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Sample records for allele contrast model

  1. A limit to the divergent allele advantage model supported by variable pathogen recognition across HLA-DRB1 allele lineages.

    PubMed

    Lau, Q; Yasukochi, Y; Satta, Y

    2015-11-01

    Genetic diversity in human leukocyte antigen (HLA) molecules is thought to have arisen from the co-evolution between host and pathogen and maintained by balancing selection. Heterozygote advantage is a common proposed scenario for maintaining high levels of diversity in HLA genes, and extending from this, the divergent allele advantage (DAA) model suggests that individuals with more divergent HLA alleles bind and recognize a wider array of antigens. While the DAA model seems biologically suitable for driving HLA diversity, there is likely an upper threshold to the amount of sequence divergence. We used peptide-binding and pathogen-recognition capacity of DRB1 alleles as a model to further explore the DAA model; within the DRB1 locus, we examined binding predictions based on two distinct phylogenetic groups (denoted group A and B) previously identified based on non-peptide-binding region (PBR) nucleotide sequences. Predictions in this study support that group A allele and group B allele lineages have contrasting binding/recognition capacity, with only the latter supporting the DAA model. Furthermore, computer simulations revealed an inconsistency in the DAA model alone with observed extent of polymorphisms, supporting that the DAA model could only work effectively in combination with other mechanisms. Overall, we support that the mechanisms driving HLA diversity are non-exclusive. By investigating the relationships among HLA alleles, and pathogens recognized, we can provide further insights into the mechanisms on how humans have adapted to infectious diseases over time.

  2. Allele frequencies at microsatellite loci: The stepwise mutation model revisited

    SciTech Connect

    Valdes, A.M.; Slatkin, M. ); Freimer, N.B. )

    1993-03-01

    The authors summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. They show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. It is also shown that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size. 39 refs., 6 figs., 4 tabs.

  3. Allelic exclusion of immunoglobulin genes: models and mechanisms.

    PubMed

    Vettermann, Christian; Schlissel, Mark S

    2010-09-01

    The allelic exclusion of immunoglobulin (Ig) genes is one of the most evolutionarily conserved features of the adaptive immune system and underlies the monospecificity of B cells. While much has been learned about how Ig allelic exclusion is established during B-cell development, the relevance of monospecificity to B-cell function remains enigmatic. Here, we review the theoretical models that have been proposed to explain the establishment of Ig allelic exclusion and focus on the molecular mechanisms utilized by developing B cells to ensure the monoallelic expression of Ig kappa and Ig lambda light chain genes. We also discuss the physiological consequences of Ig allelic exclusion and speculate on the importance of monospecificity of B cells for immune recognition.

  4. Contrasting dynamics of a mutator allele in asexual populations of differing size.

    PubMed

    Raynes, Yevgeniy; Gazzara, Matthew R; Sniegowski, Paul D

    2012-07-01

    Mutators have been shown to hitchhike in asexual populations when the anticipated beneficial mutation supply rate of the mutator subpopulation, NU(b) (for subpopulation of size N and beneficial mutation rate U(b)) exceeds that of the wild-type subpopulation. Here, we examine the effect of total population size on mutator dynamics in asexual experimental populations of Saccharomyces cerevisiae. Although mutators quickly hitchhike to fixation in smaller populations, mutator fixation requires more and more time as population size increases; this observed delay in mutator hitchhiking is consistent with the expected effect of clonal interference. Interestingly, despite their higher beneficial mutation supply rate, mutators are supplanted by the wild type in very large populations. We postulate that this striking reversal in mutator dynamics is caused by an interaction between clonal interference, the fitness cost of the mutator allele, and infrequent large-effect beneficial mutations in our experimental populations. Our work thus identifies a potential set of circumstances under which mutator hitchhiking can be inhibited in natural asexual populations, despite recent theoretical predictions that such populations should have a net tendency to evolve ever-higher genomic mutation rates.

  5. A genetic model of melanoma tumorigenesis based on allelic losses

    SciTech Connect

    Hayward, N.K.; Palmer, J.M.; Walters, M.K.

    1994-09-01

    Previous karyotypic studies have indicated a possible series of non-random chromosomal events involved in the progression of melanoma. We sought to define a model of melanocyte tumorigenesis by studying allelic deletions of polymorphic simple tandem repeat markers mapping to chromosome 1, 6q, 7, 9p, 10, 11, 17, and 21 in thirty matched pairs of melanoma and constitutional DNAs. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%) and with the exception of one case, no sample has loss of markers on another chromosome without concomitant loss of markers on 9p and/or 10q. Losses on 6q were also a frequent (32%) event that sometimes occurred in primary melanomas, whereas losses of loci on distal 1p (26%) or 11q (26%) occurred only in metastic melanomas. A background rate (0-17%) of allele loss was seen on chromosomes 7, 17, and 21. Homozygous deletions in a panel of 31 melanoma cell lines were only detected for markers on 9p (4 cases). These data strongly support the previous model of melanoma tumorigenesis based primarily on karyotypic findings in melanocytic lesions. However, we have been able to further augment the model by delimiting the regions of loss on 10q to a region distal to D10S254, and on 1p, to between D1S243 and D1S160.

  6. Allelic Richness following Population Founding Events – A Stochastic Modeling Framework Incorporating Gene Flow and Genetic Drift

    PubMed Central

    Greenbaum, Gili; Templeton, Alan R.; Zarmi, Yair; Bar-David, Shirli

    2014-01-01

    Allelic richness (number of alleles) is a measure of genetic diversity indicative of a population's long-term potential for adaptability and persistence. It is used less commonly than heterozygosity as a genetic diversity measure, partially because it is more mathematically difficult to take into account the stochastic process of genetic drift for allelic richness. This paper presents a stochastic model for the allelic richness of a newly founded population experiencing genetic drift and gene flow. The model follows the dynamics of alleles lost during the founder event and simulates the effect of gene flow on maintenance and recovery of allelic richness. The probability of an allele's presence in the population was identified as the relevant statistical property for a meaningful interpretation of allelic richness. A method is discussed that combines the probability of allele presence with a population's allele frequency spectrum to provide predictions for allele recovery. The model's analysis provides insights into the dynamics of allelic richness following a founder event, taking into account gene flow and the allele frequency spectrum. Furthermore, the model indicates that the “One Migrant per Generation” rule, a commonly used conservation guideline related to heterozygosity, may be inadequate for addressing preservation of diversity at the allelic level. This highlights the importance of distinguishing between heterozygosity and allelic richness as measures of genetic diversity, since focusing merely on the preservation of heterozygosity might not be enough to adequately preserve allelic richness, which is crucial for species persistence and evolution. PMID:25526062

  7. Allelic richness following population founding events--a stochastic modeling framework incorporating gene flow and genetic drift.

    PubMed

    Greenbaum, Gili; Templeton, Alan R; Zarmi, Yair; Bar-David, Shirli

    2014-01-01

    Allelic richness (number of alleles) is a measure of genetic diversity indicative of a population's long-term potential for adaptability and persistence. It is used less commonly than heterozygosity as a genetic diversity measure, partially because it is more mathematically difficult to take into account the stochastic process of genetic drift for allelic richness. This paper presents a stochastic model for the allelic richness of a newly founded population experiencing genetic drift and gene flow. The model follows the dynamics of alleles lost during the founder event and simulates the effect of gene flow on maintenance and recovery of allelic richness. The probability of an allele's presence in the population was identified as the relevant statistical property for a meaningful interpretation of allelic richness. A method is discussed that combines the probability of allele presence with a population's allele frequency spectrum to provide predictions for allele recovery. The model's analysis provides insights into the dynamics of allelic richness following a founder event, taking into account gene flow and the allele frequency spectrum. Furthermore, the model indicates that the "One Migrant per Generation" rule, a commonly used conservation guideline related to heterozygosity, may be inadequate for addressing preservation of diversity at the allelic level. This highlights the importance of distinguishing between heterozygosity and allelic richness as measures of genetic diversity, since focusing merely on the preservation of heterozygosity might not be enough to adequately preserve allelic richness, which is crucial for species persistence and evolution.

  8. Models of Frequency-Dependent Selection with Mutation from Parental Alleles

    PubMed Central

    Trotter, Meredith V.; Spencer, Hamish G.

    2013-01-01

    Frequency-dependent selection (FDS) remains a common heuristic explanation for the maintenance of genetic variation in natural populations. The pairwise-interaction model (PIM) is a well-studied general model of frequency-dependent selection, which assumes that a genotype’s fitness is a function of within-population intergenotypic interactions. Previous theoretical work indicated that this type of model is able to sustain large numbers of alleles at a single locus when it incorporates recurrent mutation. These studies, however, have ignored the impact of the distribution of fitness effects of new mutations on the dynamics and end results of polymorphism construction. We suggest that a natural way to model mutation would be to assume mutant fitness is related to the fitness of the parental allele, i.e., the existing allele from which the mutant arose. Here we examine the numbers and distributions of fitnesses and alleles produced by construction under the PIM with mutation from parental alleles and the impacts on such measures due to different methods of generating mutant fitnesses. We find that, in comparison with previous results, generating mutants from existing alleles lowers the average number of alleles likely to be observed in a system subject to FDS, but produces polymorphisms that are highly stable and have realistic allele-frequency distributions. PMID:23852384

  9. A computer simulation study of VNTR population genetics: Constrained recombination rules out the infinite alleles model

    SciTech Connect

    Harding, R.M.; Martinson, J.J.; Flint, J.; Clegg, J.B.; Boyce, A.J. )

    1993-11-01

    Extensive allelic diversity in variable numbers of tandem repeats (VNTRs) has been discovered in the human genome. For population genetic studies of VNTRs, such as forensic applications, it is important to know whether a neutral mutation-drift balance of VNTR polymorphism can be represented by the infinite alleles model. The assumption of the infinite alleles model that each new mutant is unique is very likely to be violated by unequal sister chromatid exchange (USCE), the primary process believed to generate VNTR mutants. The authors show that increasing both mutation rates and misalignment constraint for intrachromosomal recombination in a computer simulation model reduces simulated VNTR diversity below the expectations of the infinite alleles model. Maximal constraint, represented as slippage of single repeats, reduces simulated VNTR diversity to levels expected from the stepwise mutation model. Although misalignment rule is the more important variable, mutation rate also has an effect. At moderate rates of USCE, simulated VNTR diversity fluctuates around infinite alleles expectation. However, if rates of USCE are high, as for hypervariable VNTRs, simulated VNTR diversity is consistently lower than predicted by the infinite alleles model. This has been observed for many VNTRs and accounted for by technical problems in distinguishing alleles of neighboring size classes. The authors use sampling theory to confirm the intrinsically poor fit to the infinite model of both simulated VNTR diversity and observed VNTR polymorphisms sampled from two Papua New Guinean populations. 25 refs., 20 figs., 4 tabs.

  10. Contrast Gain Control Model Fits Masking Data

    NASA Technical Reports Server (NTRS)

    Watson, Andrew B.; Solomon, Joshua A.; Null, Cynthia H. (Technical Monitor)

    1994-01-01

    We studied the fit of a contrast gain control model to data of Foley (JOSA 1994), consisting of thresholds for a Gabor patch masked by gratings of various orientations, or by compounds of two orientations. Our general model includes models of Foley and Teo & Heeger (IEEE 1994). Our specific model used a bank of Gabor filters with octave bandwidths at 8 orientations. Excitatory and inhibitory nonlinearities were power functions with exponents of 2.4 and 2. Inhibitory pooling was broad in orientation, but narrow in spatial frequency and space. Minkowski pooling used an exponent of 4. All of the data for observer KMF were well fit by the model. We have developed a contrast gain control model that fits masking data. Unlike Foley's, our model accepts images as inputs. Unlike Teo & Heeger's, our model did not require multiple channels for different dynamic ranges.

  11. Structural modeling of contrast sensitivity in adulthood

    NASA Astrophysics Data System (ADS)

    Scialfa, Charles T.; Kline, Donald W.; Wood, Philip K.

    2002-01-01

    Structural equation modeling was used to assess the utility of the sensorineural model of contrast sensitivity proposed by Sekuler et al. [Vision Res. 24, 689 (1984)] to account for spatial vision in adulthood. In Study 1, visual acuity and contrast sensitivity (1.5-18 c/deg) were measured in 84 people between the ages of 19 and 81 yr. No three-filter model fitted the data well. Although a two-filter model was associated with good fit indices, parameter estimates for both filters were inconsistent with physiological and behavioral data. In Study 2, acuity and contrast sensitivity (1.5-18 c/deg) were assessed in 95 observers between the ages of 23 and 73 yr. All measures were gathered once per month over a three-month period. The Sekuler et al. three-filter model did not fit the data from any time of measure, but a two-filter, bandpass model provided a consistent and excellent fit for all three waves. The model suggests that age-related change in the neural mechanisms underlying contrast sensitivity is minimal once acuity is controlled. Discrepancies between this conclusion and that reported by Sekuler et al. may be related to test type, psychophysical method, reliability, and sample selection.

  12. Fixation probability and the crossing time in the Wright-Fisher multiple alleles model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2009-08-01

    The fixation probability and crossing time in the Wright-Fisher multiple alleles model, which describes a finite haploid population, were calculated by switching on an asymmetric sharply-peaked landscape with a positive asymmetric parameter, r, such that the reversal allele of the optimal allele has higher fitness than the optimal allele. The fixation probability, which was evaluated as the ratio of the first arrival time at the reversal allele to the origination time, was double the selective advantage of the reversal allele compared with the optimal allele in the strong selection region, where the fitness parameter, k, is much larger than the critical fitness parameter, kc. The crossing time in a finite population for r>0 and kallele in the first generation should be greater than one individual in an asymmetric sharply-peaked landscape. It was also found that the crossing time in a finite population for r>0 and k≫kc scaled as a power law in the fitness parameter with a similar scaling exponent as the crossing time in an infinite population for r=0, and that the critical fitness parameter decreased with increasing sequence length with a fixed population size.

  13. Phase contrast radiography: Image modeling and optimization

    NASA Astrophysics Data System (ADS)

    Arhatari, Benedicta D.; Mancuso, Adrian P.; Peele, Andrew G.; Nugent, Keith A.

    2004-12-01

    We consider image formation for the phase-contrast radiography technique where the radiation source is extended and spatially incoherent. A model is developed for this imaging process which allows us to define an objective filtering criterion that can be applied to the recovery of quantitative phase images from data obtained at different propagation distances. We test our image model with experimental x-ray data. We then apply our filter to experimental neutron phase radiography data and demonstrate improved image quality.

  14. VNTR allele frequency distributions under the stepwise mutation model: A computer simulation approach

    SciTech Connect

    Shriver, M.D.; Jin, L.; Chakraborty, R.; Boerwinkle, E. )

    1993-07-01

    Variable numbers of tandem repeats (VNTRs) are a class of highly informative and widely dispersed genetic markers. Despite their wide application in biological science, little is known about their mutational mechanisms or population dynamics. The objective of this work was to investigate four summary measures of VNTR allele frequency distributions: number of alleles, number of modes, range in allele size, and heterozygosity, using computer simulations of the one-step stepwise mutation model (SMM). The authors estimated these measures and their probability distributions for a wide range of mutation rates and compared the simulation results with predictions from analytical formulations of the one-step SMM. The average heterozygosity from the simulations agreed with the analytical expectation under the SMM. The average number of alleles, however, was larger in the simulations than the analytical expectation of the SMM. The authors then compared simulation expectations with actual data reported in the literature. They used the sample size and observed heterozygosity to determine the expected value, 5th and 95th percentiles for the other three summary measures, allelic size range, number of modes and number of alleles. The loci analyzed were classified into three groups based on the size of the repeat unit: microsatellites (1-2 base pair (bp) repeat unit), short tandem repeats [(STR) 3-5 bp repeat unit], and minisatellites (15-70 bp repeat unit). In general, STR loci were most similar to the simulation results under the SMM for the three summary measures (number of alleles, number of modes and range in allele size), followed by the microsatellite loci and then by the minisatellite loci, which showed deviations in the direction of the infinite allele model (IAM). Based on these differences, it is hypothesized that these three classes of loci are subject to different mutational forces.

  15. PKD1 Mono-Allelic Knockout Is Sufficient to Trigger Renal Cystogenesis in a Mini-Pig Model

    PubMed Central

    He, Jin; Li, Qiuyan; Fang, Suyun; Guo, Ying; Liu, Tongxin; Ye, Jianhua; Yu, Zhengquan; Zhang, Ran; Zhao, Yaofeng; Hu, Xiaoxiang; Bai, Xueyuan; Chen, Xiangmei; Li, Ning

    2015-01-01

    PKD1 and PKD2 mutations could lead to autosomal dominant polycystic kidney disease (ADPKD), which afflicts millions of people worldwide. Due to the marked differences in the lifespan, size, anatomy, and physiology from humans, rodent ADPKD models cannot fully mimic the disease. To obtain a large animal model that recapitulates the disease, we constructed a mini-pig model by mono-allelic knockout (KO) of PKD1 using zinc finger nuclease. The mono-allelic KO pigs had lower PKD1 expression than their wild-type littermates at both the transcriptional and translational levels. After approximately six months, renal cysts appeared and grew progressively in the KO pigs. Histological analysis showed that renal cysts were scatteredly distributed in the mutant pig kidneys and were lined by either cuboidal or flattened epithelial cells. Contrast-enhanced computed tomography confirmed that all of the mutant pigs had renal and hepatic cysts, when they were 11-month-old. Immunohistochemical analysis revealed that most of the cysts were derived from the proximal tubules and collecting ducts. Therefore, the PKD1 mono-allelic knockout is sufficient to trigger renal cystogenesis, and this pig model may provide a platform for future study of renal cyst formation. PMID:25798056

  16. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

    PubMed

    Cochran, Rory L; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M; Meeker, Alan K; Lauring, Josh; Park, Ben Ho

    2015-09-22

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID:26246475

  17. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes

    PubMed Central

    Cochran, Rory L.; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J.; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A.; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M.; Meeker, Alan K.; Lauring, Josh; Park, Ben Ho

    2015-01-01

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID:26246475

  18. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

    PubMed

    Cochran, Rory L; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M; Meeker, Alan K; Lauring, Josh; Park, Ben Ho

    2015-09-22

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk.

  19. A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles.

    PubMed

    Pollizzi, Kristen; Malinowska-Kolodziej, Izabela; Doughty, Cheryl; Betz, Charles; Ma, Jian; Goto, June; Kwiatkowski, David J

    2009-07-01

    Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which hamartomas develop in multiple organ systems. Knockout and conditional alleles of Tsc1 and Tsc2 have been previously reported. Here, we describe the generation of a novel hypomorphic allele of Tsc2 (del3), in which exon 3, encoding 37 amino acids near the N terminus of tuberin, is deleted. Embryos homozygous for the del3 allele survive until E13.5, 2 days longer than Tsc2 null embryos. Embryos die from underdevelopment of the liver, deficient hematopoiesis, aberrant vascular development and hemorrhage. Mice that are heterozygous for the del3 allele have a markedly reduced kidney tumor burden in comparison with conventional Tsc2(+/-) mice. Murine embryo fibroblast (MEF) cultures that are homozygous for the del3 allele express mutant tuberin at low levels, and show enhanced activation of mTORC1, similar to Tsc2 null MEFs. Furthermore, the mutant cells show prominent reduction in the activation of AKT. Similar findings were made in the analysis of homozygous del3 embryo lysates. Tsc2-del3 demonstrates GTPase activating protein activity comparable to that of wild-type Tsc2 in a functional assay. These findings indicate that the del3 allele is a hypomorphic allele of Tsc2 with partial function due to reduced expression, and highlight the consistency of AKT downregulation when Tsc1/Tsc2 function is reduced. Tsc2-del3 mice also serve as a model for hypomorphic TSC2 missense mutations reported in TSC patients.

  20. Epidemiological and Evolutionary Outcomes in Gene-for-Gene and Matching Allele Models.

    PubMed

    Thrall, Peter H; Barrett, Luke G; Dodds, Peter N; Burdon, Jeremy J

    2015-01-01

    Gene-for-gene (GFG) and matching-allele (MA) models are qualitatively different paradigms for describing the outcome of genetic interactions between hosts and pathogens. The GFG paradigm was largely built on the foundations of Flor's early work on the flax-flax rust interaction and is based on the concept of genetic recognition leading to incompatible disease outcomes, typical of host immune recognition. In contrast, the MA model is based on the assumption that genetic recognition leads to compatible interactions, which can result when pathogens require specific host factors to cause infection. Results from classical MA and GFG models have led to important predictions regarding various coevolutionary phenomena, including the role of fitness costs associated with resistance and infectivity, the distribution of resistance genes in wild populations, patterns of local adaptation and the evolution and maintenance of sexual reproduction. Empirical evidence (which we review briefly here), particularly from recent molecular advances in understanding of the mechanisms that determine the outcome of host-pathogen encounters, suggests considerable variation in specific details of the functioning of interactions between hosts and pathogens, which may contain elements of both models. In this regard, GFG and MA scenarios likely represent endpoints of a continuum of potentially more complex interactions that occur in nature. Increasingly, this has been recognized in theoretical studies of coevolutionary processes in plant host-pathogen and animal host-parasite associations (e.g., departures from strict GFG/MA assumptions, diploid genetics, multi-step infection processes). However, few studies have explored how different genetic assumptions about host resistance and pathogen infectivity might impact on disease epidemiology or pathogen persistence within and among populations. Here, we use spatially explicit simulations of the basic MA and GFG scenarios to highlight qualitative

  1. Epidemiological and Evolutionary Outcomes in Gene-for-Gene and Matching Allele Models

    PubMed Central

    Thrall, Peter H.; Barrett, Luke G.; Dodds, Peter N.; Burdon, Jeremy J.

    2016-01-01

    Gene-for-gene (GFG) and matching-allele (MA) models are qualitatively different paradigms for describing the outcome of genetic interactions between hosts and pathogens. The GFG paradigm was largely built on the foundations of Flor’s early work on the flax–flax rust interaction and is based on the concept of genetic recognition leading to incompatible disease outcomes, typical of host immune recognition. In contrast, the MA model is based on the assumption that genetic recognition leads to compatible interactions, which can result when pathogens require specific host factors to cause infection. Results from classical MA and GFG models have led to important predictions regarding various coevolutionary phenomena, including the role of fitness costs associated with resistance and infectivity, the distribution of resistance genes in wild populations, patterns of local adaptation and the evolution and maintenance of sexual reproduction. Empirical evidence (which we review briefly here), particularly from recent molecular advances in understanding of the mechanisms that determine the outcome of host–pathogen encounters, suggests considerable variation in specific details of the functioning of interactions between hosts and pathogens, which may contain elements of both models. In this regard, GFG and MA scenarios likely represent endpoints of a continuum of potentially more complex interactions that occur in nature. Increasingly, this has been recognized in theoretical studies of coevolutionary processes in plant host–pathogen and animal host-parasite associations (e.g., departures from strict GFG/MA assumptions, diploid genetics, multi-step infection processes). However, few studies have explored how different genetic assumptions about host resistance and pathogen infectivity might impact on disease epidemiology or pathogen persistence within and among populations. Here, we use spatially explicit simulations of the basic MA and GFG scenarios to highlight

  2. DIVERSE MODELS FOR SOLVING CONTRASTING OUTFALL PROBLEMS

    EPA Science Inventory

    Mixing zone initial dilution and far-field models are useful for assuring that water quality criteria will be met when specific outfall discharge criteria are applied. Presented here is a selective review of mixing zone initial dilution models and relatively simple far-field tran...

  3. Compare and Contrast Program Planning Models

    ERIC Educational Resources Information Center

    Baskas, Richard S.

    2011-01-01

    This paper will examine the differences and similarities between two program planning models, Tyler and Caffarella, to reveal their strengths and weaknesses. When adults are involved in training sessions, there are various program planning models that can be used, depending on the goal of the training session. Researchers developed these models…

  4. Modeling the effects of contrast enhancement on target acquisition performance

    NASA Astrophysics Data System (ADS)

    Du Bosq, Todd W.; Fanning, Jonathan D.

    2008-04-01

    Contrast enhancement and dynamic range compression are currently being used to improve the performance of infrared imagers by increasing the contrast between the target and the scene content, by better utilizing the available gray levels either globally or locally. This paper assesses the range-performance effects of various contrast enhancement algorithms for target identification with well contrasted vehicles. Human perception experiments were performed to determine field performance using contrast enhancement on the U.S. Army RDECOM CERDEC NVESD standard military eight target set using an un-cooled LWIR camera. The experiments compare the identification performance of observers viewing linearly scaled images and various contrast enhancement processed images. Contrast enhancement is modeled in the US Army thermal target acquisition model (NVThermIP) by changing the scene contrast temperature. The model predicts improved performance based on any improved target contrast, regardless of feature saturation or enhancement. To account for the equivalent blur associated with each contrast enhancement algorithm, an additional effective MTF was calculated and added to the model. The measured results are compared with the predicted performance based on the target task difficulty metric used in NVThermIP.

  5. Graphical modeling of the joint distribution of alleles at associated loci.

    PubMed

    Thomas, Alun; Camp, Nicola J

    2004-06-01

    Pairwise linkage disequilibrium, haplotype blocks, and recombination hotspots provide only a partial description of the patterns of dependences and independences between the allelic states at proximal loci. On the gross scale, where recombination and spatial relationships dominate, the associations can be reasonably described in these terms. However, on the fine scale of current high-density maps, the mutation process is also important and creates associations between loci that are independent of the physical ordering and that can not be summarized with pairwise measures of association. Graphical modeling provides a standard statistical framework for characterizing precisely these sorts of complex stochastic data. Although graphical models are often used in situations in which assumptions lead naturally to specific models, it is less well known that estimation of graphical models is also a developed field. We show how decomposable graphical models can be fitted to dense genetic data. The objective function is the maximized log likelihood for the model penalized by a multiple of the model's degrees of freedom. We also describe how this can be modified to incorporate prior information of locus position. Simulated annealing is used to find good solutions. Part of the appeal of this approach is that categorical phenotypes can be included in the same analysis and association with polymorphisms can be assessed jointly with the interlocus associations. We illustrate our method with genotypic data from 25 loci in the ELAC2 gene. The results contain third- and fourth-order locus interactions and show that, at this density of markers, linkage disequilibrium is not a simple function of physical distance. Graphical models provide more flexibility to express these features of the joint distribution of alleles than do monotonic functions connecting physical and genetic maps.

  6. Allele-specific RNAi Mitigates Phenotypic Progression in a Transgenic Model of Alzheimer's Disease

    PubMed Central

    Rodríguez-Lebrón, Edgardo; Gouvion, Cynthia M; Moore, Steven A; Davidson, Beverly L; Paulson, Henry L

    2009-01-01

    Despite recent advances suggesting new therapeutic targets, Alzheimer's disease (AD) remains incurable. Aberrant production and accumulation of the Aβ peptide resulting from altered processing of the amyloid precursor protein (APP) is central to the pathogenesis of disease, particularly in dominantly inherited forms of AD. Thus, modulating the production of APP is a potential route to effective AD therapy. Here, we describe the successful use of an allele-specific RNA interference (RNAi) approach targeting the Swedish variant of APP (APPsw) in a transgenic mouse model of AD. Using recombinant adeno-associated virus (rAAV), we delivered an anti-APPsw short-hairpin RNA (shRNA) to the hippocampus of AD transgenic mice (APP/PS1). In short- and long-term transduction experiments, reduced levels of APPsw transprotein were observed throughout targeted regions of the hippocampus while levels of wild-type murine APP remained unaltered. Moreover, intracellular production of transfer RNA (tRNA)-valine promoter–driven shRNAs did not lead to detectable neuronal toxicity. Finally, long-term bilateral hippocampal expression of anti-APPsw shRNA mitigated abnormal behaviors in this mouse model of AD. The difference in phenotype progression was associated with reduced levels of soluble Aβ but not with a reduced number of amyloid plaques. Our results support the development of allele-specific RNAi strategies to treat familial AD and other dominantly inherited neurodegenerative diseases. PMID:19532137

  7. The free energy method and the Wright-Fisher model with 2 alleles.

    PubMed

    Tran, Tat Dat; Hofrichter, Julian; Jost, Jürgen

    2015-12-01

    We systematically investigate the Wright-Fisher model of population genetics with the free energy functional formalism of statistical mechanics and in the light of recent mathematical work on the connection between Fokker-Planck equations and free energy functionals. In statistical physics, entropy increases, or equivalently, free energy decreases, and the asymptotic state is given by a Gibbs-type distribution. This also works for the Wright-Fisher model when rewritten in divergence to identify the correct free energy functional. We not only recover the known results about the stationary distribution, that is, the asymptotic equilibrium state of the model, in the presence of positive mutation rates and possibly also selection, but can also provide detailed formulae for the rate of convergence towards that stationary distribution. In the present paper, the method is illustrated for the simplest case only, that of two alleles.

  8. Addressing contrasting cognitive models in scientific collaboration

    NASA Astrophysics Data System (ADS)

    Diviacco, P.

    2012-04-01

    If the social aspects of scientific communities and their internal dynamics is starting to be recognized and acknowledged in the everyday lives of scientists, it is rather difficult for them to find tools that could support their activities consistently with this perspective. Issues span from gathering researchers to mutual awareness, from information sharing to building meaning, with the last one being particularly critical in research fields as the geo-sciences, that deal with the reconstruction of unique, often non-reproducible, and contingent processes. Reasoning here is, in fact, mainly abductive, allowing multiple and concurrent explanations for the same phenomenon to coexist. Scientists bias one hypothesis over another not only on strictly logical but also on sociological motivations. Following a vision, scientists tend to evolve and isolate themselves from other scientists creating communities characterized by different cognitive models, so that after some time these become incompatible and scientists stop understanding each other. We address these problems as a communication issue so that the classic distinction into three levels (syntactic, semantic and pragmatic) can be used. At the syntactic level, we highlight non-technical obstacles that condition interoperability and data availability and transparency. At the semantic level, possible incompatibilities of cognitive models are particularly evident, so that using ontologies, cross-domain reconciliation should be applied. This is a very difficult task to perform since the projection of knowledge by scientists, in the designated community, is political and thus can create a lot of tension. The strategy we propose to overcome these issues pertains to pragmatics, in the sense that it is intended to acknowledge the cultural and personal factors each partner brings into the collaboration and is based on the idea that meaning should remain a flexible and contingent representation of possibly divergent views

  9. Growth behavior of additional offspring with a beneficial reversal allele in the asymmetric sharply-peaked landscape in the coupled discrete-time mutation-selection model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2013-01-01

    The probability of additional offspring with a beneficial reversal allele for growing to a size NC for a range of population sizes N, sequence lengths L, selective advantages s, and measuring parameters C was calculated for a haploid, asexual population in the coupled discrete-time mutation-selection model in an asymmetric sharply-peaked landscape with a positive selective advantage of the reversal allele over the optimal allele. The growing probability in the stochastic region was inversely proportional to the measuring parameter when C < 1 /Ns, bent when C ≈ 1/ Ns and saturated when C > 1/ Ns. The crossing time and the time dependence of the increase in relative density of the reversal allele in the coupled discrete-time mutation-selection model was approximated using the Wright-Fisher two-allele model with the same selective advantage and corresponding effective mutation rate. The growth behavior of additional offspring with the reversal allele in the asymmetric sharply-peaked landscape in the coupled discrete-time mutation-selection model was controlled by the selective advantage of the reversal allele compared to the optimal allele and could be described by using the Wright-Fisher two-allele model, in spite of there being many other alleles with lower fitness, and in spite of there being two alleles, the optimal and reversal allele, separated by a low-fitness valley with a tunable depth and width.

  10. Monitoring SERS-based contrast agents in atherosclerosis experimental models

    NASA Astrophysics Data System (ADS)

    Machtoub, Lina H.

    2011-03-01

    There have been enormous progresses in developing a class of multimodal contrast agents, which combine MRI with optical imaging. Contrast agent targeting can provide enhanced diagnostic information, allowing differentiation between variable and stable atherosclerotic plaques. Recently an intensive efforts have been working on the development of contrast agents that can improve the ability to detect and characterize atherosclerosis in clinical and preclinical applications. Earlier studies on hyperlipidemic rabbits using in vivo MRI have shown accumulation of USPIOs in plaques with a high macrophage content that induces magnetic resonance (MR) signal changes correlated to the absolute iron content in the aortic arch. A potent new class of nanoparticles contrast agents have recently drawn much attention for its wide diverse diagnostic and potential therapeutic applications particularly in monitoring the inflammatory responses. In our previous studies we have investigated SPIO contrast agents uptakes in hepatic and spleen tissues taken from NZW rabbits. The scope of this work encompasses application of an emerging hybrid imaging modality, SERSbased nonlinear optical microscopy, in investigating atherosclerosis experimental models. In this work experiments are performed on contrast treated tissue sections taken from aortic arch of atherosclerotic animal model. Marked contrast enhancement has been observed in the treated aortic sections compared with the untreated control. The obtained images are compared with immunohistochemistry .The work presented can be promising for future studies on in vivo detection of macrophages in human plaques and early detection of atherosclerotic diseases.

  11. Reducing bias of allele frequency estimates by modeling SNP genotype data with informative missingness.

    PubMed

    Lin, Wan-Yu; Liu, Nianjun

    2012-01-01

    The presence of missing single-nucleotide polymorphism (SNP) genotypes is common in genetic studies. For studies with low-density SNPs, the most commonly used approach to dealing with genotype missingness is to simply remove the observations with missing genotypes from the analyses. This naïve method is straightforward but is valid only when the missingness is random. However, a given assay often has a different capability in genotyping heterozygotes and homozygotes, causing the phenomenon of "differential dropout" in the sense that the missing rates of heterozygotes and homozygotes are different. In practice, differential dropout among genotypes exists in even carefully designed studies, such as the data from the HapMap project and the Wellcome Trust Case Control Consortium. Under the assumption of Hardy-Weinberg equilibrium and no genotyping error, we here propose a statistical method to model the differential dropout among different genotypes. Compared with the naïve method, our method provides more accurate allele frequency estimates when the differential dropout is present. To demonstrate its practical use, we further apply our method to the HapMap data and a scleroderma data set. PMID:22719749

  12. Coastal Digital Surface Model on Low Contrast Images

    NASA Astrophysics Data System (ADS)

    Rosu, A.-M.; Assenbaum, M.; De la Torre, Y.; Pierrot-Deseilligny, M.

    2015-08-01

    Coastal sandy environments are extremely dynamic and require regular monitoring that can easily be achieved by using an unmanned aerial system (UAS) including a drone and a photo camera. The acquired images have low contrast and homogeneous texture. Using these images and with very few, if any, ground control points (GCPs), it is difficult to obtain a digital surface model (DSM) by classical correlation and automatic interest points determination approach. A possible response to this problem is to work with enhanced, contrast filtered images. To achieve this, we use and tune the free open-source software MicMac.

  13. Simulation model for contrast agent dynamics in brain perfusion scans.

    PubMed

    Bredno, Jörg; Olszewski, Mark E; Wintermark, Max

    2010-07-01

    Standardization efforts are currently under way to reduce the heterogeneity of quantitative brain perfusion methods. A brain perfusion simulation model is proposed to generate test data for an unbiased comparison of these methods. This model provides realistic simulated patient data and is independent of and different from any computational method. The flow of contrast agent solute and blood through cerebral vasculature with disease-specific configurations is simulated. Blood and contrast agent dynamics are modeled as a combination of convection and diffusion in tubular networks. A combination of a cerebral arterial model and a microvascular model provides arterial-input and time-concentration curves for a wide range of flow and perfusion statuses. The model is configured to represent an embolic stroke in one middle cerebral artery territory and provides physiologically plausible vascular dispersion operators for major arteries and tissue contrast agent retention functions. These curves are fit to simpler template curves to allow the use of the simulation results in multiple validation studies. A gamma-variate function with fit parameters is proposed as the vascular dispersion operator, and a combination of a boxcar and exponential decay function is proposed as the retention function. Such physiologically plausible operators should be used to create test data that better assess the strengths and the weaknesses of various analysis methods.

  14. Saphenous Venous Ablation with Hot Contrast in a Canine Model

    SciTech Connect

    Prasad, Amit Qian Zhong; Kirsch, David; Eissa, Marna; Narra, Pavan; Lopera, Jorge; Espinoza, Carmen G.; Castaneda, Wifrido

    2008-01-15

    Purpose. To determine the feasibility, efficacy, and safety of thermal ablation of the saphenous vein with hot contrast medium. Methods. Twelve saphenous veins of 6 dogs were percutaneously ablated with hot contrast medium. In all animals, ablation was performed in the vein of one leg, followed by ablation in the contralateral side 1 month later. An occlusion balloon catheter was placed in the infragenicular segment of the saphenous vein via a jugular access to prevent unwanted thermal effects on the non-target segment of the saphenous vein. After inflation of the balloon, 10 ml of hot contrast medium was injected under fluoroscopic control through a sheath placed in the saphenous vein above the ankle. A second 10 ml injection of hot contrast medium was made after 5 min in each vessel. Venographic follow-up of the ablated veins was performed at 1 month (n = 12) and 2 months (n = 6). Results. Follow-up venograms showed that all ablated venous segments were occluded at 1 month. In 6 veins which were followed up to 2 months, 4 (66%) remained occluded, 1 (16%) was partially patent, and the remaining vein (16%) was completely patent. In these latter 2 cases, an inadequate amount of hot contrast was delivered to the lumen due to a closed balloon catheter downstream which did not allow contrast to displace blood within the vessel. Discussion. Hot contrast medium thermal ablation of the saphenous vein appears feasible, safe, and effective in the canine model, provided an adequate amount of embolization agent is used.

  15. Allele- and Tir-Independent Functions of Intimin in Diverse Animal Infection Models

    PubMed Central

    Mallick, Emily M.; Brady, Michael J.; Luperchio, Steven A.; Vanguri, Vijay K.; Magoun, Loranne; Liu, Hui; Sheppard, Barbara J.; Mukherjee, Jean; Donohue-Rolfe, Art; Tzipori, Saul; Leong, John M.; Schauer, David B.

    2012-01-01

    Upon binding to intestinal epithelial cells, enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), and Citrobacter rodentium trigger formation of actin pedestals beneath bound bacteria. Pedestal formation has been associated with enhanced colonization, and requires intimin, an adhesin that binds to the bacterial effector translocated intimin receptor (Tir), which is translocated to the host cell membrane and promotes bacterial adherence and pedestal formation. Intimin has been suggested to also promote cell adhesion by binding one or more host receptors, and allelic differences in intimin have been associated with differences in tissue and host specificity. We assessed the function of EHEC, EPEC, or C. rodentium intimin, or a set of intimin derivatives with varying Tir-binding abilities in animal models of infection. We found that EPEC and EHEC intimin were functionally indistinguishable during infection of gnotobiotic piglets by EHEC, and that EPEC, EHEC, and C. rodentium intimin were functionally indistinguishable during infection of C57BL/6 mice by C. rodentium. A derivative of EHEC intimin that bound Tir but did not promote robust pedestal formation on cultured cells was unable to promote C. rodentium colonization of conventional mice, indicating that the ability to trigger actin assembly, not simply to bind Tir, is required for intimin-mediated intestinal colonization. Interestingly, streptomycin pre-treatment of mice eliminated the requirement for Tir but not intimin during colonization, and intimin derivatives that were defective in Tir-binding still promoted colonization of these mice. These results indicate that EPEC, EHEC, and C. rodentium intimin are functionally interchangeable during infection of gnotobiotic piglets or conventional C57BL/6 mice, and that whereas the ability to trigger Tir-mediated pedestal formation is essential for colonization of conventional mice, intimin provides a Tir-independent activity during colonization

  16. Modeled and measured image-plane polychromatic speckle contrast

    NASA Astrophysics Data System (ADS)

    Van Zandt, Noah R.; McCrae, Jack E.; Fiorino, Steven T.

    2016-02-01

    The statistical properties of speckle relevant to short- to medium-range (tactical) active tracking involving polychromatic illumination are investigated. A numerical model is developed to allow rapid simulation of speckled images including the speckle contrast reduction effects of illuminator bandwidth, surface slope, and roughness, and the polarization properties of both the source and the reflection. Regarding surface slope (relative orientation of the surface normal and illumination/observation directions), Huntley's theory for speckle contrast, which employs geometrical approximations to decrease computation time, is modified to increase accuracy by incorporation of a geometrical correction factor and better treatment of roughness and polarization. The resulting model shows excellent agreement with more exact theory over a wide range. An experiment is conducted to validate both the numerical model developed here and existing theory. A diode laser source with coherence length of 259±7 μm is reflected off of a silver-coated diffuse surface. Speckle data are gathered for 16 surface slope angles corresponding to speckle contrast between about 0.55 and 1. Taking the measured data as truth, both equations show error mean and standard deviation of less than 3%. Thus, the theory is validated over the range of this experiment.

  17. The utility of ancient human DNA for improving allele age estimates, with implications for demographic models and tests of natural selection

    PubMed Central

    Sams, Aaron J.; Hawks, John; Keinan, Alon

    2015-01-01

    The age of polymorphic alleles in humans is often estimated from population genetic patterns in extant human populations, such as allele frequencies, linkage disequilibrium, and rate of mutations. Ancient DNA can improve the accuracy of such estimates, as well as facilitate testing the validity of demographic models underlying many population genetic methods. Specifically, the presence of an allele in a genome derived from an ancient sample testifies that the allele is at least as old as that sample. In this study, we consider a common method for estimating allele age based on allele frequency as applied to variants from the US National Institutes of Health (NIH) Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project. We view these estimates in the context of the presence or absence of each allele in the genomes of the 5300 year old Tyrolean Iceman, Ötzi, and of the 50,000 year old Altai Neandertal. Our results illuminate the accuracy of these estimates and their sensitivity to demographic events that were not included in the model underlying age estimation. Specifically, allele presence in the Iceman genome provides a good fit of allele age estimates to the expectation based on the age of that specimen. The equivalent based on the Neandertal genome leads to a poorer fit. This is likely due in part to the older age of the Neandertal and the older time of the split between modern humans and Neandertals, but also due to gene flow from Neandertals to modern humans not being considered in the underlying demographic model. Thus, the incorporation of ancient DNA can improve allele age estimation, demographic modeling, and tests of natural selection. Our results also point to the importance of considering a more diverse set of ancient samples for understanding the geographic and temporal range of individual alleles. PMID:25467111

  18. The utility of ancient human DNA for improving allele age estimates, with implications for demographic models and tests of natural selection.

    PubMed

    Sams, Aaron J; Hawks, John; Keinan, Alon

    2015-02-01

    The age of polymorphic alleles in humans is often estimated from population genetic patterns in extant human populations, such as allele frequencies, linkage disequilibrium, and rate of mutations. Ancient DNA can improve the accuracy of such estimates, as well as facilitate testing the validity of demographic models underlying many population genetic methods. Specifically, the presence of an allele in a genome derived from an ancient sample testifies that the allele is at least as old as that sample. In this study, we consider a common method for estimating allele age based on allele frequency as applied to variants from the US National Institutes of Health (NIH) Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project. We view these estimates in the context of the presence or absence of each allele in the genomes of the 5300 year old Tyrolean Iceman, Ötzi, and of the 50,000 year old Altai Neandertal. Our results illuminate the accuracy of these estimates and their sensitivity to demographic events that were not included in the model underlying age estimation. Specifically, allele presence in the Iceman genome provides a good fit of allele age estimates to the expectation based on the age of that specimen. The equivalent based on the Neandertal genome leads to a poorer fit. This is likely due in part to the older age of the Neandertal and the older time of the split between modern humans and Neandertals, but also due to gene flow from Neandertals to modern humans not being considered in the underlying demographic model. Thus, the incorporation of ancient DNA can improve allele age estimation, demographic modeling, and tests of natural selection. Our results also point to the importance of considering a more diverse set of ancient samples for understanding the geographic and temporal range of individual alleles.

  19. Common alleles contribute to schizophrenia in CNV carriers

    PubMed Central

    Tansey, K E; Rees, E; Linden, D E; Ripke, S; Chambert, K D; Moran, J L; McCarroll, S A; Holmans, P; Kirov, G; Walters, J; Owen, M J; O'Donovan, M C

    2016-01-01

    The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10−17) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely. PMID:26390827

  20. Image contrast enhancement based on a local standard deviation model

    SciTech Connect

    Chang, Dah-Chung; Wu, Wen-Rong

    1996-12-31

    The adaptive contrast enhancement (ACE) algorithm is a widely used image enhancement method, which needs a contrast gain to adjust high frequency components of an image. In the literature, the gain is usually inversely proportional to the local standard deviation (LSD) or is a constant. But these cause two problems in practical applications, i.e., noise overenhancement and ringing artifact. In this paper a new gain is developed based on Hunt`s Gaussian image model to prevent the two defects. The new gain is a nonlinear function of LSD and has the desired characteristic emphasizing the LSD regions in which details are concentrated. We have applied the new ACE algorithm to chest x-ray images and the simulations show the effectiveness of the proposed algorithm.

  1. Modeling pollinator community response to contrasting bioenergy scenarios.

    PubMed

    Bennett, Ashley B; Meehan, Timothy D; Gratton, Claudio; Isaacs, Rufus

    2014-01-01

    In the United States, policy initiatives aimed at increasing sources of renewable energy are advancing bioenergy production, especially in the Midwest region, where agricultural landscapes dominate. While policy directives are focused on renewable fuel production, biodiversity and ecosystem services will be impacted by the land-use changes required to meet production targets. Using data from field observations, we developed empirical models for predicting abundance, diversity, and community composition of flower-visiting bees based on land cover. We used these models to explore how bees might respond under two contrasting bioenergy scenarios: annual bioenergy crop production and perennial grassland bioenergy production. In the two scenarios, 600,000 ha of marginal annual crop land or marginal grassland were converted to perennial grassland or annual row crop bioenergy production, respectively. Model projections indicate that expansion of annual bioenergy crop production at this scale will reduce bee abundance by 0 to 71%, and bee diversity by 0 to 28%, depending on location. In contrast, converting annual crops on marginal soil to perennial grasslands could increase bee abundance from 0 to 600% and increase bee diversity between 0 and 53%. Our analysis of bee community composition suggested a similar pattern, with bee communities becoming less diverse under annual bioenergy crop production, whereas bee composition transitioned towards a more diverse community dominated by wild bees under perennial bioenergy crop production. Models, like those employed here, suggest that bioenergy policies have important consequences for pollinator conservation.

  2. Modeling pollinator community response to contrasting bioenergy scenarios.

    PubMed

    Bennett, Ashley B; Meehan, Timothy D; Gratton, Claudio; Isaacs, Rufus

    2014-01-01

    In the United States, policy initiatives aimed at increasing sources of renewable energy are advancing bioenergy production, especially in the Midwest region, where agricultural landscapes dominate. While policy directives are focused on renewable fuel production, biodiversity and ecosystem services will be impacted by the land-use changes required to meet production targets. Using data from field observations, we developed empirical models for predicting abundance, diversity, and community composition of flower-visiting bees based on land cover. We used these models to explore how bees might respond under two contrasting bioenergy scenarios: annual bioenergy crop production and perennial grassland bioenergy production. In the two scenarios, 600,000 ha of marginal annual crop land or marginal grassland were converted to perennial grassland or annual row crop bioenergy production, respectively. Model projections indicate that expansion of annual bioenergy crop production at this scale will reduce bee abundance by 0 to 71%, and bee diversity by 0 to 28%, depending on location. In contrast, converting annual crops on marginal soil to perennial grasslands could increase bee abundance from 0 to 600% and increase bee diversity between 0 and 53%. Our analysis of bee community composition suggested a similar pattern, with bee communities becoming less diverse under annual bioenergy crop production, whereas bee composition transitioned towards a more diverse community dominated by wild bees under perennial bioenergy crop production. Models, like those employed here, suggest that bioenergy policies have important consequences for pollinator conservation. PMID:25365559

  3. Modeling Pollinator Community Response to Contrasting Bioenergy Scenarios

    PubMed Central

    Bennett, Ashley B.; Meehan, Timothy D.; Gratton, Claudio; Isaacs, Rufus

    2014-01-01

    In the United States, policy initiatives aimed at increasing sources of renewable energy are advancing bioenergy production, especially in the Midwest region, where agricultural landscapes dominate. While policy directives are focused on renewable fuel production, biodiversity and ecosystem services will be impacted by the land-use changes required to meet production targets. Using data from field observations, we developed empirical models for predicting abundance, diversity, and community composition of flower-visiting bees based on land cover. We used these models to explore how bees might respond under two contrasting bioenergy scenarios: annual bioenergy crop production and perennial grassland bioenergy production. In the two scenarios, 600,000 ha of marginal annual crop land or marginal grassland were converted to perennial grassland or annual row crop bioenergy production, respectively. Model projections indicate that expansion of annual bioenergy crop production at this scale will reduce bee abundance by 0 to 71%, and bee diversity by 0 to 28%, depending on location. In contrast, converting annual crops on marginal soil to perennial grasslands could increase bee abundance from 0 to 600% and increase bee diversity between 0 and 53%. Our analysis of bee community composition suggested a similar pattern, with bee communities becoming less diverse under annual bioenergy crop production, whereas bee composition transitioned towards a more diverse community dominated by wild bees under perennial bioenergy crop production. Models, like those employed here, suggest that bioenergy policies have important consequences for pollinator conservation. PMID:25365559

  4. Quantitative phenomenological model of the BOLD contrast mechanism

    NASA Astrophysics Data System (ADS)

    Dickson, John D.; Ash, Tom W. J.; Williams, Guy B.; Sukstanskii, Alexander L.; Ansorge, Richard E.; Yablonskiy, Dmitriy A.

    2011-09-01

    Different theoretical models of the BOLD contrast mechanism are used for many applications including BOLD quantification (qBOLD) and vessel size imaging, both in health and disease. Each model simplifies the system under consideration, making approximations about the structure of the blood vessel network and diffusion of water molecules through inhomogeneities in the magnetic field created by deoxyhemoglobin-containing blood vessels. In this study, Monte-Carlo methods are used to simulate the BOLD MR signal generated by diffusing water molecules in the presence of long, cylindrical blood vessels. Using these simulations we introduce a new, phenomenological model that is far more accurate over a range of blood oxygenation levels and blood vessel radii than existing models. This model could be used to extract physiological parameters of the blood vessel network from experimental data in BOLD-based experiments. We use our model to establish ranges of validity for the existing analytical models of Yablonskiy and Haacke, Kiselev and Posse, Sukstanskii and Yablonskiy (extended to the case of arbitrary time in the spin echo sequence) and Bauer et al. (extended to the case of randomly oriented cylinders). Although these models are shown to be accurate in the limits of diffusion under which they were derived, none of them is accurate for the whole physiological range of blood vessels radii and blood oxygenation levels. We also show the extent of systematic errors that are introduced due to the approximations of these models when used for BOLD signal quantification.

  5. Loss of one Tgfbr2 allele in fibroblasts promotes metastasis in MMTV: polyoma middle T transgenic and transplant mouse models of mammary tumor progression

    PubMed Central

    Fang, Wei Bin; Jokar, Iman; Chytil, Anna; Moses, Harold L.; Abel, Ty; Cheng, Nikki

    2012-01-01

    Accumulation of fibroblasts is a phenomenon that significantly correlates with formation of aggressive cancers. While studies have shown that the TGF-β signaling pathway is an important regulator of fibroblast activation, the functional contribution of TGF-β signaling in fibroblasts during multi-step tumor progression remains largely unclear. In previous studies, we used a sub-renal capsule transplantation model to demonstrate that homozygous knockout of the Tgfbr2 gene (Tgbr2FspKO) enhanced mammary tumor growth and metastasis. Here, we show for the first time a significant role for loss of one Tgfbr2 allele during multi-step mammary tumor progression. Heterozygous deletion of Tgfbr2 in stromal cells in MMTV–PyVmT transgenic mice (PyVmT/Tgfbr2hetFspKO mice) resulted in earlier tumor formation and increased stromal cell accumulation. In contrast to previous studies of Tgbr2FspKO fibroblasts, Tgfbr2hetFspKO fibroblasts did not significantly increase tumor growth, but enhanced lung metastasis in PyVmT transgenic mice and in co-transplantation studies with PyVmT mammary carcinoma cells. Furthermore, Tgfbr2hetFspKO fibroblasts enhanced mammary carcinoma cell invasiveness associated with expression of inflammatory cytokines including CXCL12 and CCL2. Analyses of Tgbr2FspKO and Tgfbr2hetFspKO fibroblasts revealed differences in the expression of factors associated with metastatic spread, indicating potential differences in the mechanism of action between homozygous and heterozygous deletion of Tgfbr2 in stromal cells. In summary, these studies demonstrate for the first time that loss of one Tgfbr2 allele in fibroblasts enhances mammary metastases in a multi-step model of tumor progression, and demonstrate the importance of clarifying the functional contribution of genetic alterations in stromal cells in breast cancer progression. PMID:21374085

  6. Uncovering Contrast Categories in Categorization with a Probabilistic Threshold Model

    ERIC Educational Resources Information Center

    Verheyen, Steven; De Deyne, Simon; Dry, Matthew J.; Storms, Gert

    2011-01-01

    A contrast category effect on categorization occurs when the decision to apply a category term to an entity not only involves a comparison between the entity and the target category but is also influenced by a comparison of the entity with 1 or more alternative categories from the same domain as the target. Establishing a contrast category effect…

  7. Allelic variants of ADH, ALDH and the five factor model of personality in alcohol dependence syndrome

    PubMed Central

    Salujha, S. K.; Chaudhury, S.; Menon, P. K.; Srivastava, K.; Gupta, A.

    2014-01-01

    Background: The etiology of alcohol dependence is a complex interplay of biopsychosocial factors. The genes for alcohol-metabolizing enzymes: Alcohol dehydrogenase (ADH2 and ADH3) and aldehyde dehydrogenase (ALDH2) exhibit functional polymorphisms. Vulnerability of alcohol dependence may also be in part due to heritable personality traits. Aim: To determine whether any association exists between polymorphisms of ADH2, ADH3 and ALDH2 and alcohol dependence syndrome in a group of Asian Indians. In addition, the personality of these patients was assessed to identify traits predisposing to alcoholism. Materials and Methods: In this study, 100 consecutive males with alcohol dependence syndrome attending the psychiatric outpatient department of a tertiary care service hospital and an equal number of matched healthy controls were included with their consent. Blood samples of all the study cases and controls were collected and genotyped for the ADH2, ADH3 and ALDH2 loci. Personality was evaluated using the neuroticism, extraversion, openness (NEO) personality inventory and sensation seeking scale. Results: Allele frequencies of ADH2*2 (0.50), ADH3*1 (0.67) and ALSH2*2 (0.09) were significantly low in the alcohol dependent subjects. Personality traits of NEO personality inventory and sensation seeking were significantly higher when compared to controls. Conclusions: The functional polymorphisms of genes coding for alcohol metabolizing enzymes and personality traits of NEO and sensation seeking may affect the propensity to develop dependence. PMID:25535445

  8. The Cascadia Subduction Zone: two contrasting models of lithospheric structure

    USGS Publications Warehouse

    Romanyuk, T.V.; Blakely, R.; Mooney, W.D.

    1998-01-01

    The Pacific margin of North America is one of the most complicated regions in the world in terms of its structure and present day geodynamic regime. The aim of this work is to develop a better understanding of lithospheric structure of the Pacific Northwest, in particular the Cascadia subduction zone of Southwest Canada and Northwest USA. The goal is to compare and contrast the lithospheric density structure along two profiles across the subduction zone and to interpet the differences in terms of active processes. The subduction of the Juan de Fuca plate beneath North America changes markedly along the length of the subduction zone, notably in the angle of subduction, distribution of earthquakes and volcanism, goelogic and seismic structure of the upper plate, and regional horizontal stress. To investigate these characteristics, we conducted detailed density modeling of the crust and mantle along two transects across the Cascadia subduction zone. One crosses Vancouver Island and the Canadian margin, the other crosses the margin of central Oregon.

  9. Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression.

    PubMed

    Melas, P A; Lennartsson, A; Vakifahmetoglu-Norberg, H; Wei, Y; Åberg, E; Werme, M; Rogdaki, M; Mannervik, M; Wegener, G; Brené, S; Mathé, A A; Lavebratt, C

    2013-05-07

    Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.

  10. Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans

    PubMed Central

    Morris, David L.; Taylor, Kimberly E.; Fernando, Michelle M.A.; Nititham, Joanne; Alarcón-Riquelme, Marta E.; Barcellos, Lisa F.; Behrens, Timothy W.; Cotsapas, Chris; Gaffney, Patrick M.; Graham, Robert R.; Pons-Estel, Bernardo A.; Gregersen, Peter K.; Harley, John B.; Hauser, Stephen L.; Hom, Geoffrey; Langefeld, Carl D.; Noble, Janelle A.; Rioux, John D.; Seldin, Michael F.; Criswell, Lindsey A.; Vyse, Timothy J.

    2012-01-01

    We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1∗03:01, HLA-DRB1∗08:01, and HLA-DQA1∗01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000). PMID:23084292

  11. Maximum likelihood model based on minor allele frequencies and weighted Max-SAT formulation for haplotype assembly.

    PubMed

    Mousavi, Sayyed R; Khodadadi, Ilnaz; Falsafain, Hossein; Nadimi, Reza; Ghadiri, Nasser

    2014-06-01

    Human haplotypes include essential information about SNPs, which in turn provide valuable information for such studies as finding relationships between some diseases and their potential genetic causes, e.g., for Genome Wide Association Studies. Due to expensiveness of directly determining haplotypes and recent progress in high throughput sequencing, there has been an increasing motivation for haplotype assembly, which is the problem of finding a pair of haplotypes from a set of aligned fragments. Although the problem has been extensively studied and a number of algorithms have already been proposed for the problem, more accurate methods are still beneficial because of high importance of the haplotypes information. In this paper, first, we develop a probabilistic model, that incorporates the Minor Allele Frequency (MAF) of SNP sites, which is missed in the existing maximum likelihood models. Then, we show that the probabilistic model will reduce to the Minimum Error Correction (MEC) model when the information of MAF is omitted and some approximations are made. This result provides a novel theoretical support for the MEC, despite some criticisms against it in the recent literature. Next, under the same approximations, we simplify the model to an extension of the MEC in which the information of MAF is used. Finally, we extend the haplotype assembly algorithm HapSAT by developing a weighted Max-SAT formulation for the simplified model, which is evaluated empirically with positive results. PMID:24491253

  12. Rater Stringency Error in Performance Rating: A Contrast of Three Models.

    ERIC Educational Resources Information Center

    Cason, Gerald J.; Cason, Carolyn L.

    The use of three remedies for errors in the measurement of ability that arise from differences in rater stringency is discussed. Models contrasted are: (1) Conventional; (2) Handicap; and (3) deterministic Rater Response Theory (RRT). General model requirements, power, bias of measures, computing cost, and complexity are contrasted. Contrasts are…

  13. Invasive Allele Spread under Preemptive Competition

    NASA Astrophysics Data System (ADS)

    Yasi, J. A.; Korniss, G.; Caraco, T.

    We study a discrete spatial model for invasive allele spread in which two alleles compete preemptively, initially only the "residents" (weaker competitors) being present. We find that the spread of the advantageous mutation is well described by homogeneous nucleation; in particular, in large systems the time-dependent global density of the resident allele is well approximated by Avrami's law.

  14. Matching allele dynamics and coevolution in a minimal predator prey replicator model

    NASA Astrophysics Data System (ADS)

    Sardanyés, Josep; Solé, Ricard V.

    2008-01-01

    A minimal Lotka Volterra type predator prey model describing coevolutionary traits among entities with a strength of interaction influenced by a pair of haploid diallelic loci is studied with a deterministic time continuous model. We show a Hopf bifurcation governing the transition from evolutionary stasis to periodic Red Queen dynamics. If predator genotypes differ in their predation efficiency the more efficient genotype asymptotically achieves lower stationary concentrations.

  15. Words as alleles: connecting language evolution with Bayesian learners to models of genetic drift.

    PubMed

    Reali, Florencia; Griffiths, Thomas L

    2010-02-01

    Scientists studying how languages change over time often make an analogy between biological and cultural evolution, with words or grammars behaving like traits subject to natural selection. Recent work has exploited this analogy by using models of biological evolution to explain the properties of languages and other cultural artefacts. However, the mechanisms of biological and cultural evolution are very different: biological traits are passed between generations by genes, while languages and concepts are transmitted through learning. Here we show that these different mechanisms can have the same results, demonstrating that the transmission of frequency distributions over variants of linguistic forms by Bayesian learners is equivalent to the Wright-Fisher model of genetic drift. This simple learning mechanism thus provides a justification for the use of models of genetic drift in studying language evolution. In addition to providing an explicit connection between biological and cultural evolution, this allows us to define a 'neutral' model that indicates how languages can change in the absence of selection at the level of linguistic variants. We demonstrate that this neutral model can account for three phenomena: the s-shaped curve of language change, the distribution of word frequencies, and the relationship between word frequencies and extinction rates.

  16. Effect of Osteopontin Alleles on β-Glucan-Induced Granuloma Formation in the Mouse Liver

    PubMed Central

    Tanaka, Kumiko; Morimoto, Junko; Kon, Shigeyuki; Kimura, Chiemi; Inobe, Manabu; Diao, Hongyan; Hirschfeld, Gregor; Weiss, Johannes M.; Uede, Toshimitsu

    2004-01-01

    The granuloma formation is a host defense response against persistent irritants. Osteopontin is centrally involved in the formation of granulomas. Three osteopontin alleles, designated a, b, and c, have been found in mice. Here we used a murine model of zymosan (β-glucan)-induced granuloma formation in the liver to determine possible functional differences between the osteopontin alleles in cell-mediated immunity. In contrast to mice with alleles a or c, mice with the allele b was defective in granuloma formation. As detected by mRNA expression, cytokines and chemokines known to be critically involved in granuloma formation were elicited in liver tissue, regardless of the osteopontin allele expressed. Alignment of the deduced amino acid sequences showed that unlike osteopontin c, b differs from a in 11 amino acids. All three osteopontin alleles had normal cell-binding properties. However, only the b allelic form was defective in the induction of cell migration as tested with dendritic cells. In conclusion, generation of a granulomatous response in mice depends critically on the presence of a functional osteopontin allele. Defective granuloma formation in mice with allele b is likely to be because of an impaired chemotactic function of the osteopontin b protein on immunocompetent cells. PMID:14742262

  17. Canopy resistance modelling for crops in contrasting water conditions

    NASA Astrophysics Data System (ADS)

    Rana, G.; Katerji, N.; Mastrorilli, M.

