrowding and consequently cerebellar herniation. Regardless of radiological findings, embryological genetic hypothesis or any other postulations, the real cause behind this malformation is yet not well-elucidated and remains largely unknown. The aim of this paper is to approach CM-I under a broader and new perspective, conjoining anthropology, genetics and neurosurgery, with special focus on the substantial changes that have occurred in the posterior cranial base through human evolution. Important evolutionary allometric changes occurred during brain expansion and genetics studies of human evolution demonstrated an unexpected high rate of gene flow interchange and possibly interbreeding during this process. Based upon this review we hypothesize that CM-I may be the result of an evolutionary anthropological imprint, caused by evolving species populations that eventually met each other and mingled in the last 1.7 million years. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Environmental Kuznets Curve Hypothesis. A Survey

    International Nuclear Information System (INIS)

    Dinda, Soumyananda

    2004-01-01

    The Environmental Kuznets Curve (EKC) hypothesis postulates an inverted-U-shaped relationship between different pollutants and per capita income, i.e., environmental pressure increases up to a certain level as income goes up; after that, it decreases. An EKC actually reveals how a technically specified measurement of environmental quality changes as the fortunes of a country change. A sizeable literature on EKC has grown in recent period. The common point of all the studies is the assertion that the environmental quality deteriorates at the early stages of economic development/growth and subsequently improves at the later stages. In other words, environmental pressure increases faster than income at early stages of development and slows down relative to GDP growth at higher income levels. This paper reviews some theoretical developments and empirical studies dealing with EKC phenomenon. Possible explanations for this EKC are seen in (1) the progress of economic development, from clean agrarian economy to polluting industrial economy to clean service economy; (2) tendency of people with higher income having higher preference for environmental quality, etc. Evidence of the existence of the EKC has been questioned from several corners. Only some air quality indicators, especially local pollutants, show the evidence of an EKC. However, an EKC is empirically observed, till there is no agreement in the literature on the income level at which environmental degradation starts declining. This paper provides an overview of the EKC literature, background history, conceptual insights, policy and the conceptual and methodological critique

  8. Identity of Particles and Continuum Hypothesis

    Science.gov (United States)

    Berezin, Alexander A.

    2001-04-01

    Why all electrons are the same? Unlike other objects, particles and atoms (same isotopes) are forbidden to have individuality or personal history (or reveal their hidden variables, even if they do have them). Or at least, what we commonly call physics so far was unable to disprove particle's sameness (Berezin and Nakhmanson, Physics Essays, 1990). Consider two opposing hypotheses: (A) particles are indeed absolutely same, or (B) they do have individuality, but it is beyond our capacity to demonstrate. This dilemma sounds akin to undecidability of Continuum Hypothesis of existence (or not) of intermediate cardinalities between integers and reals (P.Cohen). Both yes and no of it are true. Thus, (alleged) sameness of electrons and atoms may be a physical translation (embodiment) of this fundamental Goedelian undecidability. Experiments unlikely to help: even if we find that all electrons are same within 30 decimal digits, could their masses (or charges) still differ in100-th digit? Within (B) personalized informationally rich (infinitely rich?) digital tails (starting at, say, 100-th decimal) may carry individual record of each particle history. Within (A) parameters (m, q) are indeed exactly same in all digits and their sameness is based on some inherent (meta)physical principle akin to Platonism or Eddington-type numerology.

  9. Environmental Kuznets Curve Hypothesis. A Survey

    Energy Technology Data Exchange (ETDEWEB)

    Dinda, Soumyananda [Economic Research Unit, Indian Statistical Institute, 203, B.T. Road, Kolkata-108 (India)

    2004-08-01

    The Environmental Kuznets Curve (EKC) hypothesis postulates an inverted-U-shaped relationship between different pollutants and per capita income, i.e., environmental pressure increases up to a certain level as income goes up; after that, it decreases. An EKC actually reveals how a technically specified measurement of environmental quality changes as the fortunes of a country change. A sizeable literature on EKC has grown in recent period. The common point of all the studies is the assertion that the environmental quality deteriorates at the early stages of economic development/growth and subsequently improves at the later stages. In other words, environmental pressure increases faster than income at early stages of development and slows down relative to GDP growth at higher income levels. This paper reviews some theoretical developments and empirical studies dealing with EKC phenomenon. Possible explanations for this EKC are seen in (1) the progress of economic development, from clean agrarian economy to polluting industrial economy to clean service economy; (2) tendency of people with higher income having higher preference for environmental quality, etc. Evidence of the existence of the EKC has been questioned from several corners. Only some air quality indicators, especially local pollutants, show the evidence of an EKC. However, an EKC is empirically observed, till there is no agreement in the literature on the income level at which environmental degradation starts declining. This paper provides an overview of the EKC literature, background history, conceptual insights, policy and the conceptual and methodological critique.

  10. A NONPARAMETRIC HYPOTHESIS TEST VIA THE BOOTSTRAP RESAMPLING

    OpenAIRE

    Temel, Tugrul T.

    2001-01-01

    This paper adapts an already existing nonparametric hypothesis test to the bootstrap framework. The test utilizes the nonparametric kernel regression method to estimate a measure of distance between the models stated under the null hypothesis. The bootstraped version of the test allows to approximate errors involved in the asymptotic hypothesis test. The paper also develops a Mathematica Code for the test algorithm.

  11. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz

    2003-01-01

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

  12. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

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

  13. Updating the mild encephalitis hypothesis of schizophrenia.

    Science.gov (United States)

    Bechter, K

    2013-04-05

    Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A 'late hit' and gene-environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within changing environments, although they are associated with the disadvantage of increased susceptibility to psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome phase and the transition to a diseased status may be related to LLNI processes emerging and varying over time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders, which result from three required factors: genes, the environment, and the immune system. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided. A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from

  14. [Psychodynamic hypothesis about suicidality in elderly men].

    Science.gov (United States)

    Lindner, Reinhard

    2010-08-01

    Old men are overrepresented in the whole of all suicides. In contrast, only very few elderly men find their way to specialised treatment facilities. Elderly accept psychotherapy more rarely than younger persons. Therefore presentations on the psychodynamics of suicidality in old men are rare and mostly casuistical. By means of a stepwise reconstructable qualitative case comparison of five randomly chosen elderly suicidal men with ideal types of suicidal (younger) men concerning biography, suicidal symptoms and transference, psychodynamic hypothesis of suicidality in elderly men are developed. All patients came into psychotherapy in a specialised academic out-patient clinic for psychodynamic treatment of acute and chronic suicidality. The five elderly suicidal men predominantly were living in long-term, conflictuous sexual relationships and also had ambivalent relationships to their children. Suicidality in old age refers to lifelong existing intrapsychic conflicts, concerning (male) identity, self-esteem and a core conflict between fusion and separation wishes. The body gets a central role in suicidal experiences, being a defensive instance modified by age and/or physical illness, which brings up to consciousness aggressive and envious impulses, but also feelings of emptiness and insecurity, which have to be warded off again by projection into the body. In transference relationships there are on the one hand the regular transference, on the other hand an age specific turned around transference, with their counter transference reactions. The chosen methodological approach serves the systematic finding of hypotheses with a higher degree in evidence than hypotheses generated from single case studies. Georg Thieme Verlag KG Stuttgart - New York.

  15. Deleterious effects of neuronal accumulation of glycogen in flies and mice.

    Science.gov (United States)

    Duran, Jordi; Tevy, María Florencia; Garcia-Rocha, Mar; Calbó, Joaquim; Milán, Marco; Guinovart, Joan J

    2012-08-01

    Under physiological conditions, most neurons keep glycogen synthase (GS) in an inactive form and do not show detectable levels of glycogen. Nevertheless, aberrant glycogen accumulation in neurons is a hallmark of patients suffering from Lafora disease or other polyglucosan disorders. Although these diseases are associated with mutations in genes involved in glycogen metabolism, the role of glycogen accumulation remains elusive. Here, we generated mouse and fly models expressing an active form of GS to force neuronal accumulation of glycogen. We present evidence that the progressive accumulation of glycogen in mouse and Drosophila neurons leads to neuronal loss, locomotion defects and reduced lifespan. Our results highlight glycogen accumulation in neurons as a direct cause of neurodegeneration. Copyright © 2012 EMBO Molecular Medicine.

  16. The old age security hypothesis and optimal population growth.

    Science.gov (United States)

    Bental, B

    1989-03-01

    The application of the Samuelson-Diamond overlapping generations framework to the old age security hypothesis indicates that government intervention schemes can influence the relationship between population growth and capital accumulation. The most direct means of optimizing population growth is through taxes or subsidies that relate to the intergenerational transfer of wealth. A pay-as-you-go social security scheme, in which payment is predicated on the number of children the receiver has and is financed by taxes levied on the working population, emerges as the most likely intervention to produce the optimal steady state equilibrium. This system is able to correct any distortions the private sector may build into it. In contrast, a child support system, in which the government subsidizes or taxes workers according to their family size, can guarantee the optimal capital:labor ratio but not the optimal population growth rate. Thus, if the government seeks to decrease the population growth rate, the appropriate intervention is to levy a lump-sum social-security tax on workers and transfer the revenues to the old; the direction should be reversed if the goal is to increase population growth. Another alternative, a lump sum social security system, can guarantee optimal population growth but not a desirable capital:labor ratio. Finally, the introduction of money as a valued commodity into an economy with a high capital:labor ratio will also serve to decrease the population growth rate and solve the intergenerational transfer problem through the private sector without any need for government intervention.

  17. A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: possible relevance for Alzheimer's disease.

    Science.gov (United States)

    Agnati, L F; Guidolin, D; Baluska, F; Leo, G; Barlow, P W; Carone, C; Genedani, S

    2010-06-01

    On the basis of not only the endosymbiotic theory of eukaryotic cell organization and evolution but also of observations of transcellular communication via Tunneling NanoTubes (TNTs), the hypothesis is put forward that when mitochondria, which were once independently living prokaryote-like organisms, are subjected to detrimental genetic, toxic, or environmental conditions, including age-related endogenous factors, they can regress towards their original independent state. At that point, they can become potentially pathogenic intruders within their eukaryotic host cell. Because of the protoplasmic disequilibrium caused by an altered, or mutated, mitochondral population, certain host cells with a minimal capacity for self-renewal, such as dopaminergic neurons, risk a loss of function and degenerate. It is also proposed that altered mitochondria, as well as their mutated mtDNA, can migrate, via TNTs, into adjacent cells. In this way, neurodegenerative states are propagated between cells (glia and/or neurons) of the Central Nervous System (CNS) and that this leads to conditions such as Alzheimer's and Parkinson's disease. This proposal finds indirect support from observations on rotenone-poisoned glioblastoma cells which have been co-cultured with non-poisoned cells. Immunocytochemical techniques revealed that mitochondria, moving along the TNTs, migrated from the poisoned cells towards the healthy cells. It has also been demonstrated by means of immunocytochemistry that, in glioblastoma cell cultures, Amyloid Precursor Protein (APP) is present in TNTs, hence it may migrate from one cell to neighbouring cells. This datum may be of high relevance for a better understanding of Alzheimer's Disease (AD) since molecular, cellular, and animal model studies have revealed that the formation of amyloid beta (Abeta) and other derivatives of the APP are key pathogenic factors in AD, causing mitochondrial dysfunction, free radical generation, oxidative damage, and inflammation

  18. Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is 'too big to fail'.

    Science.gov (United States)

    Castellani, Rudy J; Smith, Mark A

    2011-06-01

    With each failure of anti-amyloid-β therapy in clinical trials, new trials are initiated with no hint of slowing down. This may be due, in part, to the fact that the amyloid cascade hypothesis has been so modified over time that it is now impossible to confirm or deny. The hypothesis now states, in effect, that invisible molecules target invisible structures. Still relevant, however, are multiple factors that surely cast some doubt but have either been rationalized or overlooked. Among these are the poor correlation between amyloid-β deposits and disease, the substantial differences between familial and sporadic disease, pathological assessment that indicates the secondary nature of lesions/proteins/cascades, the fact that soluble species are poorly reproducible laboratory phenomena, and the irrelevance of synaptic assessment to pathological interpretation. Although not yet dogma, the premature addition of mild cognitive impairment as the implied in vivo homologue to the soluble toxin-synapse interaction is also problematic. In either case, the amyloid cascade hypothesis continues to dominate the Alzheimer's disease literature and grant applications. The more the neuroscience community perseverates along these lines in the face of accumulating outcome data to the contrary, the more one is left to wonder whether the hypothesis is too big to fail. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  19. Mutations and chromosomal aberrations

    International Nuclear Information System (INIS)

    Kihlman, B.A.

    1977-01-01

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

  20. Mutations in GABRB3

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  1. New approaches for effective mutation induction in gamma field

    Energy Technology Data Exchange (ETDEWEB)

    Nagatomi, Shigeki [National Institute of Agrobiological Resources, Institute of Radiation Breeding, Omiya, Ibaraki (Japan)

    2001-03-01

    The purpose of the report is to clarify the effects of chronic irradiation using in vitro culture on inducing the mutation of two model plants. Culture technique combined with irradiation can overcome the problem of chimera formation and provided 10 times greater mutation efficiency than conventional method. Proper mutagenic treatment using cultured materials is indispensable to effective mutation induction. The chronic culture method showed the widest color spectrum in chrysanthemum and extended toward not only the negative but positive direction. However, the acute culture methods indicated a relatively low mutation rate and a very limited flower color spectrum. Flower color mutation of the regenerations could be induced more from petals and buds than from leaves. These facts is supposed that the gene loci fully expressed on floral organs may be unstable for mutation by mutagenesis or culture. It may be likely to control a direction of desired mutation. One possible reason why the chronic culture methods showed higher frequencies is that most of the cells composing the tissue and organs continually irradiated into a cell division which was highly sensitive and more mutable to irradiation. Under these conditions, many mutated sectors may accumulate in the cells of the growing organs. Regenerated mutant lines show remarkable decrease of chromosome numbers by irradiation. It is a proper indicator to monitor radiation damage. In this study, the six flower color mutant varieties registered were derived from chronic irradiation. The combined method of chronic irradiation with floral organ cultures proved to be of particularly great practical use in mutation breeding for not only flower species but any other species. (author)

  2. New approaches for effective mutation induction in gamma field

    International Nuclear Information System (INIS)

    Nagatomi, Shigeki

    2001-01-01

    The purpose of the report is to clarify the effects of chronic irradiation using in vitro culture on inducing the mutation of two model plants. Culture technique combined with irradiation can overcome the problem of chimera formation and provided 10 times greater mutation efficiency than conventional method. Proper mutagenic treatment using cultured materials is indispensable to effective mutation induction. The chronic culture method showed the widest color spectrum in chrysanthemum and extended toward not only the negative but positive direction. However, the acute culture methods indicated a relatively low mutation rate and a very limited flower color spectrum. Flower color mutation of the regenerations could be induced more from petals and buds than from leaves. These facts is supposed that the gene loci fully expressed on floral organs may be unstable for mutation by mutagenesis or culture. It may be likely to control a direction of desired mutation. One possible reason why the chronic culture methods showed higher frequencies is that most of the cells composing the tissue and organs continually irradiated into a cell division which was highly sensitive and more mutable to irradiation. Under these conditions, many mutated sectors may accumulate in the cells of the growing organs. Regenerated mutant lines show remarkable decrease of chromosome numbers by irradiation. It is a proper indicator to monitor radiation damage. In this study, the six flower color mutant varieties registered were derived from chronic irradiation. The combined method of chronic irradiation with floral organ cultures proved to be of particularly great practical use in mutation breeding for not only flower species but any other species. (author)

  3. 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.

  4. Mutation breeding newsletter. No. 45

    International Nuclear Information System (INIS)

    2001-07-01

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

  5. Mutation breeding newsletter. No. 33

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1989-01-01

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

  6. Mutation breeding newsletter. No. 33

    International Nuclear Information System (INIS)

    1989-01-01

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

  7. Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis

    OpenAIRE

    Avdievich, Elena; Reiss, Cora; Scherer, Stefan J.; Zhang, Yongwei; Maier, Sandra M.; Jin, Bo; Hou, Harry; Rosenwald, Andreas; Riedmiller, Hubertus; Kucherlapati, Raju; Cohen, Paula E.; Edelmann, Winfried; Kneitz, Burkhard

    2008-01-01

    Mutations in the human DNA mismatch repair (MMR) gene MLH1 are associated with hereditary nonpolyposis colorectal cancer (Lynch syndrome, HNPCC) and a significant proportion of sporadic colorectal cancer. The inactivation of MLH1 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of DNA damaging agents. To study the effect of MLH1 missense mutations on cancer susceptibility, we generated a mouse line carrying the ...

  8. Corporate taxation and capital accumulation

    OpenAIRE

    Stephen Bond; Jing Xing

    2010-01-01

    We present new empirical evidence that aggregate capital accumulation is strongly influenced by the user cost of capital and, in particular, by corporate tax incentives summarised in the tax-adjusted user cost. We use sectoral panel data for the USA, Japan, Australia and ten EU countries over the period 1982-2007. Our panel combines data on capital stocks, value-added and relative prices from the EU KLEMS database with measures of effective corporate tax rates from the Oxford University Centr...