    Although canopy resistance to vapour water transport (r c) depends on climatic conditions and crop water status, standard constant daily values are usually used. Thus models using r c to predict evapotranspiration (ET) fail if applied to water stressed crops. On the other hand, in the scientific literature it is possible to find daily r c models dependent on soil moisture, but, in such cases, these need to be calibrated for each crop and site. Here a “climatic resistance” (r∗) is introduced as function of available energy, vapour pressure deficit and air temperature. Therefore a model of canopy resistance is presented on a hourly and daily time scale, where r c is expressed as function of r∗, aerodynamic resistance, r a, and predawn leaf water potential (PLWP), independently on the soil type. The model has been tested in Southern Italy on grass (reference crop), sorghum, sunflower and soybean and validated in France on soybean, without further calibration. The field crops were submitted to several water stress cycles: PLWP ranged between -0.1 and -1.2 MPa. The experiments showed that this model works well both under and without soil water constraints. On an hourly scale calculated ET in function of PLWP always presented a small underestimation (maximum 6% for soybean in Italy under senescence and water stress); on a daily scale these underestimations are reduced in general. The model test showed that it is independent of the site but depends only on the crop species. On a daily scale the model is presented also with available water (AW) as input, but in this case it needs local calibration. When AW is used as input the model showed an underestimation of 5% and 7% for sorghum and sunflower respectively.

  18. Computer simulation for the growing probability of additional offspring with an advantageous reversal allele in the decoupled continuous-time mutation-selection model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2016-01-01

    This study calculated the growing probability of additional offspring with the advantageous reversal allele in an asymmetric sharply-peaked landscape using the decoupled continuous-time mutation-selection model. The growing probability was calculated for various population sizes, N, sequence lengths, L, selective advantages, s, fitness parameters, k and measuring parameters, C. The saturated growing probability in the stochastic region was approximately the effective selective advantage, s*, when C≫1/Ns* and s*≪1. The present study suggests that the growing probability in the stochastic region in the decoupled continuous-time mutation-selection model can be described using the theoretical formula for the growing probability in the Moran two-allele model. The selective advantage ratio, which represents the ratio of the effective selective advantage to the selective advantage, does not depend on the population size, selective advantage, measuring parameter and fitness parameter; instead the selective advantage ratio decreases with the increasing sequence length.

  19. Human Leukocyte Antigens-A, -B, -C, -DRB1 allele and haplotype frequencies in Americans originating from Southern Europe: Contrasting patterns of population differentiation between Italian and Spanish Americans

    PubMed Central

    Mack, Steven J.; Tu, Bin; Yang, Ruyan; Masaberg, Carly; Ng, Jennifer; Hurley, Carolyn Katovich

    2010-01-01

    High resolution DNA sequencing was used to identify the HLA-A, -B, -C, and -DRB1 alleles found in 552 individuals from the United States indicating Southern European (Italian or Spanish) heritage. A total of 46 HLA-A, 80 HLA-B, 32 HLA-C, and 50 DRB1 alleles were identified. Frequent alleles included A*02:01:01G (allele frequency = 0.26 in Italian Americans; 0.22 in Spanish Americans); B*07:02:01G (Italian Americans allele frequency = 0.11); B*44:03 (Spanish Americans allele frequency = 0.07); C*04:01:01G and C*07:01:01G (allele frequency = 0.13 and 0.16, respectively, in Italian Americans; 0.15 and 0.12, respectively, in Spanish Americans); and DRB1*07:01:01 (allele frequency = 0.12 in each population). The action of balancing selection was inferred at the HLA-B and -C loci in both populations. The A*01:01:01G-C*07:01:01G-B*08:01:01G-DRB1*03:01:01 haplotype was the most frequent A-C-B-DRB1 haplotype in Italian Americans (haplotype frequency = 0.049), and was the second most frequent haplotype in Spanish Americans (haplotype frequency = 0.021). A*29:02:01-C*16:01:01-B*44:03-DRB1*07:01:01 was the most frequent A-C-B-DRB1 haplotype in Spanish Americans (haplotype frequency = 0.023), and was observed at a frequency of 0.015 in Italian Americans. Pairwise F’st values measuring the degree of differentiation between these Southern European-American populations and European and European-American populations suggest that Spanish Americans constitute a distinct subset of the European-American population, most similar to Mexican Americans, whereas Italian Americans cannot be distinguished from the larger European-American population. PMID:20974205

  20. The contrast model method for the thermodynamical calculation of air-air wet heat exchanger

    NASA Astrophysics Data System (ADS)

    Yuan, Xiugan; Mei, Fang

    1989-02-01

    The 'contrast model' method thermodynamic calculation of air-air crossflow wet heat exchangers with initial air condensation is presented. Contrast-model equations are derived from the actual heat exchanger equations as well as imaginary ones; it is then possible to proceed to a proof that the enthalpy efficiency of the contrast model equations is similar to the temperature efficiency of the dry heat exchanger. Conditions are noted under which it becomes possible to unify thermodynamic calculations for wet and dry heat exchangers.

  1. Image Discrimination Predictions of a Single Channel Model with Contrast Gain Control

    NASA Technical Reports Server (NTRS)

    Ahumada, Albert J., Jr.; Null, Cynthia H.

    1995-01-01

    Image discrimination models predict the number of just-noticeable-differences between two images. We report the predictions of a single channel model with contrast masking for a range of standard discrimination experiments. Despite its computational simplicity, this model has performed as well as a multiple channel model in an object detection task.

  2. Long-term impacts of selective logging on two Amazonian tree species with contrasting ecological and reproductive characteristics: inferences from Eco-gene model simulations.

    PubMed

    Vinson, C C; Kanashiro, M; Sebbenn, A M; Williams, T C R; Harris, S A; Boshier, D H

    2015-08-01

    The impact of logging and subsequent recovery after logging is predicted to vary depending on specific life history traits of the logged species. The Eco-gene simulation model was used to evaluate the long-term impacts of selective logging over 300 years on two contrasting Brazilian Amazon tree species, Dipteryx odorata and Jacaranda copaia. D. odorata (Leguminosae), a slow growing climax tree, occurs at very low densities, whereas J. copaia (Bignoniaceae) is a fast growing pioneer tree that occurs at high densities. Microsatellite multilocus genotypes of the pre-logging populations were used as data inputs for the Eco-gene model and post-logging genetic data was used to verify the output from the simulations. Overall, under current Brazilian forest management regulations, there were neither short nor long-term impacts on J. copaia. By contrast, D. odorata cannot be sustainably logged under current regulations, a sustainable scenario was achieved by increasing the minimum cutting diameter at breast height from 50 to 100 cm over 30-year logging cycles. Genetic parameters were only slightly affected by selective logging, with reductions in the numbers of alleles and single genotypes. In the short term, the loss of alleles seen in J. copaia simulations was the same as in real data, whereas fewer alleles were lost in D. odorata simulations than in the field. The different impacts and periods of recovery for each species support the idea that ecological and genetic information are essential at species, ecological guild or reproductive group levels to help derive sustainable management scenarios for tropical forests. PMID:24424164

  3. Achievement Motivation in High School: Contrasting Theoretical Models in the Classroom.

    ERIC Educational Resources Information Center

    Garcia-Celay, I. Montero; Tapia, J. Alonso

    1992-01-01

    Three models of achievement motivation in the classroom are contrasted. Results with 155 high school students suggest that the model of C. S. Dweck and E. S. Elliott offers a better explanation of the relationships among achievement motivation, attributions, emotional reactions, expectancies, and performance than do the other models. (SLD)

  4. Sensitivity to gaze-contingent contrast increments in naturalistic movies: An exploratory report and model comparison

    PubMed Central

    Wallis, Thomas S. A.; Dorr, Michael; Bex, Peter J.

    2015-01-01

    Sensitivity to luminance contrast is a prerequisite for all but the simplest visual systems. To examine contrast increment detection performance in a way that approximates the natural environmental input of the human visual system, we presented contrast increments gaze-contingently within naturalistic video freely viewed by observers. A band-limited contrast increment was applied to a local region of the video relative to the observer's current gaze point, and the observer made a forced-choice response to the location of the target (≈25,000 trials across five observers). We present exploratory analyses showing that performance improved as a function of the magnitude of the increment and depended on the direction of eye movements relative to the target location, the timing of eye movements relative to target presentation, and the spatiotemporal image structure at the target location. Contrast discrimination performance can be modeled by assuming that the underlying contrast response is an accelerating nonlinearity (arising from a nonlinear transducer or gain control). We implemented one such model and examined the posterior over model parameters, estimated using Markov-chain Monte Carlo methods. The parameters were poorly constrained by our data; parameters constrained using strong priors taken from previous research showed poor cross-validated prediction performance. Atheoretical logistic regression models were better constrained and provided similar prediction performance to the nonlinear transducer model. Finally, we explored the properties of an extended logistic regression that incorporates both eye movement and image content features. Models of contrast transduction may be better constrained by incorporating data from both artificial and natural contrast perception settings. PMID:26057546

  5. Modeling organic transformations by microorganisms of soils in six contrasting ecosystems: Validation of the MOMOS model

    NASA Astrophysics Data System (ADS)

    Pansu, M.; Sarmiento, L.; Rujano, M. A.; Ablan, M.; Acevedo, D.; Bottner, P.

    2010-03-01

    The Modeling Organic Transformations by Microorganisms of Soils (MOMOS) model simulates the growth, respiration, and mortality of soil microorganisms as main drivers of the mineralization and humification processes of organic substrates. Originally built and calibrated using data from two high-altitude sites, the model is now validated with data from a 14C experiment carried out in six contrasting tropical ecosystems covering a large gradient of temperature, rainfall, vegetation, and soil types from 65 to 3968 m asl. MOMOS enabled prediction of a greater number of variables using a lower number of parameter values than for predictions previously published on this experiment. The measured 14C mineralization and transfer into microbial biomass (MB) and humified compartments were accurately modeled using (1) temperature and moisture response functions to daily adjust the model responses to weather conditions and (2) optimization of only one parameter, the respiration rate kresp of soil microorganisms at optimal temperature and moisture. This validates the parameterization and hypotheses of the previous calibration experiment. Climate and microbial respiratory activity, related to soil properties, appear as the main factors that regulate the C cycle. The kresp rate was found to be negatively related to the fine textural fraction of soil and positively related to soil pH, allowing the proposition of two transfer functions that can be helpful to generalize MOMOS application at regional or global scale.

  6. Modelling contrast sensitivity as a function of retinal illuminance and grating area.

    PubMed

    Rovamo, J; Mustonen, J; Näsänen, R

    1994-05-01

    We extended the contrast detection model of human vision [Rovamo, Luntinen & Näsänen (1993b) Vision Research, 33, 2773-2788] to low light levels by taking into account the effect of light-dependent quantal noise. The extended model comprises (i) low-pass filtering due to the optical modulation transfer function of the eye, (ii) addition of light-dependent noise at the event of quantal absorption, (iii) high-pass filtering of neural origin (lateral inhibition), (iv) addition of internal neural noise, and (v) detection by a local matched filter whose efficiency decreases with increasing grating area. To test the model we measured foveal contrast sensitivity as a function of retinal illuminance and grating area at spatial frequencies of 0.125-32 c/deg. In agreement with the model, monocular contrast sensitivity at all grating areas increased in proportion to I when retinal illuminance (I) was smaller than critical illuminance. Thereafter the increase saturated and contrast sensitivity became independent of retinal illuminance. Similarly, at all levels of retinal illuminance contrast sensitivity increased in proportion to A when grating area (A) was smaller than critical area. Thereafter the increase saturated and contrast sensitivity became independent of area. Critical level of retinal illuminance increased in proportion to the spatial frequency squared. Critical area marking the saturation of spatial integration was constant at low spatial frequencies but decreased in inverse proportion to spatial frequency squared at medium and high spatial frequencies. The maximum contrast sensitivity obtainable by spatial integration in bright light increased at low spatial frequencies in proportion to spatial frequency, was constant at medium spatial frequencies, and decreased in inverse proportion to spatial frequency cubed at high spatial frequencies. The increase was due to the neural modulation transfer function of the visual pathways whereas the decrease was due to the

  7. Closing the contrast gap between testbed and model prediction with WFIRST-CGI shaped pupil coronagraph

    NASA Astrophysics Data System (ADS)

    Zhou, Hanying; Nemati, Bijan; Krist, John; Cady, Eric; Prada, Camilo M.; Kern, Brian; Poberezhskiy, Ilya

    2016-07-01

    JPL has recently passed an important milestone in its technology development for a proposed NASA WFIRST mission coronagraph: demonstration of better than 1x10-8 contrast over broad bandwidth (10%) on both shaped pupil coronagraph (SPC) and hybrid Lyot coronagraph (HLC) testbeds with the WFIRST obscuration pattern. Challenges remain, however, in the technology readiness for the proposed mission. One is the discrepancies between the achieved contrasts on the testbeds and their corresponding model predictions. A series of testbed diagnoses and modeling activities were planned and carried out on the SPC testbed in order to close the gap. A very useful tool we developed was a derived "measured" testbed wavefront control Jacobian matrix that could be compared with the model-predicted "control" version that was used to generate the high contrast dark hole region in the image plane. The difference between these two is an estimate of the error in the control Jacobian. When the control matrix, which includes both amplitude and phase, was modified to reproduce the error, the simulated performance closely matched the SPC testbed behavior in both contrast floor and contrast convergence speed. This is a step closer toward model validation for high contrast coronagraphs. Further Jacobian analysis and modeling provided clues to the possible sources for the mismatch: DM misregistration and testbed optical wavefront error (WFE) and the deformable mirror (DM) setting for correcting this WFE. These analyses suggested that a high contrast coronagraph has a tight tolerance in the accuracy of its control Jacobian. Modifications to both testbed control model as well as prediction model are being implemented, and future works are discussed.

  8. A normalized contrast-encoding model exhibits bright/dark asymmetries similar to early visual neurons.

    PubMed

    Cooper, Emily A

    2016-04-01

    Biological sensory systems share a number of organizing principles. One such principle is the formation of parallel streams. In the visual system, information about bright and dark features is largely conveyed via two separate streams: theONandOFFpathways. While brightness and darkness can be considered symmetric and opposite forms of visual contrast, the response properties of cells in theONandOFFpathways are decidedly asymmetric. Here, we ask whether a simple contrast-encoding model predicts asymmetries for brights and darks that are similar to the asymmetries found in theONandOFFpathways. Importantly, this model does not include any explicit differences in how the visual system represents brights and darks, but it does include a common normalization mechanism. The phenomena captured by the model include (1) nonlinear contrast response functions, (2) greater nonlinearities in the responses to darks, and (3) larger responses to dark contrasts. We report a direct, quantitative comparison between these model predictions and previously published electrophysiological measurements from the retina and thalamus (guinea pig and cat, respectively). This work suggests that the simple computation of visual contrast may account for a range of early visual processing nonlinearities. Assessing explicit models of sensory representations is essential for understanding which features of neuronal activity these models can and cannot predict, and for investigating how early computations may reverberate through the sensory pathways. PMID:27044852

  9. A normalized contrast-encoding model exhibits bright/dark asymmetries similar to early visual neurons.

    PubMed

    Cooper, Emily A

    2016-04-01

    Biological sensory systems share a number of organizing principles. One such principle is the formation of parallel streams. In the visual system, information about bright and dark features is largely conveyed via two separate streams: theONandOFFpathways. While brightness and darkness can be considered symmetric and opposite forms of visual contrast, the response properties of cells in theONandOFFpathways are decidedly asymmetric. Here, we ask whether a simple contrast-encoding model predicts asymmetries for brights and darks that are similar to the asymmetries found in theONandOFFpathways. Importantly, this model does not include any explicit differences in how the visual system represents brights and darks, but it does include a common normalization mechanism. The phenomena captured by the model include (1) nonlinear contrast response functions, (2) greater nonlinearities in the responses to darks, and (3) larger responses to dark contrasts. We report a direct, quantitative comparison between these model predictions and previously published electrophysiological measurements from the retina and thalamus (guinea pig and cat, respectively). This work suggests that the simple computation of visual contrast may account for a range of early visual processing nonlinearities. Assessing explicit models of sensory representations is essential for understanding which features of neuronal activity these models can and cannot predict, and for investigating how early computations may reverberate through the sensory pathways.

  10. Power Laws for Heavy-Tailed Distributions: Modeling Allele and Haplotype Diversity for the National Marrow Donor Program

    PubMed Central

    Gragert, Loren; Maiers, Martin; Chatterjee, Ansu; Albrecht, Mark

    2015-01-01

    Measures of allele and haplotype diversity, which are fundamental properties in population genetics, often follow heavy tailed distributions. These measures are of particular interest in the field of hematopoietic stem cell transplant (HSCT). Donor/Recipient suitability for HSCT is determined by Human Leukocyte Antigen (HLA) similarity. Match predictions rely upon a precise description of HLA diversity, yet classical estimates are inaccurate given the heavy-tailed nature of the distribution. This directly affects HSCT matching and diversity measures in broader fields such as species richness. We, therefore, have developed a power-law based estimator to measure allele and haplotype diversity that accommodates heavy tails using the concepts of regular variation and occupancy distributions. Application of our estimator to 6.59 million donors in the Be The Match Registry revealed that haplotypes follow a heavy tail distribution across all ethnicities: for example, 44.65% of the European American haplotypes are represented by only 1 individual. Indeed, our discovery rate of all U.S. European American haplotypes is estimated at 23.45% based upon sampling 3.97% of the population, leaving a large number of unobserved haplotypes. Population coverage, however, is much higher at 99.4% given that 90% of European Americans carry one of the 4.5% most frequent haplotypes. Alleles were found to be less diverse suggesting the current registry represents most alleles in the population. Thus, for HSCT registries, haplotype discovery will remain high with continued recruitment to a very deep level of sampling, but population coverage will not. Finally, we compared the convergence of our power-law versus classical diversity estimators such as Capture recapture, Chao, ACE and Jackknife methods. When fit to the haplotype data, our estimator displayed favorable properties in terms of convergence (with respect to sampling depth) and accuracy (with respect to diversity estimates). This

  11. A model for oxygen-dependent backscattering spectroscopic contrast from single red blood cells (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Liu, Rongrong; Yi, Ji; Chen, Siyu; Zhang, Hao F.; Backman, Vadim

    2016-03-01

    The oxygen-dependent absorption of hemoglobin provides the fundamental contrast for all label-free techniques measuring blood oxygenation. When hemoglobin is packaged into red blood cells (RBCs), the structure of the cells creates light scattering which also depends on the absorption based on the Kramers-Kronig relationship. Thus a proper characterization of the optical behaviors of blood has been a key to any accurate measurement of blood oxygenation, particularly at the capillary level where RBCs are dispersed individually in contrast to a densely packed whole blood. Here we provided a theoretical model under Born Approximation to characterize the oxygen dependent backscattering spectroscopic contrast from single RBCs. Using this theoretical model, we conducted simulations on both oxygenated and deoxygenated single RBCs with different sizes for standard and possible deformed cell geometries in blood flow, all which suggested similar backscattering spectroscopic contrast and were confirmed by Mie Theory and experiments using visible Optical Coherence Tomography (visOCT). As long as the cell size satisfies Gaussian distribution with a coefficient variance (C.V.) large enough, there is clear absorption contrast between the backscattering spectra of oxygenated and deoxygenated single RBCs calculated by this model, so oxygen saturation can then be characterized. Thus, this theoretical model can be extended to extract absorption features of other scattering particles as long as they satisfy Born Approximation.

  12. The investigation of a relative contrast index model for fingerprint quantification.

    PubMed

    Vanderwee, Jana; Porter, Glenn; Renshaw, Adrian; Bell, Michael

    2011-01-30

    The quantification of fingerprint contrast is a relatively new concept in fingerprint enhancement research. It has emerged as a mode of fingerprint assessment to reduce the potential biased of visual qualitative assessment. Subjective qualitative methods that are currently reported in the literature include; side-by-side assessment, assigning a score to a treatment based on visible criteria and stating observed results without presenting supporting validation. These qualitative methods often do not state clearly the visual assessment parameters and produce a degree of ambiguity when defining the enhancement results. The relative contrast index model was constructed to empirically quantify the difference in contrast between fingerprint ridges and valleys, using measurements gained from a microspectrophotometer. This paper seeks to further investigate this recent research and test the model using three different microspectrophotometers. Data from these separate sources will determine whether the theoretical aspects of the model would pragmatically produce reliable and repeatable results across a range of microspectrophotometers found in forensic laboratories.

  13. A Contrast Enhancement Method for HDR Image Using a Modified Image Formation Model

    NASA Astrophysics Data System (ADS)

    Yun, Byoung-Ju; Hong, Hee-Dong; Choi, Ho-Hyoung

    Poor illumination and viewing conditions have negativeinfluences on the quality of an image, especially the contrast of the dark and bright region. Thus, captured and displayed images usually need contrast enhancement. Histogram-based or gamma correction-based methods are generally utilized for this. However, these methods are global contrast enhancement method, and since the sensitivity of the human eye changes locally according to the position of the object and the illumination in the scene, the global contrast enhancement methods have a limit. The spatial adaptive method is needed to overcome these limitations and it has led to the development of an integrated surround retinex (ISR), and estimation of dominant chromaticity (EDC) methods. However, these methods are based on Gray-World Assumption, and they use a general image formation model, so the color constancy is known to get poor results, shown through graying-out, halo-artifacts (ringing effects), and the dominated color. This paper presents a contrast enhancement method using a modified image formation model in which the image is divided into three components: global illumination, local illumination and reflectance. After applying the power constant value to control the contrast in the resulting image, the output image is obtained from their product to avoid or minimize a color distortion, based on the sRGB color representation. The experimental results show that the proposed method yields better performances than conventional methods.

  14. Momentum transfer Monte Carlo model for the simulation of laser speckle contrast imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Regan, Caitlin; Hayakawa, Carole K.; Choi, Bernard

    2016-03-01

    Laser speckle imaging (LSI) enables measurement of relative blood flow in microvasculature and perfusion in tissues. To determine the impact of tissue optical properties and perfusion dynamics on speckle contrast, we developed a computational simulation of laser speckle contrast imaging. We used a discrete absorption-weighted Monte Carlo simulation to model the transport of light in tissue. We simulated optical excitation of a uniform flat light source and tracked the momentum transfer of photons as they propagated through a simulated tissue geometry. With knowledge of the probability distribution of momentum transfer occurring in various layers of the tissue, we calculated the expected laser speckle contrast arising with coherent excitation using both reflectance and transmission geometries. We simulated light transport in a single homogeneous tissue while independently varying either absorption (.001-100mm^-1), reduced scattering (.1-10mm^-1), or anisotropy (0.05-0.99) over a range of values relevant to blood and commonly imaged tissues. We observed that contrast decreased by 49% with an increase in optical scattering, and observed a 130% increase with absorption (exposure time = 1ms). We also explored how speckle contrast was affected by the depth (0-1mm) and flow speed (0-10mm/s) of a dynamic vascular inclusion. This model of speckle contrast is important to increase our understanding of how parameters such as perfusion dynamics, vessel depth, and tissue optical properties affect laser speckle imaging.

  15. Towards an Analytical Age-Dependent Model of Contrast Sensitivity Functions for an Ageing Society.

    PubMed

    Joulan, Karine; Brémond, Roland; Hautière, Nicolas

    2015-01-01

    The Contrast Sensitivity Function (CSF) describes how the visibility of a grating depends on the stimulus spatial frequency. Many published CSF data have demonstrated that contrast sensitivity declines with age. However, an age-dependent analytical model of the CSF is not available to date. In this paper, we propose such an analytical CSF model based on visual mechanisms, taking into account the age factor. To this end, we have extended an existing model from Barten (1999), taking into account the dependencies of this model's optical and physiological parameters on age. Age-dependent models of the cones and ganglion cells densities, the optical and neural MTF, and optical and neural noise are proposed, based on published data. The proposed age-dependent CSF is finally tested against available experimental data, with fair results. Such an age-dependent model may be beneficial when designing real-time age-dependent image coding and display applications. PMID:26078994

  16. Towards an Analytical Age-Dependent Model of Contrast Sensitivity Functions for an Ageing Society

    PubMed Central

    Joulan, Karine; Brémond, Roland

    2015-01-01

    The Contrast Sensitivity Function (CSF) describes how the visibility of a grating depends on the stimulus spatial frequency. Many published CSF data have demonstrated that contrast sensitivity declines with age. However, an age-dependent analytical model of the CSF is not available to date. In this paper, we propose such an analytical CSF model based on visual mechanisms, taking into account the age factor. To this end, we have extended an existing model from Barten (1999), taking into account the dependencies of this model's optical and physiological parameters on age. Age-dependent models of the cones and ganglion cells densities, the optical and neural MTF, and optical and neural noise are proposed, based on published data. The proposed age-dependent CSF is finally tested against available experimental data, with fair results. Such an age-dependent model may be beneficial when designing real-time age-dependent image coding and display applications. PMID:26078994

  17. A spatially-distributed computational model to quantify behaviour of contrast agents in MR perfusion imaging

    PubMed Central

    Cookson, A.N.; Lee, J.; Michler, C.; Chabiniok, R.; Hyde, E.; Nordsletten, D.; Smith, N.P.

    2014-01-01

    Contrast agent enhanced magnetic resonance (MR) perfusion imaging provides an early, non-invasive indication of defects in the coronary circulation. However, the large variation of contrast agent properties, physiological state and imaging protocols means that optimisation of image acquisition is difficult to achieve. This situation motivates the development of a computational framework that, in turn, enables the efficient mapping of this parameter space to provide valuable information for optimisation of perfusion imaging in the clinical context. For this purpose a single-compartment porous medium model of capillary blood flow is developed which is coupled with a scalar transport model, to characterise the behaviour of both blood-pool and freely-diffusive contrast agents characterised by their ability to diffuse through the capillary wall into the extra-cellular space. A parameter space study is performed on the nondimensionalised equations using a 2D model for both healthy and diseased myocardium, examining the sensitivity of system behaviour to Peclet number, Damköhler number (Da), diffusivity ratio and fluid porosity. Assuming a linear MR signal response model, sample concentration time series data are calculated, and the sensitivity of clinically-relevant properties of these signals to the model parameters is quantified. Both upslope and peak values display significant non-monotonic behaviour with regard to the Damköhler number, with these properties showing a high degree of sensitivity in the parameter range relevant to contrast agents currently in use. However, the results suggest that signal upslope is the more robust and discerning metric for perfusion quantification, in particular for correlating with perfusion defect size. Finally, the results were examined in the context of nonlinear signal response, flow quantification via Fermi deconvolution and perfusion reserve index, which demonstrated that there is no single best set of contrast agent parameters

  18. Stochastic modelling of shifts in allele frequencies reveals a strongly polygynous mating system in the re-introduced Asiatic wild ass.

    PubMed

    Renan, Sharon; Greenbaum, Gili; Shahar, Naama; Templeton, Alan R; Bouskila, Amos; Bar-David, Shirli

    2015-04-01

    Small populations are prone to loss of genetic variation and hence to a reduction in their evolutionary potential. Therefore, studying the mating system of small populations and its potential effects on genetic drift and genetic diversity is of high importance for their viability assessments. The traditional method for studying genetic mating systems is paternity analysis. Yet, as small populations are often rare and elusive, the genetic data required for paternity analysis are frequently unavailable. The endangered Asiatic wild ass (Equus hemionus), like all equids, displays a behaviourally polygynous mating system; however, the level of polygyny has never been measured genetically in wild equids. Combining noninvasive genetic data with stochastic modelling of shifts in allele frequencies, we developed an alternative approach to paternity analysis for studying the genetic mating system of the re-introduced Asiatic wild ass in the Negev Desert, Israel. We compared the shifts in allele frequencies (as a measure of genetic drift) that have occurred in the wild ass population since re-introduction onset to simulated scenarios under different proportions of mating males. We revealed a strongly polygynous mating system in which less than 25% of all males participate in the mating process each generation. This strongly polygynous mating system and its potential effect on the re-introduced population's genetic diversity could have significant consequences for the long-term persistence of the population in the Negev. The stochastic modelling approach and the use of allele-frequency shifts can be further applied to systems that are affected by genetic drift and for which genetic data are limited. PMID:25728575

  19. Stochastic modelling of shifts in allele frequencies reveals a strongly polygynous mating system in the re-introduced Asiatic wild ass.

    PubMed

    Renan, Sharon; Greenbaum, Gili; Shahar, Naama; Templeton, Alan R; Bouskila, Amos; Bar-David, Shirli

    2015-04-01

    Small populations are prone to loss of genetic variation and hence to a reduction in their evolutionary potential. Therefore, studying the mating system of small populations and its potential effects on genetic drift and genetic diversity is of high importance for their viability assessments. The traditional method for studying genetic mating systems is paternity analysis. Yet, as small populations are often rare and elusive, the genetic data required for paternity analysis are frequently unavailable. The endangered Asiatic wild ass (Equus hemionus), like all equids, displays a behaviourally polygynous mating system; however, the level of polygyny has never been measured genetically in wild equids. Combining noninvasive genetic data with stochastic modelling of shifts in allele frequencies, we developed an alternative approach to paternity analysis for studying the genetic mating system of the re-introduced Asiatic wild ass in the Negev Desert, Israel. We compared the shifts in allele frequencies (as a measure of genetic drift) that have occurred in the wild ass population since re-introduction onset to simulated scenarios under different proportions of mating males. We revealed a strongly polygynous mating system in which less than 25% of all males participate in the mating process each generation. This strongly polygynous mating system and its potential effect on the re-introduced population's genetic diversity could have significant consequences for the long-term persistence of the population in the Negev. The stochastic modelling approach and the use of allele-frequency shifts can be further applied to systems that are affected by genetic drift and for which genetic data are limited.

  20. A discriminative-generative model for detecting intravenous contrast in CT images.

    PubMed

    Criminisi, Antonio; Juluru, Krishna; Pathak, Sayan

    2011-01-01

    This paper presents an algorithm for the automatic detection of intravenous contrast in CT scans. This is useful e.g. for quality control, given the unreliability of the existing DICOM contrast metadata. The algorithm is based on a hybrid discriminative-generative probabilistic model. A discriminative detector localizes enhancing regions of interest in the scan. Then a generative classifier optimally fuses evidence gathered from those regions into an efficient, probabilistic prediction. The main contribution is in the generative part. It assigns optimal weights to the detected organs based on their learned degree of enhancement under contrast material. The model is robust with respect to missing organs, patients geometry, pathology and settings. Validation is performed on a database of 400 highly variable patients CT scans. Results indicate detection accuracy greater than 91% at approximately 1 second per scan. PMID:22003683

  1. Intravenous contrast media application using cone-beam computed tomography in a rabbit model

    PubMed Central

    Kim, Min-Sung; Kim, Bok-Yeol; Choi, Hwa-Young; Choi, Yoon-Joo; Oh, Song-Hee; Kang, Ju-Hee; Lee, Sae-Rom; Kang, Ju-Han; Kim, Gyu-Tae; Choi, Yong-Suk

    2015-01-01

    Purpose This study was performed to evaluate the feasibility of visualizing soft tissue lesions and vascular structures using contrast-enhanced cone-beam computed tomography (CE-CBCT) after the intravenous administration of a contrast medium in an animal model. Materials and Methods CBCT was performed on six rabbits after a contrast medium was administered using an injection dose of 2 mL/kg body weight and an injection rate of 1 mL/s via the ear vein or femoral vein under general anesthesia. Artificial soft tissue lesions were created through the transplantation of autologous fatty tissue into the salivary gland. Volume rendering reconstruction, maximum intensity projection, and multiplanar reconstruction images were reconstructed and evaluated in order to visualize soft tissue contrast and vascular structures. Results The contrast enhancement of soft tissue was possible using all contrast medium injection parameters. An adequate contrast medium injection parameter for facilitating effective CE-CBCT was a 5-mL injection before exposure combined with a continuous 5-mL injection during scanning. Artificial soft tissue lesions were successfully created in the animals. The CE-CBCT images demonstrated adequate opacification of the soft tissues and vascular structures. Conclusion Despite limited soft tissue resolution, the opacification of vascular structures was observed and artificial soft tissue lesions were visualized with sufficient contrast to the surrounding structures. The vascular structures and soft tissue lesions appeared well delineated in the CE-CBCT images, which was probably due to the superior spatial resolution of CE-CBCT compared to other techniques, such as multislice computed tomography. PMID:25793181

  2. New prediction model for probe specificity in an allele-specific extension reaction for haplotype-specific extraction (HSE) of Y chromosome mixtures.

    PubMed

    Rothe, Jessica; Watkins, Norman E; Nagy, Marion

    2012-01-01

    Allele-specific extension reactions (ASERs) use 3' terminus-specific primers for the selective extension of completely annealed matches by polymerase. The ability of the polymerase to extend non-specific 3' terminal mismatches leads to a failure of the reaction, a process that is only partly understood and predictable, and often requires time-consuming assay design. In our studies we investigated haplotype-specific extraction (HSE) for the separation of male DNA mixtures. HSE is an ASER and provides the ability to distinguish between diploid chromosomes from one or more individuals. Here, we show that the success of HSE and allele-specific extension depend strongly on the concentration difference between complete match and 3' terminal mismatch. Using the oligonucleotide-modeling platform Visual Omp, we demonstrated the dependency of the discrimination power of the polymerase on match- and mismatch-target hybridization between different probe lengths. Therefore, the probe specificity in HSE could be predicted by performing a relative comparison of different probe designs with their simulated differences between the duplex concentration of target-probe match and mismatches. We tested this new model for probe design in more than 300 HSE reactions with 137 different probes and obtained an accordance of 88%.

  3. Initial invasion of gametophytic self-incompatibility alleles in the absence of tight linkage between pollen and pistil S alleles.

    PubMed

    Sakai, Satoki; Wakoh, Haluka

    2014-08-01

    In homomorphic self-incompatibility (SI) systems of plants, the loci controlling the pollen and pistil types are tightly linked, and this prevents the generation of compatible combinations of alleles expressing pollen and pistil types, which would result in self-fertilization. We modeled the initial invasion of the first pollen and pistil alleles in gametophytic SI to determine whether these alleles can stably coexist in a population without tight linkage. We assume pollen and pistil loci each carry an incompatibility allele S and an allele without an incompatibility function N. We assume that pollen with an S allele are incompatible with pistils carrying S alleles, whereas other crosses are compatible. Ovules in pistils carrying an S allele suffer viability costs because recognition consumes resources. We found that the cost of carrying a pistil S allele allows pollen and pistil S alleles to coexist in a stable equilibrium if linkage is partial. This occurs because parents that carry pistil S alleles but are homozygous for pollen N alleles cannot avoid self-fertilization; however, they suffer viability costs. Hence, pollen N alleles are selected again. When pollen and pistil S alleles can coexist in a polymorphic equilibrium, selection will favor tighter linkage.

  4. Modelling of a novel x-ray phase contrast imaging technique based on coded apertures

    NASA Astrophysics Data System (ADS)

    Olivo, A.; Speller, R.

    2007-11-01

    X-ray phase contrast imaging is probably the most relevant among emerging x-ray imaging techniques, and it has the proven potential of revolutionizing the field of diagnostic radiology. Impressive images of a wide range of samples have been obtained, mostly at synchrotron radiation facilities. The necessity of relying on synchrotron radiation has prevented to a large extent a widespread diffusion of phase contrast imaging, thus precluding its transfer to clinical practice. A new technique, based on the use of coded apertures, was recently developed at UCL. This technique was demonstrated to provide intense phase contrast signals with conventional x-ray sources and detectors. Unlike other attempts at making phase contrast imaging feasible with conventional sources, the coded-aperture approach does not impose substantial limitations and/or filtering of the radiation beam, and it therefore allows, for the first time, exposures compatible with clinical practice. The technique has been thoroughly modelled, and this paper describes the technique in detail by going through the different steps of the modelling. All the main factors influencing image quality are discussed, alongside the viability of realizing a prototype suitable for clinical use. The model has been experimentally validated and a section of the paper shows the comparison between simulated and experimental results.

  5. A vector model of colour contrast in a cone-excitation colour space.

    PubMed

    Shepherd, A J

    1997-01-01

    A vector model of colour contrast is examined in a colour space that is a logarithmic transformation of the MacLeod-Boynton cone-excitation diagram. Observers set matches in a haploscopic display, in which one eye viewed a standard display (a neutral target square in a coloured surround) and the other viewed a matching display (a variable square in its own surround). Contrast colours are simply represented in this colour space: the vector connecting the right-eye surround and matched chromaticities is parallel to and to the same length and direction as the vector that connects the left-eye (standard) surround and square chromaticities. This describes observers' matches to the hues induced in a neutral square for a range of inducing surround colours, a range of right-eye (match) surround colours and four different luminance contrasts.

  6. Tracer kinetic model-driven registration for dynamic contrast-enhanced MRI time-series data.

    PubMed

    Buonaccorsi, Giovanni A; O'Connor, James P B; Caunce, Angela; Roberts, Caleb; Cheung, Sue; Watson, Yvonne; Davies, Karen; Hope, Lynn; Jackson, Alan; Jayson, Gordon C; Parker, Geoffrey J M

    2007-11-01

    Dynamic contrast-enhanced MRI (DCE-MRI) time series data are subject to unavoidable physiological motion during acquisition (e.g., due to breathing) and this motion causes significant errors when fitting tracer kinetic models to the data, particularly with voxel-by-voxel fitting approaches. Motion correction is problematic, as contrast enhancement introduces new features into postcontrast images and conventional registration similarity measures cannot fully account for the increased image information content. A methodology is presented for tracer kinetic model-driven registration that addresses these problems by explicitly including a model of contrast enhancement in the registration process. The iterative registration procedure is focused on a tumor volume of interest (VOI), employing a three-dimensional (3D) translational transformation that follows only tumor motion. The implementation accurately removes motion corruption in a DCE-MRI software phantom and it is able to reduce model fitting errors and improve localization in 3D parameter maps in patient data sets that were selected for significant motion problems. Sufficient improvement was observed in the modeling results to salvage clinical trial DCE-MRI data sets that would otherwise have to be rejected due to motion corruption.

  7. Combined radio-colour contrast in the examination of ballistic head models.

    PubMed

    Schyma, C; Greschus, S; Urbach, H; Madea, B

    2012-07-01

    The conventional analysis of ballistic gelatine is performed by transillumination and scanning of 1-cm-thick slices. Previous research demonstrated the advantages of colour and radio contrast in gelatine for computed tomography (CT). The aim of this study was to determine whether this method could be applied to head models in order to facilitate their examination. Four head models of about 14 cm in diameter were prepared from two acryl hollow spheres and two polypropylene hollow spheres. Acryl paint was mixed with barium meal and sealed in a thin foil bag which was attached to the gelatine-filled sphere which was covered with about 3-mm-thick silicone. The head models were shot at using 9 mm × 19 expanding bullets from 4 m distance. The models were examined via multislice CT. The gelatine core was removed; the bullet track was photographed and cut into consecutive slices which were scanned optically. CT images were processed with Corel Photo-Paint. Optical and radiological images were analysed using the AxioVision software. The disruption of the gelatine within the head model was visualised by extensive distribution of paint up to the end of the finest cracks and fissures and along the whole bullet track. CT imaging with excellent radio contrast in the gelatine cracks caused by the temporary cavity allowed for multiplanar reconstruction. We conclude that the combination of colour contrast in gelatine with contrast material-enhanced CT facilitates accurate measurements in ballistic head models. PMID:22576293

  8. The Gravitational Effect of the Ocean Density Contrast for a Depth-Dependent Seawater Density Model

    NASA Astrophysics Data System (ADS)

    Novak, P.; Tenzer, R.; Gladkikh, V.

    2010-12-01

    In geophysical studies investigating the lithosphere structure, the topographic and consolidated crust density contrast stripping corrections are computed and applied to observed gravity data. The gravitational field generated by the ocean density contrast represents a significant amount of the signal to be modelled and subsequently subtracted from the gravity field. The ocean density contrast is typically calculated as the difference between the mean density values of the Earth’s crust and seawater. The currently available global geopotential models and the global elevation and bathymetry (ocean bottom depth) data allow modelling the topography corrected and bathymetry stripped gravity field quantities to a very high spectral resolution (up to degree 2159 of spherical harmonics) using methods for a spherical harmonic analysis and synthesis of the gravity field. The approximation of the actual seawater density distribution by the mean value yields relative errors up to 2% in computed values of the bathymetric stripping corrections. To reduce these errors, we adopt a depth-dependent theoretical model of the seawater density distribution to account for increasing seawater density with pressure/depth. The smaller lateral seawater density variations due to salinity and temperature and other oceanographic factors are not taken into consideration. The approximation of the seawater density by the depth-dependent density model reduces the maximum errors to less than 0.6%. The corresponding depth-averaged errors are below 0.1%. The depth-dependent seawater density model is facilitated in the forward modelling of the bathymetric stripping corrections. The expressions for computing the gravitational field quantities generated by the depth-dependent ocean density contrast are formulated in the spectral representation by means of the spherical bathymetric functions. These newly derived expressions are used to compute globally the bathymetric stripping corrections. The

  9. A model for ultrasound absorption and dispersion in dilute suspensions of nanometric contrast agents.

    PubMed

    Coulouvrat, François; Thomas, Jean-Louis; Astafyeva, Ksenia; Taulier, Nicolas; Conoir, Jean-Marc; Urbach, Wladimir

    2012-12-01

    Ultrasound dispersion and absorption are examined in dilute suspensions of contrast agents of nanometric size, with a typical radius around 100 nm. These kinds of contrast agents are designed for targeted delivery of drugs for cancer treatment. Compared to standard contrast agents used for imaging, particles are of smaller size to pass through the endothelial barrier, their shell, made up of biocompatible polymer, is stiffer to undergo a longer lifetime, and they have a liquid core instead of a gaseous one. Ultrasound propagation in dilute suspension is modeled by combining two modes for particle oscillations. The first one is a dilatational mode assuming an incompressible shell with a rheological behavior of Kelvin-Voigt or Maxwell type. The second one is a translational mode induced by visco-inertial interaction with the ambient fluid. The relative importance of these two modes of interaction on both dispersion and absorption is quantified and analyzed for a model system and for two radii (75 and 150 nm) and the two rheological models. The influence of shell parameters (Young modulus, viscosity, and relative thickness) is finally discussed.

  10. Development and evaluation of a 3D model observer with nonlinear spatiotemporal contrast sensitivity

    NASA Astrophysics Data System (ADS)

    Avanaki, Ali R. N.; Espig, Kathryn S.; Maidment, Andrew D. A.; Marchessoux, Cedric; Bakic, Predrag R.; Kimpe, Tom R. L.

    2014-03-01

    We investigate improvements to our 3D model observer with the goal of better matching human observer performance as a function of viewing distance, effective contrast, maximum luminance, and browsing speed. Two nonlinear methods of applying the human contrast sensitivity function (CSF) to a 3D model observer are proposed, namely the Probability Map (PM) and Monte Carlo (MC) methods. In the PM method, the visibility probability for each frequency component of the image stack, p, is calculated taking into account Barten's spatiotemporal CSF, the component modulation, and the human psychometric function. The probability p is considered to be equal to the perceived amplitude of the frequency component and thus can be used by a traditional model observer (e.g., LG-msCHO) in the space-time domain. In the MC method, each component is randomly kept with probability p or discarded with 1-p. The amplitude of the retained components is normalized to unity. The methods were tested using DBT stacks of an anthropomorphic breast phantom processed in a comprehensive simulation pipeline. Our experiments indicate that both the PM and MC methods yield results that match human observer performance better than the linear filtering method as a function of viewing distance, effective contrast, maximum luminance, and browsing speed.

  11. Signal-to-noise ratio, contrast-to-noise ratio and pharmacokinetic modeling considerations in dynamic contrast-enhanced magnetic resonance imaging.

    PubMed

    Li, Xin; Huang, Wei; Rooney, William D

    2012-11-01

    With advances in magnetic resonance imaging (MRI) technology, dynamic contrast-enhanced (DCE)-MRI is approaching the capability to simultaneously deliver both high spatial and high temporal resolutions for clinical applications. However, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) considerations and their impacts regarding pharmacokinetic modeling of the time-course data continue to represent challenges in the design of DCE-MRI acquisitions. Given that many acquisition parameters can affect the nature of DCE-MRI data, minimizing tissue-specific data acquisition discrepancy (among sites and scanner models) is as important as synchronizing pharmacokinetic modeling approaches. For cancer-related DCE-MRI studies where rapid contrast reagent (CR) extravasation is expected, current DCE-MRI protocols often adopt a three-dimensional fast low-angle shot (FLASH) sequence to achieve spatial-temporal resolution requirements. Based on breast and prostate DCE-MRI data acquired with different FLASH sequence parameters, this paper elucidates a number of SNR and CNR considerations for acquisition optimization and pharmacokinetic modeling implications therein. Simulations based on region of interest data further indicate that the effects of intercompartmental water exchange often play an important role in DCE time-course data modeling, especially for protocols optimized for post-CR SNR.

  12. Carnitine palmitoyltransferase 1B 531K allele carriers sustain a higher respiratory quotient after aerobic exercise, but β3-adrenoceptor 64R allele does not affect lipolysis: a human model.

    PubMed

    Gómez-Gómez, Eduardo; Ríos-Martínez, Martín Efrén; Castro-Rodríguez, Elena Margarita; Del-Toro-Equíhua, Mario; Ramírez-Flores, Mario; Delgado-Enciso, Ivan; Pérez-Huitimea, Ana Lilia; Baltazar-Rodríguez, Luz Margarita; Velasco-Pineda, Gilberto; Muñiz-Murguía, Jesús

    2014-01-01

    Carnitine palmitoyltransferase IB (CPT1B) and adrenoceptor beta-3 (ADRB3) are critical regulators of fat metabolism. CPT1B transports free acyl groups into mitochondria for oxidation, and ADRB3 triggers lipolysis in adipocytes, and their respective polymorphisms E531K and W64R have been identified as indicators of obesity in population studies. It is therefore important to understand the effects of these mutations on ADRB3 and CPT1B function in adipose and skeletal muscle tissue, respectively. This study aimed to analyze the rate of lipolysis of plasma indicators (glycerol, free fatty acids, and beta hydroxybutyrate) and fat oxidation (through the non-protein respiratory quotient). These parameters were measured in 37 participants during 30 min of aerobic exercise at approximately 62% of maximal oxygen uptake, followed by 30 min of recovery. During recovery, mean respiratory quotient values were higher in K allele carriers than in non-carriers, indicating low post-exercise fatty acid oxidation rates. No significant differences in lipolysis or lipid oxidation were observed between R and W allele carriers of ADRB3 at any time during the aerobic load. The substitution of glutamic acid at position 531 by lysine in the CPT1B protein decreases the mitochondrial beta-oxidation pathway, which increases the non-protein respiratory quotient value during recovery from exercise. This may contribute to weight gain or reduced weight-loss following exercise. PMID:24905907

  13. Carnitine Palmitoyltransferase 1B 531K Allele Carriers Sustain a Higher Respiratory Quotient after Aerobic Exercise, but β3-Adrenoceptor 64R Allele Does Not Affect Lipolysis: A Human Model

    PubMed Central

    Gómez-Gómez, Eduardo; Ríos-Martínez, Martín Efrén; Castro-Rodríguez, Elena Margarita; Del-Toro-Equíhua, Mario; Ramírez-Flores, Mario; Delgado-Enciso, Ivan; Pérez-Huitimea, Ana Lilia; Baltazar-Rodríguez, Luz Margarita; Velasco-Pineda, Gilberto; Muñiz-Murguía, Jesús

    2014-01-01

    Carnitine palmitoyltransferase IB (CPT1B) and adrenoceptor beta-3 (ADRB3) are critical regulators of fat metabolism. CPT1B transports free acyl groups into mitochondria for oxidation, and ADRB3 triggers lipolysis in adipocytes, and their respective polymorphisms E531K and W64R have been identified as indicators of obesity in population studies. It is therefore important to understand the effects of these mutations on ADRB3 and CPT1B function in adipose and skeletal muscle tissue, respectively. This study aimed to analyze the rate of lipolysis of plasma indicators (glycerol, free fatty acids, and beta hydroxybutyrate) and fat oxidation (through the non-protein respiratory quotient). These parameters were measured in 37 participants during 30 min of aerobic exercise at approximately 62% of maximal oxygen uptake, followed by 30 min of recovery. During recovery, mean respiratory quotient values were higher in K allele carriers than in non-carriers, indicating low post-exercise fatty acid oxidation rates. No significant differences in lipolysis or lipid oxidation were observed between R and W allele carriers of ADRB3 at any time during the aerobic load. The substitution of glutamic acid at position 531 by lysine in the CPT1B protein decreases the mitochondrial beta-oxidation pathway, which increases the non-protein respiratory quotient value during recovery from exercise. This may contribute to weight gain or reduced weight-loss following exercise. PMID:24905907

  14. Carnitine palmitoyltransferase 1B 531K allele carriers sustain a higher respiratory quotient after aerobic exercise, but β3-adrenoceptor 64R allele does not affect lipolysis: a human model.

    PubMed

    Gómez-Gómez, Eduardo; Ríos-Martínez, Martín Efrén; Castro-Rodríguez, Elena Margarita; Del-Toro-Equíhua, Mario; Ramírez-Flores, Mario; Delgado-Enciso, Ivan; Pérez-Huitimea, Ana Lilia; Baltazar-Rodríguez, Luz Margarita; Velasco-Pineda, Gilberto; Muñiz-Murguía, Jesús

    2014-01-01

    Carnitine palmitoyltransferase IB (CPT1B) and adrenoceptor beta-3 (ADRB3) are critical regulators of fat metabolism. CPT1B transports free acyl groups into mitochondria for oxidation, and ADRB3 triggers lipolysis in adipocytes, and their respective polymorphisms E531K and W64R have been identified as indicators of obesity in population studies. It is therefore important to understand the effects of these mutations on ADRB3 and CPT1B function in adipose and skeletal muscle tissue, respectively. This study aimed to analyze the rate of lipolysis of plasma indicators (glycerol, free fatty acids, and beta hydroxybutyrate) and fat oxidation (through the non-protein respiratory quotient). These parameters were measured in 37 participants during 30 min of aerobic exercise at approximately 62% of maximal oxygen uptake, followed by 30 min of recovery. During recovery, mean respiratory quotient values were higher in K allele carriers than in non-carriers, indicating low post-exercise fatty acid oxidation rates. No significant differences in lipolysis or lipid oxidation were observed between R and W allele carriers of ADRB3 at any time during the aerobic load. The substitution of glutamic acid at position 531 by lysine in the CPT1B protein decreases the mitochondrial beta-oxidation pathway, which increases the non-protein respiratory quotient value during recovery from exercise. This may contribute to weight gain or reduced weight-loss following exercise.

  15. Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells.

    PubMed

    Lin, Alex W H; Lewinski, Nastassja A; West, Jennifer L; Halas, Naomi J; Drezek, Rebekah A

    2005-01-01

    Many optical diagnostic approaches rely on changes in scattering and absorption properties to generate optical contrast between normal and diseased tissue. Recently, there has been increasing interest in using exogenous agents to enhance this intrinsic contrast with particular emphasis on the development for targeting specific molecular features of disease. Gold nanoshells are a class of core-shell nanoparticles with an extremely tunable peak optical resonance ranging from the near-UV to the mid-IR wavelengths. Using current chemistries, nanoshells of a wide variety of core and shell sizes can easily be fabricated to scatter and/or absorb light with optical cross sections often several times larger than the geometric cross section. Using gold nanoshells of different size and optical parameters, we employ Monte Carlo models to predict the effect of varying concentrations of nanoshells on tissue reflectance. The models demonstrate the importance of absorption from the nanoshells on remitted signals even when the optical extinction is dominated by scattering. Furthermore, because of the strong optical response of nanoshells, a considerable change in reflectance is observed with only a very small concentration of nanoshells. Characterizing the optical behavior of gold nanoshells in tissue will aid in developing nanoshells as contrast agents for optical diagnostics. PMID:16409100

  16. Low contrast detectability in CT for human and model observers in multi-slice data sets

    NASA Astrophysics Data System (ADS)

    Ba, Alexandre; Racine, Damien; Ott, Julien G.; Verdun, Francis R.; Kobbe-Schmidt, Sabine; Eckstein, Miguel P.; Bochud, Francois O.

    2015-03-01

    Task-based medical image quality is often assessed by model observers for single slice images. The goal of the study was to determine if model observers can predict human detection performance of low contrast signals in CT for clinical multi-slice (ms) images. We collected 24 different data subsets from a low contrast phantom: 3 dose levels (40, 90, 150 mAs), 4 signals (6 and 8 mm diameter; 10 and 20 HU at 120kV) and 2 reconstruction algorithms (FBP and iterative (IR)). Images were assessed by human and model observers in 4-alternative forced choice (4AFC) experiments with ms data set in a signal-known-exactly (SKE) paradigm. Model observers with single (msCHOa) and multiple (msCHOb) templates were implemented in a train and test method analysis with Dense Difference of Gaussian (DDoG) and Gabor spatial channels. For human observers, we found that percent correct increased with the dose and was higher for iterative reconstructed images than FBP in all investigated conditions. All model observers implemented overestimated human performance in any condition except one case (6mm and 10HU) for msCHOa and msCHOb with Gabor channels. Internal noise could be implemented and a good agreement was found but necessitates independent fits according to the reconstruction method. Generally msCHOb shows higher detection performance than msCHOa with both types of channels. Gabor channels were less efficient than DDoG in this context. These results allow further developments in 3D analysis technique for low contrast CT.

  17. Eye models for the prediction of contrast vision in patients with new intraocular lens designs

    NASA Astrophysics Data System (ADS)

    Piers, Patricia A.; Sverker Norrby, N. E.; Mester, Ulrich

    2004-04-01

    Theoretical calculations of the polychromatic modulation transfer function (MTF) and wave-front aberration were performed with physiological eye models. These eye models have an amount of spherical aberration that is representative of a normal population of pseudophakic eyes implanted with two different types of intraocular lens (IOL) made from high-refractive-index silicone. These theoretical calculations were compared with the measured contrast sensitivity function (CSF) under mesopic lighting conditions and with wave-front aberration (obtained with a Hartmann-Shack wave-front sensor) collected from 37 patients bilaterally implanted with the same types of lens. The relationships between the ocular wave-front aberration and the MTF predicted by the eye models and the CSF and the ocular wave-front aberration measured in eyes implanted with IOLs were investigated. The predicted improvements in MTF and wave-front aberration correlated well with the improvements measured in practice. Physiological eye models are therefore useful tools for IOL design.

  18. Comparison between PUN and Tofts models in the quantification of dynamic contrast-enhanced MR imaging

    NASA Astrophysics Data System (ADS)

    Mazzetti, S.; Gliozzi, A. S.; Bracco, C.; Russo, F.; Regge, D.; Stasi, M.

    2012-12-01

    Dynamic contrast-enhanced study in magnetic resonance imaging (DCE-MRI) is an important tool in oncology to visualize tissues vascularization and to define tumour aggressiveness on the basis of an altered perfusion and permeability. Pharmacokinetic models are generally used to extract hemodynamic parameters, providing a quantitative description of the contrast uptake and wash-out. Empirical functions can also be used to fit experimental data without the need of any assumption about tumour physiology, as in pharmacokinetic models, increasing their diagnostic utility, in particular when automatic diagnosis systems are implemented on the basis of an MRI multi-parametric approach. Phenomenological universalities (PUN) represent a novel tool for experimental research and offer a simple and systematic method to represent a set of data independent of the application field. DCE-MRI acquisitions can thus be advantageously evaluated by the extended PUN class, providing a convenient diagnostic tool to analyse functional studies, adding a new set of features for the classification of malignant and benign lesions in computer aided detection systems. In this work the Tofts pharmacokinetic model and the class EU1 generated by the PUN description were compared in the study of DCE-MRI of the prostate, evaluating complexity of model implementation, goodness of fitting results, classification performances and computational cost. The mean R2 obtained with the EU1 and Tofts model were equal to 0.96 and 0.90, respectively, and the classification performances achieved by the EU1 model and the Tofts implementation discriminated malignant from benign tissues with an area under the receiver operating characteristic curve equal to 0.92 and 0.91, respectively. Furthermore, the EU1 model has a simpler functional form which reduces implementation complexity and computational time, requiring 6 min to complete a patient elaboration process, instead of 8 min needed for the Tofts model analysis.

  19. Generation and modelling of megavoltage photon beams for contrast-enhanced radiation therapy

    NASA Astrophysics Data System (ADS)

    Robar, J. L.

    2006-11-01

    Contrast-enhanced radiation therapy (CERT) is a treatment approach involving the irradiation of tumours containing high atomic number (Z) contrast media, using low-quality x-ray beams. This work describes the experimental generation of x-ray beams using a linear accelerator with low-Z target materials (beryllium and aluminium), in order to produce photon energy spectra appropriate for CERT. Measurements were made to compare the experimental beams to conventional linear accelerator photon beams in terms of per cent depth dose. Monte Carlo simulation was used to model the generation of each beam, and models were validated against experimental measurement. Validated models were used to demonstrate changes in photon spectra as well as to quantify the variation of tumour dose enhancement with iodinated contrast medium concentration in a simulated tumour volume. Finally, the ratio of the linear attenuation coefficient for iodinated contrast medium relative to water was determined experimentally as a function of iodine concentration. Beams created with low-Z targets show significant changes in energy spectra compared to conventional beams. For the 4 MeV/Be beam, for example, 33% of photons have energies below 60 keV. Measurements and calculation show that both the linear attenuation coefficient ratio and dose enhancement factor (DEF) increase most rapidly at concentrations below 46 mg I ml-1. There is a significant dependence of DEF on electron energy and a lesser dependence on target material. The 4 MeV/Be beam is the most promising in terms of magnitude of DEF—for example, DEF values of 1.16 and 1.29 are obtained for concentrations of 20 mg I ml-1 and 50 mg I ml-1, respectively. DEF will increase or decrease, respectively, for shallower or deeper tumours at a rate of approximately 1.1% cm-1. In summary, we show that significant dose enhancement is possible by altering the linear accelerator target and filtration, but the magnitude is highly dependent on contrast

  20. Detection of nucleotide-specific CRISPR/Cas9 modified alleles using multiplex ligation detection

    PubMed Central

    KC, R.; Srivastava, A.; Wilkowski, J. M.; Richter, C. E.; Shavit, J. A.; Burke, D. T.; Bielas, S. L.

    2016-01-01

    CRISPR/Cas9 genome-editing has emerged as a powerful tool to create mutant alleles in model organisms. However, the precision with which these mutations are created has introduced a new set of complications for genotyping and colony management. Traditional gene-targeting approaches in many experimental organisms incorporated exogenous DNA and/or allele specific sequence that allow for genotyping strategies based on binary readout of PCR product amplification and size selection. In contrast, alleles created by non-homologous end-joining (NHEJ) repair of double-stranded DNA breaks generated by Cas9 are much less amenable to such strategies. Here we describe a novel genotyping strategy that is cost effective, sequence specific and allows for accurate and efficient multiplexing of small insertion-deletions and single-nucleotide variants characteristic of CRISPR/Cas9 edited alleles. We show that ligation detection reaction (LDR) can be used to generate products that are sequence specific and uniquely detected by product size and/or fluorescent tags. The method works independently of the model organism and will be useful for colony management as mutant alleles differing by a few nucleotides become more prevalent in experimental animal colonies. PMID:27557703

  1. Empirical evaluations of analytical issues arising from predicting HLA alleles using multiple SNPs

    PubMed Central

    2011-01-01

    Background Numerous immune-mediated diseases have been associated with the class I and II HLA genes located within the major histocompatibility complex (MHC) consisting of highly polymorphic alleles encoded by the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci. Genotyping for HLA alleles is complex and relatively expensive. Recent studies have demonstrated the feasibility of predicting HLA alleles, using MHC SNPs inside and outside of HLA that are typically included in SNP arrays and are commonly available in genome-wide association studies (GWAS). We have recently described a novel method that is complementary to the previous methods, for accurately predicting HLA alleles using unphased flanking SNPs genotypes. In this manuscript, we address several practical issues relevant to the application of this methodology. Results Applying this new methodology to three large independent study cohorts, we have evaluated the performance of the predictive models in ethnically diverse populations. Specifically, we have found that utilizing imputed in addition to genotyped SNPs generally yields comparable if not better performance in prediction accuracies. Our evaluation also supports the idea that predictive models trained on one population are transferable to other populations of the same ethnicity. Further, when the training set includes multi-ethnic populations, the resulting models are reliable and perform well for the same subpopulations across all HLA genes. In contrast, the predictive models built from single ethnic populations have superior performance within the same ethnic population, but are not likely to perform well in other ethnic populations. Conclusions The empirical explorations reported here provide further evidence in support of the application of this approach for predicting HLA alleles with GWAS-derived SNP data. Utilizing all available samples, we have built "state of the art" predictive models for HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. The HLA allele

  2. An experimental model for minimizing errors in laser speckle contrast imaging for microcirculation analysis

    NASA Astrophysics Data System (ADS)

    Sujatha, N.; Banerjee, Arnab

    2015-03-01

    Understanding the changes in microcirculatory flow and its measurements are very important for assessing the progress of various vascular malfunctions and their subsequent treatment effectiveness. Laser Speckle Contrast Imaging (LSCI) has been evolved as a whole-field, non-invasive and non-contact technique which has inherent advantages for microcirculation assessment in an in vivo environment compared to its noninvasive counterparts such as laser Doppler technique and video capillaroscopy. However, representation of flow velocity values in absolute units is still challenging and yet to be completely explored. In this paper, we propose an experimental model for estimating the flow velocity based for optimum camera exposure time. The LSCI experiments were conducted on a custom made phantom flow channel with induced flow in the microcirculation range using a syringe pump. The speckle image contrast was estimated temporally and is used to calculate velocity values. The relative error in the flow values is estimated to be a function of the calculated contrast. The estimated error has been incorporated as a correction factor in the obtained velocity term using LSCI and final velocity estimation was found to be within an acceptable error range independent of the flow velocity and scatterer concentration of the sample for optimum camera exposure duration.

  3. Optimization of a Spectral Contrast Enhancement Algorithm for Cochlear Implants Based on a Vowel Identification Model.

    PubMed

    Nogueira, Waldo; Rode, Thilo; Büchner, Andreas

    2016-01-01

    Speech intelligibility achieved with cochlear implants (CIs) shows large variability across different users. One reason that can explain this variability is the CI user's individual electrode nerve interface which can impact the spectral resolution they can achieve. Spectral resolution has been reported to be related to vowel and consonant recognition in CI listeners. One measure of spectral resolution is the spectral modulation threshold (SMT), which is defined as the smallest detectable spectral contrast in a stimulus. In this study we hypothesize that an algorithm that improves SMT may improve vowel identification, and consequently produce an improvement in speech understanding for CIs. With this purpose we implemented an algorithm, termed spectral contrast enhancement (SCE) that emphasizes peaks with respect to valleys in the audio spectrum. This algorithm can be configured with a single parameter: the amount of spectral contrast enhancement entitled "SCE factor". We would like to investigate whether the "SCE factor" can be individualized to each CI user. With this purpose we used a vowel identification model to predict the performance produced by the SCE algorithm with different "SCE factors" in a vowel identification task.In five CI users the new algorithm has been evaluated using a SMT task and a vowel identification task. The tasks were performed for SCE factors of 0 (no enhancement), 2 and 4. In general it seems that increasing the SCE factor produces a decrease in performance in both the SMT threshold and vowel identification.

  4. Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model

    PubMed Central

    Khan, Altaf-M; Maderdrut, Jerome L; Li, Min; Toliver, Herman L; Coy, David H; Simon, Eric E; Batuman, Vecihi

    2013-01-01

    We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase-deficient (eNOS−/−) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10−9–10−6 mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS−/− mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 μg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS−/− mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS−/− mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS−/− mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy. PMID:24400164

  5. Correlation between human observer performance and model observer performance in differential phase contrast CT

    SciTech Connect

    Li, Ke; Garrett, John; Chen, Guang-Hong

    2013-11-15

    Purpose: With the recently expanding interest and developments in x-ray differential phase contrast CT (DPC-CT), the evaluation of its task-specific detection performance and comparison with the corresponding absorption CT under a given radiation dose constraint become increasingly important. Mathematical model observers are often used to quantify the performance of imaging systems, but their correlations with actual human observers need to be confirmed for each new imaging method. This work is an investigation of the effects of stochastic DPC-CT noise on the correlation of detection performance between model and human observers with signal-known-exactly (SKE) detection tasks.Methods: The detectabilities of different objects (five disks with different diameters and two breast lesion masses) embedded in an experimental DPC-CT noise background were assessed using both model and human observers. The detectability of the disk and lesion signals was then measured using five types of model observers including the prewhitening ideal observer, the nonprewhitening (NPW) observer, the nonprewhitening observer with eye filter and internal noise (NPWEi), the prewhitening observer with eye filter and internal noise (PWEi), and the channelized Hotelling observer (CHO). The same objects were also evaluated by four human observers using the two-alternative forced choice method. The results from the model observer experiment were quantitatively compared to the human observer results to assess the correlation between the two techniques.Results: The contrast-to-detail (CD) curve generated by the human observers for the disk-detection experiments shows that the required contrast to detect a disk is inversely proportional to the square root of the disk size. Based on the CD curves, the ideal and NPW observers tend to systematically overestimate the performance of the human observers. The NPWEi and PWEi observers did not predict human performance well either, as the slopes of their CD

  6. NAME modelling activities for the CAST-CONTRAST-ATTREX VSLS measurements

    NASA Astrophysics Data System (ADS)

    Filus, Michal; Harris, Neil; Pyle, John; Ashfold, Matt; Atlas, Eliott; Navarro, Maria; Meneguz, Elena; Manning, Alistair

    2015-04-01

    The Numerical Atmospheric dispersion Modeling Environment (NAME) model is used to assess the spatial and temporal variability of transport of very short-lived halogenated organic species (VSLS), in particular bromoform, dibromomethane and methyl iodide, within the West Pacific tropical region. The NAME modelling results are compared with airborne measurements of VSLS taken during NASA ATTREX, NCAR CONTRAST and NERC CAST campaigns in January-March, 2014. NAME model aims to link the aircraft measurements to examine the vertical distribution of VSLS in the West Pacific troposphere. The major focus will be on assessing vertical transport in deep convection which is one of the crucial factors in redistributing chemicals within the tropical troposphere. The work presented shows the analysis of NAME runs made from the ATTREX flights over the East Pacific in January-February, 2013 and the ATTREX and CONTRAST flight tracks over the West Pacific in January-March, 2014. Each ATTREX 2013 and 2014 flight track is divided into segments, from which particles are released and followed backward to identify the low-level sources of air. Particles (15,000 per single point along the flight track) are released from the flight altitudes tracks and followed 12-days backwards. Fractions of trajectories are calculated according to particles which crossed below 5 and 1 km (corresponding to low troposphere and oceanic boundary layer, respectively). Then, initial concentrations for VSLS are assigned to particles which originated from below 5/1 km and final concentrations at flight altitudes are determined. NAME modeled results are compared with ATTREX VSLS flight measurements. Interannual variability of atmospheric transport of VSLS in the Tropics is studied by performing mock ATTREX-flight NAME runs for years: 2005-2014, with emphasis put on strong ENSO phase years.

  7. Optimized time-resolved imaging of contrast kinetics (TRICKS) in dynamic contrast-enhanced MRI after peptide receptor radionuclide therapy in small animal tumor models.

    PubMed

    Haeck, Joost; Bol, Karin; Bison, Sander; van Tiel, Sandra; Koelewijn, Stuart; de Jong, Marion; Veenland, Jifke; Bernsen, Monique

    2015-01-01

    Anti-tumor efficacy of targeted peptide-receptor radionuclide therapy (PRRT) relies on several factors, including functional tumor vasculature. Little is known about the effect of PRRT on tumor vasculature. With dynamic contrast-enhanced (DCE-) MRI, functional vasculature is imaged and quantified using contrast agents. In small animals DCE-MRI is a challenging application. We optimized a clinical sequence for fast hemodynamic acquisitions, time-resolved imaging of contrast kinetics (TRICKS), to obtain DCE-MRI images at both high spatial and high temporal resolution in mice and rats. Using TRICKS, functional vasculature was measured prior to PRRT and longitudinally to investigate the effect of treatment on tumor vascular characteristics. Nude mice bearing H69 tumor xenografts and rats bearing syngeneic CA20948 tumors were used to study perfusion following PRRT administration with (177) lutetium octreotate. Both semi-quantitative and quantitative parameters were calculated. Treatment efficacy was measured by tumor-size reduction. Optimized TRICKS enabled MRI at 0.032 mm(3) voxel size with a temporal resolution of less than 5 s and large volume coverage, a substantial improvement over routine pre-clinical DCE-MRI studies. Tumor response to therapy was reflected in changes in tumor perfusion/permeability parameters. The H69 tumor model showed pronounced changes in DCE-derived parameters following PRRT. The rat CA20948 tumor model showed more heterogeneity in both treatment outcome and perfusion parameters. TRICKS enabled the acquisition of DCE-MRI at both high temporal resolution (Tres ) and spatial resolutions relevant for small animal tumor models. With the high Tres enabled by TRICKS, accurate pharmacokinetic data modeling was feasible. DCE-MRI parameters revealed changes over time and showed a clear relationship between tumor size and Ktrans . PMID:25995102

  8. Optimized time-resolved imaging of contrast kinetics (TRICKS) in dynamic contrast-enhanced MRI after peptide receptor radionuclide therapy in small animal tumor models.

    PubMed

    Haeck, Joost; Bol, Karin; Bison, Sander; van Tiel, Sandra; Koelewijn, Stuart; de Jong, Marion; Veenland, Jifke; Bernsen, Monique

    2015-01-01

    Anti-tumor efficacy of targeted peptide-receptor radionuclide therapy (PRRT) relies on several factors, including functional tumor vasculature. Little is known about the effect of PRRT on tumor vasculature. With dynamic contrast-enhanced (DCE-) MRI, functional vasculature is imaged and quantified using contrast agents. In small animals DCE-MRI is a challenging application. We optimized a clinical sequence for fast hemodynamic acquisitions, time-resolved imaging of contrast kinetics (TRICKS), to obtain DCE-MRI images at both high spatial and high temporal resolution in mice and rats. Using TRICKS, functional vasculature was measured prior to PRRT and longitudinally to investigate the effect of treatment on tumor vascular characteristics. Nude mice bearing H69 tumor xenografts and rats bearing syngeneic CA20948 tumors were used to study perfusion following PRRT administration with (177) lutetium octreotate. Both semi-quantitative and quantitative parameters were calculated. Treatment efficacy was measured by tumor-size reduction. Optimized TRICKS enabled MRI at 0.032 mm(3) voxel size with a temporal resolution of less than 5 s and large volume coverage, a substantial improvement over routine pre-clinical DCE-MRI studies. Tumor response to therapy was reflected in changes in tumor perfusion/permeability parameters. The H69 tumor model showed pronounced changes in DCE-derived parameters following PRRT. The rat CA20948 tumor model showed more heterogeneity in both treatment outcome and perfusion parameters. TRICKS enabled the acquisition of DCE-MRI at both high temporal resolution (Tres ) and spatial resolutions relevant for small animal tumor models. With the high Tres enabled by TRICKS, accurate pharmacokinetic data modeling was feasible. DCE-MRI parameters revealed changes over time and showed a clear relationship between tumor size and Ktrans .

  9. Wavelet-based noise-model driven denoising algorithm for differential phase contrast mammography.

    PubMed

    Arboleda, Carolina; Wang, Zhentian; Stampanoni, Marco

    2013-05-01

    Traditional mammography can be positively complemented by phase contrast and scattering x-ray imaging, because they can detect subtle differences in the electron density of a material and measure the local small-angle scattering power generated by the microscopic density fluctuations in the specimen, respectively. The grating-based x-ray interferometry technique can produce absorption, differential phase contrast (DPC) and scattering signals of the sample, in parallel, and works well with conventional X-ray sources; thus, it constitutes a promising method for more reliable breast cancer screening and diagnosis. Recently, our team proved that this novel technology can provide images superior to conventional mammography. This new technology was used to image whole native breast samples directly after mastectomy. The images acquired show high potential, but the noise level associated to the DPC and scattering signals is significant, so it is necessary to remove it in order to improve image quality and visualization. The noise models of the three signals have been investigated and the noise variance can be computed. In this work, a wavelet-based denoising algorithm using these noise models is proposed. It was evaluated with both simulated and experimental mammography data. The outcomes demonstrated that our method offers a good denoising quality, while simultaneously preserving the edges and important structural features. Therefore, it can help improve diagnosis and implement further post-processing techniques such as fusion of the three signals acquired.

  10. Myocardial contrast echocardiography to assess perfusion in a mouse model of ischemia/reperfusion injury

    NASA Astrophysics Data System (ADS)

    Hossack, John A.; Li, Yinbo; Christensen, Jonathan P.; Yang, Zequan; French, Brent A.

    2004-04-01

    Noninvasive approaches for measuring anatomical and physiological changes resulting from myocardial ischemia / reperfusion injury in the mouse heart have significant value since the mouse provides a practical, low-cost model for modeling human heart disease. In this work, perfusion was assessed before, during and after an induced closed- chest, coronary ischemic event. Ultrasound contrast agent, similar to MP1950, in a saline suspension, was injected via cannulated carotid artery as a bolus and imaged using a Siemens Sequoia 512 scanner and a 15L8 intraoperative transducer operating in second harmonic imaging mode. Image sequences were transferred from the scanner to a PC for analysis. Regions of interest were defined in septal and anterior segments of the myocardium. During the ischemic event, when perfusion was diminished in the anterior segment, mean video intensity in the affected segment was reduced by one half. Furthermore, following reperfusion, hyperemia (enhanced blood flow) was observed in the anterior segment. Specifically, the mean video intensity in the affected segment was increased by approximately 50% over the original baseline level prior to ischemia. Following the approach of Kaul et al., [1], gamma variate curves were fitted to the time varying level of mean video intensity. This foundation suggests the possibility of quantifying myocardial blood flow in ischemic regions of a mouse heart using automated analysis of contrast image data sets. An improved approach to perfusion assessment using the destruction-reperfusion approach [2] is also presented.

  11. Modeling the Effect of Intra-Voxel Diffusion of Contrast Agent on the Quantitative Analysis of Dynamic Contrast Enhanced Magnetic Resonance Imaging

    PubMed Central

    Barnes, Stephanie L.; Quarles, C. Chad; Yankeelov, Thomas E.

    2014-01-01

    Quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides estimates of physiologically relevant parameters related to tissue blood flow, vascular permeability, and tissue volume fractions which can then be used for prognostic and diagnostic reasons. However, standard techniques for DCE-MRI analysis ignore intra-voxel diffusion, which may play an important role in contrast agent distribution and voxel signal intensity and, thus, will affect quantification of the aforementioned parameters. To investigate the effect of intra-voxel diffusion on quantitative DCE-MRI, we developed a finite element model of contrast enhancement at the voxel level. For diffusion in the range of that expected for gadolinium chelates in tissue (i.e., 1×10−4 to 4×10−4 mm2/s), parameterization errors range from −58% to 12% for Ktrans, −9% to 8% for ve, and −60% to 213% for vp over the range of Ktrans, ve, vp, and temporal resolutions investigated. Thus the results show that diffusion has a significant effect on parameterization using standard techniques. PMID:25275536

  12. Renormalized scattering series for frequency-domain waveform modelling of strong velocity contrasts

    NASA Astrophysics Data System (ADS)

    Jakobsen, M.; Wu, R. S.

    2016-08-01

    An improved description of scattering and inverse scattering processes in reflection seismology may be obtained on the basis of a scattering series solution to the Helmoltz equation, which allows one to separately model primary and multiple reflections. However, the popular scattering series of Born is of limited seismic modelling value, since it is only guaranteed to converge if the global contrast is relatively small. For frequency-domain waveform modelling of realistic contrasts, some kind of renormalization may be required. The concept of renormalization is normally associated with quantum field theory, where it is absolutely essential for the treatment of infinities in connection with observable quantities. However, the renormalization program is also highly relevant for classical systems, especially when there are interaction effects that act across different length scales. In the scattering series of De Wolf, a renormalization of the Green's functions is achieved by a split of the scattering potential operator into fore- and backscattering parts; which leads to an effective reorganization and partially re-summation of the different terms in the Born series, so that their order better reflects the physics of reflection seismology. It has been demonstrated that the leading (single return) term in the De Wolf series (DWS) gives much more accurate results than the corresponding Born approximation, especially for models with high contrasts that lead to a large accumulation of phase changes in the forward direction. However, the higher order terms in the DWS that are associated with internal multiples have not been studied numerically before. In this paper, we report from a systematic numerical investigation of the convergence properties of the DWS which is based on two new operator representations of the DWS. The first operator representation is relatively similar to the original scattering potential formulation, but more global and explicit in nature. The second

  13. Visualization of 3D geometric models of the breast created from contrast-enhanced MRI

    NASA Astrophysics Data System (ADS)

    Leader, J. Ken, III; Wang, Xiao Hui; Chang, Yuan-Hsiang; Chapman, Brian E.

    2002-05-01

    Contrast enhanced breast MRI is currently used as an adjuvant modality to x-ray mammography because of its ability to resolve ambiguities and determine the extent of malignancy. This study described techniques to create and visualize 3D geometric models of abnormal breast tissue. MRIs were performed on a General Electric 1.5 Tesla scanner using dual phased array breast coils. Image processing tasks included: 1) correction of image inhomogeneity caused by the coils, 2) segmentation of normal and abnormal tissue, and 3) modeling and visualization of the segmented tissue. The models were visualized using object-based surface rendering which revealed characteristics critical to differentiating benign from malignant tissue. Surface rendering illustrated the enhancement distribution and enhancement patterns. The modeling process condensed the multi-slice MRI data information and standardized its interpretation. Visualizing the 3D models should improve the radiologist's and/or surgeon's impression of the 3D shape, extent, and accessibility of the malignancy compared to viewing breast MRI data slice by slice.

  14. Name Modelling Activities for the CAST/Contrast/Attrex Very Short Lived Species Measurements

    NASA Astrophysics Data System (ADS)

    Harris, N. R. P.; Filus, M. T.; Ashfold, M.; Pyle, J. A.; Atlas, E. L.; Manning, A.; Meneguz, E.

    2014-12-01

    The UK Met Office Numerical Atmospheric dispersion Modeling Environment (NAME) is used to assess the spatial and temporal variability of transport of very short-lived halogenated organic species (VSLS), in particular bromoform, dibromomethane and methyl iodide, within the West Pacific tropical region. The NAME modelling results are compared with airborne measurements of VSLS taken during NASA ATTREX, NCAR CONTRAST and NERC CAST campaigns in January-March, 2014. In this work, the NAME model is used to link the aircraft measurements to examine the vertical distribution of VSLS in the West Pacific troposphere. The major focus will be on assessing vertical transport in deep convection which is one of the crucial factors in redistributing chemicals within the tropical troposphere. The work presented shows the analysis of NAME runs made from the ATTREX flights over the East Pacific in January-February, 2013 and the ATTREX and CONTRAST flight tracks over the West Pacific in January-March, 2014. Each ATTREX 2013 and 2014 flight track is divided into segments, from which particles are released and followed backward to identify the low-level sources of air. Particles (10,000 per single point along the flight track) are released from the flight tracks and followed 12-days backwards. Fractions of trajectories are calculated according to particles which crossed below 5 and 1 km (corresponding to low troposphere and oceanic boundary layer, respectively). Then, initial concentrations for VSLS are assigned to particles which originated from below 5/1 km and final concentrations at flight altitudes are determined based on e-folding equations. Results, obtained by running NAME, are compared with ATTREX VSLS flight measurements.

  15. A genetic investigation of various growth models to describe growth of lambs of two contrasting breeds.

    PubMed

    Lambe, N R; Navajas, E A; Simm, G; Bünger, L

    2006-10-01

    This study compared the use of various models to describe growth in lambs of 2 contrasting breeds from birth to slaughter. Live BW records (n = 7559) from 240 Texel and 231 Scottish Blackface (SBF) lambs weighed at 2-wk intervals were modeled. Biologically relevant variables were estimated for each lamb from modified versions of the logistic, Gompertz, Richards, and exponential models, and from linear regression. In both breeds, all nonlinear models fitted the data well, with an average coefficient of determination (R2) of > 0.98. The linear model had a lower average R2 than any of the nonlinear models (< 0.94). The variables used to describe the best 3 models (logistic, Gompertz, and Richards) included estimated final BW (A); maximum ADG (B); age at maximum ADG (C); position of point of inflection in relation to A (D, for Richards only). The Richards and Gompertz models provided the best fit (average R2 = 0.986 to 0.989) in both breeds. Richards estimated an extra variable, allowing increased flexibility in describing individual growth patterns, but the Akaike's information criteria value (which weighs log-likelihood by number of parameters estimated) was similar to that of the Gompertz model. Variables A, B, C, and D were moderately to highly heritable in Texel lambs (h2 = 0.33 to 0.87), and genetic correlations between variables within-model ranged from -0.80 to 0.89, suggesting some flexibility to change the shape of the growth curve when selecting for different variables. In SBF lambs, only variables from the logistic and Gompertz models had moderate heritabilities (0.17 to 0.56), but with high genetic correlations between variables within each model (< -0.88 or > 0.92). Selection on growth variables seems promising (in Texel more than SBF), but high genetic correlations between variables may restrict the possibilities to change the growth curve shape. A random regression model was also fitted to the data to allow predictions of growth rates at relevant time

  16. X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents

    NASA Astrophysics Data System (ADS)

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.

  17. X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents

    PubMed Central

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging. PMID:26511147

  18. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    SciTech Connect

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-29

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. As a result, the enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.

  19. Fluorescent and scattering contrast agents in a mouse model of colorectal cancer

    NASA Astrophysics Data System (ADS)

    Winkler, Amy M.; Rice, Photini F. S.; Troutman, Timothy S.; Backer, Marina V.; Backer, Joseph M.; Drezek, Rebekah A.; Romanowski, Marek; Barton, Jennifer K.

    2008-02-01

    In previous work we have demonstrated the utility of laser-induced fluorescence (LIF) and optical coherence tomography (OCT) to identify adenoma in mouse models of colorectal cancer with high sensitivity and specificity. However, improved sensitivity to early disease, as well as the ability to distinguish confounders (e.g. fecal contamination, natural variations in mucosal thickness), is desired. In this study, we investigated the signal enhancement of fluorescent and scattering contrast agents in the colons of AOM-treated mice. The fluorescent tracer scVEGF/Cy, targeted to receptors for vascular endothelial growth factor, was visualized on a dual modality OCT/LIF endoscopic system with 1300-nm center wavelength OCT source and 635-nm LIF excitation. Scattering agents were tested with an 890-nm center wavelength endoscopic OCT system. Agents included nanoshells, 120-nm in diameter, and nanorods, 20-nm in diameter by 80-nm in length. Following imaging, colons were excised. Tissue treated with fluorophore was imaged on an epifluorescence microscope. Histological sections were obtained and stained with H&E and silver enhancer to verify disease and identify regions of gold uptake, respectively. Non-specific signal enhancement was observed with the scattering contrast agents. Specificity for adenoma was seen with the scVEGF/Cy dye.

  20. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    DOE PAGES

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-29

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form anmore » image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. As a result, the enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.« less

  1. Comparison of deep percolation rates below contrasting land covers with a joint canopy and soil model

    NASA Astrophysics Data System (ADS)

    Domínguez, C. G.; Pryet, A.; García Vera, M.; Gonzalez, A.; Chaumont, C.; Tournebize, J.; Villacis, M.; d'Ozouville, N.; Violette, S.

    2016-01-01

    A Rutter-type canopy interception model is combined with a 1-D physically-based soil water flow model to compare deep percolation rates below distinct land covers. The joint model allows the quantification of both evaporation and transpiration rates as well as deep percolation from vegetation and soil characteristics. Experimental observations are required to constitute the input and calibration datasets. An appropriate monitoring design is described which consists in meteorological monitoring together with throughfall and soil water tension measurements. The methodology is illustrated in Santa Cruz Island in the Galapagos Archipelago, which has been affected by significant land use changes. Two adjacent study plots are investigated: a secondary forest and a pasture. The results of the model reveal that evaporation of canopy interception is higher in the pasture due to the bigger canopy storage capacity, which promotes evaporation against canopy drainage. This is however compensated by higher transpiration in the secondary forest, due to the smaller surface resistance. As a consequence, total evapotranspiration is similar for the two plots and no marked difference in deep percolation can be observed. In both cases, deep percolation reaches ca. 2 m/year which corresponds to 80% of the incoming rainfall. This methodology not only allows the quantification of deep percolation, but can also be used to identify the controlling factors of deep percolation under contrasting land covers.

  2. Intraoperative laser speckle contrast imaging improves the stability of rodent middle cerebral artery occlusion model

    NASA Astrophysics Data System (ADS)

    Yuan, Lu; Li, Yao; Li, Hangdao; Lu, Hongyang; Tong, Shanbao

    2015-09-01

    Rodent middle cerebral artery occlusion (MCAO) model is commonly used in stroke research. Creating a stable infarct volume has always been challenging for technicians due to the variances of animal anatomy and surgical operations. The depth of filament suture advancement strongly influences the infarct volume as well. We investigated the cerebral blood flow (CBF) changes in the affected cortex using laser speckle contrast imaging when advancing suture during MCAO surgery. The relative CBF drop area (CBF50, i.e., the percentage area with CBF less than 50% of the baseline) showed an increase from 20.9% to 69.1% when the insertion depth increased from 1.6 to 1.8 cm. Using the real-time CBF50 marker to guide suture insertion during the surgery, our animal experiments showed that intraoperative CBF-guided surgery could significantly improve the stability of MCAO with a more consistent infarct volume and less mortality.

  3. Characterization of the carotid and adjacent anatomy using non-contrast CT for biomechanical model development.

    PubMed

    Lambert, Callie C; Gayzik, F Scott; Stitzel, Joel D

    2007-01-01

    The path of the carotid artery and its branches through the neck is characterized through an analysis of non-contrast computed tomography (CT) scans. The distance from the vessel wall of the carotid arteries to the skin and vertebral bodies are recorded from the level of the 2nd cervical vertebrae (C2) to the 6th cervical vertebrae (C6). A total of seven individuals were included in the study. The common carotid artery exhibited the closest average distance to the skin (23.5 +/- 6.9 mm) whereas the internal carotid artery exhibited the closest average distance to the vertebral body (7.36 +/- 3.8 mm, measured to the transverse process). This study provides morphological validation data towards the development of a regional-level finite element model of the neck and may also be used for the design of biomechanical experiments for the study of carotid artery injury.

  4. Intragenic allele pyramiding combines different specificities of wheat Pm3 resistance alleles.

    PubMed

    Brunner, Susanne; Hurni, Severine; Streckeisen, Philipp; Mayr, Gabriele; Albrecht, Mario; Yahiaoui, Nabila; Keller, Beat

    2010-11-01

    Some plant resistance genes occur as allelic series, with each member conferring specific resistance against a subset of pathogen races. In wheat, there are 17 alleles of the Pm3 gene. They encode nucleotide-binding (NB-ARC) and leucine-rich-repeat (LRR) domain proteins, which mediate resistance to distinct race spectra of powdery mildew. It is not known if specificities from different alleles can be combined to create resistance genes with broader specificity. Here, we used an approach based on avirulence analysis of pathogen populations to characterize the molecular basis of Pm3 recognition spectra. A large survey of mildew races for avirulence on the Pm3 alleles revealed that Pm3a has a resistance spectrum that completely contains that of Pm3f, but also extends towards additional races. The same is true for the Pm3b and Pm3c gene pair. The molecular analysis of these allelic pairs revealed a role of the NB-ARC protein domain in the efficiency of effector-dependent resistance. Analysis of the wild-type and chimeric Pm3 alleles identified single residues in the C-terminal LRR motifs as the main determinant of allele specificity. Variable residues of the N-terminal LRRs are necessary, but not sufficient, to confer resistance specificity. Based on these data, we constructed a chimeric Pm3 gene by intragenic allele pyramiding of Pm3d and Pm3e that showed the combined resistance specificity and, thus, a broader recognition spectrum compared with the parental alleles. Our findings support a model of stepwise evolution of Pm3 recognition specificities.

  5. Dose assessment in contrast enhanced digital mammography using simple phantoms simulating standard model breasts

    NASA Astrophysics Data System (ADS)

    Bouwman, R. W.; van Engen, R. E.; Young, K. C.; Veldkamp, W. J. H.; Dance, D. R.

    2015-01-01

    Slabs of polymethyl methacrylate (PMMA) or a combination of PMMA and polyethylene (PE) slabs are used to simulate standard model breasts for the evaluation of the average glandular dose (AGD) in digital mammography (DM) and digital breast tomosynthesis (DBT). These phantoms are optimized for the energy spectra used in DM and DBT, which normally have a lower average energy than used in contrast enhanced digital mammography (CEDM). In this study we have investigated whether these phantoms can be used for the evaluation of AGD with the high energy x-ray spectra used in CEDM. For this purpose the calculated values of the incident air kerma for dosimetry phantoms and standard model breasts were compared in a zero degree projection with the use of an anti scatter grid. It was found that the difference in incident air kerma compared to standard model breasts ranges between -10% to +4% for PMMA slabs and between 6% and 15% for PMMA-PE slabs. The estimated systematic error in the measured AGD for both sets of phantoms were considered to be sufficiently small for the evaluation of AGD in quality control procedures for CEDM. However, the systematic error can be substantial if AGD values from different phantoms are compared.

  6. Allelic loss in colorectal carcinoma

    SciTech Connect

    Kern, S.E.; Fearon, E.R.; Tersmette, K.W.F.; Enterline, J.P.; Vogelstein, B.; Hamilton, S.R. ); Leppert, M.; Nakamura, Yusuke; White, R. )

    1989-06-02

    Clinical and pathological associations with molecular genetic alterations were studied in colorectal carcinomas from 83 patients. Fractional allelic loss, a measure of allelic deletions throughout the genome, and allelic deletions of specific chromosomal arms (the short arm of 17 and long arm of 18) each provided independent prognostic information by multivariate analysis when considered individually with Dukes' classification. Distant metastasis was significantly associated with high fractional allelic loss and with deletions of 17p and 18q. Mutations of ras proto-oncogenes and deletions of 5q had no prognostic importance. Statistically significant associations were also found between allelic losses and a family history of cancer, left-sided tumor location, and absence of extracellular tumor mucin. Allelic deletion analysis thus identified subsets of colorectal carcinoma with increased predilection for distant metastasis and cancer-related death. Further studies may define a subset of genetic alterations that can be used clinically to help assess prognosis.

  7. Biased Allelic Expression in Human Primary Fibroblast Single Cells

    PubMed Central

    Borel, Christelle; Ferreira, Pedro G.; Santoni, Federico; Delaneau, Olivier; Fort, Alexandre; Popadin, Konstantin Y.; Garieri, Marco; Falconnet, Emilie; Ribaux, Pascale; Guipponi, Michel; Padioleau, Ismael; Carninci, Piero; Dermitzakis, Emmanouil T.; Antonarakis, Stylianos E.

    2015-01-01

    The study of gene expression in mammalian single cells via genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblasts over 133,633 unique heterozygous single-nucleotide variants (hetSNVs). We observed that at the snapshot of analyses, each cell contained mostly transcripts from one allele from the majority of genes; indeed, 76.4% of the hetSNVs displayed stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibited a haplotype-consistent allelic ratio; in contrast, distant sites located in two different genes were independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in the majority of the single cells at a given time point were rare and enriched with highly expressed genes. The relative abundance of each allele in a cell was controlled by some regulatory mechanisms given that we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability. PMID:25557783

  8. Spatially Explicit Modeling Reveals Cephalopod Distributions Match Contrasting Trophic Pathways in the Western Mediterranean Sea

    PubMed Central

    Puerta, Patricia; Hunsicker, Mary E.; Quetglas, Antoni; Álvarez-Berastegui, Diego; Esteban, Antonio; González, María; Hidalgo, Manuel

    2015-01-01

    Populations of the same species can experience different responses to the environment throughout their distributional range as a result of spatial and temporal heterogeneity in habitat conditions. This highlights the importance of understanding the processes governing species distribution at local scales. However, research on species distribution often averages environmental covariates across large geographic areas, missing variability in population-environment interactions within geographically distinct regions. We used spatially explicit models to identify interactions between species and environmental, including chlorophyll a (Chla) and sea surface temperature (SST), and trophic (prey density) conditions, along with processes governing the distribution of two cephalopods with contrasting life-histories (octopus and squid) across the western Mediterranean Sea. This approach is relevant for cephalopods, since their population dynamics are especially sensitive to variations in habitat conditions and rarely stable in abundance and location. The regional distributions of the two cephalopod species matched two different trophic pathways present in the western Mediterranean Sea, associated with the Gulf of Lion upwelling and the Ebro river discharges respectively. The effects of the studied environmental and trophic conditions were spatially variant in both species, with usually stronger effects along their distributional boundaries. We identify areas where prey availability limited the abundance of cephalopod populations as well as contrasting effects of temperature in the warmest regions. Despite distributional patterns matching productive areas, a general negative effect of Chla on cephalopod densities suggests that competition pressure is common in the study area. Additionally, results highlight the importance of trophic interactions, beyond other common environmental factors, in shaping the distribution of cephalopod populations. Our study presents a valuable

  9. Spatially Explicit Modeling Reveals Cephalopod Distributions Match Contrasting Trophic Pathways in the Western Mediterranean Sea.

    PubMed

    Puerta, Patricia; Hunsicker, Mary E; Quetglas, Antoni; Álvarez-Berastegui, Diego; Esteban, Antonio; González, María; Hidalgo, Manuel

    2015-01-01

    Populations of the same species can experience different responses to the environment throughout their distributional range as a result of spatial and temporal heterogeneity in habitat conditions. This highlights the importance of understanding the processes governing species distribution at local scales. However, research on species distribution often averages environmental covariates across large geographic areas, missing variability in population-environment interactions within geographically distinct regions. We used spatially explicit models to identify interactions between species and environmental, including chlorophyll a (Chla) and sea surface temperature (SST), and trophic (prey density) conditions, along with processes governing the distribution of two cephalopods with contrasting life-histories (octopus and squid) across the western Mediterranean Sea. This approach is relevant for cephalopods, since their population dynamics are especially sensitive to variations in habitat conditions and rarely stable in abundance and location. The regional distributions of the two cephalopod species matched two different trophic pathways present in the western Mediterranean Sea, associated with the Gulf of Lion upwelling and the Ebro river discharges respectively. The effects of the studied environmental and trophic conditions were spatially variant in both species, with usually stronger effects along their distributional boundaries. We identify areas where prey availability limited the abundance of cephalopod populations as well as contrasting effects of temperature in the warmest regions. Despite distributional patterns matching productive areas, a general negative effect of Chla on cephalopod densities suggests that competition pressure is common in the study area. Additionally, results highlight the importance of trophic interactions, beyond other common environmental factors, in shaping the distribution of cephalopod populations. Our study presents a valuable

  10. The role of lithological contrasts in the formation of sinkholes: a Distinct Element Method modelling perspective

    NASA Astrophysics Data System (ADS)

    Al-Halbouni, Djamil; Holohan, Eoghan P.; Dahm, Torsten

    2015-04-01

    Sinkhole formation is a geological phenomenon resulting from dissolution and subrosion of rocks or sediments at depth, where large secondary pore space and cavities may develop, and from the eventual subsidence of the overburden. Although sinkholes may develop slowly as a natural process, their formation is often intensified by human activities. For instance, sinkhole hazard has intensified at the Dead Sea shoreline in the Middle East since the beginning of the recession of the Dead Sea level. Another example concerns sinkhole formation induced by solution mining of salt rock in the Lorraine district, France. Signs of precursors to collapse sinkholes have sometimes been indicated by monitoring studies, but are not well understood in terms of quantitative models. Here we report on a general, simplified approach to simulating sinkhole formation by using 2D Distinct Element Method (PFC2D) models comprising elastically bonded particles. The presence of bonds leads to elastic rock deformation under loading conditions and bond breakage may result in spontaneous formation of faults and cracks. Using different rheological parameters like Young's modulus, density, cohesion and friction coefficients, this method is able to simulate realistic rock layering contrasts. The dissolution or subrosion process leading to the formation of underground cavities is simulated via simple incremental particle deletion, whereby an arbitrary dissolution rate can be determined. Model structures preceding a sinkhole collapse, as well as precursory changes in density or porosity, are explicitly simulated and may be linked to measured geophysical parameters such as microseismicity, seismic velocity and electric conductivity. As well as examining precursory phenomena, we study the effect of lithological contrasts on (1) the geometry of sinkholes (diameter to depth ratio) and (2) the onset of collapse. Beside the formulation of general relations, we compare our simulations to well documented case

  11. Seasonal contrast in aerosol abundance over northern south Asia using a chemical transport model

    NASA Astrophysics Data System (ADS)

    Venkataraman, C.; Sadavarte, P.; Madhavan, B. L.; Kulkarni, S.; Carmichael, G. R.; Adhikary, B.; D'Allura, A.; Cherian, R.; Das, S.; Gupta, T.; Streets, D. G.; Wei, C.; Zhang, Q.

    2012-12-01

    Northern South-Asia, home to about half a billion people, experiences large aerosol abundances almost all year around. There are gaps in our understanding of seasonal variations in regional aerosol emissions, abundance and radiative effects. The present study uses chemical transport model simulations (at ~ 60km resolution), with regionally estimated emissions, to investigate the contrast in aerosol surface and columnar abundance during pre-monsoon transition, monsoon and inter-monsoon transition periods over than Gangetic plain (GP) and Tibetan plateau. The interplay between aerosol emissions and atmospheric transport is examined to explain the variability. Model predictions were evaluated with available in-situ measurements and AOD from AERONET and MODIS level-2 retrievals (at 10 km resolution) processed with quality weighting to the model resolution. During April, AOD was dominated by dust at most sites across the GP and Tibet. However, AOD from organic carbon (emitted from agricultural residue burning) is also significant at several sites (Pantnagar, Godavari, Kolkata, Dhaka, and at high altitude Pyramid and Lhasa sites), consistent with recently reported MISR climatology in this region. In contrast, during July and September, AOD was dominated by sulfate at all sites. In April, aerosols over the GP could be attributed to emissions from large industrial sources (thermal power plant, cement industries, iron & steel and other industries) and agricultural residue burning transported from the northwest, along with forest burning emissions transported from the east. Large fluxes of open burning emissions in the east GP, along with prevailing easterly wind flow into the GP led to an east-west gradient in anthropogenic aerosols. During July, there was little open burning, so aerosol concentrations were largely from industrial emissions transported out through the north. In the Tibet region, dust was predominant during both April and July. During September

  12. Colombia and Cuba, contrasting models in Latin America's health sector reform.

    PubMed

    De Vos, Pol; De Ceukelaire, Wim; Van der Stuyft, Patrick

    2006-10-01

    Latin American national health systems were drastically overhauled by the health sector reforms the 1990s. Governments were urged by donors and by the international financial institutions to make major institutional changes, including the separation of purchaser and provider functions and privatization. This article first analyses a striking paradox of the far-reaching reform measures: contrary to what is imposed on public health services, after privatization purchaser and provider functions are reunited. Then we compare two contrasting examples: Colombia, which is internationally promoted as a successful--and radical--example of 'market-oriented' health care reform, and Cuba, which followed a highly 'conservative' path to adapt its public system to the new conditions since the 1990s, going against the model of the international institutions. The Colombian reform has not been able to materialize its promises of universality, improved equity, efficiency and better quality, while Cuban health care remains free, accessible for everybody and of good quality. Finally, we argue that the basic premises of the ongoing health sector reforms in Latin America are not based on the people's needs, but are strongly influenced by the needs of foreign--especially North American--corporations. However, an alternative model of health sector reform, such as the Cuban one, can probably not be pursued without fundamental changes in the economic and political foundations of Latin American societies. PMID:17002735

  13. Estimation of Cerebral Blood Flow From Dynamic Susceptibility Contrast MRI Using A Tissue Model

    NASA Astrophysics Data System (ADS)

    Shimony, Joshua S.; Lee, John J.; Bretthorst, G. Larry

    2005-11-01

    Cerebral perfusion measurements are of great clinical and research interest. Positron emission tomography (PET) is considered the gold standard for cerebral perfusion measurement, but is not widely available and entails exposure of the subject to radioactivity. Dynamic susceptibility contrast (DSC) MRI methods are becoming more widely available on the newest generation of MRI scanners. The standard analysis methods of this data have significant disadvantages that include the use of a single, difficult to measure, arterial input function for the entire brain and the need to perform a numerical deconvolution on the logarithm of noisy data. These methods are not yet fully validated and remain qualitative in nature. Using a modification of the standard tracer kinetic principles we implemented a tissue perfusion model that has several advantages over standard methods. The model parameters were estimated using Bayes probability theory in a group of patients with varying degrees of hemodynamic impairment and were found to provide additional physiologic information that was not available using standard techniques.

  14. Mechanistic modeling of vertebrate spatial contrast sensitivity and acuity at low luminance.

    PubMed

    Jarvis, John R; Wathes, Christopher M

    2012-05-01

    The validity of the Barten theoretical model for describing the vertebrate spatial contrast sensitivity function (CSF) and acuity at scotopic light levels has been examined. Although this model (which has its basis in signal modulation transfer theory) can successfully describe vertebrate CSF, and its relation to underlying visual neurophysiology at photopic light levels, significant discrepancies between theory and experimental data have been found at scotopic levels. It is shown that in order to describe scotopic CSF, the theory must be modified to account for important mechanistic changes, which occur as cone vision switches to rod vision. These changes are divided into photon management factors [changes in optical performance (for a dilated pupil), quantum efficiency, receptor sampling] and neural factors (changes in spatial integration area, neural noise, and lateral inhibition in the retina). Predictions of both scotopic CSF and acuity obtained from the modified theory were found to be in good agreement with experimental values obtained from the human, macaque, cat, and owl monkey. The last two species have rod densities particularly suited for scotopic conditions.

  15. Ex vivo micro-CT imaging of murine brain models using non-ionic iodinated contrast

    NASA Astrophysics Data System (ADS)

    Salas Bautista, N.; Martínez-Dávalos, A.; Rodríguez-Villafuerte, M.; Murrieta-Rodríguez, T.; Manjarrez-Marmolejo, J.; Franco-Pérez, J.; Calvillo-Velasco, M. E.

    2014-11-01

    Preclinical investigation of brain tumors is frequently carried out by means of intracranial implantation of brain tumor xenografts or allografts, with subsequent analysis of tumor growth using conventional histopathology. However, very little has been reported on the use contrast-enhanced techniques in micro-CT imaging for the study of malignant brain tumors in small animal models. The aim of this study has been to test a protocol for ex vivo imaging of murine brain models of glioblastoma multiforme (GBM) after treatment with non-ionic iodinated solution, using an in-house developed laboratory micro-CT. We have found that the best compromise between acquisition time and image quality is obtained using a 50 kVp, 0.5 mAs, 1° angular step on a 360 degree orbit acquisition protocol, with 70 μm reconstructed voxel size using the Feldkamp algorithm. With this parameters up to 4 murine brains can be scanned in tandem in less than 15 minutes. Image segmentation and analysis of three sample brains allowed identifying tumor volumes as small as 0.4 mm3.

  16. Disentangling the formation of contrasting tree-line physiognomies combining model selection and Bayesian parameterization for simulation models.

    PubMed

    Martínez, Isabel; Wiegand, Thorsten; Camarero, J Julio; Batllori, Enric; Gutiérrez, Emilia

    2011-05-01

    Alpine tree-line ecotones are characterized by marked changes at small spatial scales that may result in a variety of physiognomies. A set of alternative individual-based models was tested with data from four contrasting Pinus uncinata ecotones in the central Spanish Pyrenees to reveal the minimal subset of processes required for tree-line formation. A Bayesian approach combined with Markov chain Monte Carlo methods was employed to obtain the posterior distribution of model parameters, allowing the use of model selection procedures. The main features of real tree lines emerged only in models considering nonlinear responses in individual rates of growth or mortality with respect to the altitudinal gradient. Variation in tree-line physiognomy reflected mainly changes in the relative importance of these nonlinear responses, while other processes, such as dispersal limitation and facilitation, played a secondary role. Different nonlinear responses also determined the presence or absence of krummholz, in agreement with recent findings highlighting a different response of diffuse and abrupt or krummholz tree lines to climate change. The method presented here can be widely applied in individual-based simulation models and will turn model selection and evaluation in this type of models into a more transparent, effective, and efficient exercise.

  17. Modelling of 'sub-atomic' contrast resulting from back-bonding on Si(111)-7×7.

    PubMed

    Sweetman, Adam; Jarvis, Samuel P; Rashid, Mohammad A

    2016-01-01

    It has recently been shown that 'sub-atomic' contrast can be observed during NC-AFM imaging of the Si(111)-7×7 substrate with a passivated tip, resulting in triangular shaped atoms [Sweetman et al. Nano Lett. 2014, 14, 2265]. The symmetry of the features, and the well-established nature of the dangling bond structure of the silicon adatom means that in this instance the contrast cannot arise from the orbital structure of the atoms, and it was suggested by simple symmetry arguments that the contrast could only arise from the backbonding symmetry of the surface adatoms. However, no modelling of the system has been performed in order to understand the precise origin of the contrast. In this paper we provide a detailed explanation for 'sub-atomic' contrast observed on Si(111)-7×7 using a simple model based on Lennard-Jones potentials, coupled with a flexible tip, as proposed by Hapala et al. [Phys. Rev. B 2014, 90, 085421] in the context of interpreting sub-molecular contrast. Our results show a striking similarity to experimental results, and demonstrate how 'sub-atomic' contrast can arise from a flexible tip exploring an asymmetric potential created due to the positioning of the surrounding surface atoms.

  18. Modelling of ‘sub-atomic’ contrast resulting from back-bonding on Si(111)-7×7

    PubMed Central

    Jarvis, Samuel P; Rashid, Mohammad A

    2016-01-01

    Summary It has recently been shown that ‘sub-atomic’ contrast can be observed during NC-AFM imaging of the Si(111)-7×7 substrate with a passivated tip, resulting in triangular shaped atoms [Sweetman et al. Nano Lett. 2014, 14, 2265]. The symmetry of the features, and the well-established nature of the dangling bond structure of the silicon adatom means that in this instance the contrast cannot arise from the orbital structure of the atoms, and it was suggested by simple symmetry arguments that the contrast could only arise from the backbonding symmetry of the surface adatoms. However, no modelling of the system has been performed in order to understand the precise origin of the contrast. In this paper we provide a detailed explanation for ‘sub-atomic’ contrast observed on Si(111)-7×7 using a simple model based on Lennard-Jones potentials, coupled with a flexible tip, as proposed by Hapala et al. [Phys. Rev. B 2014, 90, 085421] in the context of interpreting sub-molecular contrast. Our results show a striking similarity to experimental results, and demonstrate how ‘sub-atomic’ contrast can arise from a flexible tip exploring an asymmetric potential created due to the positioning of the surrounding surface atoms. PMID:27547610

  19. Modelling of 'sub-atomic' contrast resulting from back-bonding on Si(111)-7×7.

    PubMed

    Sweetman, Adam; Jarvis, Samuel P; Rashid, Mohammad A

    2016-01-01

    It has recently been shown that 'sub-atomic' contrast can be observed during NC-AFM imaging of the Si(111)-7×7 substrate with a passivated tip, resulting in triangular shaped atoms [Sweetman et al. Nano Lett. 2014, 14, 2265]. The symmetry of the features, and the well-established nature of the dangling bond structure of the silicon adatom means that in this instance the contrast cannot arise from the orbital structure of the atoms, and it was suggested by simple symmetry arguments that the contrast could only arise from the backbonding symmetry of the surface adatoms. However, no modelling of the system has been performed in order to understand the precise origin of the contrast. In this paper we provide a detailed explanation for 'sub-atomic' contrast observed on Si(111)-7×7 using a simple model based on Lennard-Jones potentials, coupled with a flexible tip, as proposed by Hapala et al. [Phys. Rev. B 2014, 90, 085421] in the context of interpreting sub-molecular contrast. Our results show a striking similarity to experimental results, and demonstrate how 'sub-atomic' contrast can arise from a flexible tip exploring an asymmetric potential created due to the positioning of the surrounding surface atoms. PMID:27547610

  20. Sequence analysis of the fragile X trinucleotide repeat: Correlations with stability and haplotype and implications for the origin of fragile X alleles

    SciTech Connect

    Snow, K.; Tester, D.J.; Kruckeberg, K.E.; Thibodeau, S.N.

    1994-09-01

    Fragile X (FX) syndrome is associated with amplification of a CGG trinucleotide repeat in the 5{prime} untranslated region of the gene FMR-1. To address mechanism of instability and concern related to overlap between sizes of normal stable alleles and FX unstable alleles, we have sequenced 165 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. For 17 stably transmitted alleles with total repeat lengths between 33 and 51, the longest stretch of uninterrupted CGGs was 41. In contrast, for 13 premutation alleles, the shortest stretch of uninterrupted CGGs was 48, suggesting a threshold for expansion between 41 and 48 pure CGGs. For expansion from a premutation to a full mutation, the threshold appears to be {ge}70 uninterrupted repeats. Interestingly, an AGG was detected in some carriers of a full mutation. Comparison of the number of {open_quote}shadow bands{close_quote} in PCR products from similar size alleles with different AGG interruption patterns supports replication slippage as a potential mechanism, i.e. replication slippage occurs more readily as the length of pure repeat increases. Alleles with high total repeat lengths but up to 3 AGGs may be relatively protected against expansion, whereas smaller alleles with pure CGG sequence could be at higher risk for instability. Comparison of sequence data and DXS548 (CA)n data revealed specific sequence trends for each of the DXS548 alleles, explaining the previously reported haplotype association with FX. Incorporating these observations into models for the origin of FX alleles, we consider replication slippage, unequal crossover within the CGG repeat region, recombination between FMR-1 and DXS548, and loss of AGGs by A to C transversion.

  1. siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy

    PubMed Central

    Bolduc, Véronique; Zou, Yaqun; Ko, Dayoung; Bönnemann, Carsten G

    2014-01-01

    Congenital muscular dystrophy type Ullrich (UCMD) is a severe disorder of early childhood onset for which currently there is no effective treatment. UCMD commonly is caused by dominant-negative mutations in the genes coding for collagen type VI, a major microfibrillar component of the extracellular matrix surrounding the muscle fibers. To explore RNA interference (RNAi) as a potential therapy for UCMD, we designed a series of small interfering RNA (siRNA) oligos that specifically target the most common mutations resulting in skipping of exon 16 in the COL6A3 gene and tested them in UCMD-derived dermal fibroblasts. Transcript analysis by semiquantitative and quantitative reverse transcriptase PCR showed that two of these siRNAs were the most allele-specific, i.e., they efficiently knocked down the expression from the mutant allele, without affecting the normal allele. In HEK293T cells, these siRNAs selectively suppressed protein expression from a reporter construct carrying the mutation, with no or minimal suppression of the wild-type (WT) construct, suggesting that collagen VI protein levels are as also reduced in an allele-specific manner. Furthermore, we found that treating UCMD fibroblasts with these siRNAs considerably improved the quantity and quality of the collagen VI matrix, as assessed by confocal microscopy. Our current study establishes RNAi as a promising molecular approach for treating dominant COL6-related dystrophies. PMID:24518369

  2. Contrasting Roles for Axonal Degeneration in an Autoimmune versus Viral Model of Multiple Sclerosis

    PubMed Central

    Tsunoda, Ikuo; Tanaka, Tomoko; Terry, Emily Jane; Fujinami, Robert S.

    2007-01-01

    Although demyelination is a cardinal feature in multiple sclerosis, axonal injury also occurs. We tested whether a delay in axonal degeneration could affect the disease severity in two models for multiple sclerosis: experimental autoimmune encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis virus (TMEV) infection. We compared wild-type C57BL/6 (B6) mice with C57BL/Wlds (Wld) mice, which carry a mutation that delays axonal degeneration. In EAE, both mouse strains were sensitized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide and showed a similar disease onset, MOG-specific lymphoproliferative responses, and inflammation during the acute stage of EAE. However, during the chronic stage, B6 mice continued to show paralysis with a greater extent of axonal damage, demyelination, and MOG-specific lymphoproliferative responses compared with Wld mice, which showed complete recovery. In TMEV infection, only Wld mice were paralyzed and had increased inflammation, virus antigen-positive cells, and TMEV-specific lymphoproliferative responses versus infected B6 mice. Because TMEV can use axons to disseminate in the brain, axonal degeneration in B6 mice might be a beneficial mechanism that limits the virus spread, whereas slow axonal degeneration in Wld mice could favor virus spread. Therefore, axonal degeneration plays contrasting roles (beneficial versus detrimental) depending on the initiator driving the disease. PMID:17200195

  3. Streaming flow from ultrasound contrast agents by acoustic waves in a blood vessel model.

    PubMed

    Cho, Eunjin; Chung, Sang Kug; Rhee, Kyehan

    2015-09-01

    To elucidate the effects of streaming flow on ultrasound contrast agent (UCA)-assisted drug delivery, streaming velocity fields from sonicated UCA microbubbles were measured using particle image velocimetry (PIV) in a blood vessel model. At the beginning of ultrasound sonication, the UCA bubbles formed clusters and translated in the direction of the ultrasound field. Bubble cluster formation and translation were faster with 2.25MHz sonication, a frequency close to the resonance frequency of the UCA. Translation of bubble clusters induced streaming jet flow that impinged on the vessel wall, forming symmetric vortices. The maximum streaming velocity was about 60mm/s at 2.25MHz and decreased to 15mm/s at 1.0MHz for the same acoustic pressure amplitude. The effect of the ultrasound frequency on wall shear stress was more noticeable. Maximum wall shear stress decreased from 0.84 to 0.1Pa as the ultrasound frequency decreased from 2.25 to 1.0MHz. The maximum spatial gradient of the wall shear stress also decreased from 1.0 to 0.1Pa/mm. This study showed that streaming flow was induced by bubble cluster formation and translation and was stronger upon sonication by an acoustic wave with a frequency near the UCA resonance frequency. Therefore, the secondary radiant force, which is much stronger at the resonance frequency, should play an important role in UCA-assisted drug delivery.

  4. A theoretical framework to model DSC-MRI data acquired in the presence of contrast agent extravasation

    NASA Astrophysics Data System (ADS)

    Quarles, C. C.; Gochberg, D. F.; Gore, J. C.; Yankeelov, T. E.

    2009-10-01

    Dynamic susceptibility contrast (DSC) MRI methods rely on compartmentalization of the contrast agent such that a susceptibility gradient can be induced between the contrast-containing compartment and adjacent spaces, such as between intravascular and extravascular spaces. When there is a disruption of the blood-brain barrier, as is frequently the case with brain tumors, a contrast agent leaks out of the vasculature, resulting in additional T1, T2 and T*2 relaxation effects in the extravascular space, thereby affecting the signal intensity time course and reducing the reliability of the computed hemodynamic parameters. In this study, a theoretical model describing these dynamic intra- and extravascular T1, T2 and T*2 relaxation interactions is proposed. The applicability of using the proposed model to investigate the influence of relevant MRI pulse sequences (e.g. echo time, flip angle), and physical (e.g. susceptibility calibration factors, pre-contrast relaxation rates) and physiological parameters (e.g. permeability, blood flow, compartmental volume fractions) on DSC-MRI signal time curves is demonstrated. Such a model could yield important insights into the biophysical basis of contrast-agent-extravasastion-induced effects on measured DSC-MRI signals and provide a means to investigate pulse sequence optimization and appropriate data analysis methods for the extraction of physiologically relevant imaging metrics.

  5. Monte Carlo modeling and optimization of contrast-enhanced radiotherapy of brain tumors.

    PubMed

    Pérez-López, C E; Garnica-Garza, H M

    2011-07-01

    Contrast-enhanced radiotherapy involves the use of a kilovoltage x-ray beam to impart a tumoricidal dose to a target into which a radiological contrast agent has previously been loaded in order to increase the x-ray absorption efficiency. In this treatment modality the selection of the proper x-ray spectrum is important since at the energy range of interest the penetration ability of the x-ray beam is limited. For the treatment of brain tumors, the situation is further complicated by the presence of the skull, which also absorbs kilovoltage x-ray in a very efficient manner. In this work, using Monte Carlo simulation, a realistic patient model and the Cimmino algorithm, several irradiation techniques and x-ray spectra are evaluated for two possible clinical scenarios with respect to the location of the target, these being a tumor located at the center of the head and at a position close to the surface of the head. It will be shown that x-ray spectra, such as those produced by a conventional x-ray generator, are capable of producing absorbed dose distributions with excellent uniformity in the target as well as dose differential of at least 20% of the prescribed tumor dose between this and the surrounding brain tissue, when the tumor is located at the center of the head. However, for tumors with a lateral displacement from the center and close to the skull, while the absorbed dose distribution in the target is also quite uniform and the dose to the surrounding brain tissue is within an acceptable range, hot spots in the skull arise which are above what is considered a safe limit. A comparison with previously reported results using mono-energetic x-ray beams such as those produced by a radiation synchrotron is also presented and it is shown that the absorbed dose distributions rendered by this type of beam are very similar to those obtained with a conventional x-ray beam.

  6. Allelic interactions at the nivea locus of Antirrhinum.

    PubMed Central

    Bollmann, J; Carpenter, R; Coen, E S

    1991-01-01

    Most null alleles at the nivea (niv) locus are recessive to Niv+ and, when homozygous, give white flowers rather than the red of the wild type. In contrast, the niv-571 allele is semidominant; although it gives white flowers when homozygous, very pale flowers result when this allele is heterozygous with NIV+. We showed that in heterozygotes, niv-571 acts in trans to inhibit expression of its Niv+ homology 25-fold to 50-fold. The inhibition is reversible after meiosis and partially reversible somatically. The niv-571 allele carries a transposable element Tam3 insertion and three truncated copies of the niv gene, one copy being in inverse orientation. Analysis of two further niv alleles, niv-572 and niv-527, showed that excision of Tam3 from niv-571 does not affect the ability of the allele to repress Niv+ and that one truncated niv copy alone is insufficient to confer semidominance. The detailed structures of various semidominant niv alleles suggest that their effects in trans are not readily explained by production of antisense RNA but are more easily reconciled with a direct recognition/interaction between homologous genes, reminiscent of cosuppression and transvection phenomena described in other systems. PMID:1840900

  7. Dynamic Contrast-Enhanced MR Microscopy: Functional Imaging in Preclinical Models of Cancer

    NASA Astrophysics Data System (ADS)

    Subashi, Ergys

    Dynamic contrast-enhanced (DCE) MRI has been widely used as a quantitative imaging method for monitoring tumor response to therapy. The pharmacokinetic parameters derived from this technique have been used in more than 100 phase I trials and investigator led studies. The simultaneous challenges of increasing the temporal and spatial resolution, in a setting where the signal from the much smaller voxel is weaker, have made this MR technique difficult to implement in small-animal imaging.Existing preclinical DCE-MRI protocols acquire a limited number of slices resulting in potentially lost information in the third dimension. Furthermore, drug efficacy studies measuring the effect of an anti-angiogenic treatment, often compare the derived biomarkers on manually selected tumor regions or over the entire volume. These measurements include domains where the interpretation of the biomarkers may be unclear (such as in necrotic areas). This dissertation describes and compares a family of four-dimensional (3D spatial + time), projection acquisition, keyhole-sampling strategies that support high spatial and temporal resolution. An interleaved 3D radial trajectory with a quasi-uniform distribution of points in k-space was used for sampling temporally resolved datasets. These volumes were reconstructed with three different k-space filters encompassing a range of possible keyhole strategies. The effect of k-space filtering on spatial and temporal resolution was studied in phantoms and in vivo. The statistical variation of the DCE-MRI measurement is analyzed by considering the fundamental sources of error in the MR signal intensity acquired with the spoiled gradient-echo (SPGR) pulse sequence. Finally, the technique was applied for measuring the extent of the opening of the blood-brain barrier in a mouse model of pediatric glioma and for identifying regions of therapeutic effect in a model of colorectal adenocarcinoma. It is shown that 4D radial keyhole imaging does not degrade

  8. Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

    SciTech Connect

    Thorek, Daniel L.J.; Kramer, Robin M.; Chen, Qing; Jeong, Jeho; Lupu, Mihaela E.; Lee, Alycia M.; Moynahan, Mary E.; Lowery, Maeve; Ulmert, David; Zanzonico, Pat; Deasy, Joseph O.; Humm, John L.; Russell, James

    2015-10-01

    Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.

  9. Reverse-contrast imaging and targeted radiation therapy of advanced pancreatic cancer models

    PubMed Central

    Thorek, Daniel L.J.; Kramer, Robin M.; Chen, Qing; Jeong, Jeho; Lupu, Mihaela E.; Lee, Alycia M.; Moynahan, Mary E.; Lowery, Maeve; Ulmert, H. David; Zanzonico, Pat; Deasy, Joseph O.; Humm, John L.; Russell, James

    2015-01-01

    Purpose To evaluate the feasibility of delivering experimental radiotherapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by X-ray CT. With this technique we delineated the pancreas, and both orthotopic xenografts and genetically engineered disease. CT imaging was validated by comparison with magnetic resonance (MR) imaging. Therapeutic radiation was delivered via a 1 cm diameter field. Selective X-ray radiation therapy (XRT) of the non-invasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360-degree arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic XRT to orthotopic tumors. Results Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times post-treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions This advance permits evaluation of radiation planning and dosing parameters. Accurate non-invasive longitudinal imaging and monitoring of tumor progression and therapeutic response in pre-clinical models is now possible, and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response. PMID:26238952

  10. Contrast of evolution models for agricultural contaminants in ground waters by means of fuzzy logic and data mining

    NASA Astrophysics Data System (ADS)

    Andujar, J. M.; Aroba, J.; de Torre, M. L. La; Grande, J. A.

    2006-01-01

    This work aims at contrasting, by means of a set of fuzzy logic- and data mining-based algorithms, the functioning model of a detritic aquifer undergoing overexploitation and nitrate excess input coming from strawberry and citrus intensive crops in its recharge zone. To provide researchers unskilled in data mining techniques with an easy and intuitive interpretation, the authors have developed a computer tool based on fuzzy logic that allows immediate qualitative analysis of the data contained in a data mass from the water chemical analyses, and serves as a contrast to functioning models previously proposed with classical statistics.