  9. WEALTH TAXATION AND WEALTH ACCUMULATION

    DEFF Research Database (Denmark)

    Jakobsen, Katrine Marie Tofthøj; Jakobsen, Kristian Thor; Kleven, Henrik

    Using administrative wealth records from Denmark, we study the effects of wealth taxes on wealth accumulation. Denmark used to impose one of the world's highest marginal tax rates on wealth, but this tax was drastically reduced and ultimately abolished between 1989 and 1997. Due to the specific d...... on wealth accumulation. Our simulations show that the long-run elasticity of wealth with respect to the net-of-tax return is sizeable at the top of distribution. Our paper provides the type of evidence needed to assess optimal capital taxation.......Using administrative wealth records from Denmark, we study the effects of wealth taxes on wealth accumulation. Denmark used to impose one of the world's highest marginal tax rates on wealth, but this tax was drastically reduced and ultimately abolished between 1989 and 1997. Due to the specific...... design of the wealth tax, these changes provide a compelling quasi-experiment for understanding behavioral responses among the wealthiest segments of the population. We find clear reduced-form effects of wealth taxes in the short and medium run, with larger effects on the very wealthy than...

  10. Mechanisms of intrahepatic triglyceride accumulation

    Science.gov (United States)

    Ress, Claudia; Kaser, Susanne

    2016-01-01

    Hepatic steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents in the Western World. Etiologically, obesity and associated insulin resistance or excess alcohol intake are the most frequent causes of hepatic steatosis. However, steatosis also often occurs with chronic hepatitis C virus (HCV) infection and is also found in rare but potentially life-threatening liver diseases of pregnancy. Clinical significance and outcome of hepatic triglyceride accumulation are highly dependent on etiology and histological pattern of steatosis. This review summarizes current concepts of pathophysiology of common causes of hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, chronic HCV infections, drug-induced forms of hepatic steatosis, and acute fatty liver of pregnancy. Regarding the pathophysiology of NAFLD, this work focuses on the close correlation between insulin resistance and hepatic triglyceride accumulation, highlighting the potential harmful effects of systemic insulin resistance on hepatic metabolism of fatty acids on the one side and the role of lipid intermediates on insulin signalling on the other side. Current studies on lipid droplet morphogenesis have identified novel candidate proteins and enzymes in NAFLD. PMID:26819531

  11. Mutation techniques for sustainable development in food production

    International Nuclear Information System (INIS)

    Liu Luxiang; Guo Huijun; Zhao Linshu; Li Junhui; Gu Jiayu; Wang Jing

    2010-01-01

    Ever since 1938, induced mutations have played a very significant role in solving world food and nutritional security problems through mutant germplasm enhancement and new mutant variety development. According to incomplete statistics, as of September 2009, induced mutations have made significant contributions in development and release of 3 088 mutant cultivars by more than 60 countries in the world in more than 170 crop species. China is the first country of the world, which have released the largest number of 802 mutant cultivars in 45 crop species, equivalent to more than a quarter of the total number of mutant variety in the FAO/IAEA database. The total maximum annually accumulated planting area of the mutant varieties was 9 million hectares, with the 1.5 billion kilograms additional increase of national output of grain, cotton, oil, converting to more than 2 billion RMB of social and economic benefits. The recent development and application of accelerator ion beam irradiation, the spaceflight environment and the other new mutation means, as well as the effective use of traditional radiation mutagenesis are becoming increasingly active in crop mutation improvement and new gene discovery. The advent of plant genomics and high throughput DNA techniques, such as TILLING have opened a new era in molecular mutation breeding technique that will overcome the limitations of conventional mutation breeding and play a significant role in solving China and world food security. (authors)

  12. New mutation of the MPZ gene in a family with the Dejerine-Sottas disease phenotype.

    Science.gov (United States)

    Floroskufi, Paraskewi; Panas, Marios; Karadima, Georgia; Vassilopoulos, Demetris

    2007-05-01

    Charcot-Marie-Tooth disease type 1B is associated with mutations in the myelin protein zero gene. In the present study a new myelin protein zero gene mutation (c.89T>C,Ile30Thr) was detected in a family with the Dejerine-Sottas disease phenotype. The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero.

  13. Phenomenology of an inducible mutagenic DNA repair pathway in Escherichia coli: SOS repair hypothesis

    International Nuclear Information System (INIS)

    Radman, M.

    1974-01-01

    A hypothesis is proposed according to which E. coli possesses an inducible DNA repair system. This hypothetical repair, which we call SOS repair, is manifested only following damage to DNA, and requires de novo protein synthesis. SOS repair in E. coli requires some known genetic elements: recA + , lex + and probably zab + . Mutagenesis by ultraviolet light is observed only under conditions of functional SOS repair: we therefore suspect that this is a mutation-prone repair. A number of phenomena and experiments is reviewed which at this point can best be interpreted in terms of an inducible mutagenic DNA repair system. Two recently discovered phenomena support the proposed hypothesis: existence of a mutant (tif) which, after a shift to elevated temperature, mimicks the effect of uv irradiation in regard to repair of phage lambda and uv mutagenesis, apparent activation of SOS repair by introduction into the recipient cell of damaged plasmid or Hfr DNA. Several specific predictions based on SOS repair hypothesis are presented in order to stimulate further experimental tests. (U.S.)

  14. Lack of coordination of nonverbal behaviour between patients and interviewers as a potential risk factor to depression recurrence : vulnerability accumulation in depression

    NARCIS (Netherlands)

    Bouhuys, AL; Sam, MM

    2000-01-01

    Background: Coordination of nonverbal behaviour during interactions is a prerequisite for satisfactory relationships. Lack of coordination may form a risk factor for depression. The 'vulnerability-accumulation hypothesis' assumes that vulnerability to recurrence of depression will increase with

  15. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.

    Science.gov (United States)

    Stenson, Peter D; Mort, Matthew; Ball, Edward V; Shaw, Katy; Phillips, Andrew; Cooper, David N

    2014-01-01

    The Human Gene Mutation Database (HGMD®) is a comprehensive collection of germline mutations in nuclear genes that underlie, or are associated with, human inherited disease. By June 2013, the database contained over 141,000 different lesions detected in over 5,700 different genes, with new mutation entries currently accumulating at a rate exceeding 10,000 per annum. HGMD was originally established in 1996 for the scientific study of mutational mechanisms in human genes. However, it has since acquired a much broader utility as a central unified disease-oriented mutation repository utilized by human molecular geneticists, genome scientists, molecular biologists, clinicians and genetic counsellors as well as by those specializing in biopharmaceuticals, bioinformatics and personalized genomics. The public version of HGMD (http://www.hgmd.org) is freely available to registered users from academic institutions/non-profit organizations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via BIOBASE GmbH.

  16. Mutation breeding in pepper

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-01

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

  17. Mutation breeding in pepper

    International Nuclear Information System (INIS)

    Daskalov, S.

    1986-01-01

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

  18. Deep sequencing of natural and experimental populations of Drosophila melanogaster reveals biases in the spectrum of new mutations.

    Science.gov (United States)

    Assaf, Zoe June; Tilk, Susanne; Park, Jane; Siegal, Mark L; Petrov, Dmitri A

    2017-12-01

    Mutations provide the raw material of evolution, and thus our ability to study evolution depends fundamentally on having precise measurements of mutational rates and patterns. We generate a data set for this purpose using (1) de novo mutations from mutation accumulation experiments and (2) extremely rare polymorphisms from natural populations. The first, mutation accumulation (MA) lines are the product of maintaining flies in tiny populations for many generations, therefore rendering natural selection ineffective and allowing new mutations to accrue in the genome. The second, rare genetic variation from natural populations allows the study of mutation because extremely rare polymorphisms are relatively unaffected by the filter of natural selection. We use both methods in Drosophila melanogaster , first generating our own novel data set of sequenced MA lines and performing a meta-analysis of all published MA mutations (∼2000 events) and then identifying a high quality set of ∼70,000 extremely rare (≤0.1%) polymorphisms that are fully validated with resequencing. We use these data sets to precisely measure mutational rates and patterns. Highlights of our results include: a high rate of multinucleotide mutation events at both short (∼5 bp) and long (∼1 kb) genomic distances, showing that mutation drives GC content lower in already GC-poor regions, and using our precise context-dependent mutation rates to predict long-term evolutionary patterns at synonymous sites. We also show that de novo mutations from independent MA experiments display similar patterns of single nucleotide mutation and well match the patterns of mutation found in natural populations. © 2017 Assaf et al.; Published by Cold Spring Harbor Laboratory Press.

  19. Mutated hilltop inflation revisited

    Science.gov (United States)

    Pal, Barun Kumar

    2018-05-01

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

  20. Mutation breeding in jute

    International Nuclear Information System (INIS)

    Joshua, D.C.

    1980-01-01

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

  1. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.

    Science.gov (United States)

    Pandey, Manoj K; Burrow, Thomas A; Rani, Reena; Martin, Lisa J; Witte, David; Setchell, Kenneth D; Mckay, Mary A; Magnusen, Albert F; Zhang, Wujuan; Liou, Benjamin; Köhl, Jörg; Grabowski, Gregory A

    2017-03-02

    Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

  2. Advances and prospects for induced mutation breeding in Helongjiang Province

    International Nuclear Information System (INIS)

    Sun Guangzu

    1995-12-01

    Induced mutation breeding employed on soybean, spring wheat, maize, millet, fiber flax, chinese cabbage, kidney been and garlic in Heilongjiang province. Thirty-six new varieties had introduced and released from 1980 to 1994, made up 20.6% of total released varieties for the same period, accumulated cultivated area of 3.746 million hm 2 , and increased the income of formers to US dollar 168 million; 72 mutants having specific and utilizing values and traits have also been bred in the province. Basic research such as radiation breeding in combination with distant hybridization, biotechnology, and application new induced factors, improving selection methods, have been achieved; 91 articles have been published. These researches play an important role for increasing induced mutation breeding. Three items of suggestion to develop induced mutation breeding are made. (1 tab.)

  3. Accumulation of cobalt by cephalopods

    International Nuclear Information System (INIS)

    Nakahara, Motokazu

    1981-01-01

    Accumulation of cobalt by cephalopod mollusca was investigated by radiotracer experiments and elemental analysis. In the radiotracer experiments, Octopus vulgaris took up cobalt-60 from seawater fairly well and the concentration of the nuclide in whole body attained about 150 times the level of seawater at 25th day at 20 0 C. Among the tissues and organs measured, branchial heart which is the specific organ of cephalopods showed the highest affinity for the nuclide. The organ accumulated about 50% of the radioactivity in whole body in spite of its little mass as 0.2% of total body weight. On the other hand, more than 90% of the radioactivity taken up from food (soft parts of Gomphina melanaegis labelled with cobalt-60 previously in an aquarium) was accumulated in liver at 3rd day after the single administration and then the radioactivity in the liver seemed to be distributed to other organs and tissues. The characteristic elution profiles of cobalt-60 was observed for each of the organs and tissues in Sephadex gel-filtration experiment. It was confirmed by the gel-filtration that most of cobalt-60 in the branchial heart was combined with the constituents of low molecular weights. The average concentration of stable cobalt in muscle of several species of cephalopods was 5.3 +- 3.0 μg/kg wet and it was almost comparable to the fish muscle. On the basis of soft parts, concentration of the nuclide closed association among bivalve, gastropod and cephalopod except squid that gave lower values than the others. (author)

  4. Endogenous network states predict gain or loss of functions for genetic mutations in hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Gaowei; Su, Hang; Yu, Helin; Yuan, Ruoshi; Zhu, Xiaomei; Ao, Ping

    2016-02-01

    Cancers have been typically characterized by genetic mutations. Patterns of such mutations have traditionally been analysed by posteriori statistical association approaches. One may ponder the possibility of a priori determination of any mutation regularity. Here by exploring biological processes implied in a mechanistic theory recently developed (the endogenous molecular-cellular network theory), we found that the features of genetic mutations in cancers may be predicted without any prior knowledge of mutation propensities. With hepatocellular carcinoma (HCC) as an example, we found that the normal hepatocyte and cancerous hepatocyte can be represented by robust stable states of one single endogenous network. These stable states, specified by distinct patterns of expressions or activities of proteins in the network, provide means to directly identify a set of most probable genetic mutations and their effects in HCC. As the key proteins and main interactions in the network are conserved through cell types in an organism, similar mutational features may also be found in other cancers. This analysis yielded straightforward and testable predictions on accumulated and preferred mutation spectra in normal tissue. The validation of predicted cancer state mutation patterns demonstrates the usefulness and potential of a causal dynamical framework to understand and predict genetic mutations in cancer. © 2016 The Author(s).

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

    Science.gov (United States)

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

    2010-01-01

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

  6. 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.

  7. Calreticulin Mutations in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Noa Lavi

    2014-10-01

    Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

  8. Brain white matter 1 H MRS in Leber optic neuropathy mutation carriers

    DEFF Research Database (Denmark)

    Ostojic, Jelena; Jancic, Jasna; Kozic, Dusko

    2009-01-01

    OBJECTIVE: This study was conducted in order to test the hypothesis that proton MR spectroscopic (1H MRS) profile of Leber's hereditary optic neuropathy (LHON) mutation carriers group (including both symptomatic and asymptomatic) differs from group of healthy individuals and to determine metabolite...... or ratio that contributes most to differentiation. PATIENTS AND METHODS: We performed single voxel 1H MRS in normal appearing white matter of eighteen LHON mtDNA mutation carriers bearing one of three LHON mtDNA point mutations and in fifty control subjects. RESULTS: ANOVA showed significant difference...

  9. Low acetate concentrations favor polyphosphate-accumulating organisms over glycogen-accumulating organisms in enhanced biological phosphorus removal from wastewater.

    Science.gov (United States)

    Tu, Yunjie; Schuler, Andrew J

    2013-04-16

    Glycogen-accumulating organisms (GAOs) are thought to compete with polyphosphate-accumulating organisms (PAOs) in enhanced biological phosphorus removal (EBPR) wastewater treatment systems. A laboratory sequencing batch reactor (SBR) was operated for one year to test the hypothesis that PAOs have a competitive advantage at low acetate concentrations, with a focus on low pH conditions previously shown to favor GAOs. PAOs dominated the system under conventional SBR operation with rapid acetate addition (producing high in-reactor concentrations) and pH values of 7.4-8.4. GAOs dominated when the pH was decreased (6.4-7.0). Decreasing the acetate addition rate led to very low reactor acetate concentrations, and PAOs recovered, supporting the study hypothesis. When the acetate feed rate was increased, EBPR failed again. Dominant PAOs and GAOs were Candidatus Accumulibacter phosphatis and Defluviicoccus Cluster 2, respectively, according to fluorescent in situ hybridization and 454 pyrosequencing. Surprisingly, GAOs were not the immediate causes of PAO failures, based on functional and population measurements. Pyrosequencing results suggested Dechloromonas and Tetrasphaera spp. may have also been PAOs, and additional potential GAOs were also identified. Full-scale systems typically have lower in-reactor acetate concentrations than laboratory SBRs, and so, previous laboratory studies may have overestimated the practical importance of GAOs as causes of EBPR failure.

  10. The Nature and Extent of Mutational Pleiotropy in Gene Expression of Male Drosophila serrata

    OpenAIRE

    McGuigan, Katrina; Collet, Julie M.; McGraw, Elizabeth A.; Ye, Yixin H.; Allen, Scott L.; Chenoweth, Stephen F.; Blows, Mark W.

    2014-01-01

    The nature and extent of mutational pleiotropy remain largely unknown, despite the central role that pleiotropy plays in many areas of biology, including human disease, agricultural production, and evolution. Here, we investigate the variation in 11,604 gene expression traits among 41 mutation accumulation (MA) lines of Drosophila serrata. We first confirmed that these expression phenotypes were heritable, detecting genetic variation in 96% of them in an outbred, natural population of D. serr...

  11. Men’s Perception of Raped Women: Test of the Sexually Transmitted Disease Hypothesis and the Cuckoldry Hypothesis

    Directory of Open Access Journals (Sweden)

    Prokop Pavol

    2016-06-01

    Full Text Available Rape is a recurrent adaptive problem of female humans and females of a number of non-human animals. Rape has various physiological and reproductive costs to the victim. The costs of rape are furthermore exaggerated by social rejection and blaming of a victim, particularly by men. The negative perception of raped women by men has received little attention from an evolutionary perspective. Across two independent studies, we investigated whether the risk of sexually transmitted diseases (the STD hypothesis, Hypothesis 1 or paternity uncertainty (the cuckoldry hypothesis, Hypothesis 2 influence the negative perception of raped women by men. Raped women received lower attractiveness score than non-raped women, especially in long-term mate attractiveness score. The perceived attractiveness of raped women was not influenced by the presence of experimentally manipulated STD cues on faces of putative rapists. Women raped by three men received lower attractiveness score than women raped by one man. These results provide stronger support for the cuckoldry hypothesis (Hypothesis 2 than for the STD hypothesis (Hypothesis 1. Single men perceived raped women as more attractive than men in a committed relationship (Hypothesis 3, suggesting that the mating opportunities mediate men’s perception of victims of rape. Overall, our results suggest that the risk of cuckoldry underlie the negative perception of victims of rape by men rather than the fear of disease transmission.

  12. K-Ras and β-catenin mutations cooperate with Fgfr3 mutations in mice to promote tumorigenesis in the skin and lung, but not in the bladder

    Directory of Open Access Journals (Sweden)

    Imran Ahmad

    2011-07-01

    The human fibroblast growth factor receptor 3 (FGFR3 gene is frequently mutated in superficial urothelial cell carcinoma (UCC. To test the functional significance of FGFR3 activating mutations as a ‘driver’ of UCC, we targeted the expression of mutated Fgfr3 to the murine urothelium using Cre-loxP recombination driven by the uroplakin II promoter. The introduction of the Fgfr3 mutations resulted in no obvious effect on tumorigenesis up to 18 months of age. Furthermore, even when the Fgfr3 mutations were introduced together with K-Ras or β-catenin (Ctnnb1 activating mutations, no urothelial dysplasia or UCC was observed. Interestingly, however, owing to a sporadic ectopic Cre recombinase expression in the skin and lung of these mice, Fgfr3 mutation caused papilloma and promoted lung tumorigenesis in cooperation with K-Ras and β-catenin activation, respectively. These results indicate that activation of FGFR3 can cooperate with other mutations to drive tumorigenesis in a context-dependent manner, and support the hypothesis that activation of FGFR3 signaling contributes to human cancer.