  11. Computational fluid dynamics modelling of perfusion measurements in dynamic contrast-enhanced computed tomography: development, validation and clinical applications

    NASA Astrophysics Data System (ADS)

    Peladeau-Pigeon, M.; Coolens, C.

    2013-09-01

    Dynamic contrast-enhanced computed tomography (DCE-CT) is an imaging tool that aids in evaluating functional characteristics of tissue at different stages of disease management: diagnostic, radiation treatment planning, treatment effectiveness, and monitoring. Clinical validation of DCE-derived perfusion parameters remains an outstanding problem to address prior to perfusion imaging becoming a widespread standard as a non-invasive quantitative measurement tool. One approach to this validation process has been the development of quality assurance phantoms in order to facilitate controlled perfusion ex vivo. However, most of these systems fail to establish and accurately replicate physiologically relevant capillary permeability and exchange performance. The current work presents the first step in the development of a prospective suite of physics-based perfusion simulations based on coupled fluid flow and particle transport phenomena with the goal of enhancing the understanding of clinical contrast agent kinetics. Existing knowledge about a controllable, two-compartmental fluid exchange phantom was used to validate the computational fluid dynamics (CFD) simulation model presented herein. The sensitivity of CFD-derived contrast uptake curves to contrast injection parameters, including injection duration and flow rate, were quantified and found to be within 10% accuracy. The CFD model was employed to evaluate two commonly used clinical kinetic algorithms used to derive perfusion parameters: Fick's principle and the modified Tofts model. Neither kinetic model was able to capture the true transport phenomena it aimed to represent but if the overall contrast concentration after injection remained identical, then successive DCE-CT evaluations could be compared and could indeed reflect differences in regional tissue flow. This study sets the groundwork for future explorations in phantom development and pharmaco-kinetic modelling, as well as the development of novel contrast

  12. Allelic association between marker loci.

    PubMed

    Lonjou, C; Collins, A; Morton, N E

    1999-02-16

    Allelic association has proven useful to refine the location of major genes prior to positional cloning, but it is of uncertain value for genome scans in complex inheritance. We have extended kinship theory to give information content for linkage and allelic association. Application to pairs of closely linked markers as a surrogate for marker x oligogene pairs indicates that association is largely determined by regional founders, with little effect of subsequent demography. Sub-Saharan Africa has the least allelic association, consistent with settlement of other regions by small numbers of founders. Recent speculation about substantial advantages of isolates over large populations, of constant size over expansion, and of F1 hybrids over incrosses is not supported by theory or data. On the contrary, fewer affected cases, less opportunity for replication, and more stochastic variation tend to make isolates less informative for allelic association, as they are for linkage.

  13. What Is a Recessive Allele?

    ERIC Educational Resources Information Center

    American Biology Teacher, 1991

    1991-01-01

    Presents four misconceptions students have concerning the concepts of recessive and dominant alleles. Discusses the spectrum of dominant-recessive relationships, different levels of analysis between phenotype and genotype, possible causes of dominance, and an example involving wrinkled peas. (MDH)

  14. Qualitative Contrast between Knowledge-Limited Mixed-State and Variable-Resources Models of Visual Change Detection

    ERIC Educational Resources Information Center

    Nosofsky, Robert M.; Donkin, Chris

    2016-01-01

    We report an experiment designed to provide a qualitative contrast between knowledge-limited versions of mixed-state and variable-resources (VR) models of visual change detection. The key data pattern is that observers often respond "same" on big-change trials, while simultaneously being able to discriminate between same and small-change…

  15. Phenotypic and genotypic expression of self-incompatibility haplotypes in Arabidopsis lyrata suggests unique origin of alleles in different dominance classes.

    PubMed

    Prigoda, Nadia L; Nassuth, Annette; Mable, Barbara K

    2005-07-01

    The highly divergent alleles of the SRK gene in outcrossing Arabidopsis lyrata have provided important insights into the evolutionary history of self-incompatibility (SI) alleles and serve as an ideal model for studies of the evolutionary and molecular interactions between alleles in cell-cell recognition systems in general. One tantalizing question is how new specificities arise in systems that require coordination between male and female components. Allelic recruitment via gene conversion has been proposed as one possibility, based on the division of DNA sequences at the SRK locus into two distinctive groups: (1) sequences whose relationships are not well resolved and display the long branch lengths expected for a gene under balancing selection (Class A); and (2) sequences falling into a well-supported group with shorter branch lengths (Class B) that are closely related to an unlinked paralogous locus. The purpose of this study was to determine if differences in phenotype (site of expression assayed using allele-specific reverse transcription-polymerase chain reaction) or function (dominance relationships assayed through controlled pollinations) accompany the sequence-based classification. Expression of Class A alleles was restricted to floral tissues, as predicted for genes involved in the SI response. In contrast, Class B alleles, despite being tightly linked to the SI phenotype, were unexpectedly expressed in both leaves and floral tissues; the same pattern found for a related unlinked paralogous sequence. Whereas Class A included haplotypes in three different dominance classes, all Class B haplotypes were found to be recessive to all except one Class A haplotype. In addition, mapping of expression and dominance patterns onto an S-domain-based genealogy suggested that allelic dominance may be determined more by evolutionary history than by frequency-dependent selection for lowered dominance as some theories suggest. The possibility that interlocus gene

  16. Rescue of Progeria in Trichothiodystrophy by Homozygous Lethal Xpd Alleles

    PubMed Central

    Andressoo, Jaan-Olle; Jans, Judith; de Wit, Jan; Coin, Frederic; Hoogstraten, Deborah; van de Ven, Marieke; Toussaint, Wendy; Huijmans, Jan; Thio, H. Bing; van Leeuwen, Wibeke J; de Boer, Jan; Egly, Jean-Marc; Hoeijmakers, Jan H. J; van der Horst, Gijsbertus T. J; Mitchell, James R

    2006-01-01

    Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals. PMID:17020410

  17. Delimiting Allelic Imbalance of TYMS by Allele-Specific Analysis

    PubMed Central

    Balboa-Beltrán, Emilia; Cruz, Raquel; Carracedo, Angel; Barros, Francisco

    2015-01-01

    Abstract Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5′- and 3′-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients. Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3′-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5′-UTR polymorphisms). For neither the 3′- nor the 5′-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance. The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold

  18. Pericardium based model fusion of CT and non-contrasted C-arm CT for visual guidance in cardiac interventions.

    PubMed

    Zheng, Yefeng

    2014-01-01

    Minimally invasive transcatheter cardiac interventions are being adopted rapidly to treat a range of cardiovascular diseases. Pre-operative imaging, e.g., computed tomography (CT), plays an important role in surgical planning and simulation of cardiac interventions. Overlaying a 3D cardiac model extracted from pre-operative images onto real-time fluoroscopic images provides valuable visual guidance during the intervention. However, direct 3D to 2D fusion is difficult and may require quite amounts of user interaction. Intra-operative non-contrasted C-arm CT can be used as an intermedium for model fusion. The cardiac model is first warped to C-arm CT and later overlaid onto fluoroscopy. The C-arm CT to fluoroscopy overlay is straightforward since both images are captured on the same machine and the C-arm projection geometry can be directly used for overlay. Though various image registration methods may be used to fuse pre-operative images and C-arm CT, cross-modality image registration is not robust due to the significant difference in image characteristics (contrasted vs. non-contrasted). In this work we propose a model based fusion method using the pericardium to align pre-operative CT to intra-operative C-arm CT. After automatic segmentation of the pericardium in both CT and C-arm CT, the deformation field is estimated and then applied to warp the cardiac model extracted from CT to C-arm CT. The proposed method can be applied to fuse different cardiac models (e.g., chambers, aorta, coronary arteries, and cardiac valves). A feasibility study on aortic root model fusion shows that a reasonable accuracy can be achieved using a generic model (from a different patient), while more accurate results come from a patient-specific model. Intelligently weighted fusion can further improve the accuracy by using all available cardiac models in a pre-collected training set.

  19. Delayed Contrast Enhancement Imaging of a Murine Model for Ischemia Reperfusion with Carbon Nanotube Micro-CT

    PubMed Central

    Burk, Laurel M.; Wang, Ko-Han; Wait, John Matthew; Kang, Eunice; Willis, Monte; Lu, Jianping; Zhou, Otto; Lee, Yueh Z.

    2015-01-01

    We aim to demonstrate the application of free-breathing prospectively gated carbon nanotube (CNT) micro-CT by evaluating a myocardial infarction model with a delayed contrast enhancement technique. Evaluation of murine cardiac models using micro-CT imaging has historically been limited by extreme imaging requirements. Newly-developed CNT-based x-ray sources offer precise temporal resolution, allowing elimination of physiological motion through prospective gating. Using free-breathing, cardiac-gated CNT micro-CT, a myocardial infarction model can be studied non-invasively and with high resolution. Myocardial infarction was induced in eight male C57BL/6 mice aged 8–12 weeks. The ischemia reperfusion model was achieved by surgically occluding the LAD artery for 30 minutes followed by 24 hours of reperfusion. Tail vein catheters were placed for contrast administration. Iohexol 300mgI/mL was administered followed by images obtained in diastole. Iodinated lipid blood pool contrast agent was then administered, followed with images at systole and diastole. Respiratory and cardiac signals were monitored externally and used to gate the scans of free-breathing subjects. Seven control animals were scanned using the same imaging protocol. After imaging, the heart was harvested, cut into 1mm slices and stained with TTC. Post-processing analysis was performed using ITK-Snap and MATLAB. All animals demonstrated obvious delayed contrast enhancement in the left ventricular wall following the Iohexol injection. The blood pool contrast agent revealed significant changes in cardiac function quantified by 3-D volume ejection fractions. All subjects demonstrated areas of myocardial infarct in the LAD distribution on both TTC staining and micro-CT imaging. The CNT micro-CT system aids straightforward, free-breathing, prospectively-gated 3-D murine cardiac imaging. Delayed contrast enhancement allows identification of infarcted myocardium after a myocardial ischemic event. We demonstrate

  20. Delayed contrast enhancement imaging of a murine model for ischemia reperfusion with carbon nanotube micro-CT.

    PubMed

    Burk, Laurel M; Wang, Ko-Han; Wait, John Matthew; Kang, Eunice; Willis, Monte; Lu, Jianping; Zhou, Otto; Lee, Yueh Z

    2015-01-01

    We aim to demonstrate the application of free-breathing prospectively gated carbon nanotube (CNT) micro-CT by evaluating a myocardial infarction model with a delayed contrast enhancement technique. Evaluation of murine cardiac models using micro-CT imaging has historically been limited by extreme imaging requirements. Newly-developed CNT-based x-ray sources offer precise temporal resolution, allowing elimination of physiological motion through prospective gating. Using free-breathing, cardiac-gated CNT micro-CT, a myocardial infarction model can be studied non-invasively and with high resolution. Myocardial infarction was induced in eight male C57BL/6 mice aged 8-12 weeks. The ischemia reperfusion model was achieved by surgically occluding the LAD artery for 30 minutes followed by 24 hours of reperfusion. Tail vein catheters were placed for contrast administration. Iohexol 300 mgI/mL was administered followed by images obtained in diastole. Iodinated lipid blood pool contrast agent was then administered, followed with images at systole and diastole. Respiratory and cardiac signals were monitored externally and used to gate the scans of free-breathing subjects. Seven control animals were scanned using the same imaging protocol. After imaging, the heart was harvested, cut into 1mm slices and stained with TTC. Post-processing analysis was performed using ITK-Snap and MATLAB. All animals demonstrated obvious delayed contrast enhancement in the left ventricular wall following the Iohexol injection. The blood pool contrast agent revealed significant changes in cardiac function quantified by 3-D volume ejection fractions. All subjects demonstrated areas of myocardial infarct in the LAD distribution on both TTC staining and micro-CT imaging. The CNT micro-CT system aids straightforward, free-breathing, prospectively-gated 3-D murine cardiac imaging. Delayed contrast enhancement allows identification of infarcted myocardium after a myocardial ischemic event. We demonstrate

  1. Contrast-enhanced X-ray detection of breast microcalcifications in a murine model using targeted gold nanoparticles.

    PubMed

    Cole, Lisa E; Vargo-Gogola, Tracy; Roeder, Ryan K

    2014-07-22

    Microcalcifications are deposits of hydroxyapatite (HA) mineral within breast tissue and the most common abnormality detected by mammography when screening for breast cancer due to exhibiting greater X-ray attenuation than the surrounding tissue. However, the detection of microcalcifications is limited by the sensitivity and specificity of mammography. Therefore, the objective of this study was to investigate in vivo targeted delivery of bisphosphonate-functionalized gold nanoparticles (BP-Au NPs) for contrast-enhanced detection of microcalcifications using computed tomography (CT). A murine model was developed for precise, a priori control over the level of microcalcification burden by injecting varying concentrations of HA crystals in a Matrigel carrier into mammary glands. The measured X-ray attenuation of microcalcifications containing varying HA concentrations demonstrated that the model was reproducible and able to recapitulate varying levels of microcalcification burden, including levels undetectable by CT in the absence of contrast enhancement. After intramammary delivery, BP-Au NPs provided enhanced contrast for the detection of microcalcifications that were otherwise below the CT detection limit. BP-Au NPs targeted microcalcifications due to specific binding to HA crystal surfaces, resulting in contrast between the HA microcalcification site and surrounding tissue which was visibly apparent (∼30-135 HU) within 2 days after delivery. Therefore, targeted BP-Au NPs enabled improved sensitivity and specificity for the detection of microcalcifications.

  2. Contrast-enhanced X-ray detection of breast microcalcifications in a murine model using targeted gold nanoparticles.

    PubMed

    Cole, Lisa E; Vargo-Gogola, Tracy; Roeder, Ryan K

    2014-07-22

    Microcalcifications are deposits of hydroxyapatite (HA) mineral within breast tissue and the most common abnormality detected by mammography when screening for breast cancer due to exhibiting greater X-ray attenuation than the surrounding tissue. However, the detection of microcalcifications is limited by the sensitivity and specificity of mammography. Therefore, the objective of this study was to investigate in vivo targeted delivery of bisphosphonate-functionalized gold nanoparticles (BP-Au NPs) for contrast-enhanced detection of microcalcifications using computed tomography (CT). A murine model was developed for precise, a priori control over the level of microcalcification burden by injecting varying concentrations of HA crystals in a Matrigel carrier into mammary glands. The measured X-ray attenuation of microcalcifications containing varying HA concentrations demonstrated that the model was reproducible and able to recapitulate varying levels of microcalcification burden, including levels undetectable by CT in the absence of contrast enhancement. After intramammary delivery, BP-Au NPs provided enhanced contrast for the detection of microcalcifications that were otherwise below the CT detection limit. BP-Au NPs targeted microcalcifications due to specific binding to HA crystal surfaces, resulting in contrast between the HA microcalcification site and surrounding tissue which was visibly apparent (∼30-135 HU) within 2 days after delivery. Therefore, targeted BP-Au NPs enabled improved sensitivity and specificity for the detection of microcalcifications. PMID:24992365

  3. A Novel Foam Contrast Agent Suitable for Fluoroscopic Interventional Procedure: Comparative Study of Physical Properties and Experimental Intervention in Animal Model

    PubMed Central

    Hwang, Jin Ho; Park, Hong Suk; Seo, Soowon; Choo, In Wook; Do, Young Soo; Choo, Sung Wook; Shin, Sung Wook; Park, Kwang Bo; Cho, Sung Ki; Hyun, Dongho; Lim, Sooyoun

    2015-01-01

    In fluoroscopic contrast study for interventional procedure, liquid contrast agent may be diluted in body fluid, losing its contrast effect. We developed a novel contrast agent of “foam state” to maintain contrast effect for enough time and performed a comparative study of physical properties and its usefulness in experimental intervention in animal model. The mean size of microbubble of foam contrast was 13.8 ± 3.6 µm. The viscosity was 201.0 ± 0.624 cP (centipoise) and the specific gravity was 0.616. The foam decayed slowly and it had 97.5 minutes of half-life. In terms of the sustainability in a slow flow environment, foam contrast washed out much more slowly than a conventional contrast. In experimental colonic stent placement, foam contrast revealed significantly better results than conventional contrast in procedure time, total amount of contrast usage, and the number of injections (p < 0.05). Our foam contrast has high viscosity and low specific gravity and maintains foam state for a sufficient time. Foam contrast with these properties was useful in experimental intervention in animal model. We anticipate that foam contrast may be applied to various kinds of interventional procedures. PMID:26366422

  4. A Novel Foam Contrast Agent Suitable for Fluoroscopic Interventional Procedure: Comparative Study of Physical Properties and Experimental Intervention in Animal Model.

    PubMed

    Hwang, Jin Ho; Park, Hong Suk; Seo, Soowon; Choo, In Wook; Do, Young Soo; Choo, Sung Wook; Shin, Sung Wook; Park, Kwang Bo; Cho, Sung Ki; Hyun, Dongho; Lim, Sooyoun

    2015-01-01

    In fluoroscopic contrast study for interventional procedure, liquid contrast agent may be diluted in body fluid, losing its contrast effect. We developed a novel contrast agent of "foam state" to maintain contrast effect for enough time and performed a comparative study of physical properties and its usefulness in experimental intervention in animal model. The mean size of microbubble of foam contrast was 13.8 ± 3.6 µm. The viscosity was 201.0 ± 0.624 cP (centipoise) and the specific gravity was 0.616. The foam decayed slowly and it had 97.5 minutes of half-life. In terms of the sustainability in a slow flow environment, foam contrast washed out much more slowly than a conventional contrast. In experimental colonic stent placement, foam contrast revealed significantly better results than conventional contrast in procedure time, total amount of contrast usage, and the number of injections (p < 0.05). Our foam contrast has high viscosity and low specific gravity and maintains foam state for a sufficient time. Foam contrast with these properties was useful in experimental intervention in animal model. We anticipate that foam contrast may be applied to various kinds of interventional procedures. PMID:26366422

  5. Allelic Diversity and Its Implications for the Rate of Adaptation

    PubMed Central

    Caballero, Armando; García-Dorado, Aurora

    2013-01-01

    Genetic variation is usually estimated empirically from statistics based on population gene frequencies, but alternative statistics based on allelic diversity (number of allelic types) can provide complementary information. There is a lack of knowledge, however, on the evolutionary implications attached to allelic-diversity measures, particularly in structured populations. In this article we simulated multiple scenarios of single and structured populations in which a quantitative trait subject to stabilizing selection is adapted to different fitness optima. By forcing a global change in the optima we evaluated which diversity variables are more strongly correlated with both short- and long-term adaptation to the new optima. We found that quantitative genetic variance components for the trait and gene-frequency-diversity measures are generally more strongly correlated with short-term response to selection, whereas allelic-diversity measures are more correlated with long-term and total response to selection. Thus, allelic-diversity variables are better predictors of long-term adaptation than gene-frequency variables. This observation is also extended to unlinked neutral markers as a result of the information they convey on the demographic population history. Diffusion approximations for the allelic-diversity measures in a finite island model under the infinite-allele neutral mutation model are also provided. PMID:24121776

  6. DRD4 dopamine receptor allelic diversity in various primate species

    SciTech Connect

    Adamson, M.; Higley, D.; O`Brien, S.

    1994-09-01

    The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. We have determined DRD4 genotypes in the following nonhuman primate species: chimpanzee N=2, pygmy chimpanzee N=2, gorilla N=4, siamang N=2, Gelada baboon N=1, gibbon N=1, orangutan (Bornean and Sumatran) N=62, spider monkey N=4, owl monkey N=1, Colobus monkey N=1, Patas monkey N=1, ruffed lemur N=1, rhesus macaque N=8, and vervet monkey N=28. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat allels, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.

  7. Search for novel contrast materials in dual-energy x-ray breast imaging using theoretical modeling of contrast-to-noise ratio

    NASA Astrophysics Data System (ADS)

    Karunamuni, R.; Maidment, A. D. A.

    2014-08-01

    Contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging uses a low- and high-energy x-ray spectral pair to eliminate soft-tissue signal variation and thereby increase the detectability of exogenous imaging agents. Currently, CEDE breast imaging is performed with iodinated contrast agents. These compounds are limited by several deficiencies, including rapid clearance and poor tumor targeting ability. The purpose of this work is to identify novel contrast materials whose contrast-to-noise ratio (CNR) is comparable or superior to that of iodine in the mammographic energy range. A monoenergetic DE subtraction framework was developed to calculate the DE signal intensity resulting from the logarithmic subtraction of the low- and high-energy signal intensities. A weighting factor is calculated to remove the dependence of the DE signal on the glandularity of the breast tissue. Using the DE signal intensity and weighting factor, the CNR for materials with atomic numbers (Z) ranging from 1 to 79 are computed for energy pairs between 10 and 50 keV. A group of materials with atomic numbers ranging from 42 to 63 were identified to exhibit the highest levels of CNR in the mammographic energy range. Several of these materials have been formulated as nanoparticles for various applications but none, apart from iodine, have been investigated as CEDE breast imaging agents. Within this group of materials, the necessary dose fraction to the LE image decreases as the atomic number increases. By reducing the dose to the LE image, the DE subtraction technique will not provide an anatomical image of sufficient quality to accompany the contrast information. Therefore, materials with Z from 42 to 52 provide nearly optimal values of CNR with energy pairs and dose fractions that provide good anatomical images. This work is intended to inspire further research into new materials for optimized CEDE breast functional imaging.

  8. Search for novel contrast materials in dual-energy x-ray breast imaging using theoretical modeling of contrast-to-noise ratio.

    PubMed

    Karunamuni, R; Maidment, A D A

    2014-08-01

    Contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging uses a low- and high-energy x-ray spectral pair to eliminate soft-tissue signal variation and thereby increase the detectability of exogenous imaging agents. Currently, CEDE breast imaging is performed with iodinated contrast agents. These compounds are limited by several deficiencies, including rapid clearance and poor tumor targeting ability. The purpose of this work is to identify novel contrast materials whose contrast-to-noise ratio (CNR) is comparable or superior to that of iodine in the mammographic energy range. A monoenergetic DE subtraction framework was developed to calculate the DE signal intensity resulting from the logarithmic subtraction of the low- and high-energy signal intensities. A weighting factor is calculated to remove the dependence of the DE signal on the glandularity of the breast tissue. Using the DE signal intensity and weighting factor, the CNR for materials with atomic numbers (Z) ranging from 1 to 79 are computed for energy pairs between 10 and 50 keV. A group of materials with atomic numbers ranging from 42 to 63 were identified to exhibit the highest levels of CNR in the mammographic energy range. Several of these materials have been formulated as nanoparticles for various applications but none, apart from iodine, have been investigated as CEDE breast imaging agents. Within this group of materials, the necessary dose fraction to the LE image decreases as the atomic number increases. By reducing the dose to the LE image, the DE subtraction technique will not provide an anatomical image of sufficient quality to accompany the contrast information. Therefore, materials with Z from 42 to 52 provide nearly optimal values of CNR with energy pairs and dose fractions that provide good anatomical images. This work is intended to inspire further research into new materials for optimized CEDE breast functional imaging.

  9. Assignment of SNP allelic configuration in polyploids using competitive allele-specific PCR: application to citrus triploid progeny

    PubMed Central

    Cuenca, José; Aleza, Pablo; Navarro, Luis; Ollitrault, Patrick

    2013-01-01

    Background Polyploidy is a major component of eukaryote evolution. Estimation of allele copy numbers for molecular markers has long been considered a challenge for polyploid species, while this process is essential for most genetic research. With the increasing availability and whole-genome coverage of single nucleotide polymorphism (SNP) markers, it is essential to implement a versatile SNP genotyping method to assign allelic configuration efficiently in polyploids. Scope This work evaluates the usefulness of the KASPar method, based on competitive allele-specific PCR, for the assignment of SNP allelic configuration. Citrus was chosen as a model because of its economic importance, the ongoing worldwide polyploidy manipulation projects for cultivar and rootstock breeding, and the increasing availability of SNP markers. Conclusions Fifteen SNP markers were successfully designed that produced clear allele signals that were in agreement with previous genotyping results at the diploid level. The analysis of DNA mixes between two haploid lines (Clementine and pummelo) at 13 different ratios revealed a very high correlation (average = 0·9796; s.d. = 0·0094) between the allele ratio and two parameters [θ angle = tan−1 (y/x) and y′ = y/(x + y)] derived from the two normalized allele signals (x and y) provided by KASPar. Separated cluster analysis and analysis of variance (ANOVA) from mixed DNA simulating triploid and tetraploid hybrids provided 99·71 % correct allelic configuration. Moreover, triploid populations arising from 2n gametes and interploid crosses were easily genotyped and provided useful genetic information. This work demonstrates that the KASPar SNP genotyping technique is an efficient way to assign heterozygous allelic configurations within polyploid populations. This method is accurate, simple and cost-effective. Moreover, it may be useful for quantitative studies, such as relative allele-specific expression analysis and bulk segregant analysis

  10. Highly accelerated 3D dynamic contrast enhanced MRI from sparse spiral sampling using integrated partial separability model and JSENSE

    NASA Astrophysics Data System (ADS)

    Lyu, Jingyuan; Spincemaille, Pascal; Wang, Yi; Zhou, Yihang; Ren, Fuquan; Ying, Leslie

    2014-05-01

    Dynamic contrast enhanced MRI requires high spatial resolution for morphological information and high temporal resolution for contrast pharmacokinetics. The current techniques usually have to compromise the spatial information for the required temporal resolution. This paper presents a novel method that effectively integrates sparse sampling, parallel imaging, partial separable (PS) model, and sparsity constraints for highly accelerated DCE-MRI. Phased array coils were used to continuously acquire data from a stack of variable-density spiral trajectory with a golden angle. In reconstruction, the sparsity constraints, the coil sensitivities, spatial and temporal bases of the PS model are jointly estimated through alternating optimization. Experimental results from in vivo DCE liver imaging data show that the proposed method is able to achieve high spatial and temporal resolutions at the same time.

  11. Polymorphisms in MHC-DRA and -DRB alleles of water buffalo (Bubalus bubalis) reveal different features from cattle DR alleles.

    PubMed

    Sena, L; Schneider, M P C; Brenig, B; Honeycutt, R L; Womack, J E; Skow, L C

    2003-02-01

    Seventy-five individuals of Bubalus bubalis belonging to four different breeds, three of river buffalo and one of swamp buffalo, were studied for polymorphism in MHC DRB (Bubu-DRB) and DRA (Bubu-DRA) loci. Eight alleles of Bubu-DRB were found, and all alleles in the swamp type were shared with the three river breeds. All alleles sampled from the breed of European origin (Mediterranean) were present in breeds sampled in Brazil, thus variability of this locus may have been preserved to a great extent in the more recently founded Brazilian population. Bubu-DRB alleles contained higher proportions of synonymous vs. non-synonymous substitutions in the non-peptide-binding sites (PBS) region, in contrast to the pattern of variation found in BoLA-DRB3, the orthologous locus in cattle. This indicated that either the first domain exon (exon 2) of Bubu-DRB has not undergone as much recombination and/or gene conversion as in cattle alleles, or Bubu-DRB may be more ancient than BoLA-DRB3 alleles. Phylogenetic analysis of DRB alleles from Bubalus, Syncerus c. caffer, the Cape buffalo, and domestic cattle demonstrated transspecies polymorphism. Water buffalo contained two alleles of DRA that differed from each other in two amino acid positions, including one in the PBS (alpha22) that was also shared with Anoa depressicornis, the anoa. Discovery of variation in DRA was surprising as the first domain of DRA is a highly conserved polypeptide in mammals in general and especially in ruminants, where no other substitution in PBS was seen.

  12. Impact of number of repeated scans on model observer performance for a low-contrast detection task in CT

    NASA Astrophysics Data System (ADS)

    Ma, Chi; Yu, Lifeng; Chen, Baiyu; Vrieze, Thomas; Favazza, Christopher; Leng, Shuai; McCollough, Cynthia

    2015-03-01

    In previous investigations on CT image quality, channelized Hotelling observer (CHO) models have been shown to well represent human observer performance in several phantom-based detection/discrimination tasks. In these studies, a large number of independent images was necessary to estimate the expectation images and covariance matrices for each test condition. The purpose of this study is to investigate how the number of repeated scans affects the precision and accuracy of the CHO's performance in a signal-known-exactly detection task. A phantom containing 21 low-contrast objects (3 contrast levels and 7 sizes) was scanned with a 128-slice CT scanner at three dose levels. For each dose level, 100 independent images were acquired for each test condition. All images were reconstructed using filtered-backprojection (FBP) and a commercial iterative reconstruction algorithm. For each combination of dose level and reconstruction method, the low-contrast detectability, quantified with the area under receiver operating characteristic curve (Az), was calculated using a previously validated CHO model. To determine the dependency of CHO performance on the number of repeated scans, the Az value was calculated for different number of channel filters, for each object size and contrast, and for different dose/reconstruction settings using all 100 repeated scans. The Az values were also calculated using randomly selected subsets of the scans (from 10 to 90 scans with an increment of 10 scans). Using the Az from the 100 scans as the reference, the accuracy of Az values calculated from a fewer number of scans was determined and the minimal number of scans was subsequently derived. For the studied signal-known-exactly detection task, results demonstrated that, the minimal number of scans depends on dose level, object size and contrast level, and channel filters.

  13. Development of allele-specific PCR and RT-PCR assays for clustered resistance genes using a potato late blight resistance transgene as a model.

    PubMed

    Millett, B P; Bradeen, J M

    2007-02-01

    Members of the NBS-LRR gene family impart resistance to a wide variety of pathogens and are often found clustered within a plant genome. This clustering of homologous sequences can complicate PCR-based characterizations, especially the study of transgenes. We have developed allele-specific PCR and RT-PCR assays for the potato late blight resistance gene RB. Our assay utilizes two approaches toward primer design, allowing discrimination between the RB transgene and both the endogenous RB gene and numerous RB homeologs. First, a reverse primer was designed to take advantage of an indel present in the RB transgene but absent in rb susceptibility alleles, enhancing specificity for the transgene, though not fully discriminating against RB homeologs. Second, a forward primer was designed according to the principles of mismatch amplification mutation assay (MAMA) PCR, targeting SNPs introduced during the cloning of RB. Together, the indel reverse primer and the MAMA forward primer provide an assay that is highly specific for the RB transgene, being capable of distinguishing the transgene from all RB endogenous gene copies and from all RB paralogs in a diverse collection of wild and cultivated potato genotypes. These primers have been successfully multiplexed with primers of an internal control. The multiplexed assay is useful for both PCR and RT-PCR applications. Double MAMA-PCR, in which both PCR primers target separate transgene-specific SNPs, was also tested and shown to be equally specific for the RB transgene. We propose extending the use of MAMA for the characterization of resistance transgenes. PMID:17177064

  14. Modelling and design of modified Wollaston prisms and the application in differential interference contrast microscopy

    NASA Astrophysics Data System (ADS)

    Zhang, Site; Zhong, Huiying; Wyrowski, Frank

    2016-03-01

    Wollaston prisms and the modified Wollaston prisms, which are interesting for various applications like optical metrology, topography of surfaces and biological imaging, has been theoretically studied and also been practically applied. The previous studies are mostly based on ray tracing analysis and, as a result, the information that can be obtained are somehow restricted. In this paper, we propose a geometric field tracing technique for the simulation of light propagation through Wollaston prisms. In geometric field tracing we seek for the solutions to Maxwell's equations under the geometrical optics approximation, so that all the properties of light as electromagnetic field are retained. Using the proposed simulation technique, we present the simulation of a differential interference contrast (DIC) microscopy, in which the modified Wollaston prism is used as the key component.

  15. Contrastive Lexicology.

    ERIC Educational Resources Information Center

    Hartmann, R. R. K.

    This paper deals with the relation between etymologically related words in different languages. A survey is made of seven stages in the development of contrastive lexicology. These are: prelinguistic word studies, semantics, lexicography, translation, foreign language learning, bilingualism, and finally contrastive analysis. Concerning contrastive…

  16. Allelic disequilibrium and allele frequency distribution as a function of social and demographic history.

    PubMed Central

    Thompson, E A; Neel, J V

    1997-01-01

    Allelic disequilibrium between closely linked genes is a common observation in human populations and often gives rise to speculation concerning the role of selective forces. In a previous treatment, we have developed a population model of the expected distribution of rare variants (including private polymorphisms) in Amerindians and have argued that, because of the great expansion of Amerindian numbers with the advent of agriculture, most of these rare variants are of relatively recent origin. Many other populations have similar histories of striking recent expansions. In this treatment, we demonstrate that, in consequence of this fact, a high degree of linkage disequilibrium between two nonhomologous alleles <0.5 cM apart is the "normal" expectation, even in the absence of selection. This expectation is enhanced by the previous subdivision of human populations into relatively isolated tribes characterized by a high level of endogamy and inbreeding. We also demonstrate that the alleles associated with a recessive disease phenotype are expected to exist in a population in very variable frequencies: there is no need to postulate positive selection with respect to the more common disease-associated alleles for such entities as phenylketonuria or cystic fibrosis. PMID:8981963

  17. Correlated evolution of nucleotide substitution rates and allelic variation in Mhc-DRB lineages of primates

    PubMed Central

    Garamszegi, László Z; de Groot, Natasja G; Bontrop, Ronald E

    2009-01-01

    models that control for similarity between species, due to common descent, and focused on variations within a single lineage (DRB1*03), the positive relationship between different substitution rates and allelic polymorphisms was still robust. Finally, we found the same effects to emerge in the analyses that eliminated within-species variation in MHC traits by using strictly single population-level studies. However, in a set of contrasting analyses, in which we focused on the non-functional DRB6 locus, the correlation between substitution rates and allelic variation was not prevalent. Conclusion Our results indicate that positive selection for the generation of allelic polymorphism acting on the functional part of the protein has consequences for the nucleotide substitution rate along the whole exon 2 sequence of the Mhc-DRB gene. Additionally, we proved that an increased substitution rate can promote allelic variation within lineages. Consequently, the evolution of different characteristics of genetic polymorphism is not independent. PMID:19361342

  18. [Contrastive analysis on soil alkalinization predicting models based on measured reflectance and TM image reflectance].

    PubMed

    Zhang, Fang; Xiong, Hei-Gang; Long, Tao; Lu, Wen-Juan

    2011-01-01

    Based on the monitored data of soil pH and measured Vis-NIR reflectance on spot in Qitai oasis alkalinized area in Xinjiang, as well as comparison of the relationship between measured reflectance and soil pH and the relationship between TM reflectance and soil pH, both of the reflectance multivariate linear regression models were built to evaluate soil alkalinization level, and the model accuracy of pH fitting was discussed with error inspection of post-sample. The results showed that there is a significant positive correlation between soil pH and reflectance. With pH rising the reflectance increased concurrently. So the alkalinization soil characterized by hardening had good spectral response characteristics. Both measured reflectance and TM image reflectance had good potential ability for change detection of the alkalinization soil. The pH predicting model of measured reflectance had higher accuracy and the major error was from different hardening state. If building model by TM reflectance directly, the accuracy of fitting was lower because of the vegetation information in image spectrum. With the vegetation factor removed with NDVI, the accuracy of TM predicting model was near the accuracy of measured reflectance predicting model, and both of the model levels were good. PMID:21428094

  19. [Contrastive analysis on soil alkalinization predicting models based on measured reflectance and TM image reflectance].

    PubMed

    Zhang, Fang; Xiong, Hei-Gang; Long, Tao; Lu, Wen-Juan

    2011-01-01

    Based on the monitored data of soil pH and measured Vis-NIR reflectance on spot in Qitai oasis alkalinized area in Xinjiang, as well as comparison of the relationship between measured reflectance and soil pH and the relationship between TM reflectance and soil pH, both of the reflectance multivariate linear regression models were built to evaluate soil alkalinization level, and the model accuracy of pH fitting was discussed with error inspection of post-sample. The results showed that there is a significant positive correlation between soil pH and reflectance. With pH rising the reflectance increased concurrently. So the alkalinization soil characterized by hardening had good spectral response characteristics. Both measured reflectance and TM image reflectance had good potential ability for change detection of the alkalinization soil. The pH predicting model of measured reflectance had higher accuracy and the major error was from different hardening state. If building model by TM reflectance directly, the accuracy of fitting was lower because of the vegetation information in image spectrum. With the vegetation factor removed with NDVI, the accuracy of TM predicting model was near the accuracy of measured reflectance predicting model, and both of the model levels were good.

  20. Numerical modeling of the 3D dynamics of ultrasound contrast agent microbubbles using the boundary integral method

    NASA Astrophysics Data System (ADS)

    Wang, Qianxi; Manmi, Kawa; Calvisi, Michael L.

    2015-02-01

    Ultrasound contrast agents (UCAs) are microbubbles stabilized with a shell typically of lipid, polymer, or protein and are emerging as a unique tool for noninvasive therapies ranging from gene delivery to tumor ablation. While various models have been developed to describe the spherical oscillations of contrast agents, the treatment of nonspherical behavior has received less attention. However, the nonspherical dynamics of contrast agents are thought to play an important role in therapeutic applications, for example, enhancing the uptake of therapeutic agents across cell membranes and tissue interfaces, and causing tissue ablation. In this paper, a model for nonspherical contrast agent dynamics based on the boundary integral method is described. The effects of the encapsulating shell are approximated by adapting Hoff's model for thin-shell, spherical contrast agents. A high-quality mesh of the bubble surface is maintained by implementing a hybrid approach of the Lagrangian method and elastic mesh technique. The numerical model agrees well with a modified Rayleigh-Plesset equation for encapsulated spherical bubbles. Numerical analyses of the dynamics of UCAs in an infinite liquid and near a rigid wall are performed in parameter regimes of clinical relevance. The oscillation amplitude and period decrease significantly due to the coating. A bubble jet forms when the amplitude of ultrasound is sufficiently large, as occurs for bubbles without a coating; however, the threshold amplitude required to incite jetting increases due to the coating. When a UCA is near a rigid boundary subject to acoustic forcing, the jet is directed towards the wall if the acoustic wave propagates perpendicular to the boundary. When the acoustic wave propagates parallel to the rigid boundary, the jet direction has components both along the wave direction and towards the boundary that depend mainly on the dimensionless standoff distance of the bubble from the boundary. In all cases, the jet

  1. A phase-contrast microscopy-based method for modeling the mechanical behavior of mesenchymal stem cells.

    PubMed

    Saeed, Mayssam; Sharabani-Yosef, Orna; Weihs, Daphne; Gefen, Amit

    2016-10-01

    We present three-dimensional (3D) finite element (FE) models of single, mesenchymal stem cells (MSCs), generated from images obtained by optical phase-contrast microscopy and used to quantify the structural responses of the studied cells to externally applied mechanical loads. Mechanical loading has been shown to affect cell morphology and structure, phenotype, motility and other biological functions. Cells experience mechanical loads naturally, yet under prolonged or sizable loading, damage and cell death may occur, which motivates research regarding the structural behavior of loaded cells. For example, near the weight-bearing boney prominences of the buttocks of immobile persons, tissues may become highly loaded, eventually leading to massive cell death that manifests as pressure ulcers. Cell-specific computational models have previously been developed by our group, allowing simulations of cell deformations under compressive or stretching loads. These models were obtained by reconstructing specific cell structures from series of 2D fluorescence, confocal image-slices, requiring cell-specific fluorescent-staining protocols and costly (confocal) microscopy equipment. Alternative modeling approaches represent cells simply as half-spheres or half-ellipsoids (i.e. idealized geometries), which neglects the curvature details of the cell surfaces associated with changes in concentrations of strains and stresses. Thus, we introduce here for the first time an optical image-based FE modeling, where loads are simulated on reconstructed 3D geometrical cell models from a single 2D, phase-contrast image. Our novel modeling method eliminates the need for confocal imaging and fluorescent staining preparations (both expensive), and makes cell-specific FE modeling affordable and accessible to the biomechanics community. We demonstrate the utility of this cost-effective modeling method by performing simulations of compression of MSCs embedded in a gel. PMID:26856632

  2. A phase-contrast microscopy-based method for modeling the mechanical behavior of mesenchymal stem cells.

    PubMed

    Saeed, Mayssam; Sharabani-Yosef, Orna; Weihs, Daphne; Gefen, Amit

    2016-10-01

    We present three-dimensional (3D) finite element (FE) models of single, mesenchymal stem cells (MSCs), generated from images obtained by optical phase-contrast microscopy and used to quantify the structural responses of the studied cells to externally applied mechanical loads. Mechanical loading has been shown to affect cell morphology and structure, phenotype, motility and other biological functions. Cells experience mechanical loads naturally, yet under prolonged or sizable loading, damage and cell death may occur, which motivates research regarding the structural behavior of loaded cells. For example, near the weight-bearing boney prominences of the buttocks of immobile persons, tissues may become highly loaded, eventually leading to massive cell death that manifests as pressure ulcers. Cell-specific computational models have previously been developed by our group, allowing simulations of cell deformations under compressive or stretching loads. These models were obtained by reconstructing specific cell structures from series of 2D fluorescence, confocal image-slices, requiring cell-specific fluorescent-staining protocols and costly (confocal) microscopy equipment. Alternative modeling approaches represent cells simply as half-spheres or half-ellipsoids (i.e. idealized geometries), which neglects the curvature details of the cell surfaces associated with changes in concentrations of strains and stresses. Thus, we introduce here for the first time an optical image-based FE modeling, where loads are simulated on reconstructed 3D geometrical cell models from a single 2D, phase-contrast image. Our novel modeling method eliminates the need for confocal imaging and fluorescent staining preparations (both expensive), and makes cell-specific FE modeling affordable and accessible to the biomechanics community. We demonstrate the utility of this cost-effective modeling method by performing simulations of compression of MSCs embedded in a gel.

  3. Robust identification of local adaptation from allele frequencies.

    PubMed

    Günther, Torsten; Coop, Graham

    2013-09-01

    Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of "standardized allele frequencies" that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to FST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population pools-a cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org. PMID:23821598

  4. Robust Identification of Local Adaptation from Allele Frequencies

    PubMed Central

    Günther, Torsten; Coop, Graham

    2013-01-01

    Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of “standardized allele frequencies” that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to FST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population pools—a cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org. PMID:23821598

  5. Development of fluorescent contrast agents for optical imaging of mouse disease models

    NASA Astrophysics Data System (ADS)

    Kovar, J.; Simpson, M.; Schutz-Geschwender, A.; Xu, X.; Volcheck, W. M.; Sevick-Muraca, E.; Olive, D. M.

    2008-02-01

    Optical imaging is a rapidly developing field of research aimed at non-invasively interrogating animals for disease progression, determining the effects of a drug on a particular pathology, assessing the pharmacokinetic behavior of a drug, or identifying molecular biomarkers of disease. One of the key components of molecular imaging is the development of specific, targeted imaging contrast agents to assess these biological processes. The development of robust fluorochrome-labeled optical agents is a process that is often underestimated in terms of its complexity. We describe here the development process and performance issues for three different optical agents: IRDye 800CW EGF (epidermal growth factor), IRDye (R) 800CW 2-DG (2-deoxy D-glucose), and an IRDye 680 BoneTag TM. In vitro competitive assays were developed for two of the markers to demonstrate specificity. Specificity was confirmed in animal studies. Uptake of IRDye 800CW 2-DG was also examined by near-infrared confocal microscopy. Histological examinations were performed on target and non-target tissues following the completion of the imaging studies. The issues unique to the development of each labeled marker are discussed.

  6. Physical analog (centrifuge) model investigation of contrasting structural styles in the Salt Range and Potwar Plateau, northern Pakistan

    NASA Astrophysics Data System (ADS)

    Faisal, Shah; Dixon, John M.

    2015-08-01

    We use scaled physical analog (centrifuge) modeling to investigate along- and across-strike structural variations in the Salt Range and Potwar Plateau of the Himalayan foreland fold-thrust belt of Pakistan. The models, composed of interlayered plasticine and silicone putty laminae, comprise four mechanical units representing the Neoproterozoic Salt Range Formation (basal detachment), Cambrian-Eocene carapace sequence, and Rawalpindi and Siwalik Groups (Neogene molasse), on a rigid base representing the Indian craton. Pre-cut ramps simulate basement faults with various structural geometries. A pre-existing north-dipping basement normal fault under the model foreland induces a frontal ramp and a prominent fault-bend-fold culmination, simulating the Salt Range. The ramp localizes displacement on a frontal thrust that occurs out-of-sequence with respect to other foreland folds and thrusts. With a frontal basement fault terminating to the east against a right-stepping, east-dipping lateral ramp, deformation propagates further south in the east; strata to the east of the lateral ramp are telescoped in ENE-trending detachment folds, fault-propagation folds and pop-up structures above a thick basal detachment (Salt Range Formation), in contrast to translated but less-deformed strata with E-W-trending Salt-Range structures to the west. The models are consistent with Salt Range-Potwar Plateau structural style contrasts being due to basement fault geometry and variation in detachment thickness.

  7. Correction of Hair Shaft Defects through Allele-Specific Silencing of Mutant Krt75.

    PubMed

    Liu, Ying; Snedecor, Elizabeth R; Zhang, Xu; Xu, Yanfeng; Huang, Lan; Jones, Evan C; Zhang, Lianfeng; Clark, Richard A; Roop, Dennis R; Qin, Chuan; Chen, Jiang

    2016-01-01

    Dominant mutations in keratin genes can cause a number of inheritable skin disorders characterized by intraepidermal blistering, epidermal hyperkeratosis, or abnormalities in skin appendages, such as nail plate dystrophy and structural defects in hair. Allele-specific silencing of mutant keratins through RNA interference is a promising therapeutic approach for suppressing the expression of mutant keratins and related phenotypes in the epidermis. However, its effectiveness on skin appendages remains to be confirmed in vivo. In this study, we developed allele-specific small interfering RNAs capable of selectively suppressing the expression of a mutant Krt75, which causes hair shaft structural defects characterized by the development of blebs along the hair shaft in mice. Hair regenerated from epidermal keratinocyte progenitor cells isolated from mutant Krt75 mouse models reproduced the blebbing phenotype when grafted in vivo. In contrast, mutant cells manipulated with a lentiviral vector expressing mutant Krt75-specific short hairpin RNA (shRNA) persistently suppressed this phenotype. The phenotypic correction was associated with a significant reduction of mutant Krt75 mRNA in the skin grafts. Thus, data obtained from this study demonstrated the feasibility of utilizing RNA interference to achieve durable correction of hair structural phenotypes through allele-specific silencing of mutant keratin genes. PMID:26763422

  8. Negative BOLD response and serotonin concentration within rostral subgenual portion of the anterior cingulate cortex for long-allele carriers during perceptual processing of emotional tasks

    NASA Astrophysics Data System (ADS)

    Hadi, Shamil M.; Siadat, Mohamad R.; Babajani-Feremi, Abbas

    2012-03-01

    We investigated the effect of synaptic serotonin concentration on hemodynamic responses. The stimuli paradigm involved the presentation of fearful and threatening facial expressions to a set of 24 subjects who were either5HTTLPR long- or short-allele carriers (12 of each type in each group). The BOLD signals of the rACC from subjects of each group were averaged to increase the signal-to-noise ratio. We used a Bayesian approach to estimate the parameters of the underlying hemodynamic model. Our results, during this perceptual processing of emotional task, showed a negative BOLD signal in the rACC in the subjects with long-alleles. In contrast, the subjects with short-alleles showed positive BOLD signals in the rACC. These results suggest that high synaptic serotonin concentration in the rACC inhibits neuronal activity in a fashion similar to GABA, and a consequent negative BOLD signal ensues.

  9. Contrast Materials

    MedlinePlus

    ... or other reactions to contrast materials are rare, radiology departments are well-equipped to deal with them. ... is given. However, both the American College of Radiology (ACR) and the European Society of Urogenital Radiology ...

  10. Two Contrasting Models for Mentoring as They Affect Retention of Beginning Teachers

    ERIC Educational Resources Information Center

    Hallam, Pamela R.; Chou, Po Nien; Hite, Julie M.; Hite, Steven J.

    2012-01-01

    Research indicates that mentoring programs help increase the retention of beginning teachers. School administrators may be presented with competing mentoring models, with various sources and types of support, aimed at improving beginning teacher retention. This study collected both qualitative and quantitative data under the rubric of a…

  11. Cavitation thresholds of contrast agents in an in vitro human clot model exposed to 120-kHz ultrasound

    PubMed Central

    Gruber, Matthew J.; Bader, Kenneth B.; Holland, Christy K.

    2014-01-01

    Ultrasound contrast agents (UCAs) can be employed to nucleate cavitation to achieve desired bioeffects, such as thrombolysis, in therapeutic ultrasound applications. Effective methods of enhancing thrombolysis with ultrasound have been examined at low frequencies (<1 MHz) and low amplitudes (<0.5 MPa). The objective of this study was to determine cavitation thresholds for two UCAs exposed to 120-kHz ultrasound. A commercial ultrasound contrast agent (Definity®) and echogenic liposomes were investigated to determine the acoustic pressure threshold for ultraharmonic (UH) and broadband (BB) generation using an in vitro flow model perfused with human plasma. Cavitation emissions were detected using two passive receivers over a narrow frequency bandwidth (540–900 kHz) and a broad frequency bandwidth (0.54–1.74 MHz). UH and BB cavitation thresholds occurred at the same acoustic pressure (0.3 ± 0.1 MPa, peak to peak) and were found to depend on the sensitivity of the cavitation detector but not on the nucleating contrast agent or ultrasound duty cycle. PMID:25234874

  12. Quantitative analysis of contrast-enhanced ultrasonography in acute radiation-induced liver injury: An animal model

    PubMed Central

    FENG, JUN; CHEN, SHU-BO; WU, SHU-JUN; SUN, PING; XIN, TIAN-YOU; CHEN, YING-ZHEN

    2015-01-01

    The aim of the present study was to examine and assess contrast-enhanced ultrasound in the early diagnosis of acute radiation-induced liver injury in a rat model. Sixty female rats were used, with 50 rats being utilized to produce an animal model of liver injury with a single dose of stereotactic X-ray irradiation of 20 Gy. Ten rats from the injury group and 2 rats from the control group were randomly selected on days 3, 7, 14, 21 and 28, and examined by contrast-enhanced ultrasound and histopathology of liver specimens. The rats were divided into four groups: the normal control group, mild, moderate, and severe radioactive liver injury groups based on the histopathological examination results. Hepatic artery arriving time (HAAT) and hepatic vein arriving time (HVAT) were recorded, and hepatic artery to vein transit time (HA-HVTT) was calculated. The time-intensity curve of liver parenchyma, the time to peak (TTP) and peak intensity (PI) were also obtained. Significant differences were observed between liver injury and control groups for PI and HA-HVTT (P<0.05). PI and HA-HVTT were shorter in the severe liver injury group compared to the mild and moderate liver injury groups (P<0.05). Compared to the control group, higher TTP was recorded in all the liver injury groups (P<0.05), and the highest TTP level was observed in the severe liver injury group compared to the mild or moderate group (P<0.05). However, no significant difference was observed between the mild and moderate groups for PI, HA-HVTT and TTP. In conclusion, the results showed that contrast-enhanced ultrasonography is useful for an earlier diagnosis in a rat model of acute radiation-induced liver injury. PMID:26640553

  13. Multi-model data fusion for river flow forecasting: an evaluation of six alternative methods based on two contrasting catchments

    NASA Astrophysics Data System (ADS)

    Abrahart, R. J.; See, L.

    This paper evaluates six published data fusion strategies for hydrological forecasting based on two contrasting catchments: the River Ouse and the Upper River Wye. The input level and discharge estimates for each river comprised a mixed set of single model forecasts. Data fusion was performed using: arithmetic-averaging, a probabilistic method in which the best model from the last time step is used to generate the current forecast, two different neural network operations and two different soft computing methodologies. The results from this investigation are compared and contrasted using statistical and graphical evaluation. Each location demonstrated several options and potential advantages for using data fusion tools to construct superior estimates of hydrological forecast. Fusion operations were better in overall terms in comparison to their individual modelling counterparts and two clear winners emerged. Indeed, the six different mechanisms on test revealed unequal aptitudes for fixing different categories of problematic catchment behaviour and, in such cases, the best method(s) were a good deal better than their closest rival(s). Neural network fusion of differenced data provided the best solution for a stable regime (with neural network fusion of original data being somewhat similar) — whereas a fuzzified probabilistic mechanism produced a superior output in a more volatile environment. The need for a data fusion research agenda within the hydrological sciences is discussed and some initial suggestions are presented.

  14. Contrast Enhancement of MicroCT Scans to Aid 3D Modelling of Carbon Fibre Fabric Composites

    NASA Astrophysics Data System (ADS)

    Djukic, Luke P.; Pearce, Garth M.; Herszberg, Israel; Bannister, Michael K.; Mollenhauer, David H.

    2013-12-01

    This paper presents a methodology for volume capture and rendering of plain weave and multi-layer fabric meso-architectures within a consolidated, cured laminate. Micro X-ray Computed Tomography (MicroCT) is an excellent tool for the non-destructive visualisation of material microstructures however the contrast between tows and resin is poor for carbon fibre composites. Firstly, this paper demonstrates techniques to improve the contrast of the microCT images by introducing higher density materials such as gold, iodine and glass into the fabric. Two approaches were demonstrated to be effective for enhancing the differentiation between the tows in the reconstructed microCT visualisations. Secondly, a method of generating three-dimensional volume models of woven composites using microCT scan data is discussed. The process of generating a model is explained from initial manufacture with the aid of an example plain weave fabric. These methods are to be used in the finite element modelling of three-dimensional fabric preforms in future work.

  15. A numerical analysis of the Born approximation for image formation modeling of differential interference contrast microscopy for human embryos

    NASA Astrophysics Data System (ADS)

    Trattner, Sigal; Feigin, Micha; Greenspan, Hayit; Sochen, Nir

    2008-03-01

    The differential interference contrast (DIC) microscope is commonly used for the visualization of live biological specimens. It enables the view of the transparent specimens while preserving their viability, being a non-invasive modality. Fertility clinics often use the DIC microscope for evaluation of human embryos quality. Towards quantification and reconstruction of the visualized specimens, an image formation model for DIC imaging is sought and the interaction of light waves with biological matter is examined. In many image formation models the light-matter interaction is expressed via the first Born approximation. The validity region of this approximation is defined in a theoretical bound which limits its use to very small specimens with low dielectric contrast. In this work the Born approximation is investigated via the Helmholtz equation, which describes the interaction between the specimen and light. A solution on the lens field is derived using the Gaussian Legendre quadrature formulation. This numerical scheme is considered both accurate and efficient and has shortened significantly the computation time as compared to integration methods that required a great amount of sampling for satisfying the Whittaker - Shannon sampling theorem. By comparing the numerical results with the theoretical values it is shown that the theoretical bound is not directly relevant to microscopic imaging and is far too limiting. The numerical exhaustive experiments show that the Born approximation is inappropriate for modeling the visualization of thick human embryos.

  16. Tropical precipitation regimes and mechanisms of regime transitions: contrasting two aquaplanet general circulation models

    NASA Astrophysics Data System (ADS)

    Oueslati, Boutheina; Bellon, Gilles

    2013-05-01

    The atmospheric general circulation models ARPEGE-climate and LMDz are used in an aquaplanet configuration to study the response of a zonally symmetric atmosphere to a range of sea surface temperature (SST) forcing. We impose zonally-symmetric SST distributions that are also symmetric about the equator, with varying off-equatorial SST gradients. In both models, we obtain the characteristic inter-tropical convergence zone (ITCZ) splitting that separates two regimes of equilibrium (in terms of precipitations): one with one ITCZ over the equator for large SST gradients in the tropics, and one with a double ITCZ for small tropical SST gradients. Transition between these regimes is mainly driven by changes in the low-level convergence that are forced by the SST gradients. Model-dependent, dry and moist feedbacks intervene to reinforce or weaken the effect of the SST forcing. In ARPEGE, dry advective processes reinforce the SST forcing, while a competition between sensible heat flux and convective cooling provides a complex feedback on the SST forcing in the LMDz. It is suggested that these feedbacks influence the location of the transition in the parameter range.

  17. Dynamic contrast-enhanced x-ray CT measurement of cerebral blood volume in a rabbit tumor model

    NASA Astrophysics Data System (ADS)

    Cenic, Aleksa; Lee, Ting-Yim; Craen, Rosemary A.; Gelb, Adrian W.

    1998-07-01

    Cerebral blood volume (CBV) is a major determinant of intracranial pressure (ICP). Hyperventilation is commonly employed to reduce raised ICP (e.g. in brain tumour patients) presumably through its effect on CBV. With the advent of slip- ring CT scanners, dynamic contrast-enhanced imaging allows for the measurement of CBV with high spatial resolution. Using a two-compartment model to characterize the distribution of X- ray contrast agent in the brain, we have developed a non- equilibrium CT method to measure CBV in normal and pathological regions. We used our method to investigate the effect of hyperventilation on CBV during propofol anaesthesia in rabbits with implanted brain tumours. Eight New Zealand White rabbits with implanted VX2 carcinoma brain tumours were studied. For each rabbit, regional CBV measurements were initially made at normocapnia (PaCO2 40 mmHg) and then at hyperventilation (PaCO2 25 mmHg) during propofol anaesthesia. The head was positioned such that a coronal image through the brain incorporated a significant cross-section of the brain tumour as well as a radial artery in a forelimb. Images at the rate of 1 per second were acquired for 2 minutes as Omnipaque 300 (1.5 ml/kg rabbit weight) was injected via a peripheral vein. In these CT images, regions of interest in the brain tissue (e.g. tumour, contra-lateral normal, and peri-tumoural) and the radial artery were drawn. For each region, the mean CT number in pre-contrast images was subtracted from the mean CT number in post-contrast images to produce either the tissue contrast concentration curve, or the arterial contrast concentration curve. Using our non- equilibrium analysis method based on a two-compartment model, regional CBV values were determined from the measured contrast concentration curves. From our study, the mean CBV values [+/- SD] in the tumour, peri-tumoural, and contra-lateral normal regions during normocapnia were: 5.47 plus or minus 1.97, 3.28 plus or minus 1.01, and 1

  18. Trend change detection in vegetation greenness time series: Contrasting methodologies, data sets and global vegetation models

    NASA Astrophysics Data System (ADS)

    Forkel, Matthias; Carvalhais, Nuno; Verbesselt, Jan; Mahecha, Miguel; Neigh, Christopher; Thonicke, Kirsten; Reichstein, Markus

    2014-05-01

    Newly developed satellite datasets and time series analysis methods allow the quantification of changes in vegetation greenness. However, the estimation of trends and trend changes depend often on the applied time series analysis method and the used satellite dataset. Thus, the environmental plausibility of the estimated trends and trend breakpoints is often questionable. We compared four trend and trend change detection methods to assess their performance. We applied the methods to NDVI and FAPAR time series from global satellite datasets and from global vegetation models. We generated surrogate time series with known trends and breakpoints and applied the methods to re-detect the known trends and trend changes. Our results demonstrate that the performance of methods decrease with increasing inter-annual variability of the time series. An overestimation of breakpoints in NDVI time series can result in wrong or even opposite trend estimates. Trend slope estimates based on annual aggregated time series or based on a seasonal-trend model show better performances than methods that remove the seasonal cycle of the time series. The application of the trend change detection methods to real time series allows assessing the multi-method ensemble of trend estimates. Nevertheless, the interpretation of the environmental plausibility of these trend estimates is challenging. For example, some methods suggest a weakening of greening trends in the Tundra after the early 2000s while other methods suggest an ongoing greening. Comparison with vegetation model simulations suggest that this weakening is not an artefact of the satellite dataset or of the applied trend change detection method but might be caused by real changes in environmental conditions. Our results demonstrate the need for a critical appraisal of trend change detection methods. All methods require a careful assessment of the environmental plausibility of detected trend changes in vegetation greenness time series.

  19. Contrasting Polymer Behavior Under Nanoconfinement using Thermomechanically Consistent Coarse-Grained Models

    NASA Astrophysics Data System (ADS)

    Keten, Sinan; Xia, Wenjie; Hsu, David

    2015-03-01

    We present a systematic, two-bead per monomer coarse graining strategy that simulates the thermomechanical behavior of polymers several hundred times faster than all-atom MD (Hsu et al. JCTC, 2014). The predictive capability of the technique is illustrated here for 5 different methacrylate monomers and polystyrene stereoisomers. The approach involves optimization of analytical bonded potentials from atomistic bonded distributions to emulate local structure, as validated by chain end-to-end length and the radius of gyration comparisons with experiments and random coil theory. Nonbonded Lennard-Jones potentials are tuned to reproduce the elastic modulus (E) and glass transition temperature (Tg) at a single thermodynamic state. Density-corrected parameters capture temperature-modulus dependence in the 150-600 K range. Flory-Fox constants of the CG models are commensurate with all atomistic and experimental results, even though all calibrations are done at a single molecular weight. Finally, we further demonstrate the predictive capabilities of the models by examining thin film nanoconfinement effects for different polymers, film thicknesses, interfacial energies, and molecular weights. Our technique, called thermomechanically consistent coarse graining (TCCG), is demonstrated, using polystyrene and poly(methylmethacrylate) as universal benchmarks, to be a robust and effective technique to understand the thermomechanical behavior of polymers thin films and nanocomposites.

  20. Contrast lipocryolysis

    PubMed Central

    Pinto, Hernán; Melamed, Graciela

    2014-01-01

    Alternative crystal structures are possible for all lipids and each different crystal structure is called a polymorphic form. Inter-conversion between polymorphisms would imply the possibility of leaning crystal formation toward the most effective polymorphism for adipocyte destruction. Food industry has been tempering lipids for decades. Tempering technology applied to lipocryolysis gave birth to “contrast lipocryolysis”, which involves pre- and post-lipocryolysis fat layer heating as part of a specific tempering protocol. In this study, we evaluated the skinfold thickness of 10 subjects after a single contrast lipocryolysis session and witnessed important and fast reductions. PMID:25068088

  1. Investigation of discrete imaging models and iterative image reconstruction in differential X-ray phase-contrast tomography.

    PubMed

    Xu, Qiaofeng; Sidky, Emil Y; Pan, Xiaochuan; Stampanoni, Marco; Modregger, Peter; Anastasio, Mark A

    2012-05-01

    Differential X-ray phase-contrast tomography (DPCT) refers to a class of promising methods for reconstructing the X-ray refractive index distribution of materials that present weak X-ray absorption contrast. The tomographic projection data in DPCT, from which an estimate of the refractive index distribution is reconstructed, correspond to one-dimensional (1D) derivatives of the two-dimensional (2D) Radon transform of the refractive index distribution. There is an important need for the development of iterative image reconstruction methods for DPCT that can yield useful images from few-view projection data, thereby mitigating the long data-acquisition times and large radiation doses associated with use of analytic reconstruction methods. In this work, we analyze the numerical and statistical properties of two classes of discrete imaging models that form the basis for iterative image reconstruction in DPCT. We also investigate the use of one of the models with a modern image reconstruction algorithm for performing few-view image reconstruction of a tissue specimen.

  2. Deuterium Labeling Strategies for Creating Contrast in Structure-Function Studies of Model Bacterial Outer Membranes Using Neutron Reflectometry.

    PubMed

    Le Brun, Anton P; Clifton, Luke A; Holt, Stephen A; Holden, Peter J; Lakey, Jeremy H

    2016-01-01

    Studying the outer membrane of Gram-negative bacteria is challenging due to the complex nature of its structure. Therefore, simplified models are required to undertake structure-function studies of processes that occur at the outer membrane/fluid interface. Model membranes can be created by immobilizing bilayers to solid supports such as gold or silicon surfaces, or as monolayers on a liquid support where the surface pressure and fluidity of the lipids can be controlled. Both model systems are amenable to having their structure probed by neutron reflectometry, a technique that provides a one-dimensional depth profile through a membrane detailing its thickness and composition. One of the strengths of neutron scattering is the ability to use contrast matching, allowing molecules containing hydrogen and those enriched with deuterium to be highlighted or matched out against the bulk isotopic composition of the solvent. Lipopolysaccharides, a major component of the outer membrane, can be isolated for incorporation into model membranes. Here, we describe the deuteration of lipopolysaccharides from rough strains of Escherichia coli for incorporation into model outer membranes, and how the use of deuterated materials enhances structural analysis of model membranes by neutron reflectometry.

  3. Deuterium Labeling Strategies for Creating Contrast in Structure-Function Studies of Model Bacterial Outer Membranes Using Neutron Reflectometry.

    PubMed

    Le Brun, Anton P; Clifton, Luke A; Holt, Stephen A; Holden, Peter J; Lakey, Jeremy H

    2016-01-01

    Studying the outer membrane of Gram-negative bacteria is challenging due to the complex nature of its structure. Therefore, simplified models are required to undertake structure-function studies of processes that occur at the outer membrane/fluid interface. Model membranes can be created by immobilizing bilayers to solid supports such as gold or silicon surfaces, or as monolayers on a liquid support where the surface pressure and fluidity of the lipids can be controlled. Both model systems are amenable to having their structure probed by neutron reflectometry, a technique that provides a one-dimensional depth profile through a membrane detailing its thickness and composition. One of the strengths of neutron scattering is the ability to use contrast matching, allowing molecules containing hydrogen and those enriched with deuterium to be highlighted or matched out against the bulk isotopic composition of the solvent. Lipopolysaccharides, a major component of the outer membrane, can be isolated for incorporation into model membranes. Here, we describe the deuteration of lipopolysaccharides from rough strains of Escherichia coli for incorporation into model outer membranes, and how the use of deuterated materials enhances structural analysis of model membranes by neutron reflectometry. PMID:26791981

  4. Conducting Tetrad Tests of Model Fit and Contrasts of Tetrad-Nested Models: A New SAS Macro

    ERIC Educational Resources Information Center

    Hipp, John R.; Bauer, Daniel J.; Bollen, Kenneth A.

    2005-01-01

    This article describes a SAS macro to assess model fit of structural equation models by employing a test of the model-implied vanishing tetrads. Use of this test has been limited in the past, in part due to the lack of software that fully automates the test in a user-friendly way. The current SAS macro provides a straightforward method for…

  5. Local-scale models reveal ecological niche variability in amphibian and reptile communities from two contrasting biogeographic regions

    PubMed Central

    Santos, Xavier; Felicísimo, Ángel M.

    2016-01-01

    Ecological Niche Models (ENMs) are widely used to describe how environmental factors influence species distribution. Modelling at a local scale, compared to a large scale within a high environmental gradient, can improve our understanding of ecological species niches. The main goal of this study is to assess and compare the contribution of environmental variables to amphibian and reptile ENMs in two Spanish national parks located in contrasting biogeographic regions, i.e., the Mediterranean and the Atlantic area. The ENMs were built with maximum entropy modelling using 11 environmental variables in each territory. The contributions of these variables to the models were analysed and classified using various statistical procedures (Mann–Whitney U tests, Principal Components Analysis and General Linear Models). Distance to the hydrological network was consistently the most relevant variable for both parks and taxonomic classes. Topographic variables (i.e., slope and altitude) were the second most predictive variables, followed by climatic variables. Differences in variable contribution were observed between parks and taxonomic classes. Variables related to water availability had the larger contribution to the models in the Mediterranean park, while topography variables were decisive in the Atlantic park. Specific response curves to environmental variables were in accordance with the biogeographic affinity of species (Mediterranean and non-Mediterranean species) and taxonomy (amphibians and reptiles). Interestingly, these results were observed for species located in both parks, particularly those situated at their range limits. Our findings show that ecological niche models built at local scale reveal differences in habitat preferences within a wide environmental gradient. Therefore, modelling at local scales rather than assuming large-scale models could be preferable for the establishment of conservation strategies for herptile species in natural parks. PMID

  6. One-dimensional simulation of fire injection heights in contrasted meteorological scenarios with PRM and Meso-NH models

    NASA Astrophysics Data System (ADS)

    Strada, S.; Freitas, S. R.; Mari, C.; Longo, K. M.; Paugam, R.

    2013-02-01

    Wild-fires release huge amounts of aerosol and hazardous trace gases in the atmosphere. The residence time and the dispersion of fire pollutants in the atmosphere can range from hours to days and from local to continental scales. These various scenarios highly depend on the injection height of smoke plumes. The altitude at which fire products are injected in the atmosphere is controlled by fire characteristics and meteorological conditions. Injection height however is still poorly accounted in chemistry transport models for which fires are sub-grid scale processes which need to be parametrised. Only recently, physically-based approaches for estimating the fire injection heights have been developed which consider both the convective updrafts induced by the release of fire sensible heat and the impact of background meteorological environment on the fire convection dynamics. In this work, two different models are used to simulate fire injection heights in contrasted meteorological scenarios: a Mediterranean arson fire and two Amazonian deforestation fires. A Eddy-Diffusivity/Mass-Flux approach, formerly developed to reproduce convective boundary layer in the non-hydrostatic meteorological model Meso-NH, is compared to the 1-D Plume Rise Model. For both models, radiosonde data and re-analyses from the European Center for Medium-Range Weather Forecasts (ECMWF) have been used as initial conditions to explore the sensitivity of the models responses to different meteorological forcings. The two models predict injection heights for the Mediterranean fire between 1.7 and 3.3 km with the Meso-NH/EDMF model systematically higher than the 1-D PRM model. Both models show a limited sensitivity to the meteorological forcings with a 20-30% difference in the injection height between radiosondes and ECMWF data for this case. Injection heights calculated for the two Amazonian fires ranges from 5 to 6.5 km for the 1-D PRM model and from 2 to 4 km for the Meso-NH/EDMF model. The

  7. Assessing allelic dropout and genotype reliability using maximum likelihood.

    PubMed Central

    Miller, Craig R; Joyce, Paul; Waits, Lisette P

    2002-01-01

    A growing number of population genetic studies utilize nuclear DNA microsatellite data from museum specimens and noninvasive sources. Genotyping errors are elevated in these low quantity DNA sources, potentially compromising the power and accuracy of the data. The most conservative method for addressing this problem is effective, but requires extensive replication of individual genotypes. In search of a more efficient method, we developed a maximum-likelihood approach that minimizes errors by estimating genotype reliability and strategically directing replication at loci most likely to harbor errors. The model assumes that false and contaminant alleles can be removed from the dataset and that the allelic dropout rate is even across loci. Simulations demonstrate that the proposed method marks a vast improvement in efficiency while maintaining accuracy. When allelic dropout rates are low (0-30%), the reduction in the number of PCR replicates is typically 40-50%. The model is robust to moderate violations of the even dropout rate assumption. For datasets that contain false and contaminant alleles, a replication strategy is proposed. Our current model addresses only allelic dropout, the most prevalent source of genotyping error. However, the developed likelihood framework can incorporate additional error-generating processes as they become more clearly understood. PMID:11805071

  8. Ultrasound-Triggered Phase Transition Sensitive Magnetic Fluorescent Nanodroplets as a Multimodal Imaging Contrast Agent in Rat and Mouse Model

    PubMed Central

    Chen, Yunchao; Luo, Binhua; Liu, Xuhan; Liu, Wei; Xu, Haibo; Yang, Xiangliang

    2013-01-01

    Ultrasound-triggered phase transition sensitive nanodroplets with multimodal imaging functionality were prepared via premix Shirasu porous glass (SPG) membrane emulsification method. The nanodroplets with fluorescence dye DiR and SPIO nanoparticles (DiR-SPIO-NDs) had a polymer shell and a liquid perfluoropentane (PFP) core. The as-formed DiR-SPIO-NDs have a uniform size of 385±5.0 nm with PDI of 0.169±0.011. The TEM and microscopy imaging showed that the DiR-SPIO-NDs existed as core-shell spheres, and DiR and SPIO nanoparticles dispersed in the shell or core. The MTT and hemolysis studies demonstrated that the nanodroplets were biocompatible and safe. Moreover, the proposed nanodroplets exhibited significant ultrasound-triggered phase transition property under clinical diagnostic ultrasound irradiation due to the vaporization of PFP inside. Meanwhile, the high stability and R2 relaxivity of the DiR-SPIO-NDs suggested its applicability in MRI. The in vivo T2-weighted images of MRI and fluorescence images both showed that the image contrast in liver and spleen of rats and mice model were enhanced after the intravenous injection of DiR-SPIO-NDs. Furthermore, the ultrasound imaging (US) in mice tumor as well as MRI and fluorescence imaging in liver of rats and mice showed that the DiR-SPIO-NDs had long-lasting contrast ability in vivo. These in vitro and in vivo findings suggested that DiR-SPIO-NDs could potentially be a great MRI/US/fluorescence multimodal imaging contrast agent in the diagnosis of liver tissue diseases. PMID:24391983

  9. Contrast class cues and performance facilitation in a hypothesis-testing task: evidence for an iterative counterfactual model.

    PubMed

    Gale, Maggie; Ball, Linden J

    2012-04-01

    Hypothesis-testing performance on Wason's (Quarterly Journal of Experimental Psychology 12:129-140, 1960) 2-4-6 task is typically poor, with only around 20% of participants announcing the to-be-discovered "ascending numbers" rule on their first attempt. Enhanced solution rates can, however, readily be observed with dual-goal (DG) task variants requiring the discovery of two complementary rules, one labeled "DAX" (the standard "ascending numbers" rule) and the other labeled "MED" ("any other number triples"). Two DG experiments are reported in which we manipulated the usefulness of a presented MED exemplar, where usefulness denotes cues that can establish a helpful "contrast class" that can stand in opposition to the presented 2-4-6 DAX exemplar. The usefulness of MED exemplars had a striking facilitatory effect on DAX rule discovery, which supports the importance of contrast-class information in hypothesis testing. A third experiment ruled out the possibility that the useful MED triple seeded the correct rule from the outset and obviated any need for hypothesis testing. We propose that an extension of Oaksford and Chater's (European Journal of Cognitive Psychology 6:149-169, 1994) iterative counterfactual model can neatly capture the mechanisms by which DG facilitation arises.

  10. Multi-channel analysis of surface waves MASW of models with high shear-wave velocity contrast

    USGS Publications Warehouse

    Ivanov, J.; Miller, R.D.; Peterie, S.; Zeng, C.; Xia, J.; Schwenk, T.

    2011-01-01

    We use the multi-channel analysis of surface waves MASW method to analyze synthetic seismic data calculated using models with high shear-wave velocity Vs contrast. The MASW dispersion-curve images of the Rayleigh wave are obtained using various sets of source-offset and spread-size configurations from the synthetic seismic data and compared with the theoretically calculated fundamental- and higher-mode dispersion-curves. Such tests showed that most of the dispersion-curve images are dominated by higher-mode energy at the low frequencies, especially when analyzing data from long receiver offsets and thus significantly divert from numerically expected dispersion-curve trends, which can lead to significant Vs overestimation. Further analysis showed that using data with relatively short spread lengths and source offsets can image the desired fundamental-mode of the Rayleigh wave that matches the numerically expected dispersion-curve pattern. As a result, it was concluded that it might be possible to avoid higher-mode contamination at low frequencies at sites with high Vs contrast by appropriate selection of spread size and seismic source offset. ?? 2011 Society of Exploration Geophysicists.

  11. The use of error-category mapping in pharmacokinetic model analysis of dynamic contrast-enhanced MRI data

    PubMed Central

    Gill, Andrew B.; Anandappa, Gayathri; Patterson, Andrew J.; Priest, Andrew N.; Graves, Martin J.; Janowitz, Tobias; Jodrell, Duncan I.; Eisen, Tim; Lomas, David J.

    2015-01-01

    This study introduces the use of ‘error-category mapping’ in the interpretation of pharmacokinetic (PK) model parameter results derived from dynamic contrast-enhanced (DCE-) MRI data. Eleven patients with metastatic renal cell carcinoma were enrolled in a multiparametric study of the treatment effects of bevacizumab. For the purposes of the present analysis, DCE-MRI data from two identical pre-treatment examinations were analysed by application of the extended Tofts model (eTM), using in turn a model arterial input function (AIF), an individually-measured AIF and a sample-average AIF. PK model parameter maps were calculated. Errors in the signal-to-gadolinium concentration ([Gd]) conversion process and the model-fitting process itself were assigned to category codes on a voxel-by-voxel basis, thereby forming a colour-coded ‘error-category map’ for each imaged slice. These maps were found to be repeatable between patient visits and showed that the eTM converged adequately in the majority of voxels in all the tumours studied. However, the maps also clearly indicated sub-regions of low Gd uptake and of non-convergence of the model in nearly all tumours. The non-physical condition ve ≥ 1 was the most frequently indicated error category and appeared sensitive to the form of AIF used. This simple method for visualisation of errors in DCE-MRI could be used as a routine quality-control technique and also has the potential to reveal otherwise hidden patterns of failure in PK model applications. PMID:25460333

  12. Model for Electron-Beam-Induced Current Analysis of mc-Si Addressing Defect Contrast Behavior in Heavily Contaminated PV Material: Preprint

    SciTech Connect

    Guthrey, H.; Gorman, B.; Al-Jassim, M.

    2012-06-01

    Much work has been done to correlate electron-beam-induced current (EBIC) contrast behavior of extended defects with the character and degree of impurity decoration. However, existing models fail to account for recently observed contrast behavior of defects in heavily contaminated mc-Si PV cells. We have observed large increases in defect contrast with decreasing temperature for all electrically active defects, regardless of their initial contrast signatures at ambient temperature. This negates the usefulness of the existing models in identifying defect character and levels of impurity decoration based on the temperature dependence of the contrast behavior. By considering the interactions of transition metal impurities with the silicon lattice and extended defects, we attempt to provide an explanation for these observations. Our findings will enhance the ability of the PV community to understand and mitigate the effects of these types of defects as the adoption of increasingly lower purity feedstocks for mc-Si PV production continues.

  13. Extensive allele-specific translational regulation in hybrid mice.

    PubMed

    Hou, Jingyi; Wang, Xi; McShane, Erik; Zauber, Henrik; Sun, Wei; Selbach, Matthias; Chen, Wei

    2015-08-07

    Translational regulation is mediated through the interaction between diffusible trans-factors and cis-elements residing within mRNA transcripts. In contrast to extensively studied transcriptional regulation, cis-regulation on translation remains underexplored. Using deep sequencing-based transcriptome and polysome profiling, we globally profiled allele-specific translational efficiency for the first time in an F1 hybrid mouse. Out of 7,156 genes with reliable quantification of both alleles, we found 1,008 (14.1%) exhibiting significant allelic divergence in translational efficiency. Systematic analysis of sequence features of the genes with biased allelic translation revealed that local RNA secondary structure surrounding the start codon and proximal out-of-frame upstream AUGs could affect translational efficiency. Finally, we observed that the cis-effect was quantitatively comparable between transcriptional and translational regulation. Such effects in the two regulatory processes were more frequently compensatory, suggesting that the regulation at the two levels could be coordinated in maintaining robustness of protein expression.

  14. RHD allele distribution in Africans of Mali

    PubMed Central

    Wagner, Franz F; Moulds, Joann M; Tounkara, Anatole; Kouriba, Bourema; Flegel, Willy A

    2003-01-01

    Background Aberrant and non-functional RHD alleles are much more frequent in Africans than in Europeans. The DAU cluster of RHD alleles exemplifies that the alleles frequent in Africans have evaded recognition until recently. A comprehensive survey of RHD alleles in any African population was lacking. Results We surveyed the molecular structure and frequency of RHD alleles in Mali (West Africa) by evaluating 116 haplotypes. Only 69% could be attributed to standard RHD (55%) or the RHD deletion (14%). The aberrant RHD allele DAU-0 was predicted for 19%, RHDΨ for 7% and Ccdes for 4% of all haplotypes. DAU-3 and the new RHD allele RHD(L207F), dubbed DMA, were found in one haplotype each. A PCR-RFLP for the detection of the hybrid Rhesus box diagnostic for the RHD deletion in Europeans was false positive in 9 individuals, including all carriers of RHDΨ . Including two silent mutations and the RHD deletion, a total of 9 alleles could be differentiated. Conclusion Besides standard RHD and the RHD deletion, DAU-0, RHDΨ and Ccdes are major alleles in Mali. Our survey proved that the most frequent alleles of West Africans have been recognized allowing to devise reliable genotyping and phenotyping strategies. PMID:14505497

  15. Clarifying the Relationship between Average Excesses and Average Effects of Allele Substitutions.

    PubMed

    Alvarez-Castro, José M; Yang, Rong-Cai

    2012-01-01

    Fisher's concepts of average effects and average excesses are at the core of the quantitative genetics theory. Their meaning and relationship have regularly been discussed and clarified. Here we develop a generalized set of one locus two-allele orthogonal contrasts for average excesses and average effects, based on the concept of the effective gene content of alleles. Our developments help understand the average excesses of alleles for the biallelic case. We dissect how average excesses relate to the average effects and to the decomposition of the genetic variance. PMID:22509178

  16. Effective marker alleles associated with type 2 resistance to Fusarium head blight infection in fields

    PubMed Central

    Li, Tao; Luo, Meng; Zhang, Dadong; Wu, Di; Li, Lei; Bai, Guihua

    2016-01-01

    Molecular markers associated with known quantitative trait loci (QTLs) for type 2 resistance to Fusarium head blight (FHB) in bi-parental mapping population usually have more than two alleles in breeding populations. Therefore, understanding the association of each allele with FHB response is particularly important to marker-assisted enhancement of FHB resistance. In this paper, we evaluated FHB severities of 192 wheat accessions including landraces and commercial varieties in three field growing seasons, and genotyped this panel with 364 genome-wide informative molecular markers. Among them, 11 markers showed reproducible marker-trait association (p < 0.05) in at least two experiments using a mixed model. More than two alleles were identified per significant marker locus. These alleles were classified into favorable, unfavorable and neutral alleles according to the normalized genotypic values. The distributions of effective alleles at these loci in each wheat accession were characterized. Mean FHB severities increased with decreased number of favorable alleles at the reproducible loci. Chinese wheat landraces and Japanese accessions have more favorable alleles at the majority of the reproducible marker loci. FHB resistance levels of varieties can be greatly improved by introduction of these favorable alleles and removal of unfavorable alleles simultaneously at these QTL-linked marker loci. PMID:27436944

  17. Distribution of FMR-1 and associated microsatellite alleles in a normal Chinese population

    SciTech Connect

    Zhong, N.; Houck, G.E. Jr.; Li, S.; Dobkin, C.; Brown, W.T.; Xixian Liu; Shen Gou

    1994-07-15

    The CGG repeat size distribution of the fragile X mental retardation gene (FMR-1) was studied in a population of normal Chinese X chromosomes along with that of two proximal microsatellite polymorphic markers: FRAXAC1 and DXS548. The most common CGG repeat allele was 29 (47.2%) with 30 being second most common (26%). This distribution was different from that seen in Caucasian controls, where the most common allele was 30 repeats. Other differences with Caucasian controls included a secondary model peak at 36 repeats and the absence of peaks at 20 or 23 repeats. There were only two FRAXAC1 and five DXS548 alleles found in the Chinese sample. A striking linkage disequilibrium of FMR-1 alleles with FRAXAC1 alleles was observed, in that 90% of the 29 CGG repeat alleles but only 41% of the 30 CGG repeat alleles had the FRAXAC1 152 bp allele (18 AC repeats). This disequilibrium suggests that slippage between the closely spaced normal CGG repeat alleles, 29 and 30, and between 152 and 154 FRAXAC1 alleles is very rare. This study lays the groundwork for an understanding of founder chromosome effects in comparing Asian and Caucasian populations. 29 refs., 5 tabs.

  18. Evaluating dynamic contrast-enhanced and photoacoustic CT to assess intra-tumor heterogeneity in xenograft mouse models

    NASA Astrophysics Data System (ADS)

    Stantz, Keith M.; Liu, Bo; Cao, Minsong; Reinecke, Dan; Dzemidzic, Mario; Liang, Yun; Kruger, Robert

    2006-03-01

    Purpose: To evaluate photoacoustic CT spectroscopy (PCT-S) and dynamic contrast-enhanced CT (DCE-CT) ability to measure parameters - oxygen saturation and vascular physiology - associated with the intra-tumor oxygenation status. Material and Methods: Breast (VEGF165 enhance MCF-7) and ovarian (SKOV3x) cancer cells were implanted into the fat pads and flanks of immune deficient mice and allowed to grow to a diameter of 8-15 mm. CT was used to determine physiological parameters by acquiring a sequence of scans over a 10 minute period after an i.v. injection of a radio-opaque contrast agent (Isovue). These time-dependent contrast-enhanced curves were fit to a two-compartmental model determining tumor perfusion, fractional plasma volume, permeability-surface area produce, and fractional interstitial volume on a voxel-by-voxel basis. After which, the tumors were imaged using photoacoustic CT (Optosonics, Inc., Indianapolis, IN 46202). The near infrared spectra (700-910 nm) within the vasculature was fit to linear combination of measured oxy- and deoxy-hemoglobin blood samples to obtain oxygen saturation levels (SaO II). Results: The PCT-S scanner was first calibrated using different samples of oxygenated blood, from which a statistical error ranging from 2.5-6.5% was measured and a plot of the hemoglobin dissociation curve was consistent with empirical formula. In vivo determination of tumor vasculature SaO II levels were measurably tracked, and spatially correlated to the periphery of the tumor. Tumor depend variations in SaO II - 0.32 (ovarian) and 0.60 (breast) - and in vascular physiology - perfusion, 1.03 and 0.063 mL/min/mL, and fractional plasma volume, 0.20 and 0.07 - were observed. Conclusion: Combined, PCT-S and CED-CT has the potential to measure intra-tumor levels of tumor oxygen saturation and vascular physiology, key parameters associated with hypoxia.

  19. A Platform for Interrogating Cancer-Associated p53 Alleles

    PubMed Central

    D’Brot, Alejandro; Kurtz, Paula; Regan, Erin; Jakubowski, Brandon; Abrams, John M

    2016-01-01

    p53 is the most frequently mutated gene in human cancer. Compelling evidence argues that full transformation involves loss of growth suppression encoded by wild-type p53 together with poorly understood oncogenic activity encoded by missense mutations. Furthermore, distinguishing disease alleles from natural polymorphisms is an important clinical challenge. To interrogate the genetic activity of human p53 variants, we leveraged the Drosophila model as an in vivo platform. We engineered strains that replace the fly p53 gene with human alleles, producing a collection of stocks that are, in effect, ‘humanized’ for p53 variants. Like the fly counterpart, human p53 transcriptionally activated a biosensor and induced apoptosis after DNA damage. However, all humanized strains representing common alleles found in cancer patients failed to complement in these assays. Surprisingly, stimulus-dependent activation of hp53 occurred without stabilization, demonstrating that these two processes can be uncoupled. Like its fly counterpart, hp53 formed prominent nuclear foci in germline cells but cancer-associated p53 variants did not. Moreover, these same mutant alleles disrupted hp53 foci and inhibited biosensor activity, suggesting that these properties are functionally linked. Together these findings establish a functional platform for interrogating human p53 alleles and suggest that simple phenotypes could be used to stratify disease variants. PMID:26996664

  20. Sildenafil citrate for prophylaxis of nephropathy in an animal model of contrast-induced acute kidney injury.

    PubMed

    Lauver, D Adam; Carey, E Grant; Bergin, Ingrid L; Lucchesi, Benedict R; Gurm, Hitinder S

    2014-01-01

    Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI. In this study we evaluated the protective effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate, in a rabbit model of CIAKI. New Zealand white rabbits were used due to their susceptibility to CIAKI. To evaluate the effects of sildenafil, the drug was administered before CM infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o.). Animals were sacrificed after 48 hours and kidneys were prepared for histological evaluation. Intravenous administration of CM produced marked kidney injury. Serum creatinine concentrations were elevated within two hours of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the CM were dose dependent. Treatment with sildenafil was associated with lesser degree of histological injury, attenuation in markers of acute kidney injury (48 hour creatinine 1.54±0.21 versus 4.42±1.31 mg/dl, p<0.05) and reduction in electrolyte derangement (percent change in serum K+ at 48 hours 2.55±3.80% versus 15.53±4.47%, p<0.05; serum Na+ at 48 hours -0.14±0.26% versus -1.97±1.29%, p = 0.20). The results suggest a possible role for PDE5 inhibitors in the treatment of CIAKI and warrant further evaluation to determine the exact mechanism of protection.

  1. Uncertainty of streamwater solute fluxes in five contrasting headwater catchments including model uncertainty and natural variability (Invited)

    NASA Astrophysics Data System (ADS)

    Aulenbach, B. T.; Burns, D. A.; Shanley, J. B.; Yanai, R. D.; Bae, K.; Wild, A.; Yang, Y.; Dong, Y.

    2013-12-01

    There are many sources of uncertainty in estimates of streamwater solute flux. Flux is the product of discharge and concentration (summed over time), each of which has measurement uncertainty of its own. Discharge can be measured almost continuously, but concentrations are usually determined from discrete samples, which increases uncertainty dependent on sampling frequency and how concentrations are assigned for the periods between samples. Gaps between samples can be estimated by linear interpolation or by models that that use the relations between concentration and continuously measured or known variables such as discharge, season, temperature, and time. For this project, developed in cooperation with QUEST (Quantifying Uncertainty in Ecosystem Studies), we evaluated uncertainty for three flux estimation methods and three different sampling frequencies (monthly, weekly, and weekly plus event). The constituents investigated were dissolved NO3, Si, SO4, and dissolved organic carbon (DOC), solutes whose concentration dynamics exhibit strongly contrasting behavior. The evaluation was completed for a 10-year period at five small, forested watersheds in Georgia, New Hampshire, New York, Puerto Rico, and Vermont. Concentration regression models were developed for each solute at each of the three sampling frequencies for all five watersheds. Fluxes were then calculated using (1) a linear interpolation approach, (2) a regression-model method, and (3) the composite method - which combines the regression-model method for estimating concentrations and the linear interpolation method for correcting model residuals to the observed sample concentrations. We considered the best estimates of flux to be derived using the composite method at the highest sampling frequencies. We also evaluated the importance of sampling frequency and estimation method on flux estimate uncertainty; flux uncertainty was dependent on the variability characteristics of each solute and varied for

  2. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase

    PubMed Central

    Carney, Amanda E.; Sanders, Rebecca D.; Garza, Kerry R.; McGaha, Lee Anne; Bean, Lora J. H.; Coffee, Bradford W.; Thomas, James W.; Cutler, David J.; Kurtkaya, Natalie L.; Fridovich-Keil, Judith L.

    2009-01-01

    Duarte galactosemia is a mild to asymptomatic condition that results from partial impairment of galactose-1-phosphate uridylyltransferase (GALT). Patients with Duarte galactosemia demonstrate reduced GALT activity and carry one profoundly impaired GALT allele (G) along with a second, partially impaired GALT allele (Duarte-2, D2). Molecular studies reveal at least five sequence changes on D2 alleles: a p.N314D missense substitution, three intronic base changes and a 4 bp deletion in the 5′ proximal sequence. The four non-coding sequence changes are unique to D2. The p.N314D substitution, however, is not; it is found together with a silent polymorphism, p.L218(TTA), on functionally normal Duarte-1 alleles (D1, also called Los Angeles or LA alleles). The HapMap database reveals that p.N314D is a common human variant, and cross-species comparisons implicate D314 as the ancestral allele. The p.N314D substitution is also functionally neutral in mammalian cell and yeast expression studies. In contrast, the 4 bp 5′ deletion characteristic of D2 alleles appears to be functionally impaired in reporter gene transfection studies. Here we present allele-specific qRT–PCR evidence that D2 alleles express less mRNA in vivo than their wild-type counterparts; the difference is small but statistically significant. Furthermore, we characterize the prevalence of the 4 bp deletion in GG, NN and DG populations; the deletion appears exclusive to D2 alleles. Combined, these data strongly implicate the 4 bp 5′ deletion as a causal mutation in Duarte galactosemia and suggest that direct tests for this deletion, as proposed here, could enhance or supplant current tests, which define D2 alleles on the basis of the presence and absence of linked coding sequence polymorphisms. PMID:19224951

  3. Automated segmentation of upper digestive tract from abdominal contrast-enhanced CT data using hierarchical statistical modeling of organ interrelations

    NASA Astrophysics Data System (ADS)

    Hirayama, S.; Otake, Y.; Okada, T.; Hori, M.; Tomiyama, N.; Sato, Y.

    2016-03-01

    We have been studying the automatic segmentation of multi-organ region from abdominal CT images. In previous work, we proposed an approach using a hierarchical statistical modeling using a relationship between organs. In this paper, we have proposed automatic segmentation of the upper digestive tract from abdominal contrast-enhanced CT using previously segmented multiple organs. We compared segmentation accuracy of the esophagus, stomach and duodenum between our proposed method using hierarchical statistical modeling and a conventional statistical atlas method. Additionally, preliminary experiment was performed which added the region representing gas to the candidate region at the segmentation step. The segmentation results were evaluated quantitatively by Dice coefficient, Jaccard index and the average symmetric surface distance of the segmented region and correct region data. Percentage of the average of Dice coefficient of esophagus, stomach and duodenum were 58.7, 68.3, and 38.6 with prediction-based method and 23.7, 51.1, and 24.4 with conventional atlas method.

  4. Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer’s Disease

    PubMed Central

    Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

    2016-01-01

    Aging is the main risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition. PMID:27656136

  5. Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer's Disease.

    PubMed

    Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

    2016-01-01

    Aging is the main risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition. PMID:27656136

  6. Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer’s Disease

    PubMed Central

    Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

    2016-01-01

    Aging is the main risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition.

  7. Contrasting roles of interception and transpiration in the hydrological cycle - Part 1: Simple Terrestrial Evaporation to Atmosphere Model

    NASA Astrophysics Data System (ADS)

    Wang-Erlandsson, L.; van der Ent, R. J.; Gordon, L. J.; Savenije, H. H. G.

    2014-03-01

    Terrestrial evaporation consists of biophysical (i.e., transpiration) and physical fluxes (i.e., interception, soil moisture, and open water). The partitioning between them depends on both climate and the land surface, and determines the time scale of evaporation. However, few land-surface models have analysed and evaluated evaporative partitioning based on land use, and no studies have examined their subsequent paths in the atmosphere. This paper constitutes the first of two companion papers that investigate the contrasting effects of interception and transpiration in the hydrological cycle. Here, we present STEAM (Simple Terrestrial Evaporation to Atmosphere Model) used to produce partitioned evaporation and analyse the characteristics of different evaporation fluxes on land. STEAM represents 19 land-use types (including irrigated land) at sub-grid level with a limited set of parameters, and includes phenology and stress functions to respond to changes in climate conditions. Using ERA-Interim reanalysis forcing for the years 1999-2008, STEAM estimates a mean global terrestrial evaporation of 73 800 km3 year-1, with a transpiration ratio of 59%. We show that the terrestrial residence time scale of transpiration (days to months) has larger inter-seasonal variation and is substantially longer than that of interception (hours). Furthermore, results from an offline land-use change experiment illustrate that land-use change may lead to significant changes in evaporative partitioning even when total evaporation remains similar. In agreement with previous research, our simulations suggest that the vegetation's ability to transpire by retaining and accessing soil moisture at greater depth is critical for sustained evaporation during the dry season. Despite a relatively simple model structure, validation shows that STEAM produces realistic evaporative partitioning and hydrological fluxes that compare well with other global estimates over different locations, seasons and

  8. Robust Data Driven Model Order Estimation for Independent Component Analysis of fMRI Data with Low Contrast to Noise

    PubMed Central

    Majeed, Waqas; Avison, Malcolm J.

    2014-01-01

    Independent component analysis (ICA) has been successfully utilized for analysis of functional MRI (fMRI) data for task related as well as resting state studies. Although it holds the promise of becoming an unbiased data-driven analysis technique, a few choices have to be made prior to performing ICA, selection of a method for determining the number of independent components (nIC) being one of them. Choice of nIC has been shown to influence the ICA maps, and various approaches (mostly relying on information theoretic criteria) have been proposed and implemented in commonly used ICA analysis packages, such as MELODIC and GIFT. However, there has been no consensus on the optimal method for nIC selection, and many studies utilize arbitrarily chosen values for nIC. Accurate and reliable determination of true nIC is especially important in the setting where the signals of interest contribute only a small fraction of the total variance, i.e. very low contrast-to-noise ratio (CNR), and/or very focal response. In this study, we evaluate the performance of different model order selection criteria and demonstrate that the model order selected based upon bootstrap stability of principal components yields more reliable and accurate estimates of model order. We then demonstrate the utility of this fully data-driven approach to detect weak and focal stimulus-driven responses in real data. Finally, we compare the performance of different multi-run ICA approaches using pseudo-real data. PMID:24788636

  9. A novel measurement of allele discrimination for assessment of allele-specific silencing by RNA interference.

    PubMed

    Takahashi, Masaki; Hohjoh, Hirohiko

    2014-11-01

    Allele-specific silencing by RNA interference (ASP-RNAi) is an atypical RNAi that is capable of discriminating target alleles from non-target alleles, and may be therapeutically useful for specific inhibition of disease-causing alleles without affecting their corresponding normal alleles. However, it is difficult to design and select small interfering RNA (siRNAs) that confer ASP-RNAi. A major problem is that there are few appropriate measures in determining optimal allele-specific siRNAs. Here we show two novel formulas for calculating a new measure of allele-discrimination, named "ASP-score". The formulas and ASP-score allow for an unbiased determination of optimal siRNAs, and may contribute to characterizing such allele-specific siRNAs.

  10. Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases

    PubMed Central

    Amos, Christopher I.

    2015-01-01

    Genome-wide association studies (GWAS) have generated sufficient data to assess the role of selection in shaping allelic diversity of disease-associated SNPs. Negative selection against disease risk variants is expected to reduce their frequencies making them overrepresented in the group of minor (<50%) alleles. Indeed, we found that the overall proportion of risk alleles was higher among alleles with frequency <50% (minor alleles) compared to that in the group of major alleles. We hypothesized that negative selection may have different effects on environment (or lifestyle)-dependent versus environment (or lifestyle)-independent diseases. We used an environment/lifestyle index (ELI) to assess influence of environmental/lifestyle factors on disease etiology. ELI was defined as the number of publications mentioning “environment” or “lifestyle” AND disease per 1,000 disease-mentioning publications. We found that the frequency distributions of the risk alleles for the diseases with strong environmental/lifestyle components follow the distribution expected under a selectively neutral model, while frequency distributions of the risk alleles for the diseases with weak environmental/lifestyle influences is shifted to the lower values indicating effects of negative selection. We hypothesized that previously selectively neutral variants become risk alleles when environment changes. The hypothesis of ancestrally neutral, currently disadvantageous risk-associated alleles predicts that the distribution of risk alleles for the environment/lifestyle dependent diseases will follow a neutral model since natural selection has not had enough time to influence allele frequencies. The results of our analysis suggest that prediction of SNP functionality based on the level of evolutionary conservation may not be useful for SNPs associated with environment/lifestyle dependent diseases. PMID:26201053

  11. Maximizing allele detection: Effects of analytical threshold and DNA levels on rates of allele and locus drop-out.

    PubMed

    Rakay, Christine A; Bregu, Joli; Grgicak, Catherine M

    2012-12-01

    Interpretation of DNA evidence depends upon the ability of the analyst to accurately compare the DNA profile obtained from an item of evidence and the DNA profile of a standard. This interpretation becomes progressively more difficult as the number of 'drop-out' and 'drop-in' events increase. Analytical thresholds (AT) are typically selected to ensure the false detection of noise is minimized. However, there exists a tradeoff between the erroneous labeling of noise as alleles and the false non-detection of alleles (i.e. drop-out). In this study, the effect ATs had on both types of error was characterized. Various ATs were tested, where three relied upon the analysis of baseline signals obtained from 31 negative samples. The fourth AT was determined by utilizing the relationship between RFU signal and DNA input. The other ATs were the commonly employed 50, 150 and 200 RFU thresholds. Receiver Operating Characteristic (ROC) plots showed that although high ATs completely negated the false labeling of noise, DNA analyzed with ATs derived using analysis of the baseline signal exhibited the lowest rates of drop-out and the lowest total error rates. In another experiment, the effect small changes in ATs had on drop-out was examined. This study showed that as the AT increased from ∼10 to 60 RFU, the number of heterozygous loci exhibiting the loss of one allele increased. Between ATs of 60 and 150 RFU, the frequency of allelic drop-out remained constant at 0.27 (±0.02) and began to decrease when ATs of 150 RFU or greater were utilized. In contrast, the frequency of heterozygous loci exhibiting the loss of both alleles consistently increased with AT. In summary, for samples amplified with less than 0.5ng of DNA, ATs derived from baseline analysis of negatives were shown to decrease the frequency of drop-out by a factor of 100 without significantly increasing rates of erroneous noise detection.

  12. SU-C-12A-03: The Impact of Contrast Medium On Radiation Dose in CT: A Systematic Evaluation Across 58 Patient Models

    SciTech Connect

    Sahbaee, P; Samei, E; Segars, W

    2014-06-01

    Purpose: To assess the effect of contrast medium on radiation dose as a function of time via Monte Carlo simulation from the liver CT scan across a library of 5D XCAT models Methods: A validated Monte Carlo simulation package (PENELOPE) was employed to model a CT system (LightSpeed 64 VCT, GE Healthcare). The radiation dose was estimated from a common abdomen CT examination. The dose estimation was performed on a library of adult extended cardiac-torso (5D XCAT) phantoms (35 male, 23 female, mean age 51.5 years, mean weight 80.2 kg). The 5D XCAT models were created based on patient-specific iodine concentration-time results from our computational contrast medium propagation model for different intravenous injection protocols. To enable a dynamic estimation of radiation dose, each organ in the model was assigned to its own time-concentration curve via the PENELOPE package, material.exe. Using the Monte Carlo, for each scan time point after the injection, 80 million photons were initiated and tracked through the phantoms. Finally, the dose to the liver was tallied from the deposited energy. Results: Monte Carlo simulation results of radiation dose delivered to the liver from the XCAT models indicated up to 30% increase in dose for different time after the administration of contrast medium. Conclusion: The contrast enhancement is employed in over 60% of imaging modalities, which not only remarkably affects the CT image quality, but also increases the radiation dose by as much as 70%. The postinjection multiple acquisition in several enhanced CT protocols, makes the radiation dose increment through the use of contrast medium, an inevitable factor in optimization of these protocols. The relationship between radiation dose and injected contrast medium as a function of time studied in this work allows optimization of contrast administration for vulnerable individuals.

  13. The therapeutic effect of bevacizumab on plaque neovascularization in a rabbit model of atherosclerosis during contrast-enhanced ultrasonography

    PubMed Central

    Li, Yang; Zhu, Ying; Deng, Youbin; Liu, Yani; Mao, Yuhang; Wang, Junli; Sun, Jie

    2016-01-01

    The purpose of the study was to assess the therapeutic effect of the angiogenesis inhibitor bevacizumab on plaques of various stages in rabbit models using contrast-enhanced ultrasonography (CEUS). Abdominal aortic atherosclerosis was induced in 55 rabbits. Thirty-six randomly selected rabbits were divided into 2 groups according to the timing of the bevacizumab injection: an early-stage plaque group (Group ESP) and a later-stage plaque group (Group LSP). The remainder were considered the control group. Standard ultrasonography and CEUS imaging of the abdominal aorta were performed. The animals were euthanized after CEUS, and plaque specimens were harvested for histological staining of CD31. The control group exhibited a substantially higher enhanced intensity, a higher ratio of enhanced intensity in the plaque to that in the lumen, and an increased number of CD31-positive microvessels in the plaque sections than Groups ESP and LSP (P < 0.05 for all). A higher enhanced intensity (P = 0.044), a higher ratio of enhanced intensity in the plaque to that in the lumen (P = 0.023) and more CD31-positive microvessels in the plaque sections (P = 0.006) were found in Group LSP than in Group ESP. Bevacizumab demonstrated more advanced inhibition of neovascularization in early-stage plaques in rabbits. PMID:27452862

  14. Phase-Contrast MRI and CFD Modeling of Apparent 3He Gas Flow in Rat Pulmonary Airways

    PubMed Central

    Minard, Kevin R.; Kuprat, Andrew P.; Kabilan, Senthil; Jacob, Richard E.; Einstein, Daniel R.; Carson, James P.; Corley, Richard A.

    2012-01-01

    Phase-contrast (PC) magnetic resonance imaging (MRI) with hyperpolarized 3He is potentially useful for developing and testing patient-specific models of pulmonary airflow. One challenge, however, is that PC-MRI provides apparent values of local 3He velocity that not only depend on actual airflow but also on gas diffusion. This not only blurs laminar flow patterns in narrow airways but also introduces anomalous airflow structure that reflects gas-wall interactions. Here, both effects are predicted in a live rat using computational fluid dynamics (CFD), and for the first time, simulated patterns of apparent 3He gas velocity are compared with in-vivo PC-MRI. Results show 1) that correlations (R2) between measured and simulated airflow patterns increase from 0.23 to 0.79 simply by accounting for apparent 3He transport, and 2) that remaining differences are mainly due to uncertain airway segmentation and partial volume effects stemming from relatively coarse MRI resolution. Higher-fidelity testing of pulmonary airflow predictions should therefore be possible with future imaging improvements. PMID:22771528

  15. Phase-contrast MRI and CFD modeling of apparent 3He gas flow in rat pulmonary airways

    NASA Astrophysics Data System (ADS)

    Minard, Kevin R.; Kuprat, Andrew P.; Kabilan, Senthil; Jacob, Richard E.; Einstein, Daniel R.; Carson, James P.; Corley, Richard A.

    2012-08-01

    Phase-contrast (PC) magnetic resonance imaging (MRI) with hyperpolarized 3He is potentially useful for developing and testing patient-specific models of pulmonary airflow. One challenge, however, is that PC-MRI provides apparent values of local 3He velocity that not only depend on actual airflow but also on gas diffusion. This not only blurs laminar flow patterns in narrow airways but also introduces anomalous airflow structure that reflects gas-wall interactions. Here, both effects are predicted in a live rat using computational fluid dynamics (CFD), and for the first time, simulated patterns of apparent 3He gas velocity are compared with in vivo PC-MRI. Results show (1) that correlations (R2) between measured and simulated airflow patterns increase from 0.23 to 0.79 simply by accounting for apparent 3He transport, and (2) that remaining differences are mainly due to uncertain airway segmentation and partial volume effects stemming from relatively coarse MRI resolution. Higher-fidelity testing of pulmonary airflow predictions should therefore be possible with future imaging improvements.

  16. Phase-Contrast MRI and CFD Modeling of Apparent 3He Gas Flow in Rat Pulmonary Airways

    SciTech Connect

    Minard, Kevin R.; Kuprat, Andrew P.; Kabilan, Senthil; Jacob, Rick E.; Einstein, Daniel R.; Carson, James P.; Corley, Richard A.

    2012-08-01

    Phase-contrast (PC) magnetic resonance imaging (MRI) with hyperpolarized 3He is potentially useful for developing and testing patient-specific models of pulmonary airflow. One challenge, however, is that PC-MRI provides apparent values of local 3He velocity that not only depend on actual airflow but also on gas diffusion. This not only blurs laminar flow patterns in narrow airways but also introduces anomalous airflow structure that reflects gas-wall interactions. Here, both effects are predicted in a live rat using computational fluid dynamics (CFD), and for the first time, simulated patterns of apparent 3He gas velocity are compared with in-vivo PC-MRI. Results show (1) that correlations (R2) between measured and simulated airflow patterns increase from 0.23 to 0.79 simply by accounting for apparent 3He transport, and that (2) remaining differences are mainly due to uncertain airway segmentation and partial volume effects stemming from relatively coarse MRI resolution. Higher-fidelity testing of pulmonary airflow predictions should therefore be possible with future imaging improvements.

  17. Efficient genotype elimination via adaptive allele consolidation.

    PubMed

    De Francesco, Nicoletta; Lettieri, Giuseppe; Martini, Luca

    2012-01-01

    We propose the technique of Adaptive Allele Consolidation, that greatly improves the performance of the Lange-Goradia algorithm for genotype elimination in pedigrees, while still producing equivalent output. Genotype elimination consists in removing from a pedigree those genotypes that are impossible according to the Mendelian law of inheritance. This is used to find errors in genetic data and is useful as a preprocessing step in other analyses (such as linkage analysis or haplotype imputation). The problem of genotype elimination is intrinsically combinatorial, and Allele Consolidation is an existing technique where several alleles are replaced by a single “lumped” allele in order to reduce the number of combinations of genotypes that have to be considered, possibly at the expense of precision. In existing Allele Consolidation techniques, alleles are lumped once and for all before performing genotype elimination. The idea of Adaptive Allele Consolidation is to dynamically change the set of alleles that are lumped together during the execution of the Lange-Goradia algorithm, so that both high performance and precision are achieved. We have implemented the technique in a tool called Celer and evaluated it on a large set of scenarios, with good results.

  18. Dynamic imaging of cerebral blood flow in rat reperfused mini-stroke model using laser speckle temporal contrast analysis

    NASA Astrophysics Data System (ADS)

    Wang, Zhen; Luo, Weihua; Li, Pengcheng; Zeng, Shaoqun; Luo, Qingming

    2007-05-01

    Laser speckle temporal contrast analysis (LSTCA) was used to image the cerebral blood flow (CBF) of ischemic area in reperfused mini-stroke model in rats. Focal cortical ischemia in male Sprague-Dawley rats (n=20) was induced by deliberate ligation of multiple branches of the middle cerebral artery (MCA) together with a nylon ring and the dura. LSTCA was used to monitor the spatio-temporal characteristics of cerebral blood flow dynamics in the rat somatosensory cortex in the ischemic and reperfused stages. The infarction volume was measured by 2, 3, 5- triphenyltetrazolium chloride (TTC) staining 24 hours after reperfusion. The distribution of changes in cerebral blood flow which outlined by the laser speckle imaging represented the relative CBF gradient (21.98+/-1.96%, 67.2+/-1.67 %, 107.24+/-4.71 % of the baseline) from ischemic core, penumbra zone to normal tissue immediately after cortical ischemia, in which a central ischemic core had little or no perfusion surrounded by a penumbral region with reduced perfusion, in addition, we had shown the existence of a surrounding region of hyperemic tissue; Thereafter a postrecanalization hyperperfusion occurred in the same infarct core since 24 hours after reperfusion (242.62+/-18.52% of the baseline). Histology of the ischemic regions at 24 hours after reperfusion revealed small focal infarcts that were typically 3~4 mm in diameter, approximately equal to the nylon ring in size and position and essentially accordant with the spatial distribution of the ischemic cortex with below 30% residual CBF of the pre-ischemic baseline. It was demonstrated that this technique of LSTCA was easy to implement and availably used to image the spatial and temporal evolution of CBF changes with high resolution in rat reperfused mini-stroke model.

  19. Contrasting non-local effects of shoreline stabilization methods in a model of large-scale coastline morphodynamics

    NASA Astrophysics Data System (ADS)

    Ells, K. D.; Murray, A.

    2011-12-01

    Advances in the understanding of the wave-angle dependence of large-scale sandy coastline evolution have allowed exploratory modeling investigations into the emergence of large-scale coastline features such as sandwaves, capes, and spits; the possible responses of these complex coastline shapes to changing wave climates; and the dynamic coupling of natural coastal processes with economic decisions for shoreline stabilization. Recent numerical-model experiments found that beach nourishment on a complex-shaped coastline can significantly alter rates of shoreline change on spatial scales commensurate with the alongshore distance of adjacent features (up to 100 km). While the effect of beach nourishment is to fix a given shoreline position while maintaining a saturated sediment flux locally, hard structured stabilization methods (e.g. seawalls, revetments, or groynes) tend to reduce local alongshore fluxes of sediment. In long-term numerical experiments (decades to centuries), the effects of local stabilization propagate both progressively alongshore and through a non-local mechanism (wave shadowing). Comparing these two fundamentally different methods of shoreline stabilization on various locations along a cuspate cape coastline, we find that both the local and regional responses to hard structures greatly contrast those of beach nourishment. Sustained nourishment near the tip of a cape tends to extend the cape both seaward and in the direction of alongshore flux, increasing the effect that wave shadowing would have otherwise had on distant shorelines, leading to a negative (landward) perturbation to an adjacent cape. A hard structure at the same location, however, completely fixes the cape's original location, decreasing the shadowing effect and resulting in a positive (seaward) perturbation to the downdrift cape. Recent extensions of this work examine how different stabilization methods affect long-term coastline morphodynamics on other coastline types, starting

  20. A contrast between nocturnal flow regimes: Observations and modeling simulations of katabatic intrusions in the Laramie Valley

    NASA Astrophysics Data System (ADS)

    Juliano, Timothy W.

    Katabatic winds commonly occur in mountainous regions under statically stable conditions when a sufficient deficit exists in the net radiation budget. Observations of these stable boundary layer (SBL) downslope flows have extended back to the 1930s. Their interactions with other SBL processes, including cold air pools (CAPs) and mountain waves, are quite complex, however, and have only more recently been deeply investigated. The University of Wyoming (UW) wind tower (WT) and flux tower (WT), situated in the Laramie Valley, were utilized in examining a dataset spanning from 14 December 2011 to 12 September 2013. A set of criteria were developed to determine katabatic intrusion events, and establish a climatology of these events, at the WT. The 21-22 December 2012 nighttime period was then studied in detail using data from the aforementioned towers in addition to weather stations throughout the Laramie Valley and the Weather Research and Forecasting (WRF) model. Both observations and modeling results indicated a competition between two strongly contrasting flow regimes: synoptic and katabatic. The synoptic regime was characterized by strong, southwesterly winds, warm temperatures, and turbulent flow, while the katabatic regime featured weaker, southeasterly winds, cooler temperatures, and intermittently turbulent flow. Sonic and propeller anemometers on the WT elucidated the chaotic transition between the regimes. At the WT, it was found that between regimes the wind speed decreased by up to 60%, wind direction often shifted over 120°, and potential temperature usually decreased more than 2°C. The katabatic wind depth was postulated to be variable in time and space, with its head sloping towards the trailing CAP. Topographically generated mountain waves and local terrain forcing are suspected to play an integral role in the development and evolution of the katabatic wind in the Laramie Valley. Results from this research yield promising insight into the intricate

  1. Schizotypy and leadership: a contrasting model for deficit symptoms, and a possible therapeutic role for sex hormones.

    PubMed

    Alias, A G

    2000-04-01

    Associational loosening, slow and faulty information processing, poor gating of irrelevant stimuli, poor ability to shift attention, poor working memory, passivity, ambivalence, anhedonia, and impaired motor coordination are cardinal features of schizophrenia but, unlike delusions and hallucinations, they are related more to negative/deficit symptoms. As summarized by Bass, numerous studies have correlated leadership with 'ambition, initiative and persistence' (opposite of passivity), 'speed and accuracy of thought', 'finality of decision,' or decisiveness (the opposite of ambivalence), 'mood control, optimism and sense of humor' (opposite of anhedonia), etc. Andreasen et al postulate that a disruption in the circuitry among nodes located in the prefrontal regions, the thalamic nuclei, and the cerebellum produces 'cognitive dysmetria', meaning difficulty in prioritizing, coordinating, and responding to information, and that it can account for the broad diversity of symptoms of schizophrenia. A relationship between cognitive processes and cerebellar and basal ganglia functions, and a role of neocerebellum in rapidly shifting attention, have been demonstrated. The cognitive styles, including a proficiency to quickly shift attention, of several famous leaders are used as examples of this contrasting model. Julius Caesar and Napoleon, for instance, could dictate to up to six secretaries simultaneously, using their exceptional working memories, and proficiency in quickly and effortlessly shifting attention while flawlessly gating irrelevant external and internal stimuli. It is suggested that specific brain imaging studies could illustrate this contrast. Gray et al noted positive correlations between 'dominance', an important leadership trait, and serum levels of dehydroepiandrosterone (DHEA) and testosterone (T), but not of more potent dihydrotestosterone (DHT), in over 1700 older men. Though not scientifically rigorous, the author noted positive correlations (P = 0

  2. Schizotypy and leadership: a contrasting model for deficit symptoms, and a possible therapeutic role for sex hormones.

    PubMed

    Alias, A G

    2000-04-01

    Associational loosening, slow and faulty information processing, poor gating of irrelevant stimuli, poor ability to shift attention, poor working memory, passivity, ambivalence, anhedonia, and impaired motor coordination are cardinal features of schizophrenia but, unlike delusions and hallucinations, they are related more to negative/deficit symptoms. As summarized by Bass, numerous studies have correlated leadership with 'ambition, initiative and persistence' (opposite of passivity), 'speed and accuracy of thought', 'finality of decision,' or decisiveness (the opposite of ambivalence), 'mood control, optimism and sense of humor' (opposite of anhedonia), etc. Andreasen et al postulate that a disruption in the circuitry among nodes located in the prefrontal regions, the thalamic nuclei, and the cerebellum produces 'cognitive dysmetria', meaning difficulty in prioritizing, coordinating, and responding to information, and that it can account for the broad diversity of symptoms of schizophrenia. A relationship between cognitive processes and cerebellar and basal ganglia functions, and a role of neocerebellum in rapidly shifting attention, have been demonstrated. The cognitive styles, including a proficiency to quickly shift attention, of several famous leaders are used as examples of this contrasting model. Julius Caesar and Napoleon, for instance, could dictate to up to six secretaries simultaneously, using their exceptional working memories, and proficiency in quickly and effortlessly shifting attention while flawlessly gating irrelevant external and internal stimuli. It is suggested that specific brain imaging studies could illustrate this contrast. Gray et al noted positive correlations between 'dominance', an important leadership trait, and serum levels of dehydroepiandrosterone (DHEA) and testosterone (T), but not of more potent dihydrotestosterone (DHT), in over 1700 older men. Though not scientifically rigorous, the author noted positive correlations (P = 0

  3. A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence

    PubMed Central

    Grucza, Richard A; Wang, Jen C.; Stitzel, Jerry A.; Hinrichs, Anthony L.; Saccone, Scott F.; Saccone, Nancy L.; Bucholz, Kathleen K.; Cloninger, C. Robert; Neuman, Rosalind J.; Budde, John P.; Fox, Louis; Bertelsen, Sarah; Kramer, John; Hesselbrock, Victor; Tischfield, Jay; Nurnberger, John. I.; Almasy, Laura; Porjesz, Bernice; Kuperman, Samuel; Schuckit, Marc A.; Edenberg, Howard J.; Rice, John P.; Goate, Alison M.; Bierut, Laura J.

    2008-01-01

    Background A non-synonymous coding polymorphism, rs16969968, of the CHRNA5 gene which encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence (20). The goal of the present study is to examine the association of this variant with cocaine dependence. Methods Genetic association analysis in two, independent samples of unrelated cases and controls; 1.) 504 European-American participating in the Family Study on Cocaine Dependence (FSCD); 2.) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholsim (COGA). Results In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (OR = 0.67 per allele, p = 0.0045, assuming an additive genetic model), but in the reverse direction compared to that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD. Conclusion The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways. PMID:18519132

  4. MO-E-17A-02: Incorporation of Contrast Medium Dynamics in Anthropomorphic Phantoms: The Advent of 5D XCAT Models

    SciTech Connect

    Sahbaee, P; Samei, E; Segars, W

    2014-06-15

    Purpose: To develop a unique method to incorporate the dynamics of contrast-medium propagation into the anthropomorphic phantom, to generate a five-dimensional (5D) patient model for multimodality imaging studies. Methods: A compartmental model of blood circulation network within the body was embodied into an extended cardiac-torso (4D-XCAT) patient model. To do so, a computational physiologic model of the human cardiovascular system was developed which includes a series of compartments representing heart, vessels, and organs. Patient-specific cardiac output and blood volume were used as inputs influenced by the weight, height, age, and gender of the patient's model. For a given injection protocol and given XCAT model, the contrast-medium transmission within the body was described by a series of mass balance differential equations, the solutions to which provided the contrast enhancement-time curves for each organ; thereby defining the tissue materials including the contrastmedium within the XCAT model. A library of time-dependent organ materials was then defined. Each organ in each voxelized 4D-XCAT phantom was assigned to a corresponding time-varying material to create the 5D-XCAT phantom in which the fifth dimension is blood/contrast-medium within the temporal domain. Results: The model effectively predicts the time-varying concentration behavior of various contrast-medium administration in each organ for different patient models as function of patient size (weight/height) and different injection protocol factors (injection rate and pattern, iodine concentration or volume). The contrast enhanced XCAT patient models was developed based on the concentration of iodine as a function of time after injection. Conclusion: Majority of medical imaging systems take advantage of contrast-medium administration in terms of better image quality, the effect of which was ignored in previous optimization studies. The study enables a comprehensive optimization of contrast

  5. Methylene blue microbubbles as a model dual-modality contrast agent for ultrasound and activatable photoacoustic imaging.

    PubMed

    Jeon, Mansik; Song, Wentao; Huynh, Elizabeth; Kim, Jungho; Kim, Jeesu; Helfield, Brandon L; Leung, Ben Y C; Goertz, David E; Zheng, Gang; Oh, Jungtaek; Lovell, Jonathan F; Kim, Chulhong

    2014-01-01

    Ultrasound and photoacoustic imaging are highly complementary modalities since both use ultrasonic detection for operation. Increasingly, photoacoustic and ultrasound have been integrated in terms of hardware instrumentation. To generate a broadly accessible dual-modality contrast agent, we generated microbubbles (a standard ultrasound contrast agent) in a solution of methylene blue (a standard photoacoustic dye). This MB2 solution was formed effectively and was optimized as a dual-modality contrast solution. As microbubble concentration increased (with methylene blue concentration constant), photoacoustic signal was attenuated in the MB2 solution. When methylene blue concentration increased (with microbubble concentration held constant), no ultrasonic interference was observed. Using an MB2 solution that strongly attenuated all photoacoustic signal, high powered ultrasound could be used to burst the microbubbles and dramatically enhance photoacoustic contrast (>800-fold increase), providing a new method for spatiotemporal control of photoacoustic signal generation.

  6. Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature.

    PubMed

    Adamek, Martina; Klages, Cornelia; Bauer, Manuela; Kudlek, Evelina; Drechsler, Alina; Leuser, Birte; Scherer, Sabine; Opelz, Gerhard; Tran, Thuong Hien

    2015-01-01

    The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA-DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism.

  7. Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent

    PubMed Central

    Wang, Huaijun; Felt, Stephen A.; Machtaler, Steven; Guracar, Ismayil; Luong, Richard; Bettinger, Thierry; Tian, Lu; Lutz, Amelie M.