  13. New Hypothesis for SOFC Ceramic Oxygen Electrode Mechanisms

    DEFF Research Database (Denmark)

    Mogensen, Mogens Bjerg; Chatzichristodoulou, Christodoulos; Graves, Christopher R.

    2016-01-01

    A new hypothesis for the electrochemical reaction mechanism in solid oxide cell ceramic oxygen electrodes is proposed based on literature including our own results. The hypothesis postulates that the observed thin layers of SrO-La2O3 on top of ceramic perovskite and other Ruddlesden-Popper...

  14. Assess the Critical Period Hypothesis in Second Language Acquisition

    Science.gov (United States)

    Du, Lihong

    2010-01-01

    The Critical Period Hypothesis aims to investigate the reason for significant difference between first language acquisition and second language acquisition. Over the past few decades, researchers carried out a series of studies to test the validity of the hypothesis. Although there were certain limitations in these studies, most of their results…

  15. Dynamical agents' strategies and the fractal market hypothesis

    Czech Academy of Sciences Publication Activity Database

    Vácha, Lukáš; Vošvrda, Miloslav

    2005-01-01

    Roč. 14, č. 2 (2005), s. 172-179 ISSN 1210-0455 Grant - others:GA UK(CZ) 454/2004/A EK/FSV Institutional research plan: CEZ:AV0Z10750506 Keywords : efficient market hypothesis * fractal market hypothesis * agent's investment horizons Subject RIV: AH - Economics

  16. An Exercise for Illustrating the Logic of Hypothesis Testing

    Science.gov (United States)

    Lawton, Leigh

    2009-01-01

    Hypothesis testing is one of the more difficult concepts for students to master in a basic, undergraduate statistics course. Students often are puzzled as to why statisticians simply don't calculate the probability that a hypothesis is true. This article presents an exercise that forces students to lay out on their own a procedure for testing a…

  17. A default Bayesian hypothesis test for ANOVA designs

    NARCIS (Netherlands)

    Wetzels, R.; Grasman, R.P.P.P.; Wagenmakers, E.J.

    2012-01-01

    This article presents a Bayesian hypothesis test for analysis of variance (ANOVA) designs. The test is an application of standard Bayesian methods for variable selection in regression models. We illustrate the effect of various g-priors on the ANOVA hypothesis test. The Bayesian test for ANOVA

  18. Adaptation hypothesis of biological efficiency of ionizing radiation

    International Nuclear Information System (INIS)

    Kudritskij, Yu.K.; Georgievskij, A.B.; Karpov, V.I.

    1992-01-01

    Adaptation hypothesis of biological efficiency of ionizing radiation is based on acknowledgement of invariance of fundamental laws and principles of biology related to unity of biota and media, evolution and adaptation for radiobiology. The basic arguments for adaptation hypothesis validity, its correspondence to the requirements imposed on scientific hypothes are presented

  19. New methods of testing nonlinear hypothesis using iterative NLLS estimator

    Science.gov (United States)

    Mahaboob, B.; Venkateswarlu, B.; Mokeshrayalu, G.; Balasiddamuni, P.

    2017-11-01

    This research paper discusses the method of testing nonlinear hypothesis using iterative Nonlinear Least Squares (NLLS) estimator. Takeshi Amemiya [1] explained this method. However in the present research paper, a modified Wald test statistic due to Engle, Robert [6] is proposed to test the nonlinear hypothesis using iterative NLLS estimator. An alternative method for testing nonlinear hypothesis using iterative NLLS estimator based on nonlinear hypothesis using iterative NLLS estimator based on nonlinear studentized residuals has been proposed. In this research article an innovative method of testing nonlinear hypothesis using iterative restricted NLLS estimator is derived. Pesaran and Deaton [10] explained the methods of testing nonlinear hypothesis. This paper uses asymptotic properties of nonlinear least squares estimator proposed by Jenrich [8]. The main purpose of this paper is to provide very innovative methods of testing nonlinear hypothesis using iterative NLLS estimator, iterative NLLS estimator based on nonlinear studentized residuals and iterative restricted NLLS estimator. Eakambaram et al. [12] discussed least absolute deviation estimations versus nonlinear regression model with heteroscedastic errors and also they studied the problem of heteroscedasticity with reference to nonlinear regression models with suitable illustration. William Grene [13] examined the interaction effect in nonlinear models disused by Ai and Norton [14] and suggested ways to examine the effects that do not involve statistical testing. Peter [15] provided guidelines for identifying composite hypothesis and addressing the probability of false rejection for multiple hypotheses.

  20. The Younger Dryas impact hypothesis: A critical review

    NARCIS (Netherlands)

    van Hoesel, A.; Hoek, W.Z.; Pennock, G.M.; Drury, Martyn

    2014-01-01

    The Younger Dryas impact hypothesis suggests that multiple extraterrestrial airbursts or impacts resulted in the Younger Dryas cooling, extensive wildfires, megafaunal extinctions and changes in human population. After the hypothesis was first published in 2007, it gained much criticism, as the

  1. Biota-Sediment Accumulation Factor Data

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Biota-Sediment Accumulation Factor contains approximately 20,000 biota-sediment accumulation factors (BSAFs) from 20 locations (mostly Superfund sites) for...

  2. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

    2009-01-01

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

  3. Charge accumulation in lossy dielectrics: a review

    DEFF Research Database (Denmark)

    Rasmussen, Jørgen Knøster; McAllister, Iain Wilson; Crichton, George C

    1999-01-01

    At present, the phenomenon of charge accumulation in solid dielectrics is under intense experimental study. Using a field theoretical approach, we review the basis for charge accumulation in lossy dielectrics. Thereafter, this macroscopic approach is applied to planar geometries such that the mat......At present, the phenomenon of charge accumulation in solid dielectrics is under intense experimental study. Using a field theoretical approach, we review the basis for charge accumulation in lossy dielectrics. Thereafter, this macroscopic approach is applied to planar geometries...

  4. Characteristics, causes and evolutionary consequences of male-biased mutation.

    Science.gov (United States)

    Ellegren, Hans

    2007-01-07

    Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions. One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, alpham, can be solved from the observed difference in rate of X and Y chromosome divergence. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, alpham is estimated at approximately 4-6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in alpham. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the

  5. Histone Variant HTZ1 Shows Extensive Epistasis with, but Does Not Increase Robustness to, New Mutations

    Science.gov (United States)

    Richardson, Joshua B.; Uppendahl, Locke D.; Traficante, Maria K.; Levy, Sasha F.; Siegal, Mark L.

    2013-01-01

    Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact) to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA) lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1) to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be caused by loss of

  6. Histone variant HTZ1 shows extensive epistasis with, but does not increase robustness to, new mutations.

    Directory of Open Access Journals (Sweden)

    Joshua B Richardson

    Full Text Available Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1 to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be

  7. Induced mutations in citrus

    International Nuclear Information System (INIS)

    Spiegel-Roy, P.; Vardi, Aliza

    1990-01-01

    Full text: Parthenocarpic tendency is an important prerequisite for successful induction of seedlessness in breeding and especially in mutation breeding. A gene for asynapsis and accompanying seedless fruit has been found by us in inbred progeny of cv. 'Wilking'. Using budwood irradiation by gamma rays, seedless mutants of 'Eureka' and 'Villafranca' lemon (original clone of the latter has 25 seeds) and 'Minneola' tangelo have been obtained. Ovule sterility of the three mutants is nearly complete, with some pollen fertility still remaining. A semi-compact mutant of Shamouti orange has been obtained by irradiation. A programme for inducing seedlessness in easy peeling citrus varieties and selections has been initiated. (author)

  8. Induced skeletal mutations

    International Nuclear Information System (INIS)

    Selby, P.B.

    1979-01-01

    This paper describes a large-scale experiment that, by means of breeding tests, confirmed that many dominant skeletal mutations are induced by large-dose radiation exposure. The author also discusses: (1) the major advantages and disadvantages of the skeletal method in improving estimates of genetic hazard to man; (2) future uses of the skeletal method; (3) direct estimation of risk beyond the first generation using the skeletal method; and (4) the possibility of using the skeletal method as a quick and easy screen for chemical mutagens

  9. Radiocaesium accumulation by different plant species

    International Nuclear Information System (INIS)

    Filiptsova, G.G.

    2000-01-01

    Using the model object influence of mineral nutritions level on radiocaesium accumulation by different plant species has been studied. It was shown the wheat roots accumulation the minimal value on radiocaesium on normal potassium level, the rye roots accumulation maximal level radiocaesium. (authors)

  10. 47 CFR 32.3100 - Accumulated depreciation.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 2 2010-10-01 2010-10-01 false Accumulated depreciation. 32.3100 Section 32... Accumulated depreciation. (a) This account shall include the accumulated depreciation associated with the... with depreciation amounts concurrently charged to Account 6561, Depreciation expense—telecommunications...

  11. Nickel-accumulating plant from Western Australia

    Energy Technology Data Exchange (ETDEWEB)

    Severne, B C; Brooks, R R

    1972-01-01

    A small shrub Hybanthus floribundus (Lindl.) F. Muell. Violaceae growing in Western Australia accumulates nickel and cobalt to a very high degree. Values of up to 23% nickel in leaf ash may represent the highest relative accumulation of a metal on record. The high accumulation of nickel poses interesting problems in plant physiology and plant biochemistry. 9 references, 2 figures, 1 table.

  12. Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice

    International Nuclear Information System (INIS)

    Selby, P.B.; Selby, P.R.

    1977-01-01

    Male mice were exposed to 100 R + 500 R γ-rays (60 R/min) with a 24-h fractionation interval. Skeletons of F 1 sons were examined for abnormalities, and, if any were found, the skeletons of their descendants were also examined. Of 2646 sons from treated spermatogonia, 37, or 1.4%, were diagnosed as carriers of autosomal dominant mutations affecting the skeleton, 31 by breeding tests, and six by other criteria for identifying mutations in F 1 's having no progeny. Many mutations caused a large number of anomalies in different regions of the skeleton. Most regions of the skeleton were affected by at least one mutation, and the mutations had incomplete penetrance for some or all of their effects. Three of the mutations affected skeletal size only. If certain assumptions are made, these skeletal data can be used to derive an estimate of induced genetic damage from dominant mutations affecting all parts of the body. When applied to man, the resultant risk estimate is not inconsistent with that made for dominant and irregularly inherited diseases by the BEIR Committee, by use of the doubling-dose method. Since most of the mutations can be characterized as models of irregularly inherited conditions in man, the data directly relate to the controversy over the relative importance of mutation pressure and balanced selection in maintaining man's large burden of irregularly inherited disease. Contrary to a recent hypothesis by H.B. Newcombe that man's large burden of irregularly inherited disease is maintained almost exclusively by balanced selection, these results suggest that at least an important fraction of the irregularly inherited conditions are maintained by mutation pressure. Therefore, this finding does not support the major changes in the estimate of genetic hazard to man that would be required on the basis of Newcombe's hypothesis

  13. Long G2 accumulates recombination intermediates and disturbs chromosome segregation at dysfunction telomere in Schizosaccharomyces pombe

    Energy Technology Data Exchange (ETDEWEB)

    Habib, Ahmed G.K.; Masuda, Kenta; Yukawa, Masashi; Tsuchiya, Eiko [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530 (Japan); Ueno, Masaru, E-mail: scmueno@hiroshima-u.ac.jp [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530 (Japan); Research Center for the Mathematics on Chromatin Live Dynamics, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530 (Japan)

    2015-08-14

    Protection of telomere (Pot1) is a single-stranded telomere binding protein which is essential for chromosome ends protection. Fission yeast Rqh1 is a member of RecQ helicases family which has essential roles in the maintenance of genomic stability and regulation of homologous recombination. Double mutant between fission yeast pot1Δ and rqh1 helicase dead (rqh1-hd) maintains telomere by homologous recombination. In pot1Δ rqh1-hd double mutant, recombination intermediates accumulate near telomere which disturb chromosome segregation and make cells sensitive to microtubule inhibitors thiabendazole (TBZ). Deletion of chk1{sup +} or mutation of its kinase domain shortens the G2 of pot1Δ rqh1-hd double mutant and suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of that double mutant. In this study, we asked whether the long G2 is the reason for the TBZ sensitivity of pot1Δ rqh1-hd double mutant. We found that shortening the G2 of pot1Δ rqh1-hd double mutant by additional mutations of wee1 and mik1 or gain of function mutation of Cdc2 suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of pot1Δ rqh1-hd double mutant. Our results suggest that long G2 of pot1Δ rqh1-hd double mutant may allow time for the accumulation of recombination intermediates which disturb chromosome segregation and make cells sensitive to TBZ. - Ηighlights: • We show link between long G2 and accumulation of toxic recombination intermediates. • Accumulation of recombination intermediates at telomere results in TBZ sensitivity. • Activation of DNA damage checkpoint worsens cells' viability in presence of TBZ.

  14. Mutation Breeding Newsletter. No. 39

    International Nuclear Information System (INIS)

    1992-01-01

    This newsletter contains brief articles on the use of radiation to induce mutations in plants; radiation-induced mutants in Chrysanthemum; disrupting the association between oil and protein content in soybean seeds; mutation studies on bougainvillea; a new pepper cultivar; and the use of mutation induction to improve the quality of yam beans. A short review of the seminar on the use of mutation and related biotechnology for crop improvement in the Middle East and Mediterranean regions, and a description of a Co-ordinated Research Programme on the application of DNA-based marker mutations for the improvement of cereals and other sexually reproduced crop species are also included. Two tables are given: these are based on the ''FAO/IAEA Mutant Varieties Database'' and show the number of mutated varieties and the number of officially released mutant varieties in particular crops/species. Refs and tabs

  15. Ultrastructural and flow cytometric analyses of lipid accumulation in microalgae

    Energy Technology Data Exchange (ETDEWEB)

    Solomon, J.A.; Hand, R.E. Jr.; Mann, R.C.

    1986-12-01

    Lipid accumulation in three species of microalgae was investigated with flow cytometry (FCM) and transmission electron microscopy (TEM). Previous studies using batch cultures of a algae have led to the assumption that lipid accumulation in microalgae is a gradual process requiring at least several days for completion. However, FCM reveals, through changes in the chlorophyll:lipid ratio, that the time span required for individual cells to change metabolic state is short. Simultaneous FCM measurements of chlorophyll and nile red (neutral lipid) fluorescence in individual cells of nitrogen-deficient Isochrysis populations revealed a bimodal population distribution as one stage in the lipid accumulation process. The fact that two discrete populations exist, with few cells in an intermediate stage, suggests rapid response to a liqid trigger. Interpretations of light and electron microscopic observations are consistent with this hypothesis. The time required for an entire population to achieve maximum lipid content is considerably longer than that required for a single cell, due to the variation in response time among cells. In this study high lipid cultures were sometimes obtained by using FCM to separate high lipid cells from the remainder of the population. FCM holds much promise for strain enhancement but considerable developmental work, directed at providing more consistent results, remains to be done. 8 refs., 35 figs.

  16. Bayesian inference method for stochastic damage accumulation modeling

    International Nuclear Information System (INIS)

    Jiang, Xiaomo; Yuan, Yong; Liu, Xian

    2013-01-01

    Damage accumulation based reliability model plays an increasingly important role in successful realization of condition based maintenance for complicated engineering systems. This paper developed a Bayesian framework to establish stochastic damage accumulation model from historical inspection data, considering data uncertainty. Proportional hazards modeling technique is developed to model the nonlinear effect of multiple influencing factors on system reliability. Different from other hazard modeling techniques such as normal linear regression model, the approach does not require any distribution assumption for the hazard model, and can be applied for a wide variety of distribution models. A Bayesian network is created to represent the nonlinear proportional hazards models and to estimate model parameters by Bayesian inference with Markov Chain Monte Carlo simulation. Both qualitative and quantitative approaches are developed to assess the validity of the established damage accumulation model. Anderson–Darling goodness-of-fit test is employed to perform the normality test, and Box–Cox transformation approach is utilized to convert the non-normality data into normal distribution for hypothesis testing in quantitative model validation. The methodology is illustrated with the seepage data collected from real-world subway tunnels.

  17. Energy Accumulation by Hydrogen Technologies

    Directory of Open Access Journals (Sweden)

    Jiřina Čermáková

    2012-01-01

    Full Text Available Photovoltaic power plants as a renewable energy source have been receiving rapidly growing attention in the Czech Republic and in the other EU countries. This rapid development of photovoltaic sources is having a negative effect on the electricity power system control, because they depend on the weather conditions and provide a variable and unreliable supply of electric power. One way to reduce this effect is by accumulating electricity in hydrogen. The aim of this paper is to introduce hydrogen as a tool for regulating photovoltaic energy in island mode. A configuration has been designed for connecting households with the photovoltaic hybrid system, and a simulation model has been made in order to check the validity of this system. The simulation results provide energy flows and have been used for optimal sizing of real devices. An appropriate system can deliver energy in a stand-alone installation.