    2015-01-01

    Purpose To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin–targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. Materials and Methods The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin–targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 108 MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. Results Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 108 MB/kg and plateaued between a dose of 10 and a dose of 20 × 108 MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). Conclusion Quantitative measurements of inflammation obtained by using dual-selectin–targeted US

  8. Spleen Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a New Method for Staging Liver Fibrosis in a Piglet Model

    PubMed Central

    2013-01-01

    Objective To explore spleen hemodynamic alteration in liver fibrosis with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and to determine how to stage liver fibrosis with spleen DCE-MRI parameters. Materials and Methods Sixteen piglets were prospectively used to model liver fibrosis staged by liver biopsy, and underwent spleen DCE-MRI on 0, 5th, 9th, 16th and 21st weekend after modeling this disease. DCE-MRI parameters including time to peak (TTP), positive enhancement integral (PEI), maximum slope of increase (MSI) and maximum slope of decrease (MSD) of spleen were measured, and statistically analyzed to stage this disease. Results Spearman's rank correlation tests showed that TTP tended to increase with increasing stages of liver fibrosis (r = 0.647, P<0.001), and that PEI tended to decrease from stage 0 to 4 (r = −0.709, P<0.001). MSD increased slightly from stage 0 to 2 (P>0.05), and decreased from stage 2 to 4 (P<0.05). MSI increased from stage 0 to 1, and decreased from stage 1 to 4 (all P>0.05). Mann-Whitney tests demonstrated that TTP and PEI could classify fibrosis between stage 0 and 1–4, between 0–1 and 2–4, between 0–2 and 3–4, or between 0–3 and 4 (all P<0.01). MSD could discriminate between 0–2 and 3–4 (P = 0.006), or between 0–3 and 4 (P = 0.012). MSI could not differentiate between any two stages. Receiver operating characteristic analysis illustrated that area under receiver operating characteristic curve (AUC) of TTP was larger than of PEI for classifying stage ≥1 and ≥2 (AUC = 0.851 and 0.783, respectively). PEI could best classify stage ≥3 and 4 (AUC = 0.903 and 0.96, respectively). Conclusion Spleen DCE-MRI has potential to monitor spleen hemodynamic alteration and classify liver fibrosis stages. PMID:24376732

  9. A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels.

    PubMed

    Hosseinkhah, N; Hynynen, K

    2012-02-01

    Ultrasound contrast agents inside a microvessel, when driven by ultrasound, oscillate and induce mechanical stresses on the vessel wall. These mechanical stresses can produce beneficial therapeutic effects but also induce vessel rupture if the stresses are too high. Therefore, it is important to use sufficiently low pressure amplitudes to avoid rupturing the vessels while still inducing the desired therapeutic effects. In this work, we developed a comprehensive three-dimensional model of a confined microbubble inside a vessel while considering the bubble shell properties, blood viscosity, vessel wall curvature and the mechanical properties of the vessel wall. Two bubble models with the assumption of a spherical symmetric bubble and a simple asymmetrical bubble were simulated. This work was validated with previous experimental results and enabled us to evaluate the microbubbles' behaviour and the resulting mechanical stresses induced on the vessel walls. In this study, the fluid shear and circumferential stresses were evaluated as indicators of the mechanical stresses. The effects of acoustical parameters, vessel viscoelasticity and rigidity, vessel/bubble size and off-centre bubbles on bubble behaviour and stresses on the vessel were investigated. The fluid shear and circumferential stresses acting on the vessel varied with time and location. As the frequency changed, the microbubble oscillated with the highest amplitude at its resonance frequency which was different from the resonance frequency of an unbound bubble. The bubble resonance frequency increased as the rigidity of a flexible vessel increased. The fluid shear and circumferential stresses peaked at frequencies above the bubble's resonance frequency. The more rigid the vessels were, the more damped the bubble oscillations. The synergistic effect of acoustic frequency and vessel elasticity had also been investigated since the circumferential stress showed either an increasing trend or a decreasing one

  10. Characterization of the treefrog null allele, 1991

    SciTech Connect

    Guttman, S.I.

    1992-04-01

    Spring peeper (Hyla crucifer) tadpoles collected from the waste storage area during the Biological and Ecological Site Characterization of the Feed Materials Production Center (FEMP) in 1986 and 1987 appeared to be unique. A null (inactive) allele was found at the glucose phosphate isomerase enzyme locus in significant frequencies (approximately 20%) each year; this allele did not appear to occur in the offsite sample collected approximately 15km from the FEMP. Null alleles at this locus have not been reported in other amphibian populations; when they have been found in other organisms they have invariably been lethal in the homozygous condition.

  11. Characterization of the treefrog null allele

    SciTech Connect

    Guttman, S.I. . Dept. of Zoology)

    1990-12-01

    As part of the authors intensive year-long baseline ecological study, they characterized the degree of genetic polymorphism and heterozygosity in selected Feed Materials Production Center (FMPC) populations using electrophoretic techniques. These data are being used as an indicator of stress by comparing populations on and off the FMPC site. The current study was initiated to determine whether this GPI null allele is lethal, when homozygous, in spring peepers. Also, a sampling protocol was implemented to determine whether a linear effect occurs relative to the frequency of the null allele offsite and to determine the origination site of the null allele. 18 refs., 2 figs., 4 tabs.

  12. Comparative analysis of Vening-Meinesz Moritz isostatic models using the constant and variable crust-mantle density contrast - a case study of Zealandia

    NASA Astrophysics Data System (ADS)

    Bagherbandi, Mohammad; Tenzer, Robert

    2013-04-01

    We compare three different numerical schemes of treating the Moho density contrast in gravimetric inverse problems for finding the Moho depths. The results are validated using the global crustal model CRUST2.0, which is determined based purely on seismic data. Firstly, the gravimetric recovery of the Moho depths is realized by solving Moritz's generalization of the Vening-Meinesz inverse problem of isostasy while the constant Moho density contrast is adopted. The Pratt-Hayford isostatic model is then facilitated to estimate the variable Moho density contrast. This variable Moho density contrast is subsequently used to determine the Moho depths. Finally, the combined least-squares approach is applied to estimate jointly the Moho depths and density contract based on a priori error model. The EGM2008 global gravity model and the DTM2006.0 global topographic/bathymetric model are used to generate the isostatic gravity anomalies. The comparison of numerical results reveals that the optimal isostatic inverse scheme should take into consideration both the variable depth and density of compensation. This is achieved by applying the combined least-squares approach for a simultaneous estimation of both Moho parameters. We demonstrate that the result obtained using this method has the best agreement with the CRUST2.0 Moho depths. The numerical experiments are conducted at the regional study area of New Zealand's continental shelf.

  13. Efficient nonmeiotic allele introgression in livestock using custom endonucleases

    PubMed Central

    Tan, Wenfang; Carlson, Daniel F.; Lancto, Cheryl A.; Garbe, John R.; Webster, Dennis A.; Hackett, Perry B.; Fahrenkrug, Scott C.

    2013-01-01

    We have expanded the livestock gene editing toolbox to include transcription activator-like (TAL) effector nuclease (TALEN)- and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-stimulated homology-directed repair (HDR) using plasmid, rAAV, and oligonucleotide templates. Toward the genetic dehorning of dairy cattle, we introgressed a bovine POLLED allele into horned bull fibroblasts. Single nucleotide alterations or small indels were introduced into 14 additional genes in pig, goat, and cattle fibroblasts using TALEN mRNA and oligonucleotide transfection with efficiencies of 10–50% in populations. Several of the chosen edits mimic naturally occurring performance-enhancing or disease- resistance alleles, including alteration of single base pairs. Up to 70% of the fibroblast colonies propagated without selection harbored the intended edits, of which more than one-half were homozygous. Edited fibroblasts were used to generate pigs with knockout alleles in the DAZL and APC genes to model infertility and colon cancer. Our methods enable unprecedented meiosis-free intraspecific and interspecific introgression of select alleles in livestock for agricultural and biomedical applications. PMID:24014591

  14. Nucleotide variation and identification of novel blast resistance alleles of Pib by allele mining strategy.

    PubMed

    Ramkumar, G; Madhav, M S; Devi, S J S Rama; Prasad, M S; Babu, V Ravindra

    2015-04-01

    Pib is one of significant rice blast resistant genes, which provides resistance to wide range of isolates of rice blast pathogen, Magnaporthe oryzae. Identification and isolation of novel and beneficial alleles help in crop enhancement. Allele mining is one of the best strategies for dissecting the allelic variations at candidate gene and identification of novel alleles. Hence, in the present study, Pib was analyzed by allele mining strategy, and coding and non-coding (upstream and intron) regions were examined to identify novel Pib alleles. Allelic sequences comparison revealed that nucleotide polymorphisms at coding regions affected the amino acid sequences, while the polymorphism at upstream (non-coding) region affected the motifs arrangements. Pib alleles from resistant landraces, Sercher and Krengosa showed better resistance than Pib donor variety, might be due to acquired mutations, especially at LRR region. The evolutionary distance, Ka/Ks and phylogenetic analyzes also supported these results. Transcription factor binding motif analysis revealed that Pib (Sr) had a unique motif (DPBFCOREDCDC3), while five different motifs differentiated the resistance and susceptible Pib alleles. As the Pib is an inducible gene, the identified differential motifs helps to understand the Pib expression mechanism. The identified novel Pib resistant alleles, which showed high resistance to the rice blast, can be used directly in blast resistance breeding program as alternative Pib resistant sources.

  15. Accuracies and Contrasts of Models of the Diffusion-Weighted-Dependent Attenuation of the MRI Signal at Intermediate b-values

    PubMed Central

    Nicolas, Renaud; Sibon, Igor; Hiba, Bassem

    2015-01-01

    The diffusion-weighted-dependent attenuation of the MRI signal E(b) is extremely sensitive to microstructural features. The aim of this study was to determine which mathematical model of the E(b) signal most accurately describes it in the brain. The models compared were the monoexponential model, the stretched exponential model, the truncated cumulant expansion (TCE) model, the biexponential model, and the triexponential model. Acquisition was performed with nine b-values up to 2500 s/mm2 in 12 healthy volunteers. The goodness-of-fit was studied with F-tests and with the Akaike information criterion. Tissue contrasts were differentiated with a multiple comparison corrected nonparametric analysis of variance. F-test showed that the TCE model was better than the biexponential model in gray and white matter. Corrected Akaike information criterion showed that the TCE model has the best accuracy and produced the most reliable contrasts in white matter among all models studied. In conclusion, the TCE model was found to be the best model to infer the microstructural properties of brain tissue. PMID:26106263

  16. Inferring Selection Intensity and Allele Age from Multilocus Haplotype Structure

    PubMed Central

    Chen, Hua; Slatkin, Montgomery

    2013-01-01

    It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured-coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144−0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories. PMID:23797107

  17. Combined off-resonance imaging and T2 relaxation in the rotating frame for positive contrast MR imaging of infection in a murine burn model

    PubMed Central

    Andronesi, Ovidiu C.; Mintzopoulos, Dionyssios; Righi, Valeria; Psychogios, Nikolaos; Kesarwani, Meenu; He, Jianxin; Yasuhara, Shingo; Dai, George; Rahme, Laurence G.; Tzika, Aria A.

    2010-01-01

    Purpose To develop novel magnetic resonance (MR) imaging methods to monitor accumulation of macrophages in inflammation and infection. Positive-contrast MR imaging provides an alternative to negative-contrast MRI, exploiting the chemical shift induced by ultra-small superparamagnetic iron-oxide (USPIO) nanoparticles to nearby water molecules. We introduce a novel combination of off-resonance (ORI) positive-contrast MRI and T2ρ relaxation in the rotating frame (ORI-T2ρ) for positive-contrast MR imaging of USPIO. Materials and Methods We tested ORI-T2ρ in phantoms and imaged in vivo the accumulation of USPIO-labeled macrophages at the infection site in a mouse model of burn trauma and infection with Pseudomonas aeruginosa (PA). PA infection is clinically important. The USPIO nanoparticles were injected directly in the animals in solution, and macrophage labeling occurred in vivo in the animal model. Results We observed a significant difference between ORI-T2ρ and ORI, which leads us to suggest that ORI-T2ρ is more sensitive in detecting USPIO signal. To this end, the ORI-T2ρ positive contrast method may prove to be of higher utility in future research. Conclusion Our results may have direct implications in the longitudinal monitoring of infection, and open perspectives for testing novel anti-infective compounds. PMID:21031524

  18. KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

    NASA Astrophysics Data System (ADS)

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-03-01

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

  19. KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

    PubMed Central

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-01-01

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation. PMID:27030405

  20. Alternative 3' splice acceptor sites modulate enzymic activity in derivative alleles of the maize bronze1-mutable 13 allele.

    PubMed Central

    Okagaki, R J; Sullivan, T D; Schiefelbein, J W; Nelson, O E

    1992-01-01

    The defective Suppressor-mutator (dSpm)-induced allele bronze1-mutable 13 (bz1-m13) and many of its derivative alleles are leaky mutants with measurable levels of flavonol O3-glucosyltransferase activity. This activity results from splicing at acceptor site-1, one of two cryptic 3' splice sites within the dSpm insertion in bz1-m13. In this study, splicing in bz1-m13 change-in-state (CS) alleles CS-3 and CS-64 was shown to be altered from bz1-m13; previous work found altered splicing in CS-9. CS-64 is a null allele and lacks the acceptor site-1-spliced transcript because this site is deleted. CS-3 and CS-9 had increased levels of the acceptor site-1 transcript relative to bz1-m13 and increased enzymic activities. A deletion in CS-9 altered splicing by eliminating acceptor site-2. Both acceptor sites were intact in CS-3, but a deletion removed most of a 275-bp GC-rich sequence in dSpm. This suggests that GC-rich sequences affect splicing and is consistent with models postulating a role for AU content in the splicing of plant introns. Splicing does not necessarily occur, however, at the junction of AU-rich intron sequences and GC-rich exon sequences. PMID:1477558

  1. Allele Workbench: transcriptome pipeline and interactive graphics for allele-specific expression.

    PubMed

    Soderlund, Carol A; Nelson, William M; Goff, Stephen A

    2014-01-01

    Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele-specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA-Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele-specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele

  2. Abnormal segregation of alleles in CEPH pedigree DNAs arising from allele loss in lymphoblastoid DNA

    SciTech Connect

    Royle, N.J.; Armour, J.A.L.; Crosier, M.; Jeffreys, A.J. )

    1993-01-01

    Somatic events that result in the reduction to hemior homozygosity at all loci affected by the event have been identified in lymphoblastoid DNA from mothers of two CEPH families. Using suitably informative probes, the allele deficiencies were detected by the abnormal transmission of alleles from grandparents to grandchildren, with the apparent absence of the alleles from the parent. Undetected somatic deficiencies in family DNAs could result in misscoring of recombination events and consequently introduce errors into linkage analysis. 15 refs., 2 figs.

  3. Allele Workbench: Transcriptome Pipeline and Interactive Graphics for Allele-Specific Expression

    PubMed Central

    Soderlund, Carol A.; Nelson, William M.; Goff, Stephen A.

    2014-01-01

    Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele-specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA-Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele-specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele

  4. Evidence of Still-Ongoing Convergence Evolution of the Lactase Persistence T-13910 Alleles in Humans

    PubMed Central

    Enattah, Nabil Sabri ; Trudeau, Aimee ; Pimenoff, Ville ; Maiuri, Luigi ; Auricchio, Salvatore ; Greco, Luigi ; Rossi, Mauro ; Lentze, Michael ; Seo, J. K. ; Rahgozar, Soheila ; Khalil, Insaf ; Alifrangis, Michael ; Natah, Sirajedin ; Groop, Leif ; Shaat, Nael ; Kozlov, Andrew ; Verschubskaya, Galina ; Comas, David ; Bulayeva, Kazima ; Mehdi, S. Qasim ; Terwilliger, Joseph D. ; Sahi, Timo ; Savilahti, Erkki ; Perola, Markus ; Sajantila, Antti ; Järvelä, Irma ; Peltonen, Leena 

    2007-01-01

    A single-nucleotide variant, C/T-13910, located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T-13910 variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8–H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T-13910 H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T-13910 H98 allele (∼5,000–12,000 years old) is relatively older than the other geographically restricted LP alleles (∼1,400–3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T-13910 allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans. PMID:17701907

  5. Practical Dynamic Contrast Enhanced MRI in Small Animal Models of Cancer: Data Acquisition, Data Analysis, and Interpretation

    PubMed Central

    Barnes, Stephanie L.; Whisenant, Jennifer G.; Loveless, Mary E.; Yankeelov, Thomas E.

    2012-01-01

    Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) consists of the continuous acquisition of images before, during, and after the injection of a contrast agent. DCE-MRI allows for noninvasive evaluation of tumor parameters related to vascular perfusion and permeability and tissue volume fractions, and is frequently employed in both preclinical and clinical investigations. However, the experimental and analytical subtleties of the technique are not frequently discussed in the literature, nor are its relationships to other commonly used quantitative imaging techniques. This review aims to provide practical information on the development, implementation, and validation of a DCE-MRI study in the context of a preclinical study (though we do frequently refer to clinical studies that are related to these topics). PMID:23105959

  6. Diversity of HLA-B17 alleles and haplotypes in East Asians and a novel Cw6 allele (Cw*0604) associated with B*5701.

    PubMed

    Inoue, T; Ogawa, A; Tokunaga, K; Ishikawa, Y; Kashiwase, K; Tanaka, H; Park, M H; Jia, G J; Chimge, N O; Sideltseva, E W; Akaza, T; Tadokoro, K; Takahashi, T; Juji, T

    1999-06-01

    The distribution of HLA-B17 alleles and their association with HLA-A, -C and -DRB1 alleles were investigated in seven East Asian populations Japanese, South Korean, Chinese-Korean, Man, Northern Han, Mongolian and Buryat populations). The B17 alleles were identified from genomic DNA using group-specific polymerase chain reaction (PCR) followed by hybridization with sequence-specific oligonucleotide probes (SSOP). In all of these East Asian populations, except Japanese and Chinese-Koreans, B*5701 was detected and strongly associated with A*0101, Cw*0602 and DRB1*0701. In contrast, B*5801 was detected in all the seven populations and strongly associated with A*3303, Cw*0302, DRB1*0301 and DRB1*1302. The A*3303-Cw*0302-B*5801-DRB1*1302 haplotype was observed in South Korean, Chinese-Korean, Buryat and Japanese populations, while A*3303-Cw*0302-B*5801-DRB1*0301 was predominantly observed in the Mongolian population. A similar haplotype, A*0101-Cw*0302-B*5801-DRB1*1302, was observed in the Buryat population. A novel Cw6 allele, Cw*0604, was identified in the Man population. This Cw allele was observed on the haplotype A*0101-B*5701-DRB1*0701. Thus, we confirmed, at the sequence level, that the common haplotypes carrying B*5701 and B*5801 have been conserved and shared in East Asian populations.

  7. Distribution of repeat unit differences between alleles at tandem repeat microsatellite loci

    SciTech Connect

    Jin, L. |; Zhong, Y.; Chakraborty, R.

    1994-09-01

    PCR-based assays of tandemly repeated microsatellite loci detect genetic variation from which alleles may be scored by their repeat unit lengths. Comparison of allele sizes from such data yields a probability distribution (P{sub k}) of repeat unit differences (k) between alleles segregating in a population. We show that this distribution (P{sub k}; k = 0, 1,2,...) provides insight regarding the mechanism of production of new alleles at such loci and the demographic history of populations, far better than that obtained from other summary measures (e.g., heterozygosity, number of alleles, and the range of allele sizes). The distributions of P{sub k} under multi-step stepwise models of mutation are analytically derived, which show that when a population is at equilibrium under the mutation-drift balance, the distribution of repeat unit differences between alleles is positively skewed with a mode larger than zero. However, when the heterozygosity at a locus is low (say, less than 40%), P{sub k} is a monotonically decreasing function of k. Applications of this theory to data on repeat unit sizes at over 1,240 microsatellite loci from the Caucasians, categorized by the average heterozygosity of loci, indicate that at most microsatellite loci new alleles are produced by stepwise mutations, and this is consistent with the replication slippage mechanism of mutations. The repeat size changes of mutants are probably within one or two units of alleles from which the mutants arise. Distributions of P{sub k} at microsatellite loci located within genes show evidence of allele size constraints. No significant evidence of recent expansion of population sizes in the Caucasians is detected by the distribution of P{sub k}.

  8. Negative contrast Cerenkov luminescence imaging of blood vessels in a tumor mouse model using [68Ga]gallium chloride

    PubMed Central

    2014-01-01

    Background Cerenkov luminescence imaging (CLI) is an emerging imaging technique where visible light emitted from injected beta-emitting radionuclides is detected with an optical imaging device. CLI research has mostly been focused on positive contrast imaging for ascertaining the distribution of the radiotracer in a way similar to other nuclear medicine techniques. Rather than using the conventional technique of measuring radiotracer distribution, we present a new approach of negative contrast imaging, where blood vessel attenuation of Cerenkov light emitted by [68Ga]GaCl3 is used to image vasculature. Methods BALB/c nude mice were injected subcutaneously in the right flank with HT-1080 fibrosarcoma cells 14 to 21 days prior to imaging. On the imaging day, [68Ga]GaCl3 was injected and the mice were imaged from 45 to 90 min after injection using an IVIS Spectrum in vivo imaging system. The mice were imaged one at a time, and manual focus was used to bring the skin into focus. The smallest view with pixel size around 83 μm was used to achieve a sufficiently high image resolution for blood vessel imaging. Results The blood vessels in the tumor were clearly visible, attenuating 7% to 18% of the light. Non-tumor side blood vessels had significantly reduced attenuation of 2% to 4%. The difference between the attenuation of light of tumor vessels (10% ± 4%) and the non-tumor vessels (3% ± 1%) was significant. Moreover, a necrotic core confirmed by histology was clearly visible in one of the tumors with a 21% reduction in radiance. Conclusions The negative contrast CLI technique is capable of imaging vasculature using [68Ga]GaCl3. Since blood vessels smaller than 50 μm in diameter could be imaged, CLI is able to image structures that conventional nuclear medicine techniques cannot. Thus, the negative contrast imaging technique shows the feasibility of using CLI to perform angiography on superficial blood vessels, demonstrating an advantage over conventional

  9. Synthesis and characterization of a porphyrazine–Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model

    PubMed Central

    Trivedi, Evan R.; Ma, Zhidong; Waters, Emily A.; Macrenaris, Keith W.; Subramanian, Rohit; Barrettf, Anthony G. M.; Meade, Thomas J.; Hoffman, Brian M.

    2015-01-01

    Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu–Pz–Gd(III) conjugate has been prepared via azide-alkyne Huisgen cycloaddition or ‘click’ chemistry between an azide functionalized Pz and alkyne functionalized DOTA–Gd(III) analog for use as an MRI contrast agent. This agent, Cu–Pz–Gd(III), is synthesized in good yield and exhibits solution-phase ionic relaxivity (r1 = 11.5 mm−1 s−1) that is approximately four times higher than that of a clinically used monomeric Gd (III) contrast agent, DOTA–Gd(III). Breast tumor cells (MDA-MB-231) associate with Cu–Pz–Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast-to-noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T1 of tumor regions in mice treated with 50 mg kg−1 Cu–Pz–Gd (III) decreased relative to saline-treated controls. Furthermore, the decrease in T1 was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu–Pz–Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T1 enhancement by Cu–Pz–Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue. PMID:24706615

  10. Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles.

    PubMed

    Van Neste, Christophe; Van Criekinge, Wim; Deforce, Dieter; Van Nieuwerburgh, Filip

    2016-01-01

    It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://forensic.ugent.be/FLAD/. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://forensic.ugent.be/FLAD/ and add loci and allele sequences with a short and simple application interface (API).

  11. Three allele combinations associated with Multiple Sclerosis

    PubMed Central

    Favorova, Olga O; Favorov, Alexander V; Boiko, Alexey N; Andreewski, Timofey V; Sudomoina, Marina A; Alekseenkov, Alexey D; Kulakova, Olga G; Gusev, Eugenyi I; Parmigiani, Giovanni; Ochs, Michael F

    2006-01-01

    Background Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS. Methods 286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFβ1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group. Results We identified two previously unknown MS-associated tri-allelic combinations: -509TGFβ1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Δ32, DRB1*04 were also reidentified as MS-associated. Conclusion These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles. PMID:16872485

  12. Feasibility Study of Myocardial Perfusion and Oxygenation by Non-Contrast MRI: Comparison with PET Study in a Canine Model

    PubMed Central

    McCommis, Kyle S.; Zhang, Haosen; Herrero, Pilar; Gropler, Robert J.; Zheng, Jie

    2008-01-01

    The purpose of this study was to examine the feasibility of quantifying myocardial blood flow (MBF) and rate of myocardial oxygen consumption (MVO2) during pharmacologically induced stress without using a contrast agent. The former was measured by the arterial spin labeling (ASL) method and the later was obtained by measuring the oxygen extraction fraction (OEF) with the magnetic resonance imaging (MRI) blood oxygenation level-dependent (BOLD) effect and Fick's law. The MRI results were compared with the established positron emission tomography (PET) methods. Six mongrel dogs with induced acute moderate left coronary artery stenosis were scanned using a clinical PET and a 1.5T MRI system, in the same day. Regional MBF, myocardial OEF, and MVO2 were measured with both imaging modalities. Correlation coefficients (R2) of the three myocardial indexes (MBF, OEF, and MVO2) between MRI and PET methods ranged from 0.70 to 0.93. Bland-Altman statistics demonstrated that the estimated precision of the limits of agreement between MRI and PET measurements varied from 18% (OEF), to 37% (MBF), and 45% (MVO2). The detected changes in these indexes, at rest and during dobutamine stress, were similar between two image modalities. The proposed non-contrast MRI technique is a promising method to quantitatively assess myocardial perfusion and oxygenation. PMID:17566684

  13. A Reference Agent Model for DCE MRI can be used to quantify the relative vascular permeability of two MRI contrast agents

    PubMed Central

    Cárdenas-Rodríguez, Julio; Howison, Christine M.; Matsunaga, Terry O.; Pagel, Mark D.

    2013-01-01

    Dynamic Contrast Enhancement (DCE) MRI has been used to measure the kinetic transport constant, Ktrans, which is used to assess tumor angiogenesis and the effects of anti-angiogenic therapies. Standard DCE MRI methods must measure the pharmacokinetics of a contrast agent in the blood stream, known as the Arterial Input Function (AIF), which is then used as a reference for the pharmacokinetics of the agent in tumor tissue. However, the AIF is difficult to measure in pre-clinical tumor models and in patients. Moreover the AIF is dependent on the Fahraeus effect that causes a highly variable hematocrit (Hct) in tumor microvasculature, leading to erroneous estimates of Ktrans. To overcome these problems, we have developed the Reference Agent Model (RAM) for DCE MRI analyses, which determines the ratio of Ktrans values of two contrast agents that are simultaneously co-injected and detected during a single DCE-MRI scan session. The RAM obviates the need to monitor the AIF because one contrast agent effectively serves as an internal reference in the tumor tissue for the other agent, and it also eliminates the systematic errors in the estimated Ktrans caused by assuming an erroneous Hct. Simulations demonstrated that the RAM can accurately and precisely estimate the relative Ktrans (RKtrans) of two agents. To experimentally evaluate the utility of RAM for analyzing DCE MRI results, we optimized a previously reported multiecho 19F MRI method to detect two perfluorocarbon contrast agents that were co-injected during a single in vivo study and selectively detected in the same tumor location. The results demonstrated that RAM determined RKtrans with excellent accuracy and precision. PMID:23583323

  14. Association of the HLA-B*52 allele with non-progression to AIDS in Brazilian HIV-1-infected individuals.

    PubMed

    Teixeira, S L M; de Sá, N B R; Campos, D P; Coelho, A B; Guimarães, M L; Leite, T C N F; Veloso, V G; Morgado, M G

    2014-04-01

    Several human leukocyte antigen (HLA) class I alleles are associated with the susceptibility to human immunodeficiency virus-1 (HIV-1) infection and/or AIDS progression. Of these, the HLA-B alleles are considered the strongest genetic determinant of disease outcome. We evaluated the influence of the HLA-B alleles on AIDS progression among HIV-1-positive individuals from Rio de Janeiro, Brazil, who were categorized as rapid progressors (RPs), typical progressors (TPs) or long-term non-progressors (LTNPs). In this study, significant differences in HLA-B allele frequencies were observed among the three progression groups for the B*48, B*49 and B*52 alleles. After controlling for other factors associated with AIDS progression, the presence of the B*52 allele was shown to be a significant protective factor (hazard ratio (HR) 0.49 (95% confidence interval (CI) 0.27-0.90) P<0.03). Although no direct association was observed between the presence of the B*27 or B*57 allele and the LTNP profile compared with the TP or RP groups, the adjusted model confirmed that these alleles are protective factors against AIDS progression (HR 0.62 (95% CI 0.38-0.99) P<0.05), as previously described. These data corroborate the existence of significant differences in HLA-B allele frequencies among the distinct AIDS progression profiles and further elucidate the role of HLA alleles in the outcome of HIV infections in diverse populations.

  15. Perceived contrast in complex images

    PubMed Central

    Haun, Andrew M.; Peli, Eli

    2013-01-01

    To understand how different spatial frequencies contribute to the overall perceived contrast of complex, broadband photographic images, we adapted the classification image paradigm. Using natural images as stimuli, we randomly varied relative contrast amplitude at different spatial frequencies and had human subjects determine which images had higher contrast. Then, we determined how the random variations corresponded with the human judgments. We found that the overall contrast of an image is disproportionately determined by how much contrast is between 1 and 6 c/°, around the peak of the contrast sensitivity function (CSF). We then employed the basic components of contrast psychophysics modeling to show that the CSF alone is not enough to account for our results and that an increase in gain control strength toward low spatial frequencies is necessary. One important consequence of this is that contrast constancy, the apparent independence of suprathreshold perceived contrast and spatial frequency, will not hold during viewing of natural images. We also found that images with darker low-luminance regions tended to be judged as having higher overall contrast, which we interpret as the consequence of darker local backgrounds resulting in higher band-limited contrast response in the visual system. PMID:24190908

  16. Modelling the density contrast and depth of the Moho discontinuity by seismic and gravimetric-isostatic methods with an application to Africa

    NASA Astrophysics Data System (ADS)

    Bagherbandi, Mohammad; Sjöberg, Lars E.

    2012-06-01

    The crustal thickness (Moho depth) is of interest in several geosciences applications, such as geography, geophysics and geodesy. Usually the crustal depth and density variations are estimated by seismic survey data. As such data collection is very time-consuming and expensive an attractive option could be to use a gravimetric/isostatic model. In this case, realistic estimates for the crustal density and Moho density contrast (MDC) are important. In this study, we first use the seismic crustal thickness of CRUST2.0 model as a known parameter in combination with gravimetric data in estimating the crust-mantle density contrast by the isostatic model of Vening Meinesz-Moritz. We present different models to estimate the MDC and its impact on the modelling of the gravimetric-isostatic Moho depth. The theory is applied to estimate the Moho depth of the African continental crust by using different models for the MDC: (a) constant value (0.6 g/cm3), (b) Pratt-Hayford's model, (c) CRUST2.0 as input to three gravimetric/isostatic models based on Vening Meinesz-Moritz theory. The isostatic models agree by 5.8-7.1 km in the rms with the regional seismic model at a resolution of 2° × 2°, and the smallest rms difference at a resolution of 1° × 1° is of 7.2 km. For comparison, the rms differences of CRUST2.0 and the regional seismic model are 8.8 and 9.1 km at the resolutions of 2° (interpolated) and 1°, respectively. The result suggests that the gravimetric/isostatic Moho model can be used in densification of the CRUST2.0 Moho geometry, and to improve it in areas with poor data.

  17. Conditional Allele Mouse Planner (CAMP): software to facilitate the planning and design of breeding strategies involving mice with conditional alleles.

    PubMed

    Hoffert, Jason D; Pisitkun, Trairak; Miller, R Lance

    2012-06-01

    Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially in the last 5-10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and the number of breeding rounds. Therefore, a well planned breeding strategy is critical for keeping costs to a minimum. However, designing a viable breeding strategy can be challenging. With so many different variables this would be an ideal task for a computer program. To facilitate this process, we created a Java-based program called Conditional Allele Mouse Planner (CAMP). CAMP is designed to provide an estimate of the number of breeders, amount of time, and costs associated with generating mice of a particular genotype. We provide a description of CAMP, how to use it, and offer it freely as an application.

  18. Stable microsatellite length but frequent allele loss in SV40-immortalized Werner syndrome and control cell lines

    SciTech Connect

    Brokks-Wilson, A.R.; Monnat, R.J. Jr.

    1994-09-01

    We have determined the mitotic stability of microsatellite alleles and allele lengths in SV40-immortalized Werner syndrome (WS) and control cell lines. The impetus for this work was presence of a mutator phenotype in WS cells and cell lines and the association between a DNA mismatch repair deficit and microsatellite length instability in a heritable human tumor syndrome. Thus the identification of microsatellite length instability in WS cells might provide a clue to the primary biochemical defect in WS and a partial explanation for the mutator phenotype and the elevated cancer risk of WS patients. Five microsatellite loci (D2S123, D10S197, D10S141, D8S255, and D8S87) were PCR genotyped in 88 independent clones derived from four SV40-immortalized fibroblast cell lines (two WS lines: WV1 and PSV811; and two control lines: GM637 and GM639). Stable allele lengths were transmitted from cell line to clones in every case. WS cell line WV1 contained a preexisting faint third D2S123 allele which was transmitted with the other two D2S123 alleles to a majority of WV1 clones. In contrast, microsatellite allele loss was common: complete absence of one of two alleles was seen in 30% of control and in 3% of WS clones. Complete allele loss likely results from a clonal population being derived from a cell lacking a microsatellite allele. Altered relative band intensities in clones compared to parental lines were very common in both WS and control backgrounds (40% of all clones). This suggests that allele loss is common and continues upon post-cloning cell culture. These allele losses are likely to be a consequence of the genetic instability that accompanies SV40 immortalization. These results indicate that SV40-immortalized cell lines are genetically heterogeneous, and that the genotypes of individual clones may incompletely represent the genomes of the primary cells from which they were derived.

  19. A Two-Criterion Model for Microvascular Bio-Effects Induced In Vivo by Contrast Microbubbles Exposed to Medical Ultrasound.

    PubMed

    Church, Charles C; Miller, Douglas L

    2016-06-01

    The mechanical index (MI) is a theoretical exposure parameter for cavitational bio-effects of diagnostic ultrasound. The theory for the MI assumed that bubbles of all relevant sizes exist in tissue, a condition that is approximated for tissues that include a microbubble contrast agent. Therefore, the MI should allow science-based safety guidance for contrast-enhanced diagnostic ultrasound. However, theoretical predictions of bio-effects thresholds based on the MI typically do not concur with the frequency dependence of experimentally measured thresholds for bio-effects. For example, experimental thresholds for glomerular capillary hemorrhage in rats infused with contrast microbubbles increased approximately linearly with frequency, whereas the MI predicted a square root dependence. Here, cavitation thresholds were computed for linear versions of the acoustic pulses used in that study assuming bubbles containing either air, C3F8, or a 1:1 mixture of the two and surrounded by either blood or kidney tissue. Although no single threshold criterion was successful, combining results for one criterion that maximized circumferential stress in the capillary wall with another that ensured an inertial collapse produced thresholds that were consistent with experimental data. This suggests that a contrast-specific safety metric may be achieved following validation of this two-criterion model. PMID:27033330

  20. A "successful allele" at Campylobacter jejuni contingency locus Cj0170 regulates motility; "successful alleles" at locus Cj0045 are strongly associated with mouse colonization.

    PubMed

    Artymovich, Katherine; Kim, Joo-Sung; Linz, John E; Hall, David F; Kelley, Lauren E; Kalbach, Harrison L; Kathariou, Sophia; Gaymer, Jean; Paschke, Brenda

    2013-06-01

    Campylobacter jejuni is an important foodborne pathogen of humans and its primary reservoir is the gastrointestinal (GI) tract of chickens. Our previous studies demonstrated that phase variation to specific "successful alleles" at C. jejuni contingency loci Cj0045 (successful alleles carry 9G or 10G homopolymeric tracts) and Cj0170 (successful allele carries a 10G homopolymeric tract) in C. jejuni populations is strongly associated with colonization and enteritis in C57BL/6 IL-10 deficient mice. In the current study, we strengthened the association between locus Cj0170, Cj0045, and mouse colonization. We generated 8 independent strains derived from C. jejuni 11168 strain KanR4 that carried a Cj0170 gene disruption and these were all non motile. Two randomly chosen strains with the Cj0170 gene disruption (DM0170-2 and DM0170-6) were gavaged into mice. DM0170-2 and DM0170-6 failed to colonize mice while the control strain that carried a "successful"Cj0170 10G allele was motile and did colonize mice. In parallel studies, when we inoculated C. jejuni strain 33292 into mice, the "unsuccessful"Cj0045 11G allele experienced phase variation to "successful" 9G and 10G alleles in 2 independent experiments prior to d4 post inoculation in mice while the "successful" 9G allele in the control strain remained stable through d21 post inoculation or shifted to other successful alleles. These data confirm that locus Cj0170 regulates motility in C. jejuni strain KanR4 and is a virulence factor in the mouse model. The data also support a possible role of locus Cj0045 as a virulence factor in strain 33292 in infection of mice.

  1. Magnetization transfer contrast imaging detects early white matter changes in the APP/PS1 amyloidosis mouse model.

    PubMed

    Praet, Jelle; Bigot, Christian; Orije, Jasmien; Naeyaert, Maarten; Shah, Disha; Mai, Zhenhua; Guns, Pieter-Jan; Van der Linden, Annemie; Verhoye, Marleen

    While no definitive cure for Alzheimer's disease exists yet, currently available treatments would benefit greatly from an earlier diagnosis. It has previously been shown that Magnetization transfer contrast (MTC) imaging is able to detect amyloid β plaques in old APP/PS1 mice. In the current study we investigated if MTC is also able to visualize early amyloid β (Aβ) induced pathological changes. In a cross-sectional study, a comparison was made between the MT ratio of wild type (WT) and APP/PS1 mice at 2, 4, 6, 8 and 24 months of age. We observed an increased MT-ratio in the cortex of 24 month old APP/PS1 mice as compared to WT mice. However, when comparing the MT-ratio of the cortex of WT mice with the MT-ratio of the APP/PS1 mice at 2, 4, 6 or 8 months of age, no significant changes could be observed. In contrast to the cortex, we consistently observed a decreased MT-ratio in the splenium of 4, 6 and 8 month old APP/PS1 mice as compared to age-matched WT mice. Lastly, the decreased MT-ratio in the splenium of APP/PS1 mice correlated to the Aβ plaque deposition, astrogliosis and microgliosis. This MT-ratio decrease did however not correlate to the myelin content. Combined, our results suggest that MTC is able to visualize early Aβ-induced changes in the splenium but not the cortex of APP/PS1 mice.

  2. An automated serial Grinding, Imaging and Reconstruction Instrument (GIRI) for digital modeling of samples with weak density contrasts

    NASA Astrophysics Data System (ADS)

    Maloof, A. C.; Samuels, B.; Mehra, A.; Spatzier, A.

    2013-12-01

    We present the first results from the new Princeton University Grinder Lab dedicated to the digital reconstruction of hidden objects through serial grinding and imaging. The purpose of a destructive technique like serial grinding is to facilitate the discovery of embedded objects with weak density contrasts outside the sensitivity limits of X-ray CT-scanning devices (Feature segmentation and object reconstruction are based on color and textural contrasts in the stack of images rather than density). The device we have developed is a retrofit imaging station designed for a precision CNC surface. The instrument is capable of processing a sample 20x25x40 cm in size at 1 micron resolution in x, y and z axes. Directly coupled to the vertical axis of the grinder is an 80 megapixel medium format camera and specialty macro lens capable of imaging a 4x5 cm surface at 5 micron resolution in full 16 bit color. The system is automated such that after each surface grind, the sample is cleaned, travels to the opposite end of the bed from the grinder wheel, is photographed, and then moved back to the grinding position. This process establishes a comprehensive archive of the specimen that is used for digital reconstruction and quantitative analysis. For example, in one night, a 7 cm thick sample can be imaged completely at 20 micron horizontal and vertical resolution without human supervision. Some of the initial results we present here include new digital reconstructions of early animal fossils, 3D sedimentary bedforms, the size and shape distribution of chondrules in chondritic meteorites, and the porosity structure of carbonate cemented reservoir rocks.

  3. The Joint Allele-Frequency Spectrum in Closely Related Species

    PubMed Central

    Chen, Hua; Green, Richard E.; Pääbo, Svante; Slatkin, Montgomery

    2007-01-01

    We develop the theory for computing the joint frequency spectra of alleles in two closely related species. We allow for arbitrary population growth in both species after they had a common ancestor. We focus on the case in which a single chromosome is sequenced from one of the species. We use classical diffusion theory to show that, if the ancestral species was at equilibrium under mutation and drift and a chromosome from one of the descendant species carries the derived allele, the frequency spectrum in the other species is uniform, independently of the demographic history of both species. We also predict the expected densities of segregating and fixed sites when the chromosome from the other species carries the ancestral allele. We compare the predictions of our model with the site-frequency spectra of SNPs in the four HapMap populations of humans when the nucleotide present in the Neanderthal DNA sequence is ancestral or derived, using the chimp genome as the outgroup. PMID:17603120

  4. Comparing and contrasting 2D versus 1D performance modeling in NV-IPM v1.6

    NASA Astrophysics Data System (ADS)

    Hixson, Jonathan G.; Teaney, Brian P.

    2016-05-01

    Version 1.6 of the Night Vision Integrated Performance Model (NV-IPM) introduced two-dimensional Modulation Transfer Function (MTF) and noise signals within the model architecture. These two-dimensional signals enable the model to more accurately treat systems with non-separable MTF components. These non-separable MTF components may be introduced by optical elements, electronic post-processing, or atmospheric effects. In this paper we discuss the differences between the new two-dimensional signal architecture and the one-dimensional separable representation used in earlier versions of the model and highlight some cases which demonstrate the utility of the two-dimensional signals.

  5. Quantifying the transcriptional output of single alleles in single living mammalian cells

    PubMed Central

    Yunger, Sharon; Rosenfeld, Liat; Garini, Yuval; Shav-Tal, Yaron

    2013-01-01

    Transcription kinetics of actively transcribing genes in vivo have generally been measured using tandem gene arrays. However, tandem arrays do not reflect the endogenous state of genome organization where genes appear as single alleles. We present here a robust technique for the quantification of mRNA synthesis from a single allele in real-time, in single living mammalian cells. The protocol describes how to generate cell clones harboring a tagged allele and how to detect in vivo transcription from this tagged allele at high spatial and temporal resolution throughout the cell cycle. Quantification of nascent mRNAs produced from the single tagged allele is performed using RNA fluorescence in situ hybridization (FISH) and live-cell imaging. Subsequent analyses and data modeling detailed in the protocol include measurements of: transcription rates of RNA polymerase II; determining the number of polymerases recruited to the tagged allele; and measuring the spacing between polymerases. Generating the cells containing the single tagged alleles should take up to a month; RNA FISH or live-cell imaging will require an additional week. PMID:23424748

  6. Molecular characterization of the new defective P(brescia) alpha1-antitrypsin allele.

    PubMed

    Medicina, Daniela; Montani, Nadia; Fra, Anna M; Tiberio, Laura; Corda, Luciano; Miranda, Elena; Pezzini, Alessandro; Bonetti, Fausta; Ingrassia, Rosaria; Scabini, Roberta; Facchetti, Fabio; Schiaffonati, Luisa

    2009-08-01

    Alpha1-antitrypsin (alpha(1)AT) deficiency is a hereditary disorder associated with reduced alpha(1)AT serum level, predisposing adults to pulmonary emphysema. Among the known mutations of the alpha(1)AT gene (SERPINA1) causing alpha(1)AT deficiency, a few alleles, particularly the Z allele, may also predispose adults to liver disease. We have characterized a new defective alpha(1)AT allele (c.745G>C) coding for a mutant alpha(1)AT (Gly225Arg), named P(brescia). The P(brescia) alpha(1)AT allele was first identified in combination with the rare defective M(würzburg) allele in an 11-year-old boy showing significantly reduced serum alpha(1)AT level. Subsequently, the P(brescia) allele was found in the heterozygous state with the normal M or the defective Z allele in nine and three adults respectively. In cellular models of the disease, we show that the P(brescia) mutant is retained in the endoplasmic reticulum as ordered polymers and is secreted more slowly than the normal M alpha(1)AT. This behaviour recapitulates the abnormal cellular handling and fate of the Z alpha(1)AT and suggests that the mutation present in the P(brescia) alpha(1)AT causes a conformational change of the protein which, by favouring polymer formation, is etiologic to both severe alpha(1)AT deficiency in the plasma and toxic protein-overload in the liver.

  7. Success and failure in teaching the [r]-[l] contrast to Japanese adults: tests of a Hebbian model of plasticity and stabilization in spoken language perception.

    PubMed

    McCandliss, Bruce D; Fiez, Julie A; Protopapas, Athanassios; Conway, Mary; McClelland, James L

    2002-06-01

    A Hebbian model of learning predicts that adults may be able to acquire a nonnative speech contrast if they are trained with stimuli that are exaggerated to make them perceptually distinct. To test these ideas, we asked Japanese adults to identify contrasting [r]-[l] stimuli (e.g., rock-lock) in two training conditions. In the adaptive condition, the [r]-[l] contrast was exaggerated at first and then adjusted to maintain accurate identification. In the fixed condition, a fixed pair of stimuli were used that were distinguishable by native English speakers but difficult for the Japanese learners to discriminate. To examine whether feedback contributes to learning, we ran separate groups with and without feedback in the fixed and the adaptive conditions. Without feedback, 3 days of adaptive training produced substantial improvements, but 3 days of fixed training produced no benefit relative to control, consistent with the Hebbian account. With feedback, both fixed and adaptive training led to robust improvements, and the benefit of training transferred to a second continuum (e.g., road-load). The results are consistent with Hebbian models that are augmented to be sensitive to feedback.

  8. Multiple origins of Plasmodium falciparum dihydropteroate synthetase mutant alleles associated with sulfadoxine resistance in India.

    PubMed

    Lumb, Vanshika; Das, Manoj K; Singh, Neeru; Dev, Vas; Khan, Wajihullah; Sharma, Yagya D

    2011-06-01

    With the spread of chloroquine (CQ)-resistant malaria in India, sulfadoxine-pyrimethamine (SP) alone or in combination with artesunate is used as an alternative antimalarial drug. Due to continuous drug pressure, the Plasmodium falciparum parasite is exhibiting resistance to antifolates because of mutations in candidate genes dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps). Our earlier study on flanking microsatellite markers of dhfr mutant alleles from India had shown a single origin of the pyrimethamine resistance and some minor haplotypes which shared haplotypes with Southeast Asian (Thailand) strains. In the present study, we have analyzed 193 of these Indian P. falciparum isolates for 15 microsatellite loci around dhps to investigate the genetic lineages of the mutant dhps alleles in different parts of the country. Eighty-one of these samples had mutant dhps alleles, of which 62 were from Andaman and Nicobar Islands and the remaining 19 were from mainland India. Of 112 isolates with a wild-type dhps allele, 109 were from mainland India and only 3 were from Andaman and Nicobar Islands. Consistent with the model of selection, the mean expected heterozygosity (H(e)) around mutant dhps alleles (H(e) = 0.55; n = 81) associated with sulfadoxine resistance was lower (P ≤ 0.05) than the mean H(e) around the wild-type dhps allele (H(e) = 0.80; n = 112). There was more genetic diversity in flanking microsatellites of dhps than dhfr among these isolates, which confirms the assertion that dhps mutations are at a very early stage of fixation in the parasite population. Microsatellite haplotypes around various mutant dhps alleles suggest that the resistant dhps alleles have multiple independent origins in India, especially in Andaman and Nicobar Islands. Determining the genetic lineages of the resistant dhps alleles on Andaman and Nicobar Islands and mainland India is significant, given the role of Asia in the intercontinental spread of chloroquine

  9. Assessment of a model of forest dynamics under contrasting climate and disturbance regimes in the Pacific Northwest [FORCLIM

    USGS Publications Warehouse

    Busing, Richard T.; Solomon, Allen M.

    2005-01-01

    An individual-based model of forest dynamics (FORCLIM) was tested for its ability to simulate forest composition and structure in the Pacific Northwest region of North America. Simulation results across gradients of climate and disturbance were compared to forest survey data from several vegetation zones in western Oregon. Modelled patterns of tree species composition, total basal area and stand height across climate gradients matched those in the forest survey data. However, the density of small stems (<50 cm DBH) was underestimated by the model. Thus actual size-class structure and other density-based parameters of stand structure were not simulated with high accuracy. The addition of partial-stand disturbances at moderate frequencies (<0.01 yr-1) often improved agreement between simulated and actual results. Strengths and weaknesses of the FORCLIM model in simulating forest dynamics and structure in the Pacific Northwest are discussed.

  10. The number of alleles at a microsatellite defines the allele frequency spectrum and facilitates fast accurate estimation of theta.

    PubMed

    Haasl, Ryan J; Payseur, Bret A

    2010-12-01

    Theoretical work focused on microsatellite variation has produced a number of important results, including the expected distribution of repeat sizes and the expected squared difference in repeat size between two randomly selected samples. However, closed-form expressions for the sampling distribution and frequency spectrum of microsatellite variation have not been identified. Here, we use coalescent simulations of the stepwise mutation model to develop gamma and exponential approximations of the microsatellite allele frequency spectrum, a distribution central to the description of microsatellite variation across the genome. For both approximations, the parameter of biological relevance is the number of alleles at a locus, which we express as a function of θ, the population-scaled mutation rate, based on simulated data. Discovered relationships between θ, the number of alleles, and the frequency spectrum support the development of three new estimators of microsatellite θ. The three estimators exhibit roughly similar mean squared errors (MSEs) and all are biased. However, across a broad range of sample sizes and θ values, the MSEs of these estimators are frequently lower than all other estimators tested. The new estimators are also reasonably robust to mutation that includes step sizes greater than one. Finally, our approximation to the microsatellite allele frequency spectrum provides a null distribution of microsatellite variation. In this context, a preliminary analysis of the effects of demographic change on the frequency spectrum is performed. We suggest that simulations of the microsatellite frequency spectrum under evolutionary scenarios of interest may guide investigators to the use of relevant and sometimes novel summary statistics.

  11. Poor transferability of species distribution models for a pelagic predator, the grey petrel, indicates contrasting habitat preferences across ocean basins.

    PubMed

    Torres, Leigh G; Sutton, Philip J H; Thompson, David R; Delord, Karine; Weimerskirch, Henri; Sagar, Paul M; Sommer, Erica; Dilley, Ben J; Ryan, Peter G; Phillips, Richard A

    2015-01-01

    Species distribution models (SDMs) are increasingly applied in conservation management to predict suitable habitat for poorly known populations. High predictive performance of SDMs is evident in validations performed within the model calibration area (interpolation), but few studies have assessed SDM transferability to novel areas (extrapolation), particularly across large spatial scales or pelagic ecosystems. We performed rigorous SDM validation tests on distribution data from three populations of a long-ranging marine predator, the grey petrel Procellaria cinerea, to assess model transferability across the Southern Hemisphere (25-65°S). Oceanographic data were combined with tracks of grey petrels from two remote sub-Antarctic islands (Antipodes and Kerguelen) using boosted regression trees to generate three SDMs: one for each island population, and a combined model. The predictive performance of these models was assessed using withheld tracking data from within the model calibration areas (interpolation), and from a third population, Marion Island (extrapolation). Predictive performance was assessed using k-fold cross validation and point biserial correlation. The two population-specific SDMs included the same predictor variables and suggested birds responded to the same broad-scale oceanographic influences. However, all model validation tests, including of the combined model, determined strong interpolation but weak extrapolation capabilities. These results indicate that habitat use reflects both its availability and bird preferences, such that the realized distribution patterns differ for each population. The spatial predictions by the three SDMs were compared with tracking data and fishing effort to demonstrate the conservation pitfalls of extrapolating SDMs outside calibration regions. This exercise revealed that SDM predictions would have led to an underestimate of overlap with fishing effort and potentially misinformed bycatch mitigation efforts. Although

  12. Poor transferability of species distribution models for a pelagic predator, the grey petrel, indicates contrasting habitat preferences across ocean basins.

    PubMed

    Torres, Leigh G; Sutton, Philip J H; Thompson, David R; Delord, Karine; Weimerskirch, Henri; Sagar, Paul M; Sommer, Erica; Dilley, Ben J; Ryan, Peter G; Phillips, Richard A

    2015-01-01

    Species distribution models (SDMs) are increasingly applied in conservation management to predict suitable habitat for poorly known populations. High predictive performance of SDMs is evident in validations performed within the model calibration area (interpolation), but few studies have assessed SDM transferability to novel areas (extrapolation), particularly across large spatial scales or pelagic ecosystems. We performed rigorous SDM validation tests on distribution data from three populations of a long-ranging marine predator, the grey petrel Procellaria cinerea, to assess model transferability across the Southern Hemisphere (25-65°S). Oceanographic data were combined with tracks of grey petrels from two remote sub-Antarctic islands (Antipodes and Kerguelen) using boosted regression trees to generate three SDMs: one for each island population, and a combined model. The predictive performance of these models was assessed using withheld tracking data from within the model calibration areas (interpolation), and from a third population, Marion Island (extrapolation). Predictive performance was assessed using k-fold cross validation and point biserial correlation. The two population-specific SDMs included the same predictor variables and suggested birds responded to the same broad-scale oceanographic influences. However, all model validation tests, including of the combined model, determined strong interpolation but weak extrapolation capabilities. These results indicate that habitat use reflects both its availability and bird preferences, such that the realized distribution patterns differ for each population. The spatial predictions by the three SDMs were compared with tracking data and fishing effort to demonstrate the conservation pitfalls of extrapolating SDMs outside calibration regions. This exercise revealed that SDM predictions would have led to an underestimate of overlap with fishing effort and potentially misinformed bycatch mitigation efforts. Although

  13. Poor Transferability of Species Distribution Models for a Pelagic Predator, the Grey Petrel, Indicates Contrasting Habitat Preferences across Ocean Basins

    PubMed Central

    Torres, Leigh G.; Sutton, Philip J. H.; Thompson, David R.; Delord, Karine; Weimerskirch, Henri; Sagar, Paul M.; Sommer, Erica; Dilley, Ben J.; Ryan, Peter G.; Phillips, Richard A.

    2015-01-01

    Species distribution models (SDMs) are increasingly applied in conservation management to predict suitable habitat for poorly known populations. High predictive performance of SDMs is evident in validations performed within the model calibration area (interpolation), but few studies have assessed SDM transferability to novel areas (extrapolation), particularly across large spatial scales or pelagic ecosystems. We performed rigorous SDM validation tests on distribution data from three populations of a long-ranging marine predator, the grey petrel Procellaria cinerea, to assess model transferability across the Southern Hemisphere (25-65°S). Oceanographic data were combined with tracks of grey petrels from two remote sub-Antarctic islands (Antipodes and Kerguelen) using boosted regression trees to generate three SDMs: one for each island population, and a combined model. The predictive performance of these models was assessed using withheld tracking data from within the model calibration areas (interpolation), and from a third population, Marion Island (extrapolation). Predictive performance was assessed using k-fold cross validation and point biserial correlation. The two population-specific SDMs included the same predictor variables and suggested birds responded to the same broad-scale oceanographic influences. However, all model validation tests, including of the combined model, determined strong interpolation but weak extrapolation capabilities. These results indicate that habitat use reflects both its availability and bird preferences, such that the realized distribution patterns differ for each population. The spatial predictions by the three SDMs were compared with tracking data and fishing effort to demonstrate the conservation pitfalls of extrapolating SDMs outside calibration regions. This exercise revealed that SDM predictions would have led to an underestimate of overlap with fishing effort and potentially misinformed bycatch mitigation efforts. Although

  14. Visual maladaptation in contrast domain

    NASA Astrophysics Data System (ADS)

    Pajak, Dawid; Cadík, Martin; Aydin, Tunç O.; Myszkowski, Karol; Seidel, Hans-Peter

    2010-02-01

    In this work we simulate the effect of the human eye's maladaptation to visual perception over time through a supra-threshold contrast perception model that comprises adaptation mechanisms. Specifically, we attempt to visualize maladapted vision on a display device. Given the scene luminance, the model computes a measure of perceived multi-scale contrast by taking into account spatially and temporally varying contrast sensitivity in a maladapted state, which is then processed by the inverse model and mapped to a desired display's luminance assuming perfect adaptation. Our system simulates the effect of maladaptation locally, and models the shifting of peak spatial frequency sensitivity in maladapted vision in addition to the uniform decrease in contrast sensitivity among all frequencies. Through our GPU implementation we demonstrate the visibility loss of scene details due to maladaptation over time at an interactive speed.

  15. PoMo: An Allele Frequency-Based Approach for Species Tree Estimation

    PubMed Central

    De Maio, Nicola; Schrempf, Dominik; Kosiol, Carolin

    2015-01-01

    Incomplete lineage sorting can cause incongruencies of the overall species-level phylogenetic tree with the phylogenetic trees for individual genes or genomic segments. If these incongruencies are not accounted for, it is possible to incur several biases in species tree estimation. Here, we present a simple maximum likelihood approach that accounts for ancestral variation and incomplete lineage sorting. We use a POlymorphisms-aware phylogenetic MOdel (PoMo) that we have recently shown to efficiently estimate mutation rates and fixation biases from within and between-species variation data. We extend this model to perform efficient estimation of species trees. We test the performance of PoMo in several different scenarios of incomplete lineage sorting using simulations and compare it with existing methods both in accuracy and computational speed. In contrast to other approaches, our model does not use coalescent theory but is allele frequency based. We show that PoMo is well suited for genome-wide species tree estimation and that on such data it is more accurate than previous approaches. PMID:26209413

  16. Inference of population splits and mixtures from genome-wide allele frequency data.

    PubMed

    Pickrell, Joseph K; Pritchard, Jonathan K

    2012-01-01

    Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com. PMID:23166502

  17. Inference of Population Splits and Mixtures from Genome-Wide Allele Frequency Data

    PubMed Central

    Pickrell, Joseph K.; Pritchard, Jonathan K.

    2012-01-01

    Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and “ancient” Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com. PMID:23166502

  18. Contrasting response to nutrient manipulation in Arctic mesocosms are reproduced by a minimum microbial food web model

    PubMed Central

    Larsen, Aud; Egge, Jorun K; Nejstgaard, Jens C; Di Capua, Iole; Thyrhaug, Runar; Bratbak, Gunnar; Thingstad, T Frede

    2015-01-01

    A minimum mathematical model of the marine pelagic microbial food web has previously shown to be able to reproduce central aspects of observed system response to different bottom-up manipulations in a mesocosm experiment Microbial Ecosystem Dynamics (MEDEA) in Danish waters. In this study, we apply this model to two mesocosm experiments (Polar Aquatic Microbial Ecology (PAME)-I and PAME-II) conducted at the Arctic location Kongsfjorden, Svalbard. The different responses of the microbial community to similar nutrient manipulation in the three mesocosm experiments may be described as diatom-dominated (MEDEA), bacteria-dominated (PAME-I), and flagellated-dominated (PAME-II). When allowing ciliates to be able to feed on small diatoms, the model describing the diatom-dominated MEDEA experiment give a bacteria-dominated response as observed in PAME I in which the diatom community comprised almost exclusively small-sized cells. Introducing a high initial mesozooplankton stock as observed in PAME-II, the model gives a flagellate-dominated response in accordance with the observed response also of this experiment. The ability of the model originally developed for temperate waters to reproduce population dynamics in a 10°C colder Arctic fjord, does not support the existence of important shifts in population balances over this temperature range. Rather, it suggests a quite resilient microbial food web when adapted to in situ temperature. The sensitivity of the model response to its mesozooplankton component suggests, however, that the seasonal vertical migration of Arctic copepods may be a strong forcing factor on Arctic microbial food webs. PMID:26074626

  19. Accounting for genotype uncertainty in the estimation of allele frequencies in autopolyploids.

    PubMed

    Blischak, Paul D; Kubatko, Laura S; Wolfe, Andrea D

    2016-05-01

    Despite the increasing opportunity to collect large-scale data sets for population genomic analyses, the use of high-throughput sequencing to study populations of polyploids has seen little application. This is due in large part to problems associated with determining allele copy number in the genotypes of polyploid individuals (allelic dosage uncertainty-ADU), which complicates the calculation of important quantities such as allele frequencies. Here, we describe a statistical model to estimate biallelic SNP frequencies in a population of autopolyploids using high-throughput sequencing data in the form of read counts. We bridge the gap from data collection (using restriction enzyme based techniques [e.g. GBS, RADseq]) to allele frequency estimation in a unified inferential framework using a hierarchical Bayesian model to sum over genotype uncertainty. Simulated data sets were generated under various conditions for tetraploid, hexaploid and octoploid populations to evaluate the model's performance and to help guide the collection of empirical data. We also provide an implementation of our model in the R package polyfreqs and demonstrate its use with two example analyses that investigate (i) levels of expected and observed heterozygosity and (ii) model adequacy. Our simulations show that the number of individuals sampled from a population has a greater impact on estimation error than sequencing coverage. The example analyses also show that our model and software can be used to make inferences beyond the estimation of allele frequencies for autopolyploids by providing assessments of model adequacy and estimates of heterozygosity.

  20. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene

    SciTech Connect

    Pena, S.D.J.; De Souza, K.T. ); De Andrade, M.; Chakraborty, R. )

    1994-01-18

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the same alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, the authors observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of cooperative changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

  1. Two prevalent h alleles in para-Bombay haplotypes among 250,000 Taiwanese.

    PubMed

    Chen, Ding-Ping; Tseng, Ching-Ping; Wang, Wei-Ting; Peng, Chien-Ting; Tsao, Kuo-Chien; Wu, Tsu-Lan; Lin, Kuan-Tsou; Sun, Chien-Feng

    2004-01-01

    Alpha(1,2)-fucosyltransferase catalyzes the transfer of fucose to the C-2 position of galactose on type II precursor substrate Gal beta1-4GlcNAc beta1-R. It plays an important biological role in the formation of H antigen, a precursor oligosaccharide for both A and B antigens on red blood cells. Aberration of alpha(1,2)-fucosyltransferase activity by gene mutations results in decreased synthesis of H antigen, leading to the para-Bombay phenotype. In this study, we collected about 250,000 blood samples in Taiwan during 5 yr and identified the subjects with para-Bombay phenotype. Then we analyzed the sequence of the alpha(1,2)-fucosyltransferase gene by direct sequencing and gene cloning methods, using the blood samples of 30 para-Bombay individuals and 30 control subjects who were randomly selected. The goals of this study were to search for new h alleles, to determine the h allele frequencies, and to test whether the sporadic theory is applicable in Taiwan. Six different h alleles (ha, 547-548 AG-del; hb, 880-881 TT-del; hc, R220C; hd, R220H; he, F174L; and hf, N327T) were observed. Two h alleles, he and hf, were newly discovered in Taiwan. The he allele has a nucleotide 522C>A point mutation, predicting the amino acid 174 substitution of Phe to Leu; the hf allele has missense mutation of nucleotide 980A>C, predicting the amino acid 327 substitution of Asn to Thr. Frequencies of the 6 alleles are ha 46.67%, hb 38.33%, hc 5.00%, hd 1.67%, he 3.33%, and hf 5.00%, respectively. These findings in the Taiwanese population confirm previous observations in other populations that the Bombay and para-Bombay phenotypes are due to diverse, sporadic, nonfunctional alleles, predominantly ha and hb, leading to H deficiency of red blood cells. In contrast to previous reports of non-prevalent associations of h alleles with para-Bombay phenotype, our results suggest a regional allele preference associated with para-Bombay individuals in Taiwan.