  18. Electron-Positron Accumulator (EPA)

    CERN Multimedia

    Photographic Service

    1986-01-01

    After acceleration in the low-current linac LIL-W, the electrons and positrons are accumulated in EPA to obtain a sufficient intensity and a suitable time-structure, before being passed on to the PS for further acceleration to 3.5 GeV. Electrons circulate from right to left, positrons in the other direction. Dipole bending magnets are red, focusing quadrupoles blue, sextupoles for chromaticity-control orange. The vertical tube at the left of the picture belongs to an optical transport system carrying the synchrotron radiation to detectors for beam size measurement. Construction of EPA was completed in spring 1986. LIL-W and EPA were conceived for an energy of 600 MeV, but operation was limited to 500 MeV.

  19. Nickel accumulation by Hybanthus floribundus

    Energy Technology Data Exchange (ETDEWEB)

    Severne, B C

    1974-04-26

    Several ecotypes of Hybanthus floribundus are found across the southern part of Australia. However, the three nickel accumulating ecotypes are restricted to a broad belt in Western Australia. Nickel concentrations in this shrub were observed to decrease southwards (from 8000 to 1000 p.p.m.) as the annual rainfall increased from 7 inches to more than 30 inches. Studies have shown that nickel concentrations increase from the roots through the rootstock, into the stems and reach maximum towards the leaf tips. High nickel concentrations are also seen in seed capsules (1500 p.p.m.), seeds (2000 p.p.m.) and flowers. The maximum nickel concentration recorded is 1.6% (26% nickel in ash) in mature leaf tissue. 16 references, 2 tables.

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

    Science.gov (United States)

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

    2013-02-01

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

  1. Progression inference for somatic mutations in cancer

    Directory of Open Access Journals (Sweden)

    Leif E. Peterson

    2017-04-01

    Full Text Available Computational methods were employed to determine progression inference of genomic alterations in commonly occurring cancers. Using cross-sectional TCGA data, we computed evolutionary trajectories involving selectivity relationships among pairs of gene-specific genomic alterations such as somatic mutations, deletions, amplifications, downregulation, and upregulation among the top 20 driver genes associated with each cancer. Results indicate that the majority of hierarchies involved TP53, PIK3CA, ERBB2, APC, KRAS, EGFR, IDH1, VHL, etc. Research into the order and accumulation of genomic alterations among cancer driver genes will ever-increase as the costs of nextgen sequencing subside, and personalized/precision medicine incorporates whole-genome scans into the diagnosis and treatment of cancer. Keywords: Oncology, Cancer research, Genetics, Computational biology

  2. Mutations induced in plant breeding

    International Nuclear Information System (INIS)

    Barriga B, P.

    1984-01-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented. (Author)

  3. Mutations induced in plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Barriga B, P. (Universidad Austral de Chile, Valdivia. Inst. de Produccion y Sanidad Vegetal)

    1984-10-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented.

  4. HIV populations are large and accumulate high genetic diversity in a nonlinear fashion.

    Science.gov (United States)

    Maldarelli, Frank; Kearney, Mary; Palmer, Sarah; Stephens, Robert; Mican, JoAnn; Polis, Michael A; Davey, Richard T; Kovacs, Joseph; Shao, Wei; Rock-Kress, Diane; Metcalf, Julia A; Rehm, Catherine; Greer, Sarah E; Lucey, Daniel L; Danley, Kristen; Alter, Harvey; Mellors, John W; Coffin, John M

    2013-09-01

    HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift.

  5. Hypothesis of the cause and development of neoplasms.

    Science.gov (United States)

    Hoang, Ba X; Levine, Stephen A; Pham, Phuong; Shaw, David Graeme

    2007-02-01

    Cancer, in general, is considered a disease of genetic mutation. Many questions are, however, unanswered. How exactly do mutations occur in the cells? How do gene mutations interface with the cell microenvironment and macroenvironment to create cancer phenotypes? Is mutation the cause of cancer or the consequence of special adaptive responses to aging; hormonal imbalance; physical, chemical and biologic stresses and damage? What makes cancer spread in the body and invade other organs causing death to the patient? In this paper, we hypothesize that the cellular hyperexcitability via stimulation of mineral channels (e.g. sodium voltage-gated channels) and ligand excitatory receptors (e.g. glutamate and other neuron and non-neuronal excitatory receptors) could be a significant causative and pathogenic factor of cancer. Managing hyperexcitatory states of the cells through lifestyle, nutritional changes, phytochemical and pharmaceutical medications theoretically could be a prospective direction in cancer prevention and therapy.

  6. Mutational Analysis of Oculocutaneous Albinism: A Compact Review

    Science.gov (United States)

    Kamaraj, Balu

    2014-01-01

    Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by either complete lack of or a reduction of melanin biosynthesis in the melanocytes. The OCA1A is the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3, and OCA4 show some pigment accumulation over time. Mutations in TYR, OCA2, TYRP1, and SLC45A2 are mainly responsible for causing oculocutaneous albinism. Recently, two new genes SLC24A5 and C10orf11 are identified that are responsible to cause OCA6 and OCA7, respectively. Also a locus has been mapped to the human chromosome 4q24 region which is responsible for genetic cause of OCA5. In this paper, we summarized the clinical and molecular features of OCA genes. Further, we reviewed the screening of pathological mutations of OCA genes and its molecular mechanism of the protein upon mutation by in silico approach. We also reviewed TYR (T373K, N371Y, M370T, and P313R), OCA2 (R305W), TYRP1 (R326H and R356Q) mutations and their structural consequences at molecular level. It is observed that the pathological genetic mutations and their structural and functional significance of OCA genes will aid in development of personalized medicine for albinism patients. PMID:25093188

  7. A challenge to mutation theory of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Watanabe, Masami

    2006-01-01

    This paper presents an objection against the commonly accepted mutation theory in radiation carcinogenesis. First, author's studies of X-ray irradiated syrian hamster embryo (SHE) cells on malignant morphological changes and mutational change of HGPRT gene showed that the changing patterns were quite different, and as well, other studies in mice gave the essentially similar results. Thus radiation-induced carcinogenesis in cells does not simply occur by an accumulation of radiation-induced mutation. Second, as cultured cells usually used for oncogenesis studies already have the infinitively proliferative ability, the author used the primary cell culture obtained from the rodent embryo. Even those cells became immortal to be cancerous after repeated culture passage with the higher frequency of 10 3 -10 4 relative to somatic cell mutation. Cells thus seem to be easily changeable to cancerous ones. Bystander effect can cause transformation in non-irradiated cells and genetic instability by radiation can form the potentially unstable chromatin region, which induces telomere instability. The author has found that, while short-lived radicals yielded by X-ray irradiation attack DNA to induce cell death and chromosome aberration, long-lived radicals in biomolecules do not, but can cause mutation and carcinogenesis, which are reduced by vitamine C supplementation. The author concludes that the primary target in the radiation carcinogenesis in cells and even in the whole individuals is conceivably protein and not DNA. (T.I.)

  8. Mutation breeding newsletter. No. 43

    International Nuclear Information System (INIS)

    1997-10-01

    This issue of the Newsletter includes articles dealing with radiation induced mutation based plant breeding research findings aimed at improving productivity, disease resistance and tolerance of stress conditions

  9. Mutation breeding in mangosteen

    International Nuclear Information System (INIS)

    Mohd Khalid Mohd Zain

    2002-01-01

    Mangosteen the queen of the tropical fruits is apomitic and only a cultivar is reported and it reproduces asexually. Conventional breeding is not possible and the other methods to create variabilities are through genetic engineering and mutation breeding. The former technique is still in the infantry stage in mangosteen research while the latter has been an established tool in breeding to improve cultivars. In this mutation breeding seeds of mangosteen were irradiated using gamma rays and the LD 50 for mangosteen was determined and noted to be very low at 10 Gy. After sowing in the seedbed, the seedlings were transplanted in polybags and observed in the nursery bed for about one year before planted in the field under old oil palm trees in Station MARDI, Kluang. After evaluation and screening, about 120 mutant mangosteen plants were selected and planted in Kluang. The plants were observed and some growth data taken. There were some mutant plants that have good growth vigour and more vigorous that the control plants. The trial are now in the fourth year and the plants are still in the juvenile stage. (Author)

  10. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

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

    2009-01-01

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

  11. The contribution of international trade to economic growth through human capital accumulation: Evidence from nine Asian countries

    Directory of Open Access Journals (Sweden)

    Mirajul Haq

    2014-12-01

    Full Text Available This study is an attempt to test the hypothesis “international trade contributes to economic growth through its effects on human capital accumulation.” To assess the hypothesis empirically, we employed the extended Neo-Classical growth model that reflects some features of the endogenous growth models. We thus ended up with a model in which the change in human capital is sensitive to change in trade policies. Unlike conventional approaches, the model serves to assess and determine the impact of international trade on the accumulation of human capital. The empirical analysis estimates dynamic panel growth equations by using a data-set of nine Asian countries, over the period 1972–2012. The overall evidence substantiates the fact that in countries under consideration, international trade enhances the accumulation of human capital and contributes to economic growth positively through human capital accumulation.

  12. Radionuclide accumulation peculiarities demonstrated by vegetable varieties

    International Nuclear Information System (INIS)

    Kruk, A.V.; Goncharenko, G.G.; Kilchevsky, A.V.

    2004-01-01

    This study focused on ecological and genetic aspects of radionuclide accumulation demonstrated by a number of vegetable varieties. The researches resulted in determining the cabbage varieties which were characterised by the minimal level of radionuclide accumulation. It was shown that the above varieties manifested the relation between radionuclide accumulation and morphobiological characteristics such as vegetation period duration and yield criteria. The study specified the genotypes with high ecological stability as regards to radionuclide accumulation: 'Beloruskaya 85' cabbage and 'Dokhodny' tomato showed the best response to Cs 137, while 'Beloruskaya 85', 'Rusinovka', 'Amager 611' cabbage varieties and 'Sprint' tomato showed the minimal level of Sr 90 accumulation. (authors)

  13. Guidelines for Waste Accumulation Areas (WAAs)

    International Nuclear Information System (INIS)

    1991-07-01

    The purpose of this document is to set conditions for establishing and maintaining areas for the accumulation of hazardous waste at LBL. Areas designed for accumulation of these wastes in quantities greater than 100 kg (220 lb) per month of solid waste or 55 gallons per month of liquid waste are called Waste Accumulation Areas (WAAs). Areas designed for accumulation of wastes in smaller amounts are called Satellite Accumulation Areas (SAAs). This document provides guidelines for employee and organizational responsibilities for WAAs; constructing a WAA; storing waste in a WAA; operating and maintaining a WAA, and responding to spills in a WAA. 4 figs

  14. Research progress of IDH1 and IDH2 mutations in gliomas

    Directory of Open Access Journals (Sweden)

    Shan-shan ZHANG

    2015-11-01

    Full Text Available The gene mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2 mainly occur in astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma and secondary glioblastoma. The IDH1/2 gene mutation can alter proteinase function, consume α-ketoglutarate and nicotinamide adenine dinucleotide phosphate-reduced (NADPH and thus produce carcinogenic metabolite, 2-hydroxyglutarate. The intracellular accumulation of 2-hydroxyglutarate will induce a series of downstream effects which may result in the development of gliomas mentioned above. Both IDH1/2 mutations and other concomitant hereditary variations are biomarkers for differential diagnosis and IDH1/2 mutations are also independent factors for the prognosis of gliomas. The molecular targeting therapy for IDH1/2 mutations has become the research focus of glioma treatment. This review summarizes the recent progress of this field. DOI: 10.3969/j.issn.1672-6731.2015.11.017

  15. Environmental policy without costs? A review of the Porter hypothesis

    Energy Technology Data Exchange (ETDEWEB)

    Braennlund, Runar; Lundgren, Tommy. e-mail: runar.brannlund@econ.umu.se

    2009-03-15

    This paper reviews the theoretical and empirical literature connected to the so called Porter Hypothesis. That is, to review the literature connected to the discussion about the relation between environmental policy and competitiveness. According to the conventional wisdom environmental policy, aiming for improving the environment through for example emission reductions, do imply costs since scarce resources must be diverted from somewhere else. However, this conventional wisdom has been challenged and questioned recently through what has been denoted the 'Porter hypothesis'. Those in the forefront of the Porter hypothesis challenge the conventional wisdom basically on the ground that resources are used inefficiently in the absence of the right kind of environmental regulations, and that the conventional neo-classical view is too static to take inefficiencies into account. The conclusions that can be made from this review is (1) that the theoretical literature can identify the circumstances and mechanisms that must exist for a Porter effect to occur, (2) that these circumstances are rather non-general, hence rejecting the Porter hypothesis in general, (3) that the empirical literature give no general support for the Porter hypothesis. Furthermore, a closer look at the 'Swedish case' reveals no support for the Porter hypothesis in spite of the fact that Swedish environmental policy the last 15-20 years seems to be in line the prerequisites stated by the Porter hypothesis concerning environmental policy

  16. Forty years of mutation breeding in Japan. Research and fruits

    International Nuclear Information System (INIS)

    Yamaguchi, Isao

    2003-01-01

    The radiation source used for breeding in the early years was mainly X rays. After the 2nd World War, gamma ray sources such as 60 Co and 137 Cs came to take a leading role in radiation breeding. The institute of Radiation Breeding (IRB) of the Ministry of Agriculture, Forestry and Fisheries (MAFF) was established on April 16, 1960. A gamma field with 2000Ci of a 60 Co source, the main irradiation facility of the IRB, was installed to study the genetically responses of crop plants to chronic exposures of ionizing radiation and their practical application to plant breeding. This paper consisted of 'forty years of research on radiobiology and mutation breeding in Japan', 'topics of mutation breeding research in IRB', 'outline of released varieties by mutation breeding' and 'future of mutation breeding'. The number of varieties released by the direct use of induced mutation in Japan amounts to 163 as of November 2001. Crops in which mutant varieties have been released range widely: rice and other cereals, industrial crops, forage crops, vegetables, ornamentals, mushrooms and fruit trees, the number of which reaches 48. The number of mutant varieties is highest (31) in chrysanthemum, followed by 22 in rice and 13 in soybean. By the indirect use of mutants, a total of 15 varieties of wheat, barley, soybean, mat rush and tomato have been registered by MAFF. Recent advances in biotechnological techniques have made it possible to determine DNA sequences of mutant genes. Accumulating information of DNA sequences and other molecular aspects of many mutant genes will throw light on the mechanisms of mutation induction and develop a new field of mutation breeding. (S.Y.)

  17. Distributions of Mutational Effects and the Estimation of Directional Selection in Divergent Lineages of Arabidopsis thaliana.

    Science.gov (United States)

    Park, Briton; Rutter, Matthew T; Fenster, Charles B; Symonds, V Vaughan; Ungerer, Mark C; Townsend, Jeffrey P

    2017-08-01

    Mutations are crucial to evolution, providing the ultimate source of variation on which natural selection acts. Due to their key role, the distribution of mutational effects on quantitative traits is a key component to any inference regarding historical selection on phenotypic traits. In this paper, we expand on a previously developed test for selection that could be conducted assuming a Gaussian mutation effect distribution by developing approaches to also incorporate any of a family of heavy-tailed Laplace distributions of mutational effects. We apply the test to detect directional natural selection on five traits along the divergence of Columbia and Landsberg lineages of Arabidopsis thaliana , constituting the first test for natural selection in any organism using quantitative trait locus and mutation accumulation data to quantify the intensity of directional selection on a phenotypic trait. We demonstrate that the results of the test for selection can depend on the mutation effect distribution specified. Using the distributions exhibiting the best fit to mutation accumulation data, we infer that natural directional selection caused divergence in the rosette diameter and trichome density traits of the Columbia and Landsberg lineages. Copyright © 2017 by the Genetics Society of America.

  18. The linear hypothesis - an idea whose time has passed

    International Nuclear Information System (INIS)

    Tschaeche, A.N.

    1995-01-01

    The linear no-threshold hypothesis is the basis for radiation protection standards in the United States. In the words of the National Council on Radiation Protection and Measurements (NCRP), the hypothesis is: open-quotes In the interest of estimating effects in humans conservatively, it is not unreasonable to follow the assumption of a linear relationship between dose and effect in the low dose regions for which direct observational data are not available.close quotes The International Commission on Radiological Protection (ICRP) stated the hypothesis in a slightly different manner: open-quotes One such basic assumption ... is that ... there is ... a linear relationship without threshold between dose and the probability of an effect. The hypothesis was necessary 50 yr ago when it was first enunciated because the dose-effect curve for ionizing radiation for effects in humans was not known. The ICRP and NCRP needed a model to extrapolate high-dose effects to low-dose effects. So the linear no-threshold hypothesis was born. Certain details of the history of the development and use of the linear hypothesis are presented. In particular, use of the hypothesis by the U.S. regulatory agencies is examined. Over time, the sense of the hypothesis has been corrupted. The corruption of the hypothesis into the current paradigm of open-quote a little radiation, no matter how small, can and will harm youclose quotes is presented. The reasons the corruption occurred are proposed. The effects of the corruption are enumerated, specifically, the use of the corruption by the antinuclear forces in the United States and some of the huge costs to U.S. taxpayers due to the corruption. An alternative basis for radiation protection standards to assure public safety, based on the weight of scientific evidence on radiation health effects, is proposed

  19. Selection problems and objectives in mutation breeding

    International Nuclear Information System (INIS)

    Mac Key, J.

    1984-01-01

    In plant breeding, major genes are preferably handled by inbreeding, back-crosses and selection through the family/pedigree method. Polygenic systems need gene accumulation, i.e. handling in bulk allowing natural/recurrent selection to operate. The two types of genetic control normally occur together irrespective of whether the variation is created by crossing or by mutagenesis. Cross-breeding can conveniently work with both types of variation and offers a range of genetic backgrounds. Problems are the often enormous recombination potential risking the break-down of already accomplished genic constellations or undesirable linkages. Mutation induction implies a scattered mono- to oligo-factorial variation mostly functioning as a negative load. As a result, it will be difficult and unrealistic to try to explore micromutations, as defined by Gaul, in vegetatively propagated and autogamous crop plants. Quantitative analyses have not been able to give guidance since the induced variation includes disturbed vitality and main or side-effects of events that are possible to define as macro-mutations. The possibility of better exhausting the variation induced will mainly depend on the precision in selection techniques, i.e. by dividing complex traits into their components, by improving environmental conditions for selection, and/or by sharpening the screening technique. Contrary to recombination breeding, mutation-induced variation does not fit a plan encompassing overall agronomic traits simultaneously. The progress has to go step by step. Thus, even more than in cross-breeding, it is important that accurately outlined objectives be set. Some characters, such as flower colour, can easily be defined while others, such as yield, may be more interdependent, calling for compromises difficult to foresee. The complexity of the latter category of traits is illustrated by the interaction pattern in relation to grain yield in cereals where both shoot and root are considered

  20. Novel homozygous FANCL mutation and somatic heterozygous SETBP1 mutation in a Chinese girl with Fanconi Anemia.

    Science.gov (United States)

    Wu, Weiqing; Liu, Yang; Zhou, Qinghua; Wang, Qin; Luo, Fuwei; Xu, Zhiyong; Geng, Qian; Li, Peining; Zhang, Hui Z; Xie, Jiansheng

    2017-07-01

    Fanconi Anemia (FA) is a rare genetically heterogeneous disorder with 17 known complement groups caused by mutations in different genes. FA complementation group L (FA-L, OMIM #608111) occurred in 0.2% of all FA and only eight mutant variants in the FANCL gene were documented. Phenotype and genotype correlation in FANCL associated FA is still obscure. Here we describe a Chinese girl with FA-L caused by a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) in the FANCL gene. The patient's clinical course was typical for FA with progression to bone marrow failure, and death from acute myelomonocytic leukemia (AML-M4) at 9 years of age. Mutation analysis also detected a likely somatic c.2608G > A (p.Gly870Ser) in the SETBP1 gene. Consistent copy number losses of 7q and 18p and gains of 3q and 21q and accumulated non-clonal single cell chromosomal abnormalities were detected in blood leukocytes as her FA progressed. This is the first Chinese FA-L case caused by a novel FANCL mutation. The somatic gene mutation and copy number aberrations could be used to monitor disease progression and the clinical findings provide further information for genotype-phenotype correlation for FA-L. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. Biostatistics series module 2: Overview of hypothesis testing

    Directory of Open Access Journals (Sweden)

    Avijit Hazra

    2016-01-01

    Full Text Available Hypothesis testing (or statistical inference is one of the major applications of biostatistics. Much of medical research begins with a research question that can be framed as a hypothesis. Inferential statistics begins with a null hypothesis that reflects the conservative position of no change or no difference in comparison to baseline or between groups. Usually, the researcher has reason to believe that there is some effect or some difference which is the alternative hypothesis. The researcher therefore proceeds to study samples and measure outcomes in the hope of generating evidence strong enough for the statistician to be able to reject the null hypothesis. The concept of the P value is almost universally used in hypothesis testing. It denotes the probability of obtaining by chance a result at least as extreme as that observed, even when the null hypothesis is true and no real difference exists. Usually, if P is < 0.05 the null hypothesis is rejected and sample results are deemed statistically significant. With the increasing availability of computers and access to specialized statistical software, the drudgery involved in statistical calculations is now a thing of the past, once the learning curve of the software has been traversed. The life sciences researcher is therefore free to devote oneself to optimally designing the study, carefully selecting the hypothesis tests to be applied, and taking care in conducting the study well. Unfortunately, selecting the right test seems difficult initially. Thinking of the research hypothesis as addressing one of five generic research questions helps in selection of the right hypothesis test. In addition, it is important to be clear about the nature of the variables (e.g., numerical vs. categorical; parametric vs. nonparametric and the number of groups or data sets being compared (e.g., two or more than two at a time. The same research question may be explored by more than one type of hypothesis test

  2. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation.

    Science.gov (United States)

    Fishbein, Ianai; Kuo, Yien-Ming; Giasson, Benoit I; Nussbaum, Robert L

    2014-12-01

    The involvement of the protein α-synuclein (SNCA) in the pathogenesis of Parkinson's disease is strongly supported by the facts that (i) missense and copy number mutations in the SNCA gene can cause inherited Parkinson's disease; and (ii) Lewy bodies in sporadic Parkinson's disease are largely composed of aggregated SNCA. Unaffected heterozygous carriers of Gaucher disease mutations have an increased risk for Parkinson's disease. As mutations in the GBA gene encoding glucocerebrosidase (GBA) are known to interfere with lysosomal protein degradation, GBA heterozygotes may demonstrate reduced lysosomal SNCA degradation, leading to increased steady-state SNCA levels and promoting its aggregation. We have created mouse models to investigate the interaction between GBA mutations and synucleinopathies. We investigated the rate of SNCA degradation in cultured primary cortical neurons from mice expressing wild-type mouse SNCA, wild-type human SNCA, or mutant A53T SNCA, in a background of either wild-type Gba or heterozygosity for the L444P GBA mutation associated with Gaucher disease. We also tested the effect of this Gaucher mutation on motor and enteric nervous system function in these transgenic animals. We found that human SNCA is stable, with a half-life of 61 h, and that the A53T mutation did not significantly affect its half-life. Heterozygosity for a naturally occurring Gaucher mutation, L444P, reduced GBA activity by 40%, reduced SNCA degradation and triggered accumulation of the protein in culture. This mutation also resulted in the exacerbation of motor and gastrointestinal deficits found in the A53T mouse model of Parkinson's disease. This study demonstrates that heterozygosity for a Gaucher disease-associated mutation in Gba interferes with SNCA degradation and contributes to its accumulation, and exacerbates the phenotype in a mouse model of Parkinson's disease. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain

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

    Directory of Open Access Journals (Sweden)

    Gray Jeremy C

    2012-03-01

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

  4. Reasons of carcinogenesis indicate a big-bang inside: a hypothesis for the aberration of DNA methylation.

    Science.gov (United States)

    Roy, A; Roy Chattopadhyay, N

    2013-07-01

    Cancer involves various sets of altered gene functions which embrace all the three basic mechanisms of regulation of gene expression. However, no common mechanism is inferred till date for this versatile disease and thus no full proof remedy can be offered. Here we show that the basic mechanisms are interlinked and indicate towards one of those mechanisms as being the superior one; the methylation of cytosines in specific DNA sequences, for the initiation and maintenance of carcinogenesis. The analyses of the previous reports and the nucleotide sequences of the DNA methyltransferases strongly support the assumption that the mutation(s) in the DNA-binding site(s) of DNA-methyltransferases acts as a master regulator; though it continues the cycle from mutation to repair to methylation. We anticipate that our hypothesis will start a line of study for the proposal of a treatment regime for cancers by introducing wild type methyltransferases in the diseased cells and/or germ cells, and/or by targeting ligands to the altered binding domain(s) where a mutation in the concerned enzyme(s) is seen. Copyright © 2013. Published by Elsevier Ltd.

  5. Studies on mutation techniques in rice breeding

    International Nuclear Information System (INIS)

    Wang Cailian; Chen Qiufang; Jin Wei

    2001-01-01

    Synthetical techniques for improving rice mutation breeding efficiency were studied. The techniques consist of corresponding relationship between radiosensitivity and mutation frequency, choosing appropriate materials, combination of physical and chemical mutagens, mutagenic effects of the new mutagenic agents as proton, ions, synchronous irradiation and space mutation. These techniques and methods for inducing mutations are very valuable to increase inducing mutation efficiency and breeding level

  6. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)

    OpenAIRE

    Worby, Carolyn A.; Gentry, Matthew S.; Dixon, Jack E.

    2007-01-01

    Lafora disease (LD) is an autosomal recessive neurodegenerative disease that results in progressive myoclonus epilepsy and death. LD is caused by mutations in either the E3 ubiquitin ligase malin or the dual-specificity phosphatase laforin. A hallmark of LD is the accumulation of insoluble glycogen in the cytoplasm of cells from most tissues. Glycogen metabolism is regulated by phosphorylation of key metabolic enzymes. One regulator of this phosphorylation is protein targeting to glycogen (PT...

  7. Transcriptional activation of a MYB gene controls the tissue-specific anthocyanin accumulation in a purple cauliflower mutant

    Science.gov (United States)

    Flavonoids such as anthocyanins possess significant health benefits to humans and play important physiological roles in plants. An interesting Purple gene mutation in cauliflower confers an abnormal pattern of anthocyanin accumulation, giving intense purple color in very young leaves, curds, and see...

  8. Increased superoxide accumulation in pyruvate dehydrogenase complex deficient fibroblasts.

    Science.gov (United States)

    Glushakova, Lyudmyla G; Judge, Sharon; Cruz, Alex; Pourang, Deena; Mathews, Clayton E; Stacpoole, Peter W

    2011-11-01

    The pyruvate dehydrogenase complex (PDC) oxidizes pyruvate to acetyl CoA and is critically important in maintaining normal cellular energy homeostasis. Loss-of-function mutations in PDC give rise to congenital lactic acidosis and to progressive cellular energy failure. However, the subsequent biochemical consequences of PDC deficiency that may contribute to the clinical manifestations of the disorder are poorly understood. We postulated that altered flux through PDC would disrupt mitochondrial electron transport, resulting in oxidative stress. Compared to cells from 4 healthy subjects, primary cultures of skin fibroblasts from 9 patients with variable mutations in the gene encoding the alpha subunit (E1α) of pyruvate dehydrogenase (PDA1) demonstrated reduced growth and viability. Superoxide (O(2)(.-)) from the Qo site of complex III of the electron transport chain accumulated in these cells and was associated with decreased activity of manganese superoxide dismutase. The expression of uncoupling protein 2 was also decreased in patient cells, but there were no significant changes in the expression of cellular markers of protein or DNA oxidative damage. The expression of hypoxia transcription factor 1 alpha (HIF1α) also increased in PDC deficient fibroblasts. We conclude that PDC deficiency is associated with an increase in O(2)(.-) accumulation coupled to a decrease in mechanisms responsible for its removal. Increased HIF1α expression may contribute to the increase in glycolytic flux and lactate production in PDC deficiency and, by trans-activating pyruvate dehydrogenase kinase, may further suppress residual PDC activity through phosphorylation of the E1α subunit. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Null but not void: considerations for hypothesis testing.

    Science.gov (United States)

    Shaw, Pamela A; Proschan, Michael A

    2013-01-30

    Standard statistical theory teaches us that once the null and alternative hypotheses have been defined for a parameter, the choice of the statistical test is clear. Standard theory does not teach us how to choose the null or alternative hypothesis appropriate to the scientific question of interest. Neither does it tell us that in some cases, depending on which alternatives are realistic, we may want to define our null hypothesis differently. Problems in statistical practice are frequently not as pristinely summarized as the classic theory in our textbooks. In this article, we present examples in statistical hypothesis testing in which seemingly simple choices are in fact rich with nuance that, when given full consideration, make the choice of the right hypothesis test much less straightforward. Published 2012. This article is a US Government work and is in the public domain in the USA.

  10. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.; Magistretti, Pierre J.; Pellerin, Luc

    2015-01-01

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  11. Cross-system log file analysis for hypothesis testing

    NARCIS (Netherlands)

    Glahn, Christian

    2008-01-01

    Glahn, C. (2008). Cross-system log file analysis for hypothesis testing. Presented at Empowering Learners for Lifelong Competence Development: pedagogical, organisational and technological issues. 4th TENCompetence Open Workshop. April, 10, 2008, Madrid, Spain.

  12. Hypothesis Testing Using the Films of the Three Stooges

    Science.gov (United States)

    Gardner, Robert; Davidson, Robert

    2010-01-01

    The use of The Three Stooges' films as a source of data in an introductory statistics class is described. The Stooges' films are separated into three populations. Using these populations, students may conduct hypothesis tests with data they collect.

  13. Incidence of allergy and atopic disorders and hygiene hypothesis.

    Czech Academy of Sciences Publication Activity Database

    Bencko, V.; Šíma, Petr

    2017-01-01

    Roč. 2, 6 March (2017), č. článku 1244. ISSN 2474-1663 Institutional support: RVO:61388971 Keywords : allergy disorders * atopic disorders * hygiene hypothesis Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology

  14. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.

    2015-01-14

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer\\'s disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  15. The Double-Deficit Hypothesis in Spanish Developmental Dyslexia

    Science.gov (United States)

    Jimenez, Juan E.; Hernandez-Valle, Isabel; Rodriguez, Cristina; Guzman, Remedios; Diaz, Alicia; Ortiz, Rosario

    2008-01-01

    The double-deficit hypothesis (DDH) of developmental dyslexia was investigated in seven to twelve year old Spanish children. It was observed that the double deficit (DD) group had the greatest difficulty with reading.

  16. Mutation breeding in soybean

    International Nuclear Information System (INIS)

    Baradjanegara, A.A.

    1983-01-01

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

  17. Founder Mutations in Xeroderma Pigmentosum

    Science.gov (United States)

    Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.

    2012-01-01

    In this issue, Soufir et al. report a founder mutation in the XPC DNA repair gene in 74% of families with xeroderma pigmentosum (XP) in the Maghreb region (Algeria, Morocco, and Tunisia) of northern Africa. These patients have a high frequency of skin cancer. The presence of this founder mutation provides an opportunity for genetic counseling and early diagnosis of XP. PMID:20463673

  18. Mutations causative of familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Benn, Marianne; Watts, Gerald F; Tybjærg-Hansen, Anne

    2016-01-01

    causing mutations in 98 098 participants from the general population, the Copenhagen General Population Study. METHODS AND RESULTS: We genotyped for LDLR[W23X;W66G;W556S] and APOB[R3500Q] accounting for 38.7% of pathogenic FH mutations in Copenhagen. Clinical FH assessment excluded mutation information......-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L. CONCLUSION: Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria....... The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH...

  19. The Random-Walk Hypothesis on the Indian Stock Market

    OpenAIRE

    Ankita Mishra; Vinod Mishra; Russell Smyth

    2014-01-01

    This study tests the random walk hypothesis for the Indian stock market. Using 19 years of monthly data on six indices from the National Stock Exchange (NSE) and the Bombay Stock Exchange (BSE), this study applies three different unit root tests with two structural breaks to analyse the random walk hypothesis. We find that unit root tests that allow for two structural breaks alone are not able to reject the unit root null; however, a recently developed unit root test that simultaneously accou...

  20. The Fractal Market Hypothesis: Applications to Financial Forecasting

    OpenAIRE

    Blackledge, Jonathan

    2010-01-01

    Most financial modelling systems rely on an underlying hypothesis known as the Efficient Market Hypothesis (EMH) including the famous Black-Scholes formula for placing an option. However, the EMH has a fundamental flaw: it is based on the assumption that economic processes are normally distributed and it has long been known that this is not the case. This fundamental assumption leads to a number of shortcomings associated with using the EMH to analyse financial data which includes failure to ...

  1. Dopamine and Reward: The Anhedonia Hypothesis 30 years on

    OpenAIRE

    Wise, Roy A.

    2008-01-01

    The anhedonia hypothesis – that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards – was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat ...

  2. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins.

    Directory of Open Access Journals (Sweden)

    Adam Ameur

    2011-03-01

    Full Text Available Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mtDNA mutation load in the liver of normally- and prematurely-aging mice. Mice that are homozygous for an allele expressing a proof-reading-deficient mtDNA polymerase (mtDNA mutator mice have 10-times-higher point mutation loads than their wildtype siblings. In addition, the mtDNA mutator mice have increased levels of a truncated linear mtDNA molecule, resulting in decreased sequence coverage in the deleted region. In contrast, circular mtDNA molecules with large deletions occur at extremely low frequencies in mtDNA mutator mice and can therefore not drive the premature aging phenotype. Sequence analysis shows that the main proportion of the mutation load in heterozygous mtDNA mutator mice and their wildtype siblings is inherited from their heterozygous mothers consistent with germline transmission. We found no increase in levels of point mutations or deletions in wildtype C57Bl/6N mice with increasing age, thus questioning the causative role of these changes in aging. In addition, there was no increased frequency of transversion mutations with time in any of the studied genotypes, arguing against oxidative damage as a major cause of mtDNA mutations. Our results from studies of mice thus indicate that most somatic mtDNA mutations occur as replication errors during development and do not result from damage accumulation in adult life.

  3. Poly(ADP-ribosyl)ation as a fail-safe, transcription-independent, suicide mechanism in acutely DNA-damaged cells: a hypothesis

    International Nuclear Information System (INIS)

    Nagele, A.

    1995-01-01

    Poly(ADP-ribose) polymerase is an abundant nuclear protein that is higly conserved and consitutively expressed in all higher eukaryotic cells in investigated. Today, after about two decades of intensive research, we have a fairly comprehensive picture of its remarkable enzymatic functions and of its molecular structure. Its physiological role, however, remains controversial. The present hypothesis attempts to reconcile the different findings. By extending and earlier hypothesis, it is proposed that poly(ADP-ribosy)ation is primarily a mechanism to prevent survival of mutated, possibly apoptosis-incompetent, cells after acute DNA-damage. (orig.)