  2. Restrictive flamenco alleles are maintained in Drosophila melanogaster population cages, despite the absence of their endogenous gypsy retroviral targets.

    PubMed

    Pélisson, Alain; Payen-Groschêne, Geneviève; Terzian, Christophe; Bucheton, Alain

    2007-02-01

    The flamenco (flam) locus, located at 20A1-3 in the centromeric heterochromatin of the Drosophila melanogaster X chromosome, is a major regulator of the gypsy/mdg4 endogenous retrovirus. In restrictive strains, functional flam alleles maintain gypsy proviruses in a repressed state. By contrast, in permissive strains, proviral amplification results from infection of the female germ line and subsequent insertions into the chromosomes of the progeny. A restrictive/permissive polymorphism prevails in natural and laboratory populations. This polymorphism was assumed to be maintained by the interplay of opposite selective forces; on one hand, the increase of genetic load caused by proviral insertions would favor restrictive flam alleles because they make flies resistant to these gypsy replicative transpositions and, on the other, a hypothetical resistance cost would select against such alleles in the absence of the retrovirus. However, the population cage data presented in this paper do not fit with this simple resistance cost hypothesis because restrictive alleles were not eliminated in the absence of functional gypsy proviruses; on the contrary, using 2 independent flam allelic pairs, the restrictive frequency rose to about 90% in every experimental population, whatever the pair of alleles and the allelic proportions in the initial inoculum. These data suggest that the flam polymorphism is maintained by some strong balancing selection, which would act either on flam itself, independently of the deleterious effect of gypsy, or on a hypothetical flanking gene, in linkage disequilibrium with flam. Alternatively, restrictive flam alleles might also be resistant to some other retroelements that would be still present in the cage populations, causing a positive selection for these alleles. Whatever selective forces that maintain high levels of restrictive alleles independently of gypsy, this unknown mechanism can set up an interesting kind of antiviral innate immunity, at

  3. Allele-Specific Interactions between CAST AWAY and NEVERSHED Control Abscission in Arabidopsis Flowers

    PubMed Central

    Groner, William D.; Christy, Megan E.; Kreiner, Catherine M.; Liljegren, Sarah J.

    2016-01-01

    An advantage of analyzing abscission in genetically tractable model plants is the ability to make use of classic genetic tools such as suppression analysis. We have investigated the regulation of organ abscission by carrying out suppression analysis in Arabidopsis flowers. Plants carrying mutations in the NEVERSHED (NEV) gene, which encodes an ADP-ribosylation factor GTPase-activating protein, retain their outer floral organs after fertilization. Mutant alleles of CAST AWAY (CST), which encodes a receptor-like cytoplasmic kinase, were found to restore organ abscission in nev flowers in an allele-specific manner. To further explore the basis of the interactions between CST and NEV, we tested whether the site of a nev mutation is predictive of its ability to be suppressed. Our results suggest instead that the strength of a nev allele influences whether organ abscission can be rescued by a specific allele of CST.

  4. Quantitative Myocardial Perfusion with Dynamic Contrast-Enhanced Imaging in MRI and CT: Theoretical Models and Current Implementation

    PubMed Central

    Handayani, A.; Dijkstra, H.; Prakken, N. H. J.; Slart, R. H. J. A.; Oudkerk, M.; Van Ooijen, P. M. A.; Vliegenthart, R.; Sijens, P. E.

    2016-01-01

    Technological advances in magnetic resonance imaging (MRI) and computed tomography (CT), including higher spatial and temporal resolution, have made the prospect of performing absolute myocardial perfusion quantification possible, previously only achievable with positron emission tomography (PET). This could facilitate integration of myocardial perfusion biomarkers into the current workup for coronary artery disease (CAD), as MRI and CT systems are more widely available than PET scanners. Cardiac PET scanning remains expensive and is restricted by the requirement of a nearby cyclotron. Clinical evidence is needed to demonstrate that MRI and CT have similar accuracy for myocardial perfusion quantification as PET. However, lack of standardization of acquisition protocols and tracer kinetic model selection complicates comparison between different studies and modalities. The aim of this overview is to provide insight into the different tracer kinetic models for quantitative myocardial perfusion analysis and to address typical implementation issues in MRI and CT. We compare different models based on their theoretical derivations and present the respective consequences for MRI and CT acquisition parameters, highlighting the interplay between tracer kinetic modeling and acquisition settings. PMID:27088083

  5. A comparison of type 2 diabetes risk allele load between African Americans and European Americans.

    PubMed

    Keaton, Jacob M; Cooke Bailey, Jessica N; Palmer, Nicholette D; Freedman, Barry I; Langefeld, Carl D; Ng, Maggie C Y; Bowden, Donald W

    2014-12-01

    The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result

  6. A Comparison of Type 2 Diabetes Risk Allele Load between African Americans and European Americans

    PubMed Central

    Keaton, Jacob M.; Cooke Bailey, Jessica N.; Palmer, Nicholette D.; Freedman, Barry I.; Langefeld, Carl D.; Ng, Maggie C. Y.; Bowden, Donald W.

    2014-01-01

    The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African, and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African derived populations were genotyped in 1,990 African Americans (n=963 T2D cases, n=1,027 controls) and 1,644 European Americans (n=719 T2D cases, n=925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p<0.05). African American individuals carried 38–67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p<0.05). European American individuals carried 38–65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.9 risk alleles (p=3.97×10−89) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that

  7. Spatial heterogeneity in the strength of selection against deleterious alleles and the mutation load.

    PubMed

    Roze, D

    2012-09-01

    According to current estimates of genomic deleterious mutation rates (which are often of the order 0.1-1) the mutation load (defined as a reduction in the average fitness of a population due to the presence of deleterious alleles) may be important in many populations. In this paper, I use multilocus simulations to explore the effect of spatial heterogeneity in the strength of selection against deleterious alleles on the mutation load (for example, it has been suggested that stressful environments may increase the strength of selection). These simulations show contrasted results: in some situations, spatial heterogeneity may greatly reduce the mutation load, due to the fact that migrants coming from demes under stronger selection carry relatively few deleterious alleles, and benefit from a strong advantage within demes under weaker selection (where individuals carry many more deleterious alleles); in other situations, however, deleterious alleles accumulate within demes under stronger selection, due to migration pressure from demes under weaker selection, leading to fitness erosion within those demes. This second situation is more frequent when the productivity of the different demes is proportional to their mean fitness. The effect of spatial heterogeneity is greatly reduced, however, when the response to environmental differences is inconsistent across loci.

  8. Allelic asymmetry of the Lethal hybrid rescue (Lhr) gene expression in the hybrid between Drosophila melanogaster and D. simulans: confirmation by using genetic variations of D. melanogaster.

    PubMed

    Shirata, Mika; Araye, Quenta; Maehara, Kazunori; Enya, Sora; Takano-Shimizu, Toshiyuki; Sawamura, Kyoichi

    2014-02-01

    In the cross between Drosophila melanogaster females and D. simulans males, hybrid males die at the late larval stage, and the sibling females also die at later stages at high temperatures. Removing the D. simulans allele of the Lethal hybrid rescue gene (Lhr (sim) ) improves the hybrid incompatibility phenotypes. However, the loss-of-function mutation of Lhr (sim) (Lhr (sim0) ) does not rescue the hybrid males in crosses with several D. melanogaster strains. We first describe the genetic factor possessed by the D. melanogaster strains. It has been suggested that removing the D. melanogaster allele of Lhr (Lhr (mel) ), that is Lhr (mel0) , does not have the hybrid male rescue effect, contrasting to Lhr (sim0) . Because the expression level of the Lhr gene is known to be Lhr (sim) > Lhr (mel) in the hybrid, Lhr (mel0) may not lead to enough of a reduction in total Lhr expression. Then, there is a possibility that the D. melanogaster factor changes the expression level to Lhr (sim) < Lhr (mel) . But in fact, the expression level was Lhr (sim) > Lhr (mel) in the hybrid irrespectively of the presence of the factor. At last, we showed that Lhr (mel0) slightly improves the viability of hybrid females, which was not realized previously. All of the present results are consistent with the allelic asymmetry model of the Lhr gene expression in the hybrid.

  9. Real-time tracking of dissociation of hyperpolarized 89Y-DTPA: a model for degradation of open-chain Gd3+ MRI contrast agents

    NASA Astrophysics Data System (ADS)

    Ferguson, Sarah; Niedbalski, Peter; Parish, Christopher; Kiswandhi, Andhika; Kovacs, Zoltan; Lumata, Lloyd

    Gadolinium (Gd) complexes are widely used relaxation-based clinical contrast agents in magnetic resonance imaging (MRI). Gd-based MRI contrast agents with open-chain ligand such as Gd-DTPA, commercially known as magnevist, are less stable compared to Gd complexes with macrocyclic ligands such as GdDOTA (Dotarem). The dissociation of Gd-DPTA into Gd ion and DTPA ligand under certain biological conditions such as high zinc levels can potentially cause kidney damage. Since Gd is paramagnetic, direct NMR detection of the Gd-DTPA dissociation is quite challenging due to ultra-short relaxation times. In this work, we have investigated Y-DTPA as a model for Gd-DPTA dissociation under high zinc content solutions. Using dissolution dynamic nuclear polarization (DNP), the 89Y NMR signal is amplified by several thousand-fold. Due to the the relatively long T1 relaxation time of 89Y which translates to hyperpolarization lifetime of several minutes, the dissociation of Y-DTPA can be tracked in real-time by hyperpolarized 89Y NMR spectroscopy. Dissociation kinetic rates and implications on the degradation of open-chain Gd3+ MRI contrast agents will be discussed. This work was supported by the U.S. Department of Defense Award Number W81XWH-14-1-0048 and by the Robert A. Welch Foundation research Grant Number AT-1877.

  10. CT Pulmonary Angiography at Reduced Radiation Exposure and Contrast Material Volume Using Iterative Model Reconstruction and iDose4 Technique in Comparison to FBP

    PubMed Central

    Laqmani, Azien; Kurfürst, Maximillian; Butscheidt, Sebastian; Sehner, Susanne; Schmidt-Holtz, Jakob; Behzadi, Cyrus; Nagel, Hans Dieter; Adam, Gerhard; Regier, Marc

    2016-01-01

    Purpose To assess image quality of CT pulmonary angiography (CTPA) at reduced radiation exposure (RD-CTPA) and contrast medium (CM) volume using two different iterative reconstruction (IR) algorithms (iDose4 and iterative model reconstruction (IMR)) in comparison to filtered back projection (FBP). Materials and Methods 52 patients (body weight < 100 kg, mean BMI: 23.9) with suspected pulmonary embolism (PE) underwent RD-CTPA (tube voltage: 80 kV; mean CTDIvol: 1.9 mGy) using 40 ml CM. Data were reconstructed using FBP and two different IR algorithms (iDose4 and IMR). Subjective and objective image quality and conspicuity of PE were assessed in central, segmental, and subsegmental arteries. Results Noise reduction of 55% was achieved with iDose4 and of 85% with IMR compared to FBP. Contrast-to-noise ratio significantly increased with iDose4 and IMR compared to FBP (p<0.05). Subjective image quality was rated significantly higher at IMR reconstructions in comparison to iDose4 and FBP. Conspicuity of central and segmental PE significantly improved with the use of IMR. In subsegmental arteries, iDose4 was superior to IMR. Conclusions CTPA at reduced radiation exposure and contrast medium volume is feasible with the use of IMR, which provides improved image quality and conspicuity of pulmonary embolism in central and segmental arteries. PMID:27611448

  11. Contrast-enhanced, real-time volumetric ultrasound imaging of tissue perfusion: preliminary results in a rabbit model of testicular torsion

    NASA Astrophysics Data System (ADS)

    Paltiel, H. J.; Padua, H. M.; Gargollo, P. C.; Cannon, G. M., Jr.; Alomari, A. I.; Yu, R.; Clement, G. T.

    2011-04-01

    Contrast-enhanced ultrasound (US) imaging is potentially applicable to the clinical investigation of a wide variety of perfusion disorders. Quantitative analysis of perfusion is not widely performed, and is limited by the fact that data are acquired from a single tissue plane, a situation that is unlikely to accurately reflect global perfusion. Real-time perfusion information from a tissue volume in an experimental rabbit model of testicular torsion was obtained with a two-dimensional matrix phased array US transducer. Contrast-enhanced imaging was performed in 20 rabbits during intravenous infusion of the microbubble contrast agent Definity® before and after unilateral testicular torsion and contralateral orchiopexy. The degree of torsion was 0° in 4 (sham surgery), 180° in 4, 360° in 4, 540° in 4, and 720° in 4. An automated technique was developed to analyze the time history of US image intensity in experimental and control testes. Comparison of mean US intensity rate of change and of ratios between mean US intensity rate of change in experimental and control testes demonstrated good correlation with testicular perfusion and mean perfusion ratios obtained with radiolabeled microspheres, an accepted 'gold standard'. This method is of potential utility in the clinical evaluation of testicular and other organ perfusion.

  12. Genomic landscape of human allele-specific DNA methylation.

    PubMed

    Fang, Fang; Hodges, Emily; Molaro, Antoine; Dean, Matthew; Hannon, Gregory J; Smith, Andrew D

    2012-05-01

    DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species. PMID:22523239

  13. Genomic landscape of human allele-specific DNA methylation

    PubMed Central

    Fang, Fang; Hodges, Emily; Molaro, Antoine; Dean, Matthew; Hannon, Gregory J.; Smith, Andrew D.

    2012-01-01

    DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species. PMID:22523239

  14. Modeling the Evolution of Riparian Woodlands Facing Climate Change in Three European Rivers with Contrasting Flow Regimes

    PubMed Central

    Rivaes, Rui P.; Rodríguez-González, Patricia M.; Ferreira, Maria Teresa; Pinheiro, António N.; Politti, Emilio; Egger, Gregory; García-Arias, Alicia; Francés, Felix

    2014-01-01

    Global circulation models forecasts indicate a future temperature and rainfall pattern modification worldwide. Such phenomena will become particularly evident in Europe where climate modifications could be more severe than the average change at the global level. As such, river flow regimes are expected to change, with resultant impacts on aquatic and riparian ecosystems. Riparian woodlands are among the most endangered ecosystems on earth and provide vital services to interconnected ecosystems and human societies. However, they have not been the object of many studies designed to spatially and temporally quantify how these ecosystems will react to climate change-induced flow regimes. Our goal was to assess the effects of climate-changed flow regimes on the existing riparian vegetation of three different European flow regimes. Cases studies were selected in the light of the most common watershed alimentation modes occurring across European regions, with the objective of appraising expected alterations in the riparian elements of fluvial systems due to climate change. Riparian vegetation modeling was performed using the CASiMiR-vegetation model, which bases its computation on the fluvial disturbance of the riparian patch mosaic. Modeling results show that riparian woodlands may undergo not only at least moderate changes for all flow regimes, but also some dramatic adjustments in specific areas of particular vegetation development stages. There are circumstances in which complete annihilation is feasible. Pluvial flow regimes, like the ones in southern European rivers, are those likely to experience more pronounced changes. Furthermore, regardless of the flow regime, younger and more water-dependent individuals are expected to be the most affected by climate change. PMID:25330151

  15. Do Heliconius butterfly species exchange mimicry alleles?

    PubMed

    Smith, Joel; Kronforst, Marcus R

    2013-08-23

    Hybridization has the potential to transfer beneficial alleles across species boundaries, and there are a growing number of examples in which this has apparently occurred. Recent studies suggest that Heliconius butterflies have transferred wing pattern mimicry alleles between species via hybridization, but ancestral polymorphism could also produce a signature of shared ancestry around mimicry genes. To distinguish between these alternative hypotheses, we measured DNA sequence divergence around putatively introgressed mimicry loci and compared this with the rest of the genome. Our results reveal that putatively introgressed regions show strongly reduced sequence divergence between co-mimetic species, suggesting that their divergence times are younger than the rest of the genome. This is consistent with introgression and not ancestral variation. We further show that this signature of introgression occurs at sites throughout the genome, not just around mimicry genes.

  16. Norm-Resolvent Convergence of One-Dimensional High-Contrast Periodic Problems to a Kronig-Penney Dipole-Type Model

    NASA Astrophysics Data System (ADS)

    Cherednichenko, Kirill D.; Kiselev, Alexander V.

    2016-07-01

    We prove operator-norm resolvent convergence estimates for one-dimensional periodic differential operators with rapidly oscillating coefficients in the non-uniformly elliptic high-contrast setting, which has been out of reach of the existing homogenisation techniques. Our asymptotic analysis is based on a special representation of the resolvent of the operator in terms of the M-matrix of an associated boundary triple ("Krein resolvent formula"). The resulting asymptotic behaviour is shown to be described, up to a unitary transformation, by a non-standard version of the Kronig-Penney model on R.

  17. Comparison between human and model observer performance in low-contrast detection tasks in CT images: application to images reconstructed with filtered back projection and iterative algorithms

    PubMed Central

    Calzado, A; Geleijns, J; Joemai, R M S; Veldkamp, W J H

    2014-01-01

    Objective: To compare low-contrast detectability (LCDet) performance between a model [non–pre-whitening matched filter with an eye filter (NPWE)] and human observers in CT images reconstructed with filtered back projection (FBP) and iterative [adaptive iterative dose reduction three-dimensional (AIDR 3D; Toshiba Medical Systems, Zoetermeer, Netherlands)] algorithms. Methods: Images of the Catphan® phantom (Phantom Laboratories, New York, NY) were acquired with Aquilion ONE™ 320-detector row CT (Toshiba Medical Systems, Tokyo, Japan) at five tube current levels (20–500 mA range) and reconstructed with FBP and AIDR 3D. Samples containing either low-contrast objects (diameters, 2–15 mm) or background were extracted and analysed by the NPWE model and four human observers in a two-alternative forced choice detection task study. Proportion correct (PC) values were obtained for each analysed object and used to compare human and model observer performances. An efficiency factor (η) was calculated to normalize NPWE to human results. Results: Human and NPWE model PC values (normalized by the efficiency, η = 0.44) were highly correlated for the whole dose range. The Pearson's product-moment correlation coefficients (95% confidence interval) between human and NPWE were 0.984 (0.972–0.991) for AIDR 3D and 0.984 (0.971–0.991) for FBP, respectively. Bland–Altman plots based on PC results showed excellent agreement between human and NPWE [mean absolute difference 0.5 ± 0.4%; range of differences (−4.7%, 5.6%)]. Conclusion: The NPWE model observer can predict human performance in LCDet tasks in phantom CT images reconstructed with FBP and AIDR 3D algorithms at different dose levels. Advances in knowledge: Quantitative assessment of LCDet in CT can accurately be performed using software based on a model observer. PMID:24837275

  18. Allelic variation contributes to bacterial host specificity.

    PubMed

    Yue, Min; Han, Xiangan; De Masi, Leon; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S; Fraser, George P; Zhao, Shaohua; McDermott, Patrick F; Weill, François-Xavier; Mainil, Jacques G; Arze, Cesar; Fricke, W Florian; Edwards, Robert A; Brisson, Dustin; Zhang, Nancy R; Rankin, Shelley C; Schifferli, Dieter M

    2015-01-01

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID:26515720

  19. Allelic variation contributes to bacterial host specificity

    SciTech Connect

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; Zhao, Shaohua; McDermott, Patrick F.; Weill, François-Xavier; Mainil, Jacques G.; Arze, Cesar; Fricke, W. Florian; Edwards, Robert A.; Brisson, Dustin; Zhang, Nancy R.; Rankin, Shelley C.; Schifferli, Dieter M.

    2015-10-30

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.

  20. Allelic variation contributes to bacterial host specificity

    DOE PAGES

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; et al

    2015-10-30

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population andmore » functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.« less

  1. Allelic variation contributes to bacterial host specificity

    PubMed Central

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; Zhao, Shaohua; McDermott, Patrick F.; Weill, François-Xavier; Mainil, Jacques G.; Arze, Cesar; Fricke, W. Florian; Edwards, Robert A.; Brisson, Dustin; Zhang, Nancy R.; Rankin, Shelley C.; Schifferli, Dieter M.

    2015-01-01

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID:26515720

  2. Vulnerable but aloof versus naughty and nice: contrasting the presentation of male and female nude models in Viva and Playboy.

    PubMed

    Beggan, James K; Vencill, Jennifer A; Garos, Sheila

    2014-01-01

    The current research examined contested meanings of nudity by comparing images of nude men and women that appeared in Viva, a 1970s women's magazine founded with the intention of foregrounding male nudity, to corresponding issues of Playboy. A major difference was obtained between male models and Playboy Playmates regarding direction of gaze and nudity. Although gaze aversion is often interpreted as a sign of submission and direct gaze is seen as a dominance cue, men in Viva displayed a high level of gaze aversion and women in Playboy often gazed directly at the camera, especially when their pubic area was exposed. Additional content analysis examined the personality characteristics attributed to male models in Viva and Playmates in Playboy in their biographical sketches. In Viva, men were presented as possessing "bad boy" traits that may have been intended to compensate for the loss of power associated with male nudity. Playmates could be viewed as being naughty (by virtue of posing nude) and nice in the characterization of their personalities. PMID:23829482

  3. 21st century projections of ocean ecology and productivity across the CMIP5 models: contrasting the Southern Ocean and the Arctic

    NASA Astrophysics Data System (ADS)

    Marinov, I.; Cabre, A.; Leung, S.

    2014-12-01

    We use the newest generation of fully-coupled earth system models to study and contrast the response of Southern Ocean and Arctic phytoplankton productivity and biomass to 21st century climate change. The Arctic is warming at a rate much higher than the Southern high latitudes. Despite fundamental differences between the physical responses to climate in these regions, CMIP5 modes predict small increases in biological production both in the SO and the Arctic, partially compensating for the severe loss of primary production in the rest of the oceans. South of 40ºS, the CMIP5 models predict a complex, zonally-banded pattern of phytoplankton abundance and productivity changes driven by shifts in light and iron availability with future warming, in agreement with patterns and mechanisms emerging from a satellite trend analysis and other recent observational work. Increased SAM plays a major role in these projections, as increased Southern Ocean westerlies act both to increase mixing and phytoplankton light limitation in a band around 50S, and to modify iron supply to the surface in regions where phytoplankton are iron limited. By contrast, phytoplankton are light and nitrate co-limited in the strongly stratified Arctic ocean. Here we find that over 100 years, release of light limitation due to sea ice retreat is counter-balanced by an increase in nitrogen limitation due to increased stratification. While most models predict net increases in Arctic production by the end of the 21st century, the different strengths of nutrient-light co-limitation among models result in different magnitude changes in production across models. We assess the multi-model 100-year trend significance using a novel technique based on bootstrap combined with a weighting scheme based in similarity across models. We find that model uncertainty in ecological and biogeochemical parameters is higher than for the physical parameters. Additionally, the spread in model predictions is smaller than the

  4. Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model

    NASA Astrophysics Data System (ADS)

    Wang, Po-Hsun; Liu, Hao-Li; Hsu, Po-Hung; Lin, Chia-Yu; Chris Wang, Churng-Ren; Chen, Pin-Yuan; Wei, Kuo-Chen; Yen, Tzu-Chen; Li, Meng-Lin

    2012-06-01

    In this study, we develop a novel photoacoustic imaging technique based on gold nanorods (AuNRs) for quantitatively monitoring focused-ultrasound (FUS) induced blood-brain barrier (BBB) opening in a rat model in vivo. This study takes advantage of the strong near-infrared absorption (peak at ~800 nm) of AuNRs and the extravasation tendency from BBB opening foci due to their nano-scale size to passively label the BBB disruption area. Experimental results show that AuNR contrast-enhanced photoacoustic microscopy (PAM) successfully reveals the spatial distribution and temporal response of BBB disruption area in the rat brains. The quantitative measurement of contrast enhancement has potential to estimate the local concentration of AuNRs and even the dosage of therapeutic molecules when AuNRs are further used as nano-carrier for drug delivery or photothermal therapy. The photoacoustic results also provide complementary information to MRI, being helpful to discover more details about FUS induced BBB opening in small animal models.

  5. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, Oliver E.; Pan, David

    1994-01-01

    A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating.

  6. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, O.E.; Pan, D.

    1994-07-19

    A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating. 2 figs.

  7. Increasing long term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  8. Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance.

    PubMed

    Majumdar, Arunabha; Witte, John S; Ghosh, Saurabh

    2015-12-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE.

  9. Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance.

    PubMed

    Majumdar, Arunabha; Witte, John S; Ghosh, Saurabh

    2015-12-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE

  10. PCR Strategies for Complete Allele Calling in Multigene Families Using High-Throughput Sequencing Approaches.

    PubMed

    Marmesat, Elena; Soriano, Laura; Mazzoni, Camila J; Sommer, Simone; Godoy, José A

    2016-01-01

    The characterization of multigene families with high copy number variation is often approached through PCR amplification with highly degenerate primers to account for all expected variants flanking the region of interest. Such an approach often introduces PCR biases that result in an unbalanced representation of targets in high-throughput sequencing libraries that eventually results in incomplete detection of the targeted alleles. Here we confirm this result and propose two different amplification strategies to alleviate this problem. The first strategy (called pooled-PCRs) targets different subsets of alleles in multiple independent PCRs using different moderately degenerate primer pairs, whereas the second approach (called pooled-primers) uses a custom-made pool of non-degenerate primers in a single PCR. We compare their performance to the common use of a single PCR with highly degenerate primers using the MHC class I of the Iberian lynx as a model. We found both novel approaches to work similarly well and better than the conventional approach. They significantly scored more alleles per individual (11.33 ± 1.38 and 11.72 ± 0.89 vs 7.94 ± 1.95), yielded more complete allelic profiles (96.28 ± 8.46 and 99.50 ± 2.12 vs 63.76 ± 15.43), and revealed more alleles at a population level (13 vs 12). Finally, we could link each allele's amplification efficiency with the primer-mismatches in its flanking sequences and show that ultra-deep coverage offered by high-throughput technologies does not fully compensate for such biases, especially as real alleles may reach lower coverage than artefacts. Adopting either of the proposed amplification methods provides the opportunity to attain more complete allelic profiles at lower coverages, improving confidence over the downstream analyses and subsequent applications. PMID:27294261

  11. Contrasting gene expression patterns induced by levodopa and pramipexole treatments in the rat model of Parkinson's disease.

    PubMed

    Taravini, Irene R; Larramendy, Celia; Gomez, Gimena; Saborido, Mariano D; Spaans, Floor; Fresno, Cristóbal; González, Germán A; Fernández, Elmer; Murer, Mario G; Gershanik, Oscar S

    2016-02-01

    Whether the treatment of Parkinson's disease has to be initiated with levodopa or a D2 agonist like pramipexole remains debatable. Levodopa is more potent against symptoms than D2 agonists, but D2 agonists are less prone to induce motor complications and may have neuroprotective effects. Although regulation of plastic changes in striatal circuits may be the key to their different therapeutic potential, the gene expression patterns induced by de novo treatments with levodopa or D2 agonists are currently unknown. By studying the whole striatal transcriptome in a rodent model of early stage Parkinson's disease, we have identified the gene expression patterns underlying therapeutically comparable chronic treatments with levodopa or pramipexole. Despite the overall relatively small size of mRNA expression changes at the level of individual transcripts, our data show a robust and complete segregation of the transcript expression patterns induced by both treatments. Moreover, transcripts related to oxidative metabolism and mitochondrial function were enriched in levodopa-treated compared to vehicle-treated and pramipexole-treated animals, whereas transcripts related to olfactory transduction pathways were enriched in both treatment groups compared to vehicle-treated animals. Thus, our data reveal the plasticity of genetic striatal networks possibly contributing to the therapeutic effects of the most common initial treatments for Parkinson's disease, suggesting a role for oxidative stress in the long term complications induced by levodopa and identifying previously overlooked signaling cascades as potentially new therapeutic targets.

  12. Tumor transcriptome sequencing reveals allelic expression imbalances associated with copy number alterations.

    PubMed

    Tuch, Brian B; Laborde, Rebecca R; Xu, Xing; Gu, Jian; Chung, Christina B; Monighetti, Cinna K; Stanley, Sarah J; Olsen, Kerry D; Kasperbauer, Jan L; Moore, Eric J; Broomer, Adam J; Tan, Ruoying; Brzoska, Pius M; Muller, Matthew W; Siddiqui, Asim S; Asmann, Yan W; Sun, Yongming; Kuersten, Scott; Barker, Melissa A; De La Vega, Francisco M; Smith, David I

    2010-02-19

    Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq) should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor.

  13. Binocular contrast discrimination needs monocular multiplicative noise

    PubMed Central

    Ding, Jian; Levi, Dennis M.

    2016-01-01

    The effects of signal and noise on contrast discrimination are difficult to separate because of a singularity in the signal-detection-theory model of two-alternative forced-choice contrast discrimination (Katkov, Tsodyks, & Sagi, 2006). In this article, we show that it is possible to eliminate the singularity by combining that model with a binocular combination model to fit monocular, dichoptic, and binocular contrast discrimination. We performed three experiments using identical stimuli to measure the perceived phase, perceived contrast, and contrast discrimination of a cyclopean sine wave. In the absence of a fixation point, we found a binocular advantage in contrast discrimination both at low contrasts (<4%), consistent with previous studies, and at high contrasts (≥34%), which has not been previously reported. However, control experiments showed no binocular advantage at high contrasts in the presence of a fixation point or for observers without accommodation. We evaluated two putative contrast-discrimination mechanisms: a nonlinear contrast transducer and multiplicative noise (MN). A binocular combination model (the DSKL model; Ding, Klein, & Levi, 2013b) was first fitted to both the perceived-phase and the perceived-contrast data sets, then combined with either the nonlinear contrast transducer or the MN mechanism to fit the contrast-discrimination data. We found that the best model combined the DSKL model with early MN. Model simulations showed that, after going through interocular suppression, the uncorrelated noise in the two eyes became anticorrelated, resulting in less binocular noise and therefore a binocular advantage in the discrimination task. Combining a nonlinear contrast transducer or MN with a binocular combination model (DSKL) provides a powerful method for evaluating the two putative contrast-discrimination mechanisms. PMID:26982370

  14. Binocular contrast discrimination needs monocular multiplicative noise.

    PubMed

    Ding, Jian; Levi, Dennis M

    2016-01-01

    The effects of signal and noise on contrast discrimination are difficult to separate because of a singularity in the signal-detection-theory model of two-alternative forced-choice contrast discrimination (Katkov, Tsodyks, & Sagi, 2006). In this article, we show that it is possible to eliminate the singularity by combining that model with a binocular combination model to fit monocular, dichoptic, and binocular contrast discrimination. We performed three experiments using identical stimuli to measure the perceived phase, perceived contrast, and contrast discrimination of a cyclopean sine wave. In the absence of a fixation point, we found a binocular advantage in contrast discrimination both at low contrasts (<4%), consistent with previous studies, and at high contrasts (≥34%), which has not been previously reported. However, control experiments showed no binocular advantage at high contrasts in the presence of a fixation point or for observers without accommodation. We evaluated two putative contrast-discrimination mechanisms: a nonlinear contrast transducer and multiplicative noise (MN). A binocular combination model (the DSKL model; Ding, Klein, & Levi, 2013b) was first fitted to both the perceived-phase and the perceived-contrast data sets, then combined with either the nonlinear contrast transducer or the MN mechanism to fit the contrast-discrimination data. We found that the best model combined the DSKL model with early MN. Model simulations showed that, after going through interocular suppression, the uncorrelated noise in the two eyes became anticorrelated, resulting in less binocular noise and therefore a binocular advantage in the discrimination task. Combining a nonlinear contrast transducer or MN with a binocular combination model (DSKL) provides a powerful method for evaluating the two putative contrast-discrimination mechanisms.

  15. Binocular contrast discrimination needs monocular multiplicative noise.

    PubMed

    Ding, Jian; Levi, Dennis M

    2016-01-01

    The effects of signal and noise on contrast discrimination are difficult to separate because of a singularity in the signal-detection-theory model of two-alternative forced-choice contrast discrimination (Katkov, Tsodyks, & Sagi, 2006). In this article, we show that it is possible to eliminate the singularity by combining that model with a binocular combination model to fit monocular, dichoptic, and binocular contrast discrimination. We performed three experiments using identical stimuli to measure the perceived phase, perceived contrast, and contrast discrimination of a cyclopean sine wave. In the absence of a fixation point, we found a binocular advantage in contrast discrimination both at low contrasts (<4%), consistent with previous studies, and at high contrasts (≥34%), which has not been previously reported. However, control experiments showed no binocular advantage at high contrasts in the presence of a fixation point or for observers without accommodation. We evaluated two putative contrast-discrimination mechanisms: a nonlinear contrast transducer and multiplicative noise (MN). A binocular combination model (the DSKL model; Ding, Klein, & Levi, 2013b) was first fitted to both the perceived-phase and the perceived-contrast data sets, then combined with either the nonlinear contrast transducer or the MN mechanism to fit the contrast-discrimination data. We found that the best model combined the DSKL model with early MN. Model simulations showed that, after going through interocular suppression, the uncorrelated noise in the two eyes became anticorrelated, resulting in less binocular noise and therefore a binocular advantage in the discrimination task. Combining a nonlinear contrast transducer or MN with a binocular combination model (DSKL) provides a powerful method for evaluating the two putative contrast-discrimination mechanisms. PMID:26982370

  16. The Minor Allele of rs7574865 in the STAT4 Gene Is Associated with Increased mRNA and Protein Expression

    PubMed Central

    Lamana, Amalia; López-Santalla, Mercedes; Castillo-González, Raquel; Ortiz, Ana María; Martín, Javier; García-Vicuña, Rosario; González-Álvaro, Isidoro

    2015-01-01

    Objective The T allele of rs7574865 in STAT4 confers risk of developing autoimmune disorders. However, its functional significance remains unclear. Here we analyze how rs7574865 affects the transcription of STAT4 and its protein expression. Methods We studied 201 patients (80% female; median age, 54 years; median disease duration, 5.4 months) from PEARL study. Demographic, clinical, laboratory and therapeutic data were collected at each visit. IL-6 serum levels were measured by enzyme immune assay. The rs7574865 was genotyped using TaqMan probes. The expression levels of STAT4 mRNA were determined at 182 visits from 69 patients using quantitative real-time polymerase chain reaction. STAT4 protein was assessed by western blot in 62 samples from 34 patients. To determine the effect of different variables on the expression of STAT4 mRNA and protein, we performed multivariate longitudinal analyses using generalized linear models. Results After adjustment for age, disease activity and glucocorticoid dose as confounders, the presence of at least one copy of the T allele of rs7574865 was significantly associated with higher levels of STAT4 mRNA. Similarly, TT patients showed significantly higher levels of STAT4 protein than GG patients. IL-6 induced STAT4 and STAT5 phosphorylation in peripheral blood lymphocytes. Patients carrying at least one T allele of rs7574865 displayed lower levels of serum IL-6 compared to GG homozygous; by contrast the production of C-reactive protein was similar in both populations. Conclusion Our data suggest that the presence of the rs7574865 T allele enhances STAT4 mRNA transcription and protein expression. It may enhance the signaling of molecules depending on the STAT4 pathway. PMID:26569609

  17. Automated analysis of sequence polymorphism in STR alleles by PCR and direct electrospray ionization mass spectrometry.

    PubMed

    Planz, John V; Sannes-Lowery, Kristen A; Duncan, David D; Manalili, Sheri; Budowle, Bruce; Chakraborty, Ranajit; Hofstadler, Steven A; Hall, Thomas A

    2012-09-01

    Short tandem repeats (STRs) are the primary genetic markers used for the analysis of biological samples in forensic and human identity testing. The discrimination power of a combination of STRs is sufficient in many human identity testing comparisons unless the evidence is substantially compromised and/or there are insufficient relatives or a potential mutation may have arisen in kinship analyses. An automated STR assay system that is based on electrospray ionization mass spectrometry (ESI-MS) has been developed that can increase the discrimination power of some of the CODIS core STR loci and thus provide more information in typical and challenged samples and cases. Data from the ESI-MS STR system is fully backwards compatible with existing STR typing results generated by capillary electrophoresis. In contrast, however, the ESI-MS analytical system also reveals nucleotide polymorphisms residing within the STR alleles. The presence of these polymorphisms expands the number of alleles at a locus. Population studies were performed on the 13 core CODIS STR loci from African Americans, Caucasians and Hispanics capturing both the length of the allele, as well as nucleotide variations contained within repeat motifs or flanking regions. Such additional polymorphisms were identified in 11 of the 13 loci examined whereby several nominal length alleles were subdivided. A substantial increase in heterozygosity was observed, with close to or greater than 5% of samples analyzed being heterozygous with equal-length alleles in at least one of five of the core CODIS loci. This additional polymorphism increases discrimination power significantly, whereby the seven most polymorphic STR loci have a discrimination power equivalent to the 10 most discriminating of the CODIS core loci. An analysis of substructure among the three population groups revealed a higher θ than would be observed compared with using alleles designated by nominal length, i.e., repeats solely. Two loci, D3S1358

  18. Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern.

    PubMed

    Picanço, Juliane Bentes; Raimann, Paulo Eduardo; da Motta, Carlos Henrique Ares Silveira; Rodenbusch, Rodrigo; Gusmão, Leonor; Alho, Clarice Sampaio

    2015-05-01

    Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications.

  19. Evaluating litter decomposition and soil organic matter dynamics in earth system models: contrasting analysis of long-term litter decomposition and steady-state soil carbon

    NASA Astrophysics Data System (ADS)

    Bonan, G. B.; Wieder, W. R.

    2012-12-01

    litterfall and model-derived climatic decomposition index. While comparison with the LIDET 10-year litterbag study reveals sharp contrasts between CLM4 and DAYCENT, simulations of steady-state soil carbon show less difference between models. Both CLM4 and DAYCENT significantly underestimate soil carbon. Sensitivity analyses highlight causes of the low soil carbon bias. The terrestrial biogeochemistry of earth system models must be critically tested with observations, and the consequences of particular model choices must be documented. Long-term litter decomposition experiments such as LIDET provide a real-world process-oriented benchmark to evaluate models and can critically inform model development. Analysis of steady-state soil carbon estimates reveal additional, but here different, inferences about model performance.

  20. Update on allele nomenclature for human cytochromes P450 and the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Database.

    PubMed

    Sim, Sarah C; Ingelman-Sundberg, Magnus

    2013-01-01

    Interindividual variability in xenobiotic metabolism and drug response is extensive and genetic factors play an important role in this variation. A majority of clinically used drugs are substrates for the cytochrome P450 (CYP) enzyme system and interindividual variability in expression and function of these enzymes is a major factor for explaining individual susceptibility for adverse drug reactions and drug response. Because of the existence of many polymorphic CYP genes, for many of which the number of allelic variants is continually increasing, a universal and official nomenclature system is important. Since 1999, all functionally relevant polymorphic CYP alleles are named and published on the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Web site (http://www.cypalleles.ki.se). Currently, the database covers nomenclature of more than 660 alleles in a total of 30 genes that includes 29 CYPs as well as the cytochrome P450 oxidoreductase (POR) gene. On the CYP-allele Web site, each gene has its own Webpage, which lists the alleles with their nucleotide changes, their functional consequences, and links to publications identifying or characterizing the alleles. CYP2D6, CYP2C9, CYP2C19, and CYP3A4 are the most important CYPs in terms of drug metabolism, which is also reflected in their corresponding highest number of Webpage hits at the CYP-allele Web site.The main advantage of the CYP-allele database is that it offers a rapid online publication of CYP-alleles and their effects and provides an overview of peer-reviewed data to the scientific community. Here, we provide an update of the CYP-allele database and the associated nomenclature.

  1. Predictive model for contrast-enhanced ultrasound of the breast: Is it feasible in malignant risk assessment of breast imaging reporting and data system 4 lesions?

    PubMed Central

    Luo, Jun; Chen, Ji-Dong; Chen, Qing; Yue, Lin-Xian; Zhou, Guo; Lan, Cheng; Li, Yi; Wu, Chi-Hua; Lu, Jing-Qiao

    2016-01-01

    AIM: To build and evaluate predictive models for contrast-enhanced ultrasound (CEUS) of the breast to distinguish between benign and malignant lesions. METHODS: A total of 235 breast imaging reporting and data system (BI-RADS) 4 solid breast lesions were imaged via CEUS before core needle biopsy or surgical resection. CEUS results were analyzed on 10 enhancing patterns to evaluate diagnostic performance of three benign and three malignant CEUS models, with pathological results used as the gold standard. A logistic regression model was developed basing on the CEUS results, and then evaluated with receiver operating curve (ROC). RESULTS: Except in cases of enhanced homogeneity, the rest of the 9 enhancement appearances were statistically significant (P < 0.05). These 9 enhancement patterns were selected in the final step of the logistic regression analysis, with diagnostic sensitivity and specificity of 84.4% and 82.7%, respectively, and the area under the ROC curve of 0.911. Diagnostic sensitivity, specificity, and accuracy of the malignant vs benign CEUS models were 84.38%, 87.77%, 86.38% and 86.46%, 81.29% and 83.40%, respectively. CONCLUSION: The breast CEUS models can predict risk of malignant breast lesions more accurately, decrease false-positive biopsy, and provide accurate BI-RADS classification. PMID:27358688

  2. Differential effects of the APOE e4 allele on different domains of cognitive ability across the life-course.

    PubMed

    Marioni, Riccardo E; Campbell, Archie; Scotland, Generation; Hayward, Caroline; Porteous, David J; Deary, Ian J

    2016-06-01

    The association between APOE genotype and cognitive function suggests a positive role for the e2 allele and a negative role for the e4 allele. Both alleles have relatively low frequencies in the general population; hence, meta-analyses have been based on many small, heterogeneous studies. Here, we report the APOE-cognition associations in the largest single analysis to date. APOE status and cognitive ability were measured in 18 337 participants from the Generation Scotland study between 2006 and 2011. The age range was 18-94 years with a mean of 47 (SD 15). Four cognitive domains were assessed: verbal declarative memory (paragraph recall), processing speed (digit symbol substitution), verbal fluency (phonemic verbal fluency), and vocabulary (Mill Hill synonyms). Linear regression was used to assess the associations between APOE genetic status and cognition. Possession of the e4 allele was associated with lower scores on the measures of memory and processing speed in subjects aged >60. Across all age ranges, the e4 allele was linked to better verbal fluency scores. In younger subjects (≤60 years) the e4 allele was linked to higher vocabulary scores. There were no associations between the e2 allele and cognitive ability. As seen in previous meta-analyses, the APOE e4 allele is linked to poorer cognitive performance in the domains of memory and processing speed. By contrast, positive associations were seen between the e4 allele and measures of verbal fluency and vocabulary. All associations were relatively small and, in many cases, nominally significant despite the very large sample size. PMID:26395552

  3. Chromosome 5 allele loss in human colorectal carcinomas.

    PubMed

    Solomon, E; Voss, R; Hall, V; Bodmer, W F; Jass, J R; Jeffreys, A J; Lucibello, F C; Patel, I; Rider, S H

    That the sporadic and inherited forms of a particular cancer could both result from mutations in the same gene was first proposed by Knudson. He further proposed that these mutations act recessively at the cellular level, and that both copies of the gene must be lost for the cancer to develop. In sporadic cases both events occur somatically whereas in dominant familial cases susceptibility is inherited through a germline mutation and the cancer develops after a somatic change in the homologous allele. This model has since been substantiated in the case of retinoblastoma, Wilms tumour, acoustic neuroma and several other tumours, in which loss of heterozygosity was shown in tumour material compared to normal tissue from the same patient. The dominantly inherited disorder, familial adenomatous polyposis (FAP, also called familial polyposis coli), which gives rise to multiple adenomatous polyps in the colon that have a relatively high probability of progressing to a malignant adenocarcinoma, provides a basis for studying recessive genes in the far more common colorectal carcinomas using this approach. Following a clue as to the location of the FAP gene given by a case report of an individual with an interstitial deletion of chromosome 5q, who had FAP and multiple developmental abnormalities, we have examined sporadic colorectal adenocarcinomas for loss of alleles on chromosome 5. Using a highly polymorphic 'minisatellite' probe which maps to chromosome 5q we have shown that at least 20% of this highly heterogeneous set of tumours lose one of the alleles present in matched normal tissue. This parallels the assignment of the FAP gene to chromosome 5 (see accompanying paper) and suggests that becoming recessive for this gene may be a critical step in the progression of a relatively high proportion of colorectal cancers. PMID:2886919

  4. Determination of DQB1 alleles using PCR amplification and allele-specific primers.

    PubMed

    Lepage, V; Ivanova, R; Loste, M N; Mallet, C; Douay, C; Naoumova, E; Charron, D

    1995-10-01

    Molecular genotyping of HLA class II genes is commonly carried out using polymerase chain reaction (PCR) in combination with sequence-specific oligotyping (PCR-SSO) or a combination of the PCR and restriction fragment length polymorphism methods (PCR-RFLP). However, the identification of the DQB1 type by PCR-SSO and PCR-RFLP is very time-consuming which is disadvantageous for the typing of cadaveric organ donors. We have developed a DQB1 typing method using PCR in combination with allele-specific amplification (PCR-ASA), which allows the identification of the 17 most frequent alleles in one step using seven amplification mixtures. PCR allele-specific amplification HLA-DQB1 typing is easy to perform, and the results are easy to interpret in routine clinical practice. The PCR-ASA method is therefore better suited to DQB1 typing for organ transplantation than other methods.

  5. Introgressive hybridization: brown bears as vectors for polar bear alleles.

    PubMed

    Hailer, Frank

    2015-03-01

    The dynamics and consequences of introgression can inform about numerous evolutionary processes. Biologists have therefore long been interested in hybridization. One challenge, however, lies in the identification of nonadmixed genotypes that can serve as a baseline for accurate quantification of admixture. In this issue of Molecular Ecology, Cahill et al. (2015) analyse a genomic data set of 28 polar bears, eight brown bears and one American black bear. Polar bear alleles are found to be introgressed into brown bears not only near a previously identified admixture zone on the Alaskan Admiralty, Baranof and Chichagof (ABC) Islands, but also far into the North American mainland. Elegantly contrasting admixture levels at autosomal and X chromosomal markers, Cahill and colleagues infer that male-biased dispersal has spread these introgressed alleles away from the Late Pleistocene contact zone. Compared to a previous study on the ABC Island population in which an Alaskan brown bear served as a putatively admixture-free reference, Cahill et al. (2015) utilize a newly sequenced Swedish brown bear as admixture baseline. This approach reveals that brown bears have been impacted by introgression from polar bears to a larger extent (up to 8.8% of their genome), than previously known, including the bear that had previously served as admixture baseline. No evidence for introgression of brown bear into polar bear is found, which the authors argue could be a consequence of selection. Besides adding new exciting pieces to the puzzle of polar/brown bear evolutionary history, the study by Cahill and colleagues highlights that wildlife genomics is moving from analysing single genomes towards a landscape genomics approach. PMID:25775930

  6. Introgressive hybridization: brown bears as vectors for polar bear alleles.

    PubMed

    Hailer, Frank

    2015-03-01

    The dynamics and consequences of introgression can inform about numerous evolutionary processes. Biologists have therefore long been interested in hybridization. One challenge, however, lies in the identification of nonadmixed genotypes that can serve as a baseline for accurate quantification of admixture. In this issue of Molecular Ecology, Cahill et al. (2015) analyse a genomic data set of 28 polar bears, eight brown bears and one American black bear. Polar bear alleles are found to be introgressed into brown bears not only near a previously identified admixture zone on the Alaskan Admiralty, Baranof and Chichagof (ABC) Islands, but also far into the North American mainland. Elegantly contrasting admixture levels at autosomal and X chromosomal markers, Cahill and colleagues infer that male-biased dispersal has spread these introgressed alleles away from the Late Pleistocene contact zone. Compared to a previous study on the ABC Island population in which an Alaskan brown bear served as a putatively admixture-free reference, Cahill et al. (2015) utilize a newly sequenced Swedish brown bear as admixture baseline. This approach reveals that brown bears have been impacted by introgression from polar bears to a larger extent (up to 8.8% of their genome), than previously known, including the bear that had previously served as admixture baseline. No evidence for introgression of brown bear into polar bear is found, which the authors argue could be a consequence of selection. Besides adding new exciting pieces to the puzzle of polar/brown bear evolutionary history, the study by Cahill and colleagues highlights that wildlife genomics is moving from analysing single genomes towards a landscape genomics approach.

  7. HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens

    PubMed Central

    Iliopoulou, Bettina Panagiota; Guerau-de-Arellano, Mireia; Huber, Brigitte T.

    2010-01-01

    Objective Arthritis is a prominent manifestation of Lyme disease, caused upon infection with Borrelia burgdorferi (Bb). Persistent chronic Lyme arthritis, even after antibiotic treatment, is linked to HLA-DRB1*0401 (DR4) and related alleles. On the contrary, Lyme patients who resolve arthritis within 3 months post-infection show an increased frequency of HLA-DRB1*1101 (DR11). The aim of this study was to analyze the underlying mechanism by which HLA-DR alleles confer genetic susceptibility or resistance to antibiotic-refractory Lyme arthritis. Methods We generated DR11 transgenic (tg) mice on a murine class II−/− background and compared their immune response to Bb-antigens to that of DR4 tg mice after immunization with Bb outer surface protein (Osp)A or infection with live Bb. Results We report that the T cells of OspA-immunized and Bb-infected DR11 tg mice were defective in IFN-γ production compared to those of DR4 mice. On the other hand, DR11 tg mice developed higher titers of anti-OspA and anti-Bb Abs, respectively, than DR4 mice. In accordance with this observation, we found that Bb-infected DR11 tg mice had decreased spirochetal burden compared to DR4 mice, measured by qPCR. Conclusion This study provides direct evidence that in the presence of HLA-DR11 the immune response against Bb-antigens is directed towards a protective Ab response. In contrast, an inflammatory Th1 response is induced in the presence of DR4. These observations offer an explanation for the differential genetic susceptibility of DR4+ and DR11+ individuals for the development of chronic Lyme arthritis and eventually the progression to antibiotic-refractory Lyme arthritis. PMID:19950279

  8. A theory of behavioral contrast.

    PubMed

    Killeen, Peter R

    2014-11-01

    The reinforcers that maintain target instrumental responses also reinforce other responses that compete with them for expression. This competition, and its imbalance at points of transition between different schedules of reinforcement, causes behavioral contrast. The imbalance is caused by differences in the rates at which different responses come under the control of component stimuli. A model for this theory of behavioral contrast is constructed by expanding the coupling coefficient of MPR (Killeen, 1994). The coupling coefficient gives the degree of association of a reinforcer with the target response (as opposed to other competing responses). Competing responses, often identified as interim or adjunctive or superstitious behavior, are intrinsic to reinforcement schedules, especially interval schedules. In addition to that base-rate of competition, additional competing responses may spill over from the prior component, causing initial contrast; and they may be modulated by conditioned reinforcement or punishment from stimuli associated with subsequent component change, causing terminal contrast. A formalization of these hypotheses employed (a) a hysteresis model of off-target responses giving rise to initial contrast, and (b) a competing traces model of the suppression or enhancement of ongoing competitive responses by signals of following-schedule transition. The theory was applied to transient contrast, the following schedule effect, and the component duration effect. PMID:25244535

  9. A theory of behavioral contrast.

    PubMed

    Killeen, Peter R

    2014-11-01

    The reinforcers that maintain target instrumental responses also reinforce other responses that compete with them for expression. This competition, and its imbalance at points of transition between different schedules of reinforcement, causes behavioral contrast. The imbalance is caused by differences in the rates at which different responses come under the control of component stimuli. A model for this theory of behavioral contrast is constructed by expanding the coupling coefficient of MPR (Killeen, 1994). The coupling coefficient gives the degree of association of a reinforcer with the target response (as opposed to other competing responses). Competing responses, often identified as interim or adjunctive or superstitious behavior, are intrinsic to reinforcement schedules, especially interval schedules. In addition to that base-rate of competition, additional competing responses may spill over from the prior component, causing initial contrast; and they may be modulated by conditioned reinforcement or punishment from stimuli associated with subsequent component change, causing terminal contrast. A formalization of these hypotheses employed (a) a hysteresis model of off-target responses giving rise to initial contrast, and (b) a competing traces model of the suppression or enhancement of ongoing competitive responses by signals of following-schedule transition. The theory was applied to transient contrast, the following schedule effect, and the component duration effect.

  10. Borrowed alleles and convergence in serpentine adaptation.

    PubMed

    Arnold, Brian J; Lahner, Brett; DaCosta, Jeffrey M; Weisman, Caroline M; Hollister, Jesse D; Salt, David E; Bomblies, Kirsten; Yant, Levi

    2016-07-19

    Serpentine barrens represent extreme hazards for plant colonists. These sites are characterized by high porosity leading to drought, lack of essential mineral nutrients, and phytotoxic levels of metals. Nevertheless, nature forged populations adapted to these challenges. Here, we use a population-based evolutionary genomic approach coupled with elemental profiling to assess how autotetraploid Arabidopsis arenosa adapted to a multichallenge serpentine habitat in the Austrian Alps. We first demonstrate that serpentine-adapted plants exhibit dramatically altered elemental accumulation levels in common conditions, and then resequence 24 autotetraploid individuals from three populations to perform a genome scan. We find evidence for highly localized selective sweeps that point to a polygenic, multitrait basis for serpentine adaptation. Comparing our results to a previous study of independent serpentine colonizations in the closely related diploid Arabidopsis lyrata in the United Kingdom and United States, we find the highest levels of differentiation in 11 of the same loci, providing candidate alleles for mediating convergent evolution. This overlap between independent colonizations in different species suggests that a limited number of evolutionary strategies are suited to overcome the multiple challenges of serpentine adaptation. Interestingly, we detect footprints of selection in A. arenosa in the context of substantial gene flow from nearby off-serpentine populations of A. arenosa, as well as from A. lyrata In several cases, quantitative tests of introgression indicate that some alleles exhibiting strong selective sweep signatures appear to have been introgressed from A. lyrata This finding suggests that migrant alleles may have facilitated adaptation of A. arenosa to this multihazard environment. PMID:27357660

  11. Borrowed alleles and convergence in serpentine adaptation

    PubMed Central

    Arnold, Brian J.; Lahner, Brett; DaCosta, Jeffrey M.; Weisman, Caroline M.; Hollister, Jesse D.; Salt, David E.; Bomblies, Kirsten; Yant, Levi

    2016-01-01

    Serpentine barrens represent extreme hazards for plant colonists. These sites are characterized by high porosity leading to drought, lack of essential mineral nutrients, and phytotoxic levels of metals. Nevertheless, nature forged populations adapted to these challenges. Here, we use a population-based evolutionary genomic approach coupled with elemental profiling to assess how autotetraploid Arabidopsis arenosa adapted to a multichallenge serpentine habitat in the Austrian Alps. We first demonstrate that serpentine-adapted plants exhibit dramatically altered elemental accumulation levels in common conditions, and then resequence 24 autotetraploid individuals from three populations to perform a genome scan. We find evidence for highly localized selective sweeps that point to a polygenic, multitrait basis for serpentine adaptation. Comparing our results to a previous study of independent serpentine colonizations in the closely related diploid Arabidopsis lyrata in the United Kingdom and United States, we find the highest levels of differentiation in 11 of the same loci, providing candidate alleles for mediating convergent evolution. This overlap between independent colonizations in different species suggests that a limited number of evolutionary strategies are suited to overcome the multiple challenges of serpentine adaptation. Interestingly, we detect footprints of selection in A. arenosa in the context of substantial gene flow from nearby off-serpentine populations of A. arenosa, as well as from A. lyrata. In several cases, quantitative tests of introgression indicate that some alleles exhibiting strong selective sweep signatures appear to have been introgressed from A. lyrata. This finding suggests that migrant alleles may have facilitated adaptation of A. arenosa to this multihazard environment. PMID:27357660

  12. Borrowed alleles and convergence in serpentine adaptation.

    PubMed

    Arnold, Brian J; Lahner, Brett; DaCosta, Jeffrey M; Weisman, Caroline M; Hollister, Jesse D; Salt, David E; Bomblies, Kirsten; Yant, Levi

    2016-07-19

    Serpentine barrens represent extreme hazards for plant colonists. These sites are characterized by high porosity leading to drought, lack of essential mineral nutrients, and phytotoxic levels of metals. Nevertheless, nature forged populations adapted to these challenges. Here, we use a population-based evolutionary genomic approach coupled with elemental profiling to assess how autotetraploid Arabidopsis arenosa adapted to a multichallenge serpentine habitat in the Austrian Alps. We first demonstrate that serpentine-adapted plants exhibit dramatically altered elemental accumulation levels in common conditions, and then resequence 24 autotetraploid individuals from three populations to perform a genome scan. We find evidence for highly localized selective sweeps that point to a polygenic, multitrait basis for serpentine adaptation. Comparing our results to a previous study of independent serpentine colonizations in the closely related diploid Arabidopsis lyrata in the United Kingdom and United States, we find the highest levels of differentiation in 11 of the same loci, providing candidate alleles for mediating convergent evolution. This overlap between independent colonizations in different species suggests that a limited number of evolutionary strategies are suited to overcome the multiple challenges of serpentine adaptation. Interestingly, we detect footprints of selection in A. arenosa in the context of substantial gene flow from nearby off-serpentine populations of A. arenosa, as well as from A. lyrata In several cases, quantitative tests of introgression indicate that some alleles exhibiting strong selective sweep signatures appear to have been introgressed from A. lyrata This finding suggests that migrant alleles may have facilitated adaptation of A. arenosa to this multihazard environment.

  13. Biased gene conversion skews allele frequencies in human populations, increasing the disease burden of recessive alleles.

    PubMed

    Lachance, Joseph; Tishkoff, Sarah A

    2014-10-01

    Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.

  14. Catalogue of alleles of gliadin-coding loci in durum wheat (Triticum durum Desf.).

    PubMed

    Melnikova, N V; Kudryavtseva, A V; Kudryavtsev, A M

    2012-02-01

    Gliadins are seed storage proteins which are characterized by high intervarietal polymorphism and can be used as genetic markers. As a result of our work, a considerably extended catalogue of allelic variants of gliadin component blocks was compiled for durum wheat; 74 allelic variants for four gliadin-coding loci were identified for the first time. The extended catalogue includes a total of 131 allelic variants: 16 for locus Gli-A1(d), 19 for locus Gli-B1(d), 41 for locus Gli-A2(d), and 55 for locus Gli-B2(d). The electrophoretic pattern of the standard cultivar and a diagram are provided for every block identified. The number of alleles per family is quite small for loci Gli-A1(d) and Gli-B1(d) of durum wheat, as contrasted to loci Gli-A2(d) and Gli-B2(d) that are characterized by large families including many alleles. The presence of large block families determines a higher diversity of durum wheat for loci Gli-A2(d) and Gli-B2(d) as compared to Gli-A1(d) and Gli-B1(d). The catalogue of allelic variants of gliadin component blocks can be used by seed farmers to identify durum wheat cultivars and evaluate their purity; by breeders, to obtain homogenous cultivars and control the initial stages of selection; by gene bank experts, to preserve native varieties and the original biotypic composition of cultivars. PMID:21946233

  15. Characterizing allelic association in the genome era

    PubMed Central

    WEIR, B. S.; LAURIE, C. C.