  4. MPL mutations in myeloproliferative disorders

    DEFF Research Database (Denmark)

    Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.

    2008-01-01

    Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet c......DNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F......(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin...

  5. Mutation induction by heavy ions

    Science.gov (United States)

    Kiefer, J.; Stoll, U.; Schneider, E.

    1994-10-01

    Mutation induction by heavy ions is compared in yeast and mammalian cells. Since mutants can only be recovered in survivors the influence of inactivation cross sections has to be taken into account. It is shown that both the size of the sensitive cellular site as well as track structure play an important role. Another parameter which influences the probability of mutation induction is repair: Contrary to naive assumptions primary radiation damage does not directly lead to mutations but requires modification to reconstitute the genetic machinery so that mutants can survive. The molecular structure of mutations was analyzed after exposure to deuterons by amplification with the aid of polymerase chain reaction. The results-although preliminary-demonstrate that even with densely ionizing particles a large fraction does not carry big deletions which suggests that point mutations may also be induced by heavy ions.

  6. Mutation breeding in ornamental plants

    International Nuclear Information System (INIS)

    Datta, S.K.

    1990-01-01

    Full text: Mutation induction produced a large number of new promising varieties in ornamental species. 37 new mutants of Chrysanthemum and 14 of rose have been developed by mutations and released for commercialisation. The mutations in flower colour/shape were detected as chimeras in M 1 V 1 , M 1 V 2 , M 1 V 3 generations. The mutation frequency varied with the cultivar and exposure to gamma rays. Comparative analysis of original cultivars and their respective induced mutants on cytomorphological, anatomical and biochemical characters are being carried out for better understanding of the mechanism involved in the origin and evolution of somatic flower colour/shape mutations. Cytological analysis with reference to chromosomal aberrations, chromosome number, ICV, INV and DNA content gave no differences between the original and mutant cultivars. Analysis of florets/petal pigments by TLC and spectrophotometric methods indicated both qualitative and quantitative changes. (author)

  7. Testing the null hypothesis: the forgotten legacy of Karl Popper?

    Science.gov (United States)

    Wilkinson, Mick

    2013-01-01

    Testing of the null hypothesis is a fundamental aspect of the scientific method and has its basis in the falsification theory of Karl Popper. Null hypothesis testing makes use of deductive reasoning to ensure that the truth of conclusions is irrefutable. In contrast, attempting to demonstrate the new facts on the basis of testing the experimental or research hypothesis makes use of inductive reasoning and is prone to the problem of the Uniformity of Nature assumption described by David Hume in the eighteenth century. Despite this issue and the well documented solution provided by Popper's falsification theory, the majority of publications are still written such that they suggest the research hypothesis is being tested. This is contrary to accepted scientific convention and possibly highlights a poor understanding of the application of conventional significance-based data analysis approaches. Our work should remain driven by conjecture and attempted falsification such that it is always the null hypothesis that is tested. The write up of our studies should make it clear that we are indeed testing the null hypothesis and conforming to the established and accepted philosophical conventions of the scientific method.

  8. FET Proteins TAF15 and EWS Are Selective Markers that Distinguish FTLD with FUS Pathology from Amyotrophic Lateral Sclerosis with "FUS" Mutations

    Science.gov (United States)

    Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R. A.

    2011-01-01

    Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in "FUS" as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with "FUS" mutations. The mechanisms…

  9. HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia.

    Science.gov (United States)

    Ota, Sara; Zhou, Zi-Qiang; Romero, Megan P; Yang, Guang; Hurlin, Peter J

    2016-10-01

    Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6. The reduced accumulation of FGFR3 was linked to increased FGFR3 degradation that occurred through a lysosome-dependent mechanism. Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth. Defective endochondral growth in TDII is associated with reduced proliferation and poor hypertrophic differentiation and the improved bone growth was associated with increased chondrocyte proliferation and expansion of the differentiation compartment within the growth plate. These findings further define the mechanisms that control FGFR3 accumulation and contribute to skeletal pathology caused by mutations in FGFR3. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. ACCUMULATION AND CONSUMPTION IN MICROECONOMIC SYSTEM

    Directory of Open Access Journals (Sweden)

    Serghey A. Amelkin

    2004-12-01

    Full Text Available Two main processes are common for an economic system. They are consumption and accumulation. The first one is described by utility function, either cardinal or ordinal one. The mathematical model for accumulation process can be constructed using wealth function introduced within the frame of irreversible microeconomics. Characteristics of utility and wealth functions are compared and a problem of extreme performance of resources exchange process is solved for a case when both the consumption and accumulation exist.

  11. Diabetes Insipidus in Mice with a Mutation in Aquaporin-2.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Congenital nephrogenic diabetes insipidus (NDI is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2 gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2 gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI.

  12. mtDNA mutation C1494T, haplogroup A, and hearing loss in Chinese

    International Nuclear Information System (INIS)

    Wang Chengye; Kong Qingpeng; Yao Yonggang; Zhang Yaping

    2006-01-01

    Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To test this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL

  13. Genetic etiology of hereditary colorectal cancer: new mechanisms and advanced mutation detection techniques

    NARCIS (Netherlands)

    Gazzoli, I.

    2006-01-01

    The human DNA mismatch repair (MMR) system functions to repair mispaired bases in DNA that result from DNA replication errors and thereby prevents the accumulation of mutations due to such replication errors. Hereditary nonpolyposis colorectal cancer (HNPCC), the most common form of inherited colon

  14. Minisequencing mitochondrial DNA pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Carracedo Ángel

    2008-04-01

    Full Text Available Abstract Background There are a number of well-known mutations responsible of common mitochondrial DNA (mtDNA diseases. In order to overcome technical problems related to the analysis of complete mtDNA genomes, a variety of different techniques have been proposed that allow the screening of coding region pathogenic mutations. Methods We here propose a minisequencing assay for the analysis of mtDNA mutations. In a single reaction, we interrogate a total of 25 pathogenic mutations distributed all around the whole mtDNA genome in a sample of patients suspected for mtDNA disease. Results We have detected 11 causal homoplasmic mutations in patients suspected for Leber disease, which were further confirmed by standard automatic sequencing. Mutations m.11778G>A and m.14484T>C occur at higher frequency than expected by change in the Galician (northwest Spain patients carrying haplogroup J lineages (Fisher's Exact test, P-value Conclusion We here developed a minisequencing genotyping method for the screening of the most common pathogenic mtDNA mutations which is simple, fast, and low-cost. The technique is robust and reproducible and can easily be implemented in standard clinical laboratories.

  15. Mutation breeding in malting barley

    Energy Technology Data Exchange (ETDEWEB)

    Hiraki, Makoto; Sanada, Matsuyoshi

    1984-03-01

    The released varieties of malting barley through mutation breeding is more than ten in number, including foreign varieties. In Japan four varieties has been released so far. We started mutation breeding in 1956 together with cross breeding that we employed before. Until now, Gamma 4, Amagi Nijo 1 and Fuji Nijo 2 have been produced from the direct use of induced mutations and Nirasaki Nijo 8 from the indirect use of them. Mutation breeding has been used mainly in the partial improvement of agronomic characteristics since the selection for malting quality was very complicated. As the variety bred by induced mutation is usually equivalent to the original variety in malting quality, both this new variety and the original one could be cultivated in the same area without any problem on later malt production. Particularly when one farmer cultivates barley in an extensive acreage, he can harvest at the best time according to the different maturing time of each variety. From these points of view, mutation breeding is an efficient tool in malting barley breeding. Mutagens we have used so far are X-rays, ..gamma..-rays, neutron and chemicals such as dES. From our experience in selection, the low dose of radiation and chemical mutagens are more effective in selection of point mutation than the high dose of radiation which tends to produce many abnormal but few practical mutants. (author).

  16. Ideas and perspectives: hydrothermally driven redistribution and sequestration of early Archaean biomass - the "hydrothermal pump hypothesis"

    Science.gov (United States)

    Duda, Jan-Peter; Thiel, Volker; Bauersachs, Thorsten; Mißbach, Helge; Reinhardt, Manuel; Schäfer, Nadine; Van Kranendonk, Martin J.; Reitner, Joachim

    2018-03-01

    Archaean hydrothermal chert veins commonly contain abundant organic carbon of uncertain origin (abiotic vs. biotic). In this study, we analysed kerogen contained in a hydrothermal chert vein from the ca. 3.5 Ga Dresser Formation (Pilbara Craton, Western Australia). Catalytic hydropyrolysis (HyPy) of this kerogen yielded n-alkanes up to n-C22, with a sharp decrease in abundance beyond n-C18. This distribution ( ≤ n-C18) is very similar to that observed in HyPy products of recent bacterial biomass, which was used as reference material, whereas it differs markedly from the unimodal distribution of abiotic compounds experimentally formed via Fischer-Tropsch-type synthesis. We therefore propose that the organic matter in the Archaean chert veins has a primarily microbial origin. The microbially derived organic matter accumulated in anoxic aquatic (surface and/or subsurface) environments and was then assimilated, redistributed and sequestered by the hydrothermal fluids (hydrothermal pump hypothesis).

  17. Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

    Directory of Open Access Journals (Sweden)

    Meng Yang

    2017-05-01

    are consistent with cancer progression or response to EGFR drug treatment. Conclusions This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

  18. Detection of MPL exon10 mutations in 103 Chinese patients with JAK2V617F-negative myeloproliferative neoplasms.

    Science.gov (United States)

    Chen, Xiuhua; Qi, Xiling; Tan, Yanhong; Xu, Zhifang; Xu, Aining; Zhang, Linlin; Wang, Hongwei

    2011-06-15

    JAK2V617F mutation has been reported in 90% of patients with polycythemia vera (PV) and about 50% of patients with essential thromobocythemia (ET) and primary myelofibrosis (PMF). Recently, acquired mutations in the transmembrane-juxtamembrane region of MPL (MPLW515 mutations) have been reported in approximately 5% of JAK2V617F-negative PMF and about 1% of all cases of ET. MPL is the receptor for thrombopoietin that regulates the production of platelets by bone marrow. It is likely that some mutations more closely related to ET in MPL exon10 may have been missed by current assays. We inferred that there might be other mutations in MPL exon10 for MPN patients in addition to MPLW515 mutations. To investigate its mutation types and prevalence in Chinese patients with myeloproliferative neoplasms (MPN), we performed mutation detection on MPL exon10 in 103 JAK2V617F-negative MPN patients by single strand conformation polymorphism (SSCP) and allele-specific PCR (AS-PCR) combined with sequencing. As a result, one previously unrecognized MPL mutation (12-bp in-frame insertion) was identified in one patient with ET in addition to an MPLW515K mutation identified in one PMF patient. This confirms our hypothesis that BCR/ABL negative and JAK2V617F-negative MPN patients have other mutations besides W515 mutation in MPL exon10 and mutations other than single nucleotide exchange also exist. In addition, MPL mutation was associated with Chinese MPN patients. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. HNPCC: Six new pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Epplen Joerg T

    2004-06-01

    Full Text Available Abstract Background Hereditary non-polyposis colorectal cancer (HNPCC is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR. HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6. Methods Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out. Results We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6 resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702], three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298] and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]. All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H. Conclusions HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations.

  20. Factor V Leiden Mutation and PT 20210 Mutation Test

    Science.gov (United States)

    ... Disorders Fibromyalgia Food and Waterborne Illness Fungal Infections Gout Graves Disease Guillain-Barré Syndrome Hashimoto Thyroiditis Heart ... Tested? To determine whether you have an inherited gene mutation that increases your risk of developing a ...

  1. Novel mutations in TARDBP (TDP-43 in patients with familial amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Nicola J Rutherford

    2008-09-01

    Full Text Available The TAR DNA-binding protein 43 (TDP-43 has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U, defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V were identified in the analysis of 92 familial ALS patients (3.3%, while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

  2. Mutations induced by ultraviolet light

    International Nuclear Information System (INIS)

    Pfeifer, Gerd P.; You, Young-Hyun; Besaratinia, Ahmad

    2005-01-01

    The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA

  3. Rate of ice accumulation during ice storms

    Energy Technology Data Exchange (ETDEWEB)

    Feknous, N. [SNC-Lavalin, Montreal, PQ (Canada); Chouinard, L. [McGill Univ., Montreal, PQ (Canada); Sabourin, G. [Hydro-Quebec, Montreal, PQ (Canada)

    2005-07-01

    The rate of glaze ice accumulation is the result of a complex process dependent on numerous meteorological and physical factors. The aim of this paper was to estimate the distribution rate of glaze ice accumulation on conductors in southern Quebec for use in the design of mechanical and electrical de-icing devices. The analysis was based on direct observations of ice accumulation collected on passive ice meters. The historical database of Hydro-Quebec, which contains observations at over 140 stations over period of 25 years, was used to compute accumulation rates. Data was processed so that each glaze ice event was numbered in a chronological sequence. Each event consisted of the time series of ice accumulations on each of the 8 cylinders of the ice meters, as well as on 5 of its surfaces. Observed rates were converted to represent the average ice on a 30 mm diameter conductor at 30 m above ground with a span of 300 m. Observations were corrected to account for the water content of the glaze ice as evidenced by the presence of icicles. Results indicated that despite significant spatial variations in the expected severity of ice storms as a function of location, the distribution function for rates of accumulation were fairly similar and could be assumed to be independent of location. It was concluded that the observations from several sites could be combined in order to obtain better estimates of the distribution of hourly rates of ice accumulation. However, the rates were highly variable. For de-icing strategies, it was suggested that average accumulation rates over 12 hour periods were preferable, and that analyses should be performed for other time intervals to account for the variability in ice accumulation rates over time. In addition, accumulation rates did not appear to be highly correlated with average wind speed for maximum hourly accumulation rates. 3 refs., 2 tabs., 10 figs.

  4. A large scale test of the gaming-enhancement hypothesis

    Directory of Open Access Journals (Sweden)

    Andrew K. Przybylski

    2016-11-01

    Full Text Available A growing research literature suggests that regular electronic game play and game-based training programs may confer practically significant benefits to cognitive functioning. Most evidence supporting this idea, the gaming-enhancement hypothesis, has been collected in small-scale studies of university students and older adults. This research investigated the hypothesis in a general way with a large sample of 1,847 school-aged children. Our aim was to examine the relations between young people’s gaming experiences and an objective test of reasoning performance. Using a Bayesian hypothesis testing approach, evidence for the gaming-enhancement and null hypotheses were compared. Results provided no substantive evidence supporting the idea that having preference for or regularly playing commercially available games was positively associated with reasoning ability. Evidence ranged from equivocal to very strong in support for the null hypothesis over what was predicted. The discussion focuses on the value of Bayesian hypothesis testing for investigating electronic gaming effects, the importance of open science practices, and pre-registered designs to improve the quality of future work.

  5. A large scale test of the gaming-enhancement hypothesis.

    Science.gov (United States)

    Przybylski, Andrew K; Wang, John C

    2016-01-01

    A growing research literature suggests that regular electronic game play and game-based training programs may confer practically significant benefits to cognitive functioning. Most evidence supporting this idea, the gaming-enhancement hypothesis , has been collected in small-scale studies of university students and older adults. This research investigated the hypothesis in a general way with a large sample of 1,847 school-aged children. Our aim was to examine the relations between young people's gaming experiences and an objective test of reasoning performance. Using a Bayesian hypothesis testing approach, evidence for the gaming-enhancement and null hypotheses were compared. Results provided no substantive evidence supporting the idea that having preference for or regularly playing commercially available games was positively associated with reasoning ability. Evidence ranged from equivocal to very strong in support for the null hypothesis over what was predicted. The discussion focuses on the value of Bayesian hypothesis testing for investigating electronic gaming effects, the importance of open science practices, and pre-registered designs to improve the quality of future work.

  6. Investigating the environmental Kuznets curve hypothesis in Vietnam

    International Nuclear Information System (INIS)

    Al-Mulali, Usama; Saboori, Behnaz; Ozturk, Ilhan

    2015-01-01

    This study investigates the existence of the environmental Kuznets curve (EKC) hypothesis in Vietnam during the period 1981–2011. To realize the goals of this study, a pollution model was established applying the Autoregressive Distributed Lag (ARDL) methodology. The results revealed that the pollution haven hypothesis does exist in Vietnam because capital increases pollution. In addition, imports also increase pollution which indicates that most of Vietnam's imported products are energy intensive and highly polluted. However, exports have no effect on pollution which indicates that the level of exports is not significant enough to affect pollution. Moreover, fossil fuel energy consumption increases pollution while renewable energy consumption has no significant effect in reducing pollution. Furthermore, labor force reduces pollution since most of Vietnam's labor force is in the agricultural and services sectors which are less energy intensive than the industrial sector. Based on the obtained results, the EKC hypothesis does not exist because the relationship between GDP and pollution is positive in both the short and long run. - Highlights: • The environmental Kuznets curve (EKC) hypothesis in Vietnam is investigated. • The Autoregressive Distributed Lag (ARDL) methodology was utilized. • The EKC hypothesis does not exist

  7. Social learning and evolution: the cultural intelligence hypothesis

    Science.gov (United States)

    van Schaik, Carel P.; Burkart, Judith M.

    2011-01-01

    If social learning is more efficient than independent individual exploration, animals should learn vital cultural skills exclusively, and routine skills faster, through social learning, provided they actually use social learning preferentially. Animals with opportunities for social learning indeed do so. Moreover, more frequent opportunities for social learning should boost an individual's repertoire of learned skills. This prediction is confirmed by comparisons among wild great ape populations and by social deprivation and enculturation experiments. These findings shaped the cultural intelligence hypothesis, which complements the traditional benefit hypotheses for the evolution of intelligence by specifying the conditions in which these benefits can be reaped. The evolutionary version of the hypothesis argues that species with frequent opportunities for social learning should more readily respond to selection for a greater number of learned skills. Because improved social learning also improves asocial learning, the hypothesis predicts a positive interspecific correlation between social-learning performance and individual learning ability. Variation among primates supports this prediction. The hypothesis also predicts that more heavily cultural species should be more intelligent. Preliminary tests involving birds and mammals support this prediction too. The cultural intelligence hypothesis can also account for the unusual cognitive abilities of humans, as well as our unique mechanisms of skill transfer. PMID:21357223

  8. Dopamine and reward: the anhedonia hypothesis 30 years on.

    Science.gov (United States)

    Wise, Roy A

    2008-10-01

    The anhedonia hypothesis--that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards--was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat a condition involving anhedonia (schizophrenia), attenuated in laboratory animals the positive reinforcement that we normally associate with pleasure. The hypothesis held only brief interest for psychiatrists, who pointed out that the animal studies reflected acute actions of neuroleptics whereas the treatment of schizophrenia appears to result from neuroadaptations to chronic neuroleptic administration, and that it is the positive symptoms of schizophrenia that neuroleptics alleviate, rather than the negative symptoms that include anhedonia. Perhaps for these reasons, the hypothesis has had minimal impact in the psychiatric literature. Despite its limited heuristic value for the understanding of schizophrenia, however, the anhedonia hypothesis has had major impact on biological theories of reinforcement, motivation, and addiction. Brain dopamine plays a very important role in reinforcement of response habits, conditioned preferences, and synaptic plasticity in cellular models of learning and memory. The notion that dopamine plays a dominant role in reinforcement is fundamental to the psychomotor stimulant theory of addiction, to most neuroadaptation theories of addiction, and to current theories of conditioned reinforcement and reward prediction. Properly understood, it is also fundamental to recent theories of incentive motivation.

  9. Social learning and evolution: the cultural intelligence hypothesis.

    Science.gov (United States)

    van Schaik, Carel P; Burkart, Judith M

    2011-04-12

    If social learning is more efficient than independent individual exploration, animals should learn vital cultural skills exclusively, and routine skills faster, through social learning, provided they actually use social learning preferentially. Animals with opportunities for social learning indeed do so. Moreover, more frequent opportunities for social learning should boost an individual's repertoire of learned skills. This prediction is confirmed by comparisons among wild great ape populations and by social deprivation and enculturation experiments. These findings shaped the cultural intelligence hypothesis, which complements the traditional benefit hypotheses for the evolution of intelligence by specifying the conditions in which these benefits can be reaped. The evolutionary version of the hypothesis argues that species with frequent opportunities for social learning should more readily respond to selection for a greater number of learned skills. Because improved social learning also improves asocial learning, the hypothesis predicts a positive interspecific correlation between social-learning performance and individual learning ability. Variation among primates supports this prediction. The hypothesis also predicts that more heavily cultural species should be more intelligent. Preliminary tests involving birds and mammals support this prediction too. The cultural intelligence hypothesis can also account for the unusual cognitive abilities of humans, as well as our unique mechanisms of skill transfer.

  10. Photosynthesis Activates Plasma Membrane H+-ATPase via Sugar Accumulation.

    Science.gov (United States)

    Okumura, Masaki; Inoue, Shin-Ichiro; Kuwata, Keiko; Kinoshita, Toshinori

    2016-05-01

    Plant plasma membrane H(+)-ATPase acts as a primary transporter via proton pumping and regulates diverse physiological responses by controlling secondary solute transport, pH homeostasis, and membrane potential. Phosphorylation of the penultimate threonine and the subsequent binding of 14-3-3 proteins in the carboxyl terminus of the enzyme are required for H(+)-ATPase activation. We showed previously that photosynthesis induces phosphorylation of the penultimate threonine in the nonvascular bryophyte Marchantia polymorpha However, (1) whether this response is conserved in vascular plants and (2) the process by which photosynthesis regulates H(+)-ATPase phosphorylation at the plasma membrane remain unresolved issues. Here, we report that photosynthesis induced the phosphorylation and activation of H(+)-ATPase in Arabidopsis (Arabidopsis thaliana) leaves via sugar accumulation. Light reversibly phosphorylated leaf H(+)-ATPase, and this process was inhibited by pharmacological and genetic suppression of photosynthesis. Immunohistochemical and biochemical analyses indicated that light-induced phosphorylation of H(+)-ATPase occurred autonomously in mesophyll cells. We also show that the phosphorylation status of H(+)-ATPase and photosynthetic sugar accumulation in leaves were positively correlated and that sugar treatment promoted phosphorylation. Furthermore, light-induced phosphorylation of H(+)-ATPase was strongly suppressed in a double mutant defective in ADP-glucose pyrophosphorylase and triose phosphate/phosphate translocator (adg1-1 tpt-2); these mutations strongly inhibited endogenous sugar accumulation. Overall, we show that photosynthesis activated H(+)-ATPase via sugar production in the mesophyll cells of vascular plants. Our work provides new insight into signaling from chloroplasts to the plasma membrane ion transport mechanism. © 2016 American Society of Plant Biologists. All Rights Reserved.

  11. Molecular nature of X-ray-induced mutations compared with that of spontaneous ones in human c-hprt gene integrated into mammalian chromosomal DNA

    International Nuclear Information System (INIS)

    Kimura, Hiroshi; Kato, Takesi.

    1992-01-01

    X-ray-induced mutations were analysed at molecular levels in comparison with spontaneous mutations. Altered sequences were determined tentatively of 30 independent X-ray-induced mutations in a cDNA of the human hprt gene which was integrated into mammalian chromosome as a part of a shuttle vector. Mutations consisted of base substitutions (37 %), frameshifts (27 %), deletions (27 %) and others (10 %). All these mutational events were distributed randomly over the gene without there being hot spots. The spectrum and distribution of X-ray-induced mutations resembled those of spontaneous mutations. Among base substitutions, transversions were predominant and base substitution mutations occurred more at A:T sites than at G:C sites, which is also the case in spontaneous mutations. Most of the frameshift and deletion mutations induced by X-rays, as well as those spontaneously arising, were characterized by the existence of short direct repeats of several identical bases in a row at the sites of the mutations. A slippage misalignment mechanism in replication well accounts for the generation of these classes of mutations. Judging from the data accumulated so far, it can be concluded that X-ray-induced mutations at molecular levels are similar to those spontaneously occurring. (author)

  12. 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

  13. 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.

  14. Mutation breeding in wheat

    International Nuclear Information System (INIS)

    Amer, I.M.

    2002-01-01

    The study aims to improve the productivity of wheat by using gamma ray (100 - 600 Gy) in mutation breading. Five local varieties were used and the program continued for the Sakha 69 for seven generations. Seeds irradiated with 600 Gy were not germinated in the field, while low doses (100-150 Gy) stimulated the root growth and spike length. The higher doses caused gradual decrease of growth with differences in varieties response. in the second generation, a genetic differences were noticed in most varieties using doses of 100-300 Gy, and the dispike was disappeared when 250 Gy was used. 79 plants from irradiated Sakha 69 were selected according to spike length and the number of grains and planted with the control to test the third generation. differences between the varieties were noticed and 8 mutants with high productivity were selected and evaluated in the fourth and fifth generations with the local variety. The mutants improve the productivity and in particular the mutants Nos.. (19-1), (14-3), and (30-2). The experiment showed the relation between the planting sites and the mutants in the sixth and seven generations

  15. Induced mutations in castor

    International Nuclear Information System (INIS)

    Ganesan, K.; Javad Hussain, H.S.; Vindhiyavarman, P.

    2001-01-01

    Castor (Ricinus communis L.) is an important oilseed crop in India. To create variability mutations were induced in two cultivars 'TMV5' (maturing in 130-140 days) and 'CO1' (perennial type). Gamma rays and diethyl sulphate and ethidium bromide were used for seed treatment. Ten doses, from 100 to 1000 Gy were employed. For chemical mutagenesis five concentrations of mutagenes from 10 to 50 mM were tried. No economic mutants could be isolated after treatment with the chemical mutagens. The following economic mutants were identified in the dose 300 Gy of gamma rays. Annual types from perennial CO 1 castor CO 1 is a perennial variety (8-10 years) with bold seeds (100 seed weight 90 g) and high oil content (57%). Twenty-one lines were isolated with annual types (160-180 days) with high yield potential as well as bold seeds and high oil content. These mutants, identified in M 3 generation were bred true in subsequent generations up to M 8 generation. Critical evaluation of the mutants in yield evaluation trials is in progress

  16. An experimental test of the habitat-amount hypothesis for saproxylic beetles in a forested region.

    Science.gov (United States)

    Seibold, Sebastian; Bässler, Claus; Brandl, Roland; Fahrig, Lenore; Förster, Bernhard; Heurich, Marco; Hothorn, Torsten; Scheipl, Fabian; Thorn, Simon; Müller, Jörg

    2017-06-01

    The habitat-amount hypothesis challenges traditional concepts that explain species richness within habitats, such as the habitat-patch hypothesis, where species number is a function of patch size and patch isolation. It posits that effects of patch size and patch isolation are driven by effects of sample area, and thus that the number of species at a site is basically a function of the total habitat amount surrounding this site. We tested the habitat-amount hypothesis for saproxylic beetles and their habitat of dead wood by using an experiment comprising 190 plots with manipulated patch sizes situated in a forested region with a high variation in habitat amount (i.e., density of dead trees in the surrounding landscape). Although dead wood is a spatio-temporally dynamic habitat, saproxylic insects have life cycles shorter than the time needed for habitat turnover and they closely track their resource. Patch size was manipulated by adding various amounts of downed dead wood to the plots (~800 m³ in total); dead trees in the surrounding landscape (~240 km 2 ) were identified using airborne laser scanning (light detection and ranging). Over 3 yr, 477 saproxylic species (101,416 individuals) were recorded. Considering 20-1,000 m radii around the patches, local landscapes were identified as having a radius of 40-120 m. Both patch size and habitat amount in the local landscapes independently affected species numbers without a significant interaction effect, hence refuting the island effect. Species accumulation curves relative to cumulative patch size were not consistent with either the habitat-patch hypothesis or the habitat-amount hypothesis: several small dead-wood patches held more species than a single large patch with an amount of dead wood equal to the sum of that of the small patches. Our results indicate that conservation of saproxylic beetles in forested regions should primarily focus on increasing the overall amount of dead wood without considering its

  17. Elevated HbA1c levels and the accumulation of differentiated T cells in CMV+ individuals

    NARCIS (Netherlands)

    Rector, J.L.; Thomas, G.N.; Burns, V.E.; Dowd, J.B.; Herr, R.M.; Moss, P.A.; Jarczok, M.N.; Hoffman, K.; Fischer, J.E.; Bosch, J.A.

    2015-01-01

    Aims/hypothesis: Biological ageing of the immune system, or immunosenescence, predicts poor health and increased mortality. A hallmark of immunosenescence is the accumulation of differentiated cytotoxic T cells (CD27−CD45RA+/−; or dCTLs), partially driven by infection with the cytomegalovirus (CMV).

  18. Mutations to Less-Preferred Synonymous Codons in a Highly Expressed Gene of Escherichia coli: Fitness and Epistatic Interactions.

    Directory of Open Access Journals (Sweden)

    David J Hauber

    Full Text Available Codon-tRNA coevolution to maximize protein production has been, until recently, the dominant hypothesis to explain codon-usage bias in highly expressed bacterial genes. Two predictions of this hypothesis are 1 selection is weak; and 2 similar silent replacements at different codons should have similar fitness consequence. We used an allele-replacement strategy to change five specific 3rd-codon-position (silent sites in the highly expressed Escherichia coli ribosomal protein gene rplQ from the wild type to a less-preferred alternative. We introduced the five mutations within a 10-codon region. Four of the silent sites were chosen to test the second prediction, with a CTG to CTA mutation being introduced at two closely linked leucine codons and an AAA to AAG mutation being introduced at two closely linked lysine codons. We also introduced a fifth silent mutation, a GTG to GTA mutation at a valine codon in the same genic region. We measured the fitness effect of the individual mutations by competing each single-mutant strain against the parental wild-type strain, using a disrupted form of the araA gene as a selectively neutral phenotypic marker to distinguish between strains in direct competition experiments. Three of the silent mutations had a fitness effect of |s| > 0.02, which is contradictory to the prediction that selection will be weak. The two leucine mutations had significantly different fitness effects, as did the two lysine mutations, contradictory to the prediction that similar mutations at different codons should have similar fitness effects. We also constructed a strain carrying all five silent mutations in combination. Its fitness effect was greater than that predicted from the individual fitness values, suggesting that negative synergistic epistasis acts on the combination allele.

  19. Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors

    Energy Technology Data Exchange (ETDEWEB)

    Toki, Hideaki; Minowa, Osamu; Inoue, Maki; Motegi, Hiromi; Karashima, Yuko; Ikeda, Ami [Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki (Japan); Kaneda, Hideki [Technology and Development Team for Mouse Phenotype Analysis, Riken BRC, Tsukuba, Ibaraki (Japan); Sakuraba, Yoshiyuki [Mutagenesis and Genomics Team, Riken BRC, Tsukuba, Ibaraki (Japan); Saiki, Yuriko [Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi (Japan); Wakana, Shigeharu [Technology and Development Team for Mouse Phenotype Analysis, Riken BRC, Tsukuba, Ibaraki (Japan); Suzuki, Hiroshi [Department of Biochemistry, Asahikawa Medical University, Asahikawa, Hokkaido (Japan); Gondo, Yoichi [Mutagenesis and Genomics Team, Riken BRC, Tsukuba, Ibaraki (Japan); Shiroishi, Toshihiko [Mammalian Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka (Japan); Noda, Tetsuo, E-mail: tnoda@jfcr.or.jp [Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), Tsukuba, Ibaraki (Japan); Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo (Japan)

    2016-08-05

    Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca{sup 2+}-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway. -- Highlights: •Novel mutations in murine Serca2 caused early onset or late onset of tumorigenesis. •They also caused higher or lower incidence of Darier Disease phenotype. •3D structure model suggested the former mutations led to severer defect on ATPase. •Driver gene mutations via long-range effect on Ca2+ distributions are suggested.

  20. Association of a novel point mutation in MSH2 gene with familial multiple primary cancers

    Directory of Open Access Journals (Sweden)

    Hai Hu

    2017-10-01

    Full Text Available Abstract Background Multiple primary cancers (MPC have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues. Methods We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC. Results We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients. Conclusion Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome.

  1. Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.

    Science.gov (United States)

    Vilboux, Thierry; Kayser, Michael; Introne, Wendy; Suwannarat, Pim; Bernardini, Isa; Fischer, Roxanne; O'Brien, Kevin; Kleta, Robert; Huizing, Marjan; Gahl, William A

    2009-12-01

    Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease.

  2. Human aging and somatic point mutations in mtDNA: a comparative study of generational differences (grandparents and grandchildren

    Directory of Open Access Journals (Sweden)

    Anderson Nonato do Rosário Marinho

    2011-01-01

    Full Text Available The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years and their 62 grandchildren (mean age: 15 ± 4.1 years, the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old mutations (homoplasia and heteroplasmy. It is possible that both of these situations (homoplasia and heteroplasmy were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.

  3. A comparator-hypothesis account of biased contingency detection.

    Science.gov (United States)

    Vadillo, Miguel A; Barberia, Itxaso

    2018-02-12

    Our ability to detect statistical dependencies between different events in the environment is strongly biased by the number of coincidences between them. Even when there is no true covariation between a cue and an outcome, if the marginal probability of either of them is high, people tend to perceive some degree of statistical contingency between both events. The present paper explores the ability of the Comparator Hypothesis to explain the general pattern of results observed in this literature. Our simulations show that this model can account for the biasing effects of the marginal probabilities of cues and outcomes. Furthermore, the overall fit of the Comparator Hypothesis to a sample of experimental conditions from previous studies is comparable to that of the popular Rescorla-Wagner model. These results should encourage researchers to further explore and put to the test the predictions of the Comparator Hypothesis in the domain of biased contingency detection. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. The large numbers hypothesis and a relativistic theory of gravitation

    International Nuclear Information System (INIS)

    Lau, Y.K.; Prokhovnik, S.J.

    1986-01-01

    A way to reconcile Dirac's large numbers hypothesis and Einstein's theory of gravitation was recently suggested by Lau (1985). It is characterized by the conjecture of a time-dependent cosmological term and gravitational term in Einstein's field equations. Motivated by this conjecture and the large numbers hypothesis, we formulate here a scalar-tensor theory in terms of an action principle. The cosmological term is required to be spatially dependent as well as time dependent in general. The theory developed is appled to a cosmological model compatible with the large numbers hypothesis. The time-dependent form of the cosmological term and the scalar potential are then deduced. A possible explanation of the smallness of the cosmological term is also given and the possible significance of the scalar field is speculated

  5. Universality hypothesis breakdown at one-loop order

    Science.gov (United States)

    Carvalho, P. R. S.

    2018-05-01

    We probe the universality hypothesis by analytically computing the at least two-loop corrections to the critical exponents for q -deformed O (N ) self-interacting λ ϕ4 scalar field theories through six distinct and independent field-theoretic renormalization group methods and ɛ -expansion techniques. We show that the effect of q deformation on the one-loop corrections to the q -deformed critical exponents is null, so the universality hypothesis is broken down at this loop order. Such an effect emerges only at the two-loop and higher levels, and the validity of the universality hypothesis is restored. The q -deformed critical exponents obtained through the six methods are the same and, furthermore, reduce to their nondeformed values in the appropriated limit.

  6. Unicorns do exist: a tutorial on "proving" the null hypothesis.

    Science.gov (United States)

    Streiner, David L

    2003-12-01

    Introductory statistics classes teach us that we can never prove the null hypothesis; all we can do is reject or fail to reject it. However, there are times when it is necessary to try to prove the nonexistence of a difference between groups. This most often happens within the context of comparing a new treatment against an established one and showing that the new intervention is not inferior to the standard. This article first outlines the logic of "noninferiority" testing by differentiating between the null hypothesis (that which we are trying to nullify) and the "nill" hypothesis (there is no difference), reversing the role of the null and alternate hypotheses, and defining an interval within which groups are said to be equivalent. We then work through an example and show how to calculate sample sizes for noninferiority studies.

  7. Almost-Quantum Correlations Violate the No-Restriction Hypothesis.

    Science.gov (United States)

    Sainz, Ana Belén; Guryanova, Yelena; Acín, Antonio; Navascués, Miguel

    2018-05-18

    To identify which principles characterize quantum correlations, it is essential to understand in which sense this set of correlations differs from that of almost-quantum correlations. We solve this problem by invoking the so-called no-restriction hypothesis, an explicit and natural axiom in many reconstructions of quantum theory stating that the set of possible measurements is the dual of the set of states. We prove that, contrary to quantum correlations, no generalized probabilistic theory satisfying the no-restriction hypothesis is able to reproduce the set of almost-quantum correlations. Therefore, any theory whose correlations are exactly, or very close to, the almost-quantum correlations necessarily requires a rule limiting the possible measurements. Our results suggest that the no-restriction hypothesis may play a fundamental role in singling out the set of quantum correlations among other nonsignaling ones.

  8. Motor synergies and the equilibrium-point hypothesis.

    Science.gov (United States)

    Latash, Mark L

    2010-07-01

    The article offers a way to unite three recent developments in the field of motor control and coordination: (1) The notion of synergies is introduced based on the principle of motor abundance; (2) The uncontrolled manifold hypothesis is described as offering a computational framework to identify and quantify synergies; and (3) The equilibrium-point hypothesis is described for a single muscle, single joint, and multijoint systems. Merging these concepts into a single coherent scheme requires focusing on control variables rather than performance variables. The principle of minimal final action is formulated as the guiding principle within the referent configuration hypothesis. Motor actions are associated with setting two types of variables by a controller, those that ultimately define average performance patterns and those that define associated synergies. Predictions of the suggested scheme are reviewed, such as the phenomenon of anticipatory synergy adjustments, quick actions without changes in synergies, atypical synergies, and changes in synergies with practice. A few models are briefly reviewed.

  9. On Using Taylor's Hypothesis for Three-Dimensional Mixing Layers

    Science.gov (United States)

    LeBoeuf, Richard L.; Mehta, Rabindra D.

    1995-01-01

    In the present study, errors in using Taylor's hypothesis to transform measurements obtained in a temporal (or phase) frame onto a spatial one were evaluated. For the first time, phase-averaged ('real') spanwise and streamwise vorticity data measured on a three-dimensional grid were compared directly to those obtained using Taylor's hypothesis. The results show that even the qualitative features of the spanwise and streamwise vorticity distributions given by the two techniques can be very different. This is particularly true in the region of the spanwise roller pairing. The phase-averaged spanwise and streamwise peak vorticity levels given by Taylor's hypothesis are typically lower (by up to 40%) compared to the real measurements.

  10. The possible role of meditation in myofascial pain syndrome: A new hypothesis

    Directory of Open Access Journals (Sweden)

    Prashanth Panta

    2017-01-01

    Full Text Available Background of Hypothesis: Myofascial pain syndrome (MPS is the most common musculoskeletal pain disorder of the head and neck area. In the past, several theories were put forth to explain its origin and nature, but none proved complete. Myofascial pain responds to changing psychological states and stress, anxiety, lack of sleep, anger, depression and chronic pain are direct contributional factors. Myofascial pain syndrome may be considered as a psychosomatic disorder. There are numerous accepted palliative approaches, but of all, relaxation techniques stand out and initiate healing at the base level. In this article, the connection between mental factors, MPS and meditation are highlighted. Recent literature has shed light on the fundamental role of free radicals in the emergence of myofascial pain. The accumulating free radicals disrupt mitochondrial integrity and function, leading to sustenance and progression of MPS. Meditation on the other hand was shown to reduce free radical load and can result in clinical improvement. 'Mindfulness' is the working principle behind the effect of all meditations, and I emphasize that it can serve as a potential tool to reverse the neuro-architectural, neurobiological and cellular changes that occur in MPS. Conclusions: The findings described in this paper were drawn from studies on myofascial pain, fibromyalgia, similar chronic pain models and most importantly from self experience (experimentation. Till date, no hypothesis is available connecting MPS and meditation. Mechanisms linking MPS and meditation were identified, and this paper can ignite novel research in this direction.

  11. A test of the cerebellar hypothesis of dyslexia in adequate and inadequate responders to reading intervention.

    Science.gov (United States)

    Barth, Amy E; Denton, Carolyn A; Stuebing, Karla K; Fletcher, Jack M; Cirino, Paul T; Francis, David J; Vaughn, Sharon

    2010-05-01

    The cerebellar hypothesis of dyslexia posits that cerebellar deficits are associated with reading disabilities and may explain why some individuals with reading disabilities fail to respond to reading interventions. We tested these hypotheses in a sample of children who participated in a grade 1 reading intervention study (n = 174) and a group of typically achieving children (n = 62). At posttest, children were classified as adequately responding to the intervention (n = 82), inadequately responding with decoding and fluency deficits (n = 36), or inadequately responding with only fluency deficits (n = 56). Based on the Bead Threading and Postural Stability subtests from the Dyslexia Screening Test-Junior, we found little evidence that assessments of cerebellar functions were associated with academic performance or responder status. In addition, we did not find evidence supporting the hypothesis that cerebellar deficits are more prominent for poor readers with "specific" reading disabilities (i.e., with discrepancies relative to IQ) than for poor readers with reading scores consistent with IQ. In contrast, measures of phonological awareness, rapid naming, and vocabulary were strongly associated with responder status and academic outcomes. These results add to accumulating evidence that fails to associate cerebellar functions with reading difficulties.

  12. Damage accumulation of bovine bone under variable amplitude loads

    Directory of Open Access Journals (Sweden)

    Abbey M. Campbell

    2016-12-01

    Full Text Available Stress fractures, a painful injury, are caused by excessive fatigue in bone. This study on damage accumulation in bone sought to determine if the Palmgren-Miner rule (PMR, a well-known linear damage accumulation hypothesis, is predictive of fatigue failure in bone. An electromagnetic shaker apparatus was constructed to conduct cyclic and variable amplitude tests on bovine bone specimens. Three distinct damage regimes were observed following fracture. Fractures due to a low cyclic amplitude loading appeared ductile (4000 μϵ, brittle due to high cyclic amplitude loading (>9000 μϵ, and a combination of ductile and brittle from mid-range cyclic amplitude loading (6500 –6750 μϵ. Brittle and ductile fracture mechanisms were isolated and mixed, in a controlled way, into variable amplitude loading tests. PMR predictions of cycles to failure consistently over-predicted fatigue life when mixing isolated fracture mechanisms. However, PMR was not proven ineffective when used with a single damage mechanism. Keywords: Bone fatigue, Bone fracture, Health system monitoring, Failure prediction

  13. Iron deficiency stimulates anthocyanin accumulation in grapevine apical leaves.

    Science.gov (United States)

    Caramanico, Leila; Rustioni, Laura; De Lorenzis, Gabriella

    2017-10-01

    Iron chlorosis is a diffuse disorder affecting Mediterranean vineyards. Beside the commonly described symptom of chlorophyll decrease, an apex reddening was recently observed. Secondary metabolites, such as anthocyanins, are often synthetized to cope with stresses in plants. The present work aimed to evaluate grapevine responses to iron deficiency, in terms of anthocyanin metabolism (reflectance spectrum, total anthocyanin content, HPLC profile and gene expression) in apical leaves of Cabernet sauvignon and Sangiovese grown in hydroponic conditions. Iron supply interruption produced after one month an increasing of anthocyanin content associated to a more stable profile in both cultivars. In Cabernet sauvignon, the higher red pigment accumulation was associated to a lower intensity of chlorotic symptoms, while in Sangiovese, despite the activation of the metabolism, the lower anthocyanin accumulation was associated to a stronger decrease in chlorophyll concentration. Gene expression data showed a significant increase of anthocyanin biosynthesis. The effects on the expression of structural and transcription factor genes of phenylpropanoid pathway were cultivar dependent. F3H, F3'H, F3'5'H and LDOX genes, in Cabernet sauvignon, and AOMT1 and AOMT genes, in Sangiovese, were positively affected by the treatment in response to iron deficiency. All data support the hypothesis of an anthocyanin biosynthesis stimulation rather than a decreased degradation of them due to iron chlorosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. The positron accumulator ring for the APS

    International Nuclear Information System (INIS)

    Crosbie, E.A.

    1989-01-01

    The Positron Accumulator Ring (PAR) is designed to accumulate and damp positrons from the 450-MeV linac during the 0.5-s cycle time of the injector synchrotron for the APS 7-GeV storage ring. During 0.4 s of each synchrotron cycle, up to 24 linac pulses are injected into the horizontal phase space of the PAR at a 60-Hz rate. Each injected pulse occupies about 1.3 of the circumference of the accumulator ring. After 0.1 s for longitudinal damping, the single accumulated bunch is transferred to one of the 353-MHz buckets of the injector synchrotron RF system. The bunch is accelerated to 7 GeV and transferred to the storage ring, while the PAR accumulates the next bunch of positrons. 2 refs., 3 figs., 2 tabs

  15. The positron accumulator ring for the APS

    International Nuclear Information System (INIS)

    Crosbie, E.A.

    1989-01-01

    The Positron Accumulator Ring (PAR) is designed to accumulate and damp positrons from the 450-MeV linac during the 0.5-s cycle time of the injector synchrotron for the APS 7-GeV storage ring. During 0.4 s of each synchrotron cycle, up to 24 linac pulses are injected into the horizontal phase space of the PAR at a 60-Hz rate. Each injected pulse occupies about 1/3 of the circumference of the accumulator ring. After 0.1 s for longitudinal damping, the single accumulated bunch is transferred to one of the 353-MHz buckets of the injector synchrotron RF system. The bunch is accelerated to 7 GeV and transferred to the storage ring, while the PAR accumulates the next bunch of positrons. 2 refs., 3 figs., 2 tabs

  16. The frequentist implications of optional stopping on Bayesian hypothesis tests.

    Science.gov (United States)

    Sanborn, Adam N; Hills, Thomas T

    2014-04-01

    Null hypothesis significance testing (NHST) is the most commonly used statistical methodology in psychology. The probability of achieving a value as extreme or more extreme than the statistic obtained from the data is evaluated, and if it is low enough, the null hypothesis is rejected. However, because common experimental practice often clashes with the assumptions underlying NHST, these calculated probabilities are often incorrect. Most commonly, experimenters use tests that assume that sample sizes are fixed in advance of data collection but then use the data to determine when to stop; in the limit, experimenters can use data monitoring to guarantee that the null hypothesis will be rejected. Bayesian hypothesis testing (BHT) provides a solution to these ills because the stopping rule used is irrelevant to the calculation of a Bayes factor. In addition, there are strong mathematical guarantees on the frequentist properties of BHT that are comforting for researchers concerned that stopping rules could influence the Bayes factors produced. Here, we show that these guaranteed bounds have limited scope and often do not apply in psychological research. Specifically, we quantitatively demonstrate the impact of optional stopping on the resulting Bayes factors in two common situations: (1) when the truth is a combination of the hypotheses, such as in a heterogeneous population, and (2) when a hypothesis is composite-taking multiple parameter values-such as the alternative hypothesis in a t-test. We found that, for these situations, while the Bayesian interpretation remains correct regardless of the stopping rule used, the choice of stopping rule can, in some situations, greatly increase the chance of experimenters finding evidence in the direction they desire. We suggest ways to control these frequentist implications of stopping rules on BHT.

  17. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.

    Science.gov (United States)

    Estep, Anne L; Tidyman, William E; Teitell, Michael A; Cotter, Philip D; Rauen, Katherine A

    2006-01-01

    Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well-characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G --> A transition in codon 12. Less frequent mutations included 35G --> C (codon 12) and 37G --> T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G --> A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G --> C had cardiac arrhythmias whereas one patient with a 37G --> T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G --> A mutation. Loss of the wild-type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio-facio-cutaneous (CFC) syndromes, the HRAS coding region was sequenced in a well-characterized CFC cohort

  18. Mutation breeding newsletter. No. 22

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1983-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  19. Mutation breeding newsletter. No. 34

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1989-07-01

    This issue of the Newsletter presents abstracts and short communications of research results on radiation and chemical induced mutation breeding projects. Positive traits such as disease resistance and increased productivity are highlighted.

  20. Mutation breeding newsletter. No. 29

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1987-02-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  1. Mutation breeding newsletter. No. 15

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1980-02-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  2. Mutation breeding newsletter. No. 5

    International Nuclear Information System (INIS)

    1975-02-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  3. Mutation breeding newsletter. No. 15

    International Nuclear Information System (INIS)

    1980-02-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  4. Mutation breeding newsletter. No. 14

    International Nuclear Information System (INIS)

    1979-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  5. Mutation breeding newsletter. No. 16

    International Nuclear Information System (INIS)

    1980-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  6. Mutation breeding newsletter. No. 12

    International Nuclear Information System (INIS)

    1978-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  7. Mutation breeding newsletter. No. 28

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1986-09-01

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  8. Mutation breeding newsletter. No. 29

    International Nuclear Information System (INIS)

    1987-02-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  9. Mutation breeding newsletter. No. 9

    International Nuclear Information System (INIS)

    1977-01-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  10. Mutation breeding newsletter. No. 7

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1976-01-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  11. Mutation Breeding Newsletter. No. 37

    International Nuclear Information System (INIS)

    1991-01-01

    This newsletter contains a brief account of FAO/IAEA meetings held in 1990 on plant breeding involving the use of induced mutations. It also features a list of commercially available plant cultivars produced by such techniques. Refs and tabs

  12. Mutation breeding newsletter. No. 4

    International Nuclear Information System (INIS)

    1974-08-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  13. Mutation breeding newsletter. No. 18

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1981-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  14. Mutation breeding newsletter. No. 9

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1977-01-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  15. Mutation breeding newsletter. No. 34

    International Nuclear Information System (INIS)

    1989-07-01

    This issue of the Newsletter presents abstracts and short communications of research results on radiation and chemical induced mutation breeding projects. Positive traits such as disease resistance and increased productivity are highlighted

  16. Mutation breeding newsletter. No. 24

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1984-07-01

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  17. Mutation breeding newsletter. No. 32

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1988-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  18. Mutation breeding newsletter. No. 36

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1990-07-01

    This issue of the Newsletter presents abstracts and short communications of research results on radiation and chemical induced mutation breeding projects. Positive traits such as disease resistance and increased productivity are highlighted.

  19. Mutation breeding newsletter. No. 3

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1974-01-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  20. Mutation breeding newsletter. No. 3

    International Nuclear Information System (INIS)

    1974-01-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  1. Mutation breeding newsletter. No. 11

    International Nuclear Information System (INIS)

    1978-02-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  2. Mutation breeding newsletter. No. 6

    International Nuclear Information System (INIS)

    1975-08-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  3. Mutation breeding newsletter. No. 1

    International Nuclear Information System (INIS)

    1972-05-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  4. Mutation breeding newsletter. No. 31

    International Nuclear Information System (INIS)

    1988-03-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  5. Mutation breeding newsletter. No. 44

    International Nuclear Information System (INIS)

    1999-04-01

    This issue of the Newsletter presents research reports on the role of radiation induced mutation and chemical mutagens in improving productivity, disease resistance; cold and salinity tolerance of various crops and ornamental plants

  6. Mutation breeding newsletter. No. 1

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1972-05-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  7. Mutation breeding newsletter. No. 25

    International Nuclear Information System (INIS)

    1985-01-01

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  8. Mutation breeding newsletter. No. 32

    International Nuclear Information System (INIS)

    1988-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  9. Mutation breeding newsletter. No. 5

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1975-02-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  10. Mutation breeding newsletter. No. 20

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1982-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  11. Mutation breeding newsletter. No. 28

    International Nuclear Information System (INIS)

    1986-09-01

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  12. Mutation breeding newsletter. No. 17

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1981-03-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  13. Mutation breeding newsletter. No. 16

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1980-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  14. Mutation breeding newsletter. No. 8

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1976-09-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  15. Mutation breeding newsletter. No. 4

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1974-08-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  16. Mutation breeding newsletter. No. 12

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1978-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  17. Mutation breeding newsletter. No. 6

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1975-08-01

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  18. Mutation breeding newsletter. No. 10

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1977-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  19. Mutation breeding newsletter. No. 14

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1979-07-01

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants.

  20. Mutation breeding newsletter. No. 36

    International Nuclear Information System (INIS)

    1990-07-01

    This issue of the Newsletter presents abstracts and short communications of research results on radiation and chemical induced mutation breeding projects. Positive traits such as disease resistance and increased productivity are highlighted