    2015-01-01

    Summary Whole genome data are allowing the estimation of population genetic parameters with an accuracy not imagined 50 years ago. Variation in these parameters along the genome is being found empirically where once only approximate theoretical values were available. Along with increased information, however, has come the issue of multiple testing and the realization that high values of the coefficients of variation of quantities such as relatedness measures may make it difficult to draw inferences. This review concentrates on measures of allelic association within and between individuals and within and between populations. PMID:21429275

  16. Enhanced low-template DNA analysis conditions and investigation of allele dropout patterns.

    PubMed

    Hedell, Ronny; Dufva, Charlotte; Ansell, Ricky; Mostad, Petter; Hedman, Johannes

    2015-01-01

    Forensic DNA analysis applying PCR enables profiling of minute biological samples. Enhanced analysis conditions can be applied to further push the limit of detection, coming with the risk of visualising artefacts and allele imbalances. We have evaluated the consecutive increase of PCR cycles from 30 to 35 to investigate the limitations of low-template (LT) DNA analysis, applying the short tandem repeat (STR) analysis kit PowerPlex ESX 16. Mock crime scene DNA extracts of four different quantities (from around 8-84 pg) were tested. All PCR products were analysed using 5, 10 and 20 capillary electrophoresis (CE) injection seconds. Bayesian models describing allele dropout patterns, allele peak heights and heterozygote balance were developed to assess the overall improvements in EPG quality with altered PCR/CE settings. The models were also used to evaluate the impact of amplicon length, STR marker and fluorescent label on the risk for allele dropout. The allele dropout probability decreased for each PCR cycle increment from 30 to 33 PCR cycles. Irrespective of DNA amount, the dropout probability was not affected by further increasing the number of PCR cycles. For the 42 and 84 pg samples, mainly complete DNA profiles were generated applying 32 PCR cycles. For the 8 and 17 pg samples, the allele dropouts decreased from 100% using 30 cycles to about 75% and 20%, respectively. The results for 33, 34 and 35 PCR cycles indicated that heterozygote balance and stutter ratio were mainly affected by DNA amount, and not directly by PCR cycle number and CE injection settings. We found 32 and 33 PCR cycles with 10 CE injection seconds to be optimal, as 34 and 35 PCR cycles did not improve allele detection and also included CE saturation problems. We find allele dropout probability differences between several STR markers. Markers labelled with the fluorescent dyes CXR-ET (red in electropherogram) and TMR-ET (shown as black) generally have higher dropout risks compared with those

  17. Noninvasive monitoring of radiotherapy-induced microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor model

    SciTech Connect

    Ceelen, Wim . E-mail: Wim.ceelen@ugent.be; Smeets, Peter; Backes, Walter; Van Damme, Nancy; Boterberg, Tom; Demetter, Pieter; Bouckenooghe, Isabel; De Visschere, Marieke; Peeters, Marc; Pattyn, Piet

    2006-03-15

    Purpose: To examine dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a macromolecular contrast agent (P792) to visualize effects of radiotherapy (RT) on microvascular leakage in a colorectal cancer model. Methods and Materials: CC531 tumors were induced in WAG/Rij rats. DCE-MRI was performed before and 5 days after 5 x 5 Gy of RT and parametric maps generated of the endothelial transfer constant (K{sup trans} ) and the fractional interstitial space (V{sub e} ) according to the Tofts model. Tissue pO{sub 2} mapping was performed in each tumor core and rim before and after RT. Microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, and pimonidazole hypoxia staining were compared with a control group of tumor-bearing rats. Results: Mean K{sup trans} and v{sub e} were significantly reduced after RT in all tumor regions. Mean pO{sub 2} was 6.8 mm Hg before RT vs. 7.7 mm Hg after RT (p < 0.001) in the tumor rim and 3.5 mm Hg before RT vs. 4.4 mm Hg after RT (p < 0.001) in the tumor core. Mean MVD in the tumor rim was 10.4 in the RT treated group vs. 16.9 in the control group (p = 0.061). VEGF expression was significantly higher in RT-treated rats. After RT, no correlation was found between DCE-MRI parameters and histologic parameters. A correlation was seen after RT between pO{sub 2} and K{sup trans} (r -0.57, p = 0.08) and between pO{sub 2} and v{sub e} (r = -0.65, p = 0.04). Conclusions: Dynamic contrast-enhanced-MRI with P792 allows quantification of microvascular changes in this colorectal model. RT significantly reduces neovascular leakage and enhances tissue oxygenation and VEGF expression. After RT, DCE-MRI parameters are related to tumor pO{sub 2}, but not to MVD or VEGF expression.

  18. Dual-Energy Computed Tomography Imaging of Atherosclerotic Plaques in a Mouse Model Using a Liposomal-Iodine Nanoparticle Contrast Agent

    PubMed Central

    Bhavane, Rohan; Badea, Cristian; Ghaghada, Ketan B.; Clark, Darin; Vela, Deborah; Moturu, Anoosha; Annapragada, Akshaya; Johnson, G. Allan; Willerson, James T.; Annapragada, Ananth

    2013-01-01

    Background The accumulation of macrophages in inflamed atherosclerotic plaques has been long recognized. In an attempt to develop an imaging agent for detection of vulnerable plaques, we evaluated the feasibility of a liposomal-iodine nanoparticle contrast agent for computed tomography (CT) imaging of macrophage-rich atherosclerotic plaques in a mouse model. Methods and Results Liposomal-iodine formulations varying in particle size and polyethylene glycol coating were fabricated, and shown to stably encapsulate the iodine compound. In vitro uptake studies using optical and CT imaging in the RAW264.7 macrophage cell line identified the formulation that promoted maximal uptake. Dual-energy CT imaging using this formulation in Apolipoprotein E deficient (ApoE−/−) mice (n=8) and control C57BL/6 mice (n=6) followed by spectral decomposition of the dual-energy images enabled imaging of the liposomes localized in the plaque. Imaging cytometry confirmed the presence of liposomes in the plaque and their co-localization with a small fraction (~2%) of the macrophages in the plaque. Conclusions The results demonstrate the feasibility of imaging macrophage-rich atherosclerotic plaques using a liposomal-iodine nanoparticle contrast agent and dual-energy CT. PMID:23349231

  19. Characterization of bone perfusion by dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography in the Dunkin-Hartley guinea pig model of advanced osteoarthritis.

    PubMed

    Dyke, Jonathan P; Synan, Michael; Ezell, Paula; Ballon, Douglas; Racine, Jennifer; Aaron, Roy K

    2015-03-01

    This study characterizes changes in subchondral bone circulation in OA and examines relationships to bone structure and cartilage degeneration in Dunkin-Hartley guinea pigs. We have used dynamic contrast-enhanced MRI (DCE-MRI) and PET, with pharmacokinetic modeling, to characterize subchondral bone perfusion. Assessments are made of perfusion kinetics and vascular permeability by MRI, and blood volume and flow, and radionuclide incorporation into bone, by PET. These parameters are compared to cartilage lesion severity and bone histomorphometry. Assessments of intraosseous thrombi are made morphologically. Prolonged signal enhancement during the clearance phase of MRI correlated with OA severity and suggested venous stasis. Vascular permeability was not increased indicating that transvascular migration of contrast agent was not responsible for signal enhancement. Intraosseous thrombi were not observed. Decreased perfusion associated with severe OA was confirmed by PET and was associated with reduced radionuclide incorporation and osteoporosis. MRI and PET can be used to characterize kinetic parameters of circulation in OA and correlate them with subchondral bone metabolism of interest to the pathophysiology of OA. The significance of these observations may lie in alterations induced in the expression of cytokines by OA osteoblasts that are related to bone remodeling and cartilage breakdown.

  20. Characterization of Bone Perfusion by Dynamic Contrast-Enhanced Magnetic Resonance Imaging and Positron Emission Tomography in the Dunkin-Hartley Guinea Pig Model of Advanced Osteoarthritis

    PubMed Central

    Dyke, Jonathan P.; Synan, Michael; Ezell, Paula; Ballon, Douglas; Racine, Jennifer; Aaron, Roy K.

    2014-01-01

    Purpose This study characterizes changes in subchondral bone circulation in OA and examines relationships to bone structure and cartilage degeneration in Dunkin-Hartley guinea pigs. Methods We have used dynamic contrast-enhanced MRI (DCE-MRI) and PET, with pharmacokinetic modeling, to characterize subchondral bone perfusion. Assessments are made of perfusion kinetics and vascular permeability by MRI, and blood volume and flow, and radionuclide incorporation into bone, by PET. These parameters are compared to cartilage lesion severity and bone histomorphometry. Assessments of intraosseous thrombi are made morphologically. Results Prolonged signal enhancement during the clearance phase of MRI correlated with OA severity and suggested venous stasis. Vascular permeability was not increased indicating that transvascular migration of contrast agent was not responsible for signal enhancement. Intraosseous thrombi were not observed. Decreased perfusion associated with severe OA was confirmed by PET and was associated with reduced radionuclide incorporation and osteoporosis. Discussion MRI and PET can be used to characterize kinetic parameters of circulation in OA and correlate them with subchondral bone metabolism of interest to the pathophysiology of OA. The significance of these observations may lie in alterations induced in the expression of cytokines by OA osteoblasts that are related to bone remodeling and cartilage breakdown. PMID:25410523

  1. Allelic analysis of sheath blight resistance with association mapping in rice.

    PubMed

    Jia, Limeng; Yan, Wengui; Zhu, Chengsong; Agrama, Hesham A; Jackson, Aaron; Yeater, Kathleen; Li, Xiaobai; Huang, Bihu; Hu, Biaolin; McClung, Anna; Wu, Dianxing

    2012-01-01

    Sheath blight (ShB) caused by the soil-borne pathogen Rhizoctonia solani is one of the most devastating diseases in rice world-wide. Global attention has focused on examining individual mapping populations for quantitative trait loci (QTLs) for ShB resistance, but to date no study has taken advantage of association mapping to examine hundreds of lines for potentially novel QTLs. Our objective was to identify ShB QTLs via association mapping in rice using 217 sub-core entries from the USDA rice core collection, which were phenotyped with a micro-chamber screening method and genotyped with 155 genome-wide markers. Structure analysis divided the mapping panel into five groups, and model comparison revealed that PCA5 with genomic control was the best model for association mapping of ShB. Ten marker loci on seven chromosomes were significantly associated with response to the ShB pathogen. Among multiple alleles in each identified loci, the allele contributing the greatest effect to ShB resistance was named the putative resistant allele. Among 217 entries, entry GSOR 310389 contained the most putative resistant alleles, eight out of ten. The number of putative resistant alleles presented in an entry was highly and significantly correlated with the decrease of ShB rating (r = -0.535) or the increase of ShB resistance. Majority of the resistant entries that contained a large number of the putative resistant alleles belonged to indica, which is consistent with a general observation that most ShB resistant accessions are of indica origin. These findings demonstrate the potential to improve breeding efficiency by using marker-assisted selection to pyramid putative resistant alleles from various loci in a cultivar for enhanced ShB resistance in rice.

  2. Allele-Specific Deletions in Mouse Tumors Identify Fbxw7 as Germline Modifier of Tumor Susceptibility

    PubMed Central

    Perez-Losada, Jesus; Wu, Di; DelRosario, Reyno; Balmain, Allan; Mao, Jian-Hua

    2012-01-01

    Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5–10%). There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001), but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility. PMID:22348067

  3. Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history.

    PubMed

    Eisenberg, Dan T A; Kuzawa, Christopher W; Hayes, M Geoffrey

    2010-09-01

    The epsilon4 allele of the apolipoprotein E (APOE) gene is associated with increased cholesterol levels and heart disease. Population allele frequencies of APOE have previously been shown to vary, with epsilon4 frequencies generally increasing with latitude. We hypothesize that this trend resulted from natural selection protecting against low-cholesterol levels. In high-latitude cold environments and low-latitude hot environments, metabolic rate is elevated, which could require higher cholesterol levels. To explore this hypothesis, we compiled APOE allele frequencies, latitude, temperature, and elevation from populations around the world. epsilon4 allele frequencies show a curvilinear relationship with absolute latitude, with lowest frequencies found in the mid-latitudes where temperatures generally require less expenditure on cooling/thermogenesis. Controlling for population structure in a subset of populations did not appreciably change this pattern of association, consistent with selection pressures that vary by latitude shaping epsilon4 allele frequencies. Temperature records also predict APOE frequency in a curvilinear fashion, with lowest epsilon4 frequencies at moderate temperatures. The model fit between historical temperatures and epsilon4 is less than between latitude and epsilon4, but strengthened after correcting for estimated temperature differences during the Paleolithic. Contrary to our hypothesis, we find that elevation did not improve predictive power, and an integrated measure of the cholesterol effect of multiple APOE alleles was less related to latitude than was epsilon4 alone. Our results lend mixed support for a link between past temperature and human APOE allele distribution and point to the need to develop better models of past climate in future analyses.

  4. Combining measurements and modelling to quantify the contribution of atmospheric fallout, local industry and road traffic to PAH stocks in contrasting catchments.

    PubMed

    Gateuille, David; Evrard, Olivier; Lefevre, Irène; Moreau-Guigon, Elodie; Alliot, Fabrice; Chevreuil, Marc; Mouchel, Jean-Marie

    2014-06-01

    Various sources supply PAHs that accumulate in soils. The methodology we developed provided an evaluation of the contribution of local sources (road traffic, local industries) versus remote sources (long range atmospheric transport, fallout and gaseous exchanges) to PAH stocks in two contrasting subcatchments (46-614 km²) of the Seine River basin (France). Soil samples (n = 336) were analysed to investigate the spatial pattern of soil contamination across the catchments and an original combination with radionuclide measurements provided new insights into the evolution of the contamination with depth. Relationships between PAH concentrations and the distance to the potential sources were modelled. Despite both subcatchments are mainly rural, roadside areas appeared to concentrate 20% of the contamination inside the catchment while a local industry was found to be responsible for up to 30% of the stocks. Those results have important implications for understanding and controlling PAH contamination in rural areas of early-industrialized regions. PMID:24662001

  5. Differences in the ability to suppress interferon β production between allele A and allele B NS1 proteins from H10 influenza A viruses

    PubMed Central

    2010-01-01

    Background In our previous study concerning the genetic relationship among H10 avian influenza viruses with different pathogenicity in mink (Mustela vison), we found that these differences were related to amino acid variations in the NS1 protein. In this study, we extend our previous work to further investigate the effect of the NS1 from different gene pools on type I IFN promoter activity, the production of IFN-β, as well as the expression of the IFN-β mRNA in response to poly I:C. Results Using a model system, we first demonstrated that NS1 from A/mink/Sweden/84 (H10N4) (allele A) could suppress an interferon-stimulated response element (ISRE) reporter system to about 85%. The other NS1 (allele B), from A/chicken/Germany/N/49 (H10N7), was also able to suppress the reporter system, but only to about 20%. The differences in the abilities of the two NS1s from different alleles to suppress the ISRE reporter system were clearly reflected by the protein and mRNA expressions of IFN-β as shown by ELISA and RT-PCR assays. Conclusions These studies reveal that different non-structural protein 1 (NS1) of influenza viruses, one from allele A and another from allele B, show different abilities to suppress the type I interferon β expression. It has been hypothesised that some of the differences in the different abilities of the alleles to suppress ISRE were because of the interactions and inhibitions at later stages from the IFN receptor, such as the JAK/STAT pathway. This might reflect the additional effects of the immune evasion potential of different NS1s. PMID:21194454

  6. [Contrast sensitivity in glaucoma].

    PubMed

    Bartos, D

    1989-05-01

    Author reports on results of the contrast sensitivity examinations using the Cambridge low-contrast lattice test supplied by Clement Clarke International LTD, in patients with open-angle glaucoma and ocular hypertension. In glaucoma patients there was observed statistically significant decrease of the contrast sensitivity. In patients with ocular hypertension decrease of the contrast sensitivity was in patients affected by corresponding changes of the visual field and of the optical disc. The main advantages of the Cambridge low-contrast lattice test were simplicity, rapidity and precision of its performance. PMID:2743444

  7. Inferring the age of a fixed beneficial allele.

    PubMed

    Ormond, Louise; Foll, Matthieu; Ewing, Gregory B; Pfeifer, Susanne P; Jensen, Jeffrey D

    2016-01-01

    Estimating the age and strength of beneficial alleles is central to understanding how adaptation proceeds in response to changing environmental conditions. Several haplotype-based estimators exist for inferring the age of segregating beneficial mutations. Here, we develop an approximate Bayesian-based approach that rather estimates these parameters for fixed beneficial mutations in single populations. We integrate a range of existing diversity, site frequency spectrum, haplotype- and linkage disequilibrium-based summary statistics. We show that for strong selective sweeps on de novo mutations the method can estimate allele age and selection strength even in nonequilibrium demographic scenarios. We extend our approach to models of selection on standing variation, and co-infer the frequency at which selection began to act upon the mutation. Finally, we apply our method to estimate the age and selection strength of a previously identified mutation underpinning cryptic colour adaptation in a wild deer mouse population, and compare our findings with previously published estimates as well as with geological data pertaining to the presumed shift in selective pressure. PMID:26576754

  8. Assessment of allele-specific gene silencing by RNA interference with mutant and wild-type reporter alleles.

    PubMed

    Ohnishi, Yusuke; Tokunaga, Katsushi; Kaneko, Kiyotoshi; Hohjoh, Hirohiko

    2006-02-28

    Allele-specific gene silencing by RNA interference (RNAi) is therapeutically useful for specifically suppressing the expression of alleles associated with disease. To realize such allele-specific RNAi (ASPRNAi), the design and assessment of small interfering RNA (siRNA) duplexes conferring ASP-RNAi is vital, but is also difficult. Here, we show ASP-RNAi against the Swedish- and London-type amyloid precursor protein (APP) variants related to familial Alzheimer's disease using two reporter alleles encoding the Photinus and Renilla luciferase genes and carrying mutant and wild-type allelic sequences in their 3'-untranslated regions. We examined the effects of siRNA duplexes against the mutant alleles in allele-specific gene silencing and off-target silencing against the wild-type allele under heterozygous conditions, which were generated by cotransfecting the reporter alleles and siRNA duplexes into cultured human cells. Consistently, the siRNA duplexes determined to confer ASP-RNAi also inhibited the expression of the bona fide mutant APP and the production of either amyloid beta 40- or 42-peptide in Cos-7 cells expressing both the full-length Swedish- and wild-type APP alleles. The present data suggest that the system with reporter alleles may permit the preclinical assessment of siRNA duplexes conferring ASP-RNAi, and thus contribute to the design and selection of the most suitable of such siRNA duplexes.

  9. Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.

    PubMed

    Kiezun, Adam; Pulit, Sara L; Francioli, Laurent C; van Dijk, Freerk; Swertz, Morris; Boomsma, Dorret I; van Duijn, Cornelia M; Slagboom, P Eline; van Ommen, G J B; Wijmenga, Cisca; de Bakker, Paul I W; Sunyaev, Shamil R

    2013-01-01

    Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

  10. Microarrays for high-throughput genotyping of MICA alleles using allele-specific primer extension.

    PubMed

    Baek, I C; Jang, J-P; Choi, H-B; Choi, E-J; Ko, W-Y; Kim, T-G

    2013-10-01

    The role of major histocompatibility complex (MHC) class I chain-related gene A (MICA), a ligand of NKG2D, has been defined in human diseases by its allele associations with various autoimmune diseases, hematopoietic stem cell transplantation (HSCT) and cancer. This study describes a practical system to develop MICA genotyping by allele-specific primer extension (ASPE) on microarrays. From the results of 20 control primers, strict and reliable cut-off values of more than 30,000 mean fluorescence intensity (MFI) as positive and less than 3000 MFI as negative, were applied to select high-quality specific extension primers. Among 55 allele-specific primers, 44 primers could be initially selected as optimal primer. Through adjusting the length, six primers were improved. The other failed five primers were corrected by refractory modification. MICA genotypes by ASPE on microarrays showed the same results as those by nucleotide sequencing. On the basis of these results, ASPE on microarrays may provide high-throughput genotyping for MICA alleles for population studies, disease-gene associations and HSCT.

  11. DQB1*06:02 allele specific expression varies by allelic dosage, not narcolepsy status

    PubMed Central

    lachmi, Karin Weiner; Lin, Ling; Kornum, Birgitte Rahbek; Rico, Tom; Lo, Betty; Aran, Adi; Mignot, Emmanuel

    2012-01-01

    The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single allele HLA associations. In this study, we explored genome wide expression in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and found the largest differences between the groups to be in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did not reveal any difference, a result we explain by the lack of proper control of allelic diversity in Affymetrix HLA probes. Rather, a clear effect of DQB1*06:02 allelic dosage on DQB1*06:02 mRNA levels (1.65 fold) and protein (1.59 fold) could be demonstrated independent of the disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes. PMID:22326585

  12. DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status.

    PubMed

    Weiner Lachmi, Karin; Lin, Ling; Kornum, Birgitte Rahbek; Rico, Tom; Lo, Betty; Aran, Adi; Mignot, Emmanuel

    2012-04-01

    The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single-allele human leukocyte antigen (HLA) associations. In this study, we explored genome-wide expression in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and observed the largest differences between the groups in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did not reveal any difference, a result we explain by the lack of proper control of allelic diversity in Affymetrix HLA probes. Rather, a clear effect of DQB1*06:02 allelic dosage on DQB1*06:02 mRNA levels (1.65-fold) and protein (1.59-fold) could be demonstrated independent of disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain the increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes.

  13. Mixed allele malaria vaccines: Host protection and within-host selection

    PubMed Central

    Barclay, Victoria C.; Chan, Brian H.K.; Anders, Robin F.; Read, Andrew F.

    2008-01-01

    Malaria parasites are frequently polymorphic at the antigenic targets of many candidate vaccines, presumably as a consequence of selection pressure from protective immune responses. Conventional wisdom is therefore that vaccines directed against a single variant could select for non-target variants, rendering the vaccine useless. Many people have argued that a solution is to develop vaccines containing the products of more than one variant of the target. However, we are unaware of any evidence that multi-allele vaccines better protect hosts against parasites or morbidity. Moreover, selection of antigen-variants is not the only evolution that could occur in response to vaccination. Increased virulence could also be favored if more aggressive strains are less well controlled by vaccine-induced immunity. Virulence and antigenic identity have been confounded in all studies so far, and so we do not know formally from any animal or human studies whether vaccine failure has been due to evasion of protective responses by variants at target epitopes, or whether vaccines are just less good at protecting against more aggressive strains. Using the rodent malaria model Plasmodium chabaudi and recombinant apical membrane antigen-1 (AMA-1), we tested whether a bi-allelic vaccine afforded greater protection from parasite infection and morbidity than did vaccination with the component alleles alone. We also tested the effect of mono- and bi-allelic vaccination on within-host selection of mixed P. chabaudi infections, and whether parasite virulence mediates pathogen titres in immunized hosts. We found that vaccination with the bi-allelic AMA-1 formulation did not afford the host greater protection from parasite infection or morbidity than did mono-allelic AMA-1 immunization. Mono-allelic immunization increased the frequency of heterologous clones in mixed clone infections. There was no evidence that any type of immunization regime favored virulence. A single AMA-1 variant is a

  14. Haplotypic Background of a Private Allele at High Frequency in the Americas

    PubMed Central

    Schroeder, Kari B.; Jakobsson, Mattias; Crawford, Michael H.; Schurr, Theodore G.; Boca, Simina M.; Conrad, Donald F.; Tito, Raul Y.; Osipova, Ludmilla P.; Tarskaia, Larissa A.; Zhadanov, Sergey I.; Wall, Jeffrey D.; Pritchard, Jonathan K.; Malhi, Ripan S.; Smith, David G.; Rosenberg, Noah A.

    2009-01-01

    Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 single nucleotide polymorphisms across ∼500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the “American Modal Haplotype” (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared with that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all

  15. Correlation of quantitative dynamic contrast-enhanced MRI with microvascular density in necrotic, partial necrotic, and viable liver tumors in a rabbit model.

    PubMed

    Moon, Jungwon; Kim, Jae-Hun; Choi, Dongil; Yang, Jehoon; Lee, Min Woo; Choi, Yoon-La; Rhim, Hyunchul

    2016-01-01

    The purpose of this study was to examine the correlation of quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) with microvessel density (MVD) in necrotic, partial necrotic, and viable tumors using a rabbit VX2 liver tumor model. Nine rabbits were used for this study. The complete necrotic area (CNA), partial necrotic area (PNA), and viable tumor area (VTA) of liver tumors were experimentally induced by radiofrequency ablation (RFA). DCE-MRI data were processed based on the extended Kety model to estimate Ktrans, ve and vp parameters. The boundaries among CNA, PNA, and VTA were delineated based on H&E stain images, and MVD was assessed for each subregion of each VX2 tumor based. There were no correlations between ph-parameters (Ktrans, ve, and vp) and MVD for CNA. For PNA, the Ktrans values were positively correlated with the MVD (r = 0.8124, p < 0.001). For VTA, we found a positive correlation between Ktrans values and the MVD (r = 0.5743, p < 0.05). Measuring from both the PNA and the VTA, mean Ktrans values were positively correlated with mean MVD (r = 0.8470, p < 0.0001). In a rabbit VX2 liver tumor model, Ktrans values correlated well with MVD counts of PNA and VTA in liver tumors. PMID:27685133

  16. Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck.

    PubMed

    Balick, Daniel J; Do, Ron; Cassa, Christopher A; Reich, David; Sunyaev, Shamil R

    2015-08-01

    Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, [Formula: see text], where xi represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a BR indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection. PMID:26317225

  17. Allele identification for transcriptome-based population genomics in the invasive plant Centaurea solstitialis.

    PubMed

    Dlugosch, Katrina M; Lai, Zhao; Bonin, Aurélie; Hierro, José; Rieseberg, Loren H

    2013-02-01

    Transcriptome sequences are becoming more broadly available for multiple individuals of the same species, providing opportunities to derive population genomic information from these datasets. Using the 454 Life Science Genome Sequencer FLX and FLX-Titanium next-generation platforms, we generated 11-430 Mbp of sequence for normalized cDNA for 40 wild genotypes of the invasive plant Centaurea solstitialis, yellow starthistle, from across its worldwide distribution. We examined the impact of sequencing effort on transcriptome recovery and overlap among individuals. To do this, we developed two novel publicly available software pipelines: SnoWhite for read cleaning before assembly, and AllelePipe for clustering of loci and allele identification in assembled datasets with or without a reference genome. AllelePipe is designed specifically for cases in which read depth information is not appropriate or available to assist with disentangling closely related paralogs from allelic variation, as in transcriptome or previously assembled libraries. We find that modest applications of sequencing effort recover most of the novel sequences present in the transcriptome of this species, including single-copy loci and a representative distribution of functional groups. In contrast, the coverage of variable sites, observation of heterozygosity, and overlap among different libraries are all highly dependent on sequencing effort. Nevertheless, the information gained from overlapping regions was informative regarding coarse population structure and variation across our small number of population samples, providing the first genetic evidence in support of hypothesized invasion scenarios.

  18. Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck

    PubMed Central

    Balick, Daniel J.; Do, Ron; Cassa, Christopher A.; Reich, David; Sunyaev, Shamil R.

    2015-01-01

    Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, BR≡∑xipop1/∑xjpop2, where x i represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a B R indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection. PMID:26317225

  19. Structural analysis of substitution patterns in alleles of human immunoglobulin VH genes.

    PubMed

    Romo-González, Tania; Vargas-Madrazo, Enrique

    2005-05-01

    The diversity in repertoires of antibodies (Abs) needed in response to the antigen challenge is produced by evolutionary and somatic processes. The mechanisms operating at a somatic level have been studied in great detail. In contrast, neither the mechanisms nor the strategies of diversification at an evolutionary level have yet been understood in similar detail. Particularly, the substitution patterns in alleles of immunoglobulin genes (Igs) have not been systematically studied. Furthermore, there is a scarcity of studies which link the analysis at a genetic level of the diversification of repertoires with the structural consequences at the protein level of the changes in DNA information. For the purpose of systematically characterizing the strategies of evolutionary diversification through sequence variation at alleles, in this work, we built a database for all the alleles of the IGHV locus in humans reported until now. Based on these data, we performed diverse analyses of substitution patterns and linked these results with studies at the protein level. We found that the sequence diversification in different alleles does not operate with equal intensity for all V genes. Our studies, both of the number of substitutions and of the type of amino acid change per sub-segment of the V-REGION evidenced differences in the selective pressure to which these regions are exposed. The implications of these results for understanding the evolutionary diversification strategies, as well as for the somatic generation of antibody repertoires are discussed.

  20. Allele Identification for Transcriptome-Based Population Genomics in the Invasive Plant Centaurea solstitialis

    PubMed Central

    Dlugosch, Katrina M.; Lai, Zhao; Bonin, Aurélie; Hierro, José; Rieseberg, Loren H.

    2013-01-01

    Transcriptome sequences are becoming more broadly available for multiple individuals of the same species, providing opportunities to derive population genomic information from these datasets. Using the 454 Life Science Genome Sequencer FLX and FLX-Titanium next-generation platforms, we generated 11−430 Mbp of sequence for normalized cDNA for 40 wild genotypes of the invasive plant Centaurea solstitialis, yellow starthistle, from across its worldwide distribution. We examined the impact of sequencing effort on transcriptome recovery and overlap among individuals. To do this, we developed two novel publicly available software pipelines: SnoWhite for read cleaning before assembly, and AllelePipe for clustering of loci and allele identification in assembled datasets with or without a reference genome. AllelePipe is designed specifically for cases in which read depth information is not appropriate or available to assist with disentangling closely related paralogs from allelic variation, as in transcriptome or previously assembled libraries. We find that modest applications of sequencing effort recover most of the novel sequences present in the transcriptome of this species, including single-copy loci and a representative distribution of functional groups. In contrast, the coverage of variable sites, observation of heterozygosity, and overlap among different libraries are all highly dependent on sequencing effort. Nevertheless, the information gained from overlapping regions was informative regarding coarse population structure and variation across our small number of population samples, providing the first genetic evidence in support of hypothesized invasion scenarios. PMID:23390612

  1. Extensive allele-specific translational regulation in hybrid mice

    PubMed Central

    Hou, Jingyi; Wang, Xi; McShane, Erik; Zauber, Henrik; Sun, Wei; Selbach, Matthias; Chen, Wei

    2015-01-01

    Translational regulation is mediated through the interaction between diffusible trans-factors and cis-elements residing within mRNA transcripts. In contrast to extensively studied transcriptional regulation, cis-regulation on translation remains underexplored. Using deep sequencing-based transcriptome and polysome profiling, we globally profiled allele-specific translational efficiency for the first time in an F1 hybrid mouse. Out of 7,156 genes with reliable quantification of both alleles, we found 1,008 (14.1%) exhibiting significant allelic divergence in translational efficiency. Systematic analysis of sequence features of the genes with biased allelic translation revealed that local RNA secondary structure surrounding the start codon and proximal out-of-frame upstream AUGs could affect translational efficiency. Finally, we observed that the cis-effect was quantitatively comparable between transcriptional and translational regulation. Such effects in the two regulatory processes were more frequently compensatory, suggesting that the regulation at the two levels could be coordinated in maintaining robustness of protein expression. PMID:26253569

  2. Allele identification for transcriptome-based population genomics in the invasive plant Centaurea solstitialis.

    PubMed

    Dlugosch, Katrina M; Lai, Zhao; Bonin, Aurélie; Hierro, José; Rieseberg, Loren H

    2013-02-01

    Transcriptome sequences are becoming more broadly available for multiple individuals of the same species, providing opportunities to derive population genomic information from these datasets. Using the 454 Life Science Genome Sequencer FLX and FLX-Titanium next-generation platforms, we generated 11-430 Mbp of sequence for normalized cDNA for 40 wild genotypes of the invasive plant Centaurea solstitialis, yellow starthistle, from across its worldwide distribution. We examined the impact of sequencing effort on transcriptome recovery and overlap among individuals. To do this, we developed two novel publicly available software pipelines: SnoWhite for read cleaning before assembly, and AllelePipe for clustering of loci and allele identification in assembled datasets with or without a reference genome. AllelePipe is designed specifically for cases in which read depth information is not appropriate or available to assist with disentangling closely related paralogs from allelic variation, as in transcriptome or previously assembled libraries. We find that modest applications of sequencing effort recover most of the novel sequences present in the transcriptome of this species, including single-copy loci and a representative distribution of functional groups. In contrast, the coverage of variable sites, observation of heterozygosity, and overlap among different libraries are all highly dependent on sequencing effort. Nevertheless, the information gained from overlapping regions was informative regarding coarse population structure and variation across our small number of population samples, providing the first genetic evidence in support of hypothesized invasion scenarios. PMID:23390612

  3. Contrasting strategic and Milan therapies.

    PubMed

    MacKinnon, L

    1983-12-01

    Three related models of therapy are often grouped together as the strategic therapies. These are brief therapy model associated with the Mental Research Institute, approaches developed by Jay Haley and Cloë Madanes, and the model developed by the Milan associates. Controversy exists, however, as to whether the Milan model should be included as a strategic therapy. It appears that the similarities among the three models can mask deeper differences, thus confounding the confusion. This paper contrast the models in their development, theory, and practice.

  4. The rs1024611 regulatory region polymorphism is associated with CCL2 allelic expression imbalance.

    PubMed

    Pham, Minh-Hieu T; Bonello, Gregory B; Castiblanco, John; Le, Tuan; Sigala, Jose; He, Weijing; Mummidi, Srinivas

    2012-01-01

    CC chemokine ligand 2 (CCL2) is the most potent monocyte chemoattractant and inter-individual differences in its expression level have been associated with genetic variants mapping to the cis-regulatory regions of the gene. An A to G polymorphism in the CCL2 enhancer region at position -2578 (rs1024611; A>G), was found in most studies to be associated with higher serum CCL2 levels and increased susceptibility to a variety of diseases such as HIV-1 associated neurological disorders, tuberculosis, and atherosclerosis. However, the precise mechanism by which rs1024611influences CCL2 expression is not known. To address this knowledge gap, we tested the hypothesis that rs1024611G polymorphism is associated with allelic expression imbalance (AEI) of CCL2. We used haplotype analysis and identified a transcribed SNP in the 3'UTR (rs13900; C>T) can serve as a proxy for the rs1024611 and demonstrated that the rs1024611G allele displayed a perfect linkage disequilibrium with rs13900T allele. Allele-specific transcript quantification in lipopolysaccharide treated PBMCs obtained from heterozygous donors showed that rs13900T allele were expressed at higher levels when compared to rs13900C allele in all the donors examined suggesting that CCL2 is subjected to AEI and that that the allele containing rs1024611G is preferentially transcribed. We also found that AEI of CCL2 is a stable trait and could be detected in newly synthesized RNA. In contrast to these in vivo findings, in vitro assays with haplotype-specific reporter constructs indicated that the haplotype bearing rs1024611G had a lower or similar transcriptional activity when compared to the haplotype containing rs1024611A. This discordance between the in vivo and in vitro expression studies suggests that the CCL2 regulatory region polymorphisms may be functioning in a complex and context-dependent manner. In summary, our studies provide strong functional evidence and a rational explanation for the phenotypic effects of the

  5. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.

    PubMed

    Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J; Smith, Conor; LaDu, Mary Jo; Sullivan, Patrick M; Morgan, Todd E; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olof; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E

    2016-01-01

    The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition. PMID:26686669

  6. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.

    PubMed

    Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J; Smith, Conor; LaDu, Mary Jo; Sullivan, Patrick M; Morgan, Todd E; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olof; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E

    2016-01-01

    The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

  7. Contrasting two models of academic self-efficacy--domain-specific versus cross-domain--in children receiving and not receiving special instruction in mathematics.

    PubMed

    Jungert, Tomas; Hesser, Hugo; Träff, Ulf

    2014-10-01

    In social cognitive theory, self-efficacy is domain-specific. An alternative model, the cross-domain influence model, would predict that self-efficacy beliefs in one domain might influence performance in other domains. Research has also found that children who receive special instruction are not good at estimating their performance. The aim was to test two models of how self-efficacy beliefs influence achievement, and to contrast children receiving special instruction in mathematics with normally-achieving children. The participants were 73 fifth-grade children who receive special instruction and 70 children who do not receive any special instruction. In year four and five, the children's skills in mathematics and reading were assessed by national curriculum tests, and in their fifth year, self-efficacy in mathematics and reading were measured. Structural equation modeling showed that in domains where children do not receive special instruction in mathematics, self-efficacy is a mediating variable between earlier and later achievement in the same domain. Achievement in mathematics was not mediated by self-efficacy in mathematics for children who receive special instruction. For normal achieving children, earlier achievement in the language domain had an influence on later self-efficacy in the mathematics domain, and self-efficacy beliefs in different domains were correlated. Self-efficacy is mostly domain specific, but may play a different role in academic performance depending on whether children receive special instruction. The results of the present study provided some support of the Cross-Domain Influence Model for normal achieving children.

  8. PCR Strategies for Complete Allele Calling in Multigene Families Using High-Throughput Sequencing Approaches

    PubMed Central

    Marmesat, Elena; Soriano, Laura; Mazzoni, Camila J.; Sommer, Simone

    2016-01-01

    The characterization of multigene families with high copy number variation is often approached through PCR amplification with highly degenerate primers to account for all expected variants flanking the region of interest. Such an approach often introduces PCR biases that result in an unbalanced representation of targets in high-throughput sequencing libraries that eventually results in incomplete detection of the targeted alleles. Here we confirm this result and propose two different amplification strategies to alleviate this problem. The first strategy (called pooled-PCRs) targets different subsets of alleles in multiple independent PCRs using different moderately degenerate primer pairs, whereas the second approach (called pooled-primers) uses a custom-made pool of non-degenerate primers in a single PCR. We compare their performance to the common use of a single PCR with highly degenerate primers using the MHC class I of the Iberian lynx as a model. We found both novel approaches to work similarly well and better than the conventional approach. They significantly scored more alleles per individual (11.33 ± 1.38 and 11.72 ± 0.89 vs 7.94 ± 1.95), yielded more complete allelic profiles (96.28 ± 8.46 and 99.50 ± 2.12 vs 63.76 ± 15.43), and revealed more alleles at a population level (13 vs 12). Finally, we could link each allele’s amplification efficiency with the primer-mismatches in its flanking sequences and show that ultra-deep coverage offered by high-throughput technologies does not fully compensate for such biases, especially as real alleles may reach lower coverage than artefacts. Adopting either of the proposed amplification methods provides the opportunity to attain more complete allelic profiles at lower coverages, improving confidence over the downstream analyses and subsequent applications. PMID:27294261

  9. Allele-Specific Quantitative PCR for Accurate, Rapid, and Cost-Effective Genotyping.

    PubMed

    Lee, Han B; Schwab, Tanya L; Koleilat, Alaa; Ata, Hirotaka; Daby, Camden L; Cervera, Roberto Lopez; McNulty, Melissa S; Bostwick, Hannah S; Clark, Karl J

    2016-06-01

    Customizable endonucleases such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) enable rapid generation of mutant strains at genomic loci of interest in animal models and cell lines. With the accelerated pace of generating mutant alleles, genotyping has become a rate-limiting step to understanding the effects of genetic perturbation. Unless mutated alleles result in distinct morphological phenotypes, mutant strains need to be genotyped using standard methods in molecular biology. Classic restriction fragment length polymorphism (RFLP) or sequencing is labor-intensive and expensive. Although simpler than RFLP, current versions of allele-specific PCR may still require post-polymerase chain reaction (PCR) handling such as sequencing, or they are more expensive if allele-specific fluorescent probes are used. Commercial genotyping solutions can take weeks from assay design to result, and are often more expensive than assembling reactions in-house. Key components of commercial assay systems are often proprietary, which limits further customization. Therefore, we developed a one-step open-source genotyping method based on quantitative PCR. The allele-specific qPCR (ASQ) does not require post-PCR processing and can genotype germline mutants through either threshold cycle (Ct) or end-point fluorescence reading. ASQ utilizes allele-specific primers, a locus-specific reverse primer, universal fluorescent probes and quenchers, and hot start DNA polymerase. Individual laboratories can further optimize this open-source system as we completely disclose the sequences, reagents, and thermal cycling protocol. We have tested the ASQ protocol to genotype alleles in five different genes. ASQ showed a 98-100% concordance in genotype scoring with RFLP or Sanger sequencing outcomes. ASQ is time-saving because a single qPCR without post-PCR handling suffices to score

  10. Allele-Specific Quantitative PCR for Accurate, Rapid, and Cost-Effective Genotyping.

    PubMed

    Lee, Han B; Schwab, Tanya L; Koleilat, Alaa; Ata, Hirotaka; Daby, Camden L; Cervera, Roberto Lopez; McNulty, Melissa S; Bostwick, Hannah S; Clark, Karl J

    2016-06-01

    Customizable endonucleases such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) enable rapid generation of mutant strains at genomic loci of interest in animal models and cell lines. With the accelerated pace of generating mutant alleles, genotyping has become a rate-limiting step to understanding the effects of genetic perturbation. Unless mutated alleles result in distinct morphological phenotypes, mutant strains need to be genotyped using standard methods in molecular biology. Classic restriction fragment length polymorphism (RFLP) or sequencing is labor-intensive and expensive. Although simpler than RFLP, current versions of allele-specific PCR may still require post-polymerase chain reaction (PCR) handling such as sequencing, or they are more expensive if allele-specific fluorescent probes are used. Commercial genotyping solutions can take weeks from assay design to result, and are often more expensive than assembling reactions in-house. Key components of commercial assay systems are often proprietary, which limits further customization. Therefore, we developed a one-step open-source genotyping method based on quantitative PCR. The allele-specific qPCR (ASQ) does not require post-PCR processing and can genotype germline mutants through either threshold cycle (Ct) or end-point fluorescence reading. ASQ utilizes allele-specific primers, a locus-specific reverse primer, universal fluorescent probes and quenchers, and hot start DNA polymerase. Individual laboratories can further optimize this open-source system as we completely disclose the sequences, reagents, and thermal cycling protocol. We have tested the ASQ protocol to genotype alleles in five different genes. ASQ showed a 98-100% concordance in genotype scoring with RFLP or Sanger sequencing outcomes. ASQ is time-saving because a single qPCR without post-PCR handling suffices to score

  11. Allele-Specific Quantitative PCR for Accurate, Rapid, and Cost-Effective Genotyping

    PubMed Central

    Lee, Han B.; Schwab, Tanya L.; Koleilat, Alaa; Ata, Hirotaka; Daby, Camden L.; Cervera, Roberto Lopez; McNulty, Melissa S.; Bostwick, Hannah S.; Clark, Karl J.

    2016-01-01

    Customizable endonucleases such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) enable rapid generation of mutant strains at genomic loci of interest in animal models and cell lines. With the accelerated pace of generating mutant alleles, genotyping has become a rate-limiting step to understanding the effects of genetic perturbation. Unless mutated alleles result in distinct morphological phenotypes, mutant strains need to be genotyped using standard methods in molecular biology. Classic restriction fragment length polymorphism (RFLP) or sequencing is labor-intensive and expensive. Although simpler than RFLP, current versions of allele-specific PCR may still require post-polymerase chain reaction (PCR) handling such as sequencing, or they are more expensive if allele-specific fluorescent probes are used. Commercial genotyping solutions can take weeks from assay design to result, and are often more expensive than assembling reactions in-house. Key components of commercial assay systems are often proprietary, which limits further customization. Therefore, we developed a one-step open-source genotyping method based on quantitative PCR. The allele-specific qPCR (ASQ) does not require post-PCR processing and can genotype germline mutants through either threshold cycle (Ct) or end-point fluorescence reading. ASQ utilizes allele-specific primers, a locus-specific reverse primer, universal fluorescent probes and quenchers, and hot start DNA polymerase. Individual laboratories can further optimize this open-source system as we completely disclose the sequences, reagents, and thermal cycling protocol. We have tested the ASQ protocol to genotype alleles in five different genes. ASQ showed a 98–100% concordance in genotype scoring with RFLP or Sanger sequencing outcomes. ASQ is time-saving because a single qPCR without post-PCR handling suffices to score

  12. Carbonated Eclogite Solidus Between 14 and 20 GPa: Results from the Model CMAS-CO2 System and Contrasting Solidus Behavior to Carbonated Peridotite

    NASA Astrophysics Data System (ADS)

    Keshav, S.; Gudfinnsson, G. H.

    2007-12-01

    , and magnesite. From average calculated melting reactions along these isobarically univariant curves, stishovite is produced upon melting at all pressures investigated. Significantly, cpx at 14 and 16 GPa and capv at 20 GPa are the dominant contributors toward melt production/composition, in contrast to lower pressures (3-8 GPa) where carbonate dominantly contributes toward melt generation/composition at the solidus. The solidus of model carbonated eclogite at 14, 16, and 20 GPa, lies at 1350, 1450, and 1600 degrees C, respectively, and is nearly linear in P-T space. Melts in equilibrium with all the crystalline phases are highly calcic (Ca no.-0.70), resembling calcio-carbonatites. When magnesite is exhausted from the crystalline assemblage, the melts become slightly less calcic (Ca no.-65). The model carbonated eclogite solidus is always lower than the model carbonated peridotite solidus in the same pressure range. The most remarkable feature of this work is the absence of a drop in the solidus of model carbonated eclogite between 14 and 16 GPa, a result that is in stark contrast to that observed for the model carbonated peridotite at identical pressures. Therefore, even though the solidus temperatures in both carbonated peridotite and eclogite are strongly influenced by the presence of crystalline carbonate, melt compositions and the shape of the solidus in the pressure range investigated seem to be dominantly controlled by the silicate component of the rock in question. Given these results, it is fair to say that a wide range of petrological and geochemical processes operate at these depths in the mantle, and that we have barely scratched the surface in our investigation.

  13. Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector

    PubMed Central

    Ibrahim, Sulaiman S.; Riveron, Jacob M.; Bibby, Jaclyn; Irving, Helen; Yunta, Cristina; Paine, Mark J. I.; Wondji, Charles S.

    2015-01-01

    Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies. PMID:26517127

  14. Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector.

    PubMed

    Ibrahim, Sulaiman S; Riveron, Jacob M; Bibby, Jaclyn; Irving, Helen; Yunta, Cristina; Paine, Mark J I; Wondji, Charles S

    2015-10-01

    Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies. PMID:26517127

  15. Kinetic analysis of superparamagnetic iron oxide nanoparticles in the liver of body-temperature-controlled mice using dynamic susceptibility contrast magnetic resonance imaging and an empirical mathematical model.

    PubMed

    Murase, Kenya; Assanai, Purapan; Takata, Hiroshige; Matsumoto, Nozomi; Saito, Shigeyoshi; Nishiura, Motoko

    2015-06-01

    The purpose of this study was to develop a method for analyzing the kinetic behavior of superparamagnetic iron oxide nanoparticles (SPIONs) in the murine liver under control of body temperature using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) and an empirical mathematical model (EMM). First, we investigated the influence of body temperature on the kinetic behavior of SPIONs in the liver by controlling body temperature using our temperature-control system. Second, we investigated the kinetic behavior of SPIONs in the liver when mice were injected with various doses of GdCl3, while keeping the body temperature at 36°C. Finally, we investigated it when mice were injected with various doses of zymosan, while keeping the body temperature at 36°C. We also investigated the effect of these substances on the number of Kupffer cells by immunohistochemical analysis using the specific surface antigen of Kupffer cells (CD68). To quantify the kinetic behavior of SPIONs in the liver, we calculated the upper limit of the relative enhancement (A), the rates of early contrast uptake (α) and washout or late contrast uptake (β), the parameter related to the slope of early uptake (q), the area under the curve (AUC), the maximum change of transverse relaxation rate (ΔR2) (ΔR2(max)), the time to ΔR2(max) (Tmax), and ΔR2 at the last time point (ΔR2(last)) from the time courses of ΔR2 using the EMM. The β and Tmax values significantly decreased and increased, respectively, with decreasing body temperature, suggesting that the phagocytic activity of Kupffer cells is significantly affected by body temperature. The AUC, ΔR2(max), and ΔR2(last) values decreased significantly with increasing dose of GdCl3, which was consistent with the change in the number of CD68-positive cells. They increased with increasing dose of zymosan, which was also consistent with the change in the number of CD68-positive cells. These results suggest that AUC, ΔR2(max), and ΔR2

  16. Measurement of glomerular filtration rate by dynamic contrast-enhanced magnetic resonance imaging using a subject-specific two-compartment model.

    PubMed

    Tipirneni-Sajja, Aaryani; Loeffler, Ralf B; Oesingmann, Niels; Bissler, John; Song, Ruitian; McCarville, Beth; Jones, Deborah P; Hudson, Melissa; Spunt, Sheri L; Hillenbrand, Claudia M

    2016-04-01

    Measuring glomerular filtration rate (GFR) by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as part of standard of care clinicalMRIexams (e.g., in pediatric solid tumor patients) has the potential to reduce diagnostic burden. However, enthusiasm for this relatively newGFRtest may be curbed by the limited amount of cross-calibration studies with referenceGFRtechniques and the vast variety ofMRtracer model algorithms causing confusion on the choice of model. To advanceMRI-basedGFRquantification via improvedGFRmodeling and comparison with associated(99m)Tc-DTPA-GFR, 29 long-term Wilms' tumor survivors (19.0-43.3 years, [median 32.0 ± 6.0 years]) treated with nephrectomy, nonnephrotoxic chemotherapy ± radiotherapy underwentMRIwith Gd-DTPAadministration and a(99m)Tc-DTPA GFRtest. ForDCE-MRI-basedGFRestimation, a subject-specific two-compartment (SS-2C) model was developed that uses individual hematocrit values, automatically defines subject-specific uptake intervals, and fits tracer-uptake curves by incorporating these measures. The association between reference(99m)Tc-DTPA GFRandMR-GFRs obtained bySS-2C, three published 2C uptake, and inflow-outflow models was investigated via linear regression analysis. Uptake intervals varied from 64 sec to 141 sec [96 sec ± 21 sec] and hematocrit values ranged from 30% to 49% [41% ± 4%]; these parameters can therefore not be assumed as constants in 2C modeling. OurMR-GFRestimates using theSS-2C model showed accordingly the highest correlation with(99m)Tc-DTPA-GFRs (R(2) = 0.76,P < 0.001) compared with other models (R(2)-range: 0.36-0.66). In conclusion,SS-2C modeling ofDCE-MRIdata improved the association betweenGFRobtained by(99m)Tc-DTPAand Gd-DTPA DCE-MRIto such a degree that this approach could turn into a viable, diagnosticGFRassay without radiation exposure to the patient.

  17. Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations

    PubMed Central

    Vina, Marcelo A. Fernandez; Hollenbach, Jill A.; Lyke, Kirsten E.; Sztein, Marcelo B.; Maiers, Martin; Klitz, William; Cano, Pedro; Mack, Steven; Single, Richard; Brautbar, Chaim; Israel, Shosahna; Raimondi, Eduardo; Khoriaty, Evelyne; Inati, Adlette; Andreani, Marco; Testi, Manuela; Moraes, Maria Elisa; Thomson, Glenys; Stastny, Peter; Cao, Kai

    2012-01-01

    The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans. PMID:22312049

  18. Four novel PEPD alleles causing prolidase deficiency

    SciTech Connect

    Ledoux, P.; Scriver, C.; Hechtman, P. )

    1994-06-01

    Mutations at the PEPD locus cause prolidase (an enzyme specific for proline- and hydroxyproline-terminated dipeptides) deficiency (McKusick 170100), a rare autosomal recessive disorder characterized by iminodipeptiduria, skin ulcers, mental retardation, and recurrent infections. Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse-transcribed, PCR-amplified (RT-PCR) cDNA. The authors used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragments spanning all or part of exons 13-15 in three of the probands. Direct sequencing of the mutant cDNAs showed a G[yields]A, 1342 substitution (G448R) in two patients and a 3-bp deletion ([Delta]E452 or [Delta]E453) in another. In the other two probands the amplified products were of reduced size. Direct sequencing of these mutant cDNAs revealed a deletion of exon 5 in one patient and of exon 7 in the other. Intronic sequences flanking exons 5 and 7 were identified using inverse PCR followed by direct sequencing. Conventional PCR and direct sequencing then established the intron-exon borders of the mutant genomic DNA revealing two splice acceptor mutations: a G[yields]C substitution at position -1 of intron 4 and an A[yields]G substitution at position -2 of intron 6. The results indicate that the severe form of prolidase deficiency is caused by multiple PEPD alleles. In this report the authors attempt to begin the process of describing these alleles and cataloging their phenotype expression. 31 refs., 8 figs., 2 tabs.

  19. Experimental validation of a simple model capable of predicting the phase contrast imaging capabilities of any x-ray imaging system

    NASA Astrophysics Data System (ADS)

    Olivo, A.; Speller, R.

    2006-06-01

    Phase contrast (PC) imaging is one of the most exciting emerging x-ray imaging techniques, with the potential of removing some of the main limitations of conventional radiology. After extensive experimentation carried out particularly at synchrotron radiation (SR) facilities, the scientific community agrees that it is now time to translate these ideas towards the first clinical implementations. In this framework, a complete model, based on Fresnel/Kirchoff diffraction integrals, was devised. This model accounts for source dimensions, beam spectrum and divergence and detector point spread function (PSF), and can thus be applied to any x-ray imaging system. In particular, by accepting in input the above parameters along with the ones describing the sample, the model can be used to optimize the geometry of the set-up, i.e. to assess the source-to-sample and sample-to-detector distances which maximize feature detection. The model was evaluated by acquiring a range of images of different samples with a laboratory source, and a good agreement was found between simulated and experimental data in all cases. In order to maximize the generality of the results, all acquisitions were carried out using a polychromatic source and an energy-resolving detector; in this way, a range of monochromatic images could be obtained as well as polychromatic images, which can be created by integrating different parts of the acquired spectra. One of the most notable results obtained is that in many practical cases polychromatic PC imaging can provide the same image quality as its monochromatic counterpart. This is an important step in the wider application of PC using conventional sources.

  20. Contrast Intravasation During Hysterosalpingography

    PubMed Central

    Bhoil, Rohit; Sood, Dinesh; Sharma, Tanupriya; Sood, Shilpa; Sharma, Jiten; Kumar, Nitesh; Ahluwalia, Ajay; Parekh, Dipen; Mistry, Kewal A.; Sood, Saurav

    2016-01-01

    Summary Hysterosalpingography is an imaging method to evaluate the endometrial and uterine morphology and fallopian tube patency. Contrast intravasation implies backflow of injected contrast into the adjoining vessels mostly the veins and may be related to factors altering endometrial vascularity and permeability. Radiologists and gynaecologists should be well acquainted with the technique of hysterosalpingography, its interpretation, and intravasation of contrast agents for safer procedure and to minimize the associated complications. PMID:27279925

  1. Automatic segmentation of the liver using multi-planar anatomy and deformable surface model in abdominal contrast-enhanced CT images

    NASA Astrophysics Data System (ADS)

    Jang, Yujin; Hong, Helen; Chung, Jin Wook; Yoon, Young Ho

    2012-02-01

    We propose an effective technique for the extraction of liver boundary based on multi-planar anatomy and deformable surface model in abdominal contrast-enhanced CT images. Our method is composed of four main steps. First, for extracting an optimal volume circumscribing a liver, lower and side boundaries are defined by positional information of pelvis and rib. An upper boundary is defined by separating the lungs and heart from CT images. Second, for extracting an initial liver volume, optimal liver volume is smoothed by anisotropic diffusion filtering and is segmented using adaptively selected threshold value. Third, for removing neighbor organs from initial liver volume, morphological opening and connected component labeling are applied to multiple planes. Finally, for refining the liver boundaries, deformable surface model is applied to a posterior liver surface and missing left robe in previous step. Then, probability summation map is generated by calculating regional information of the segmented liver in coronal plane, which is used for restoring the inaccurate liver boundaries. Experimental results show that our segmentation method can accurately extract liver boundaries without leakage to neighbor organs in spite of various liver shape and ambiguous boundary.

  2. Different evolutionary pathway of B*570101 and B*5801 (B17 group) alleles based in intron sequences.

    PubMed

    Martinez-Laso, Jorge; Moscoso, Juan; Zamora, Jorge; Martin-Villa, Manuel; Lowy, Ernesto; Vargas-Alarcon, Gilberto; Serrano-Vela, Juan Ignacio; Gomez-Casado, Eduardo; Arnaiz-Villena, Antonio

    2004-03-01

    Two theories about MHC allele generation have been put forward: (1) point mutation diversification and/or (2) gene conversion events. A model supporting the existence of both of these mechanisms is shown in this paper; the possible evolution of the HLA-B*570101 and HLA-B*5801 alleles (which belong to the HLA-B17 serology group) is studied. The hypothesis favoured is that gene conversion events have originated these alleles, because intron sequences are also analysed. Evolution by point mutation should only be accepted if flanking introns have also been sequenced.

  3. Alleles versus genotypes: Genetic interactions and the dynamics of selection in sexual populations

    NASA Astrophysics Data System (ADS)

    Neher, Richard

    2010-03-01

    Physical interactions between amino-acids are essential for protein structure and activity, while protein-protein interactions and regulatory interactions are central to cellular function. As a consequence of these interactions, the combined effect of two mutations can differ from the sum of the individual effects of the mutations. This phenomenon of genetic interaction is known as epistasis. However, the importance of epistasis and its effects on evolutionary dynamics are poorly understood, especially in sexual populations where recombination breaks up existing combinations of alleles to produce new ones. Here, we present a computational model of selection dynamics involving many epistatic loci in a recombining population. We demonstrate that a large number of polymorphic interacting loci can, despite frequent recombination, exhibit cooperative behavior that locks alleles into favorable genotypes leading to a population consisting of a set of competing clones. As the recombination rate exceeds a certain critical value this ``genotype selection'' phase disappears in an abrupt transition giving way to ``allele selection'' - the phase where different loci are only weakly correlated as expected in sexually reproducing populations. Clustering of interacting sets of genes on a chromosome leads to the emergence of an intermediate regime, where localized blocks of cooperating alleles lock into genetic modules. Large populations attain highest fitness at a recombination rate just below critical, suggesting that natural selection might tune recombination rates to balance the beneficial aspect of exploration of genotype space with the breaking up of synergistic allele combinations.

  4. HLA-DR alleles in amyloid beta-peptide autoimmunity: a highly immunogenic role for the DRB1*1501 allele.

    PubMed

    Zota, Victor; Nemirovsky, Anna; Baron, Rona; Fisher, Yair; Selkoe, Dennis J; Altmann, Daniel M; Weiner, Howard L; Monsonego, Alon

    2009-09-01

    Active amyloid beta-peptide (Abeta) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in approximately 6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Abeta Ab responses, which correlate with the extent of Abeta clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Abeta T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with Abeta-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of Abeta. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Abeta challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-gamma and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, Abeta was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific Abeta T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Abeta-reactive T cells and Abeta immunogenicity among humans.

  5. BMI-Associated Alleles Do Not Constitute Risk Alleles for Polycystic Ovary Syndrome Independently of BMI: A Case-Control Study

    PubMed Central

    Louwers, Yvonne V.; Rayner, Nigel W.; Herrera, Blanca M.; Stolk, Lisette; Groves, Christopher J.; Barber, Thomas M.; Uitterlinden, Andre G.; Franks, Stephen

    2014-01-01

    Introduction Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Methods Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. Results None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. Conclusion In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI. PMID:24498077

  6. A novel HLA-A allele: A*0257.

    PubMed

    García-Ortiz, J E; Cox, S T; Sandoval-Ramirez, L; Little, A M; Marsh, S G E; Madrigal, J A; Argüello, J R

    2004-01-01

    A novel human leucocyte antigen-A*02 (HLA-A*02) allele was detected by reference strand-mediated conformation analysis (RSCA) of a DNA sample from a Tarahumara individual. Direct sequencing of HLA-A locus polymerase chain reaction products identified a mutation in one of the alleles. Cloning and sequencing confirmed the presence of a new allele, A*0257 which differed from A*0206 by two nucleotides at positions 355 and 362, inducing changes in residues 95 and 97, respectively, within the peptide-binding site. Those changes suggest that allele A*0257 may have resulted from an intralocus recombination event.

  7. Mutated tumor alleles are expressed according to their DNA frequency.

    PubMed

    Castle, John C; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2014-04-22

    The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

  8. Nomenclature for human CYP2D6 alleles.

    PubMed

    Daly, A K; Brockmöller, J; Broly, F; Eichelbaum, M; Evans, W E; Gonzalez, F J; Huang, J D; Idle, J R; Ingelman-Sundberg, M; Ishizaki, T; Jacqz-Aigrain, E; Meyer, U A; Nebert, D W; Steen, V M; Wolf, C R; Zanger, U M

    1996-06-01

    To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented. PMID:8807658

  9. A noncomplementation screen for quantitative trait alleles in saccharomyces cerevisiae.

    PubMed

    Kim, Hyun Seok; Huh, Juyoung; Riles, Linda; Reyes, Alejandro; Fay, Justin C

    2012-07-01

    Both linkage and linkage disequilibrium mapping provide well-defined approaches to mapping quantitative trait alleles. However, alleles of small effect are particularly difficult to refine to individual genes and causative mutations. Quantitative noncomplementation provides a means of directly testing individual genes for quantitative trait alleles in a fixed genetic background. Here, we implement a genome-wide noncomplementation screen for quantitative trait alleles that affect colony color or size by using the yeast deletion collection. As proof of principle, we find a previously known allele of CYS4 that affects colony color and a novel allele of CTT1 that affects resistance to hydrogen peroxide. To screen nearly 4700 genes in nine diverse yeast strains, we developed a high-throughput robotic plating assay to quantify colony color and size. Although we found hundreds of candidate alleles, reciprocal hemizygosity analysis of a select subset revealed that many of the candidates were false positives, in part the result of background-dependent haploinsufficiency or second-site mutations within the yeast deletion collection. Our results highlight the difficulty of identifying small-effect alleles but support the use of noncomplementation as a rapid means of identifying quantitative trait alleles of large effect. PMID:22870398

  10. Non-Equilibrium Allele Frequency Spectra Via Spectral Methods

    PubMed Central

    Hey, Jody; Chen, Kevin

    2011-01-01

    A major challenge in the analysis of population genomics data consists of isolating signatures of natural selection from background noise caused by random drift and gene flow. Analyses of massive amounts of data from many related populations require high-performance algorithms to determine the likelihood of different demographic scenarios that could have shaped the observed neutral single nucleotide polymorphism (SNP) allele frequency spectrum. In many areas of applied mathematics, Fourier Transforms and Spectral Methods are firmly established tools to analyze spectra of signals and model their dynamics as solutions of certain Partial Differential Equations (PDEs). When spectral methods are applicable, they have excellent error properties and are the fastest possible in high dimension; see [15]. In this paper we present an explicit numerical solution, using spectral methods, to the forward Kolmogorov equations for a Wright-Fisher process with migration of K populations, influx of mutations, and multiple population splitting events. PMID:21376069

  11. Tri-allelic pattern of short tandem repeats identifies the murderer among identical twins and suggests an embryonic mutational origin.

    PubMed

    Wang, Li-Feng; Yang, Ying; Zhang, Xiao-Nan; Quan, Xiao-Liang; Wu, Yuan-Ming

    2015-05-01

    Monozygotic twins can be co-identified by genotyping of short tandem repeats (STRs); however, for distinguishing them, STR genotyping is ineffective, especially in the case of murder. Here, a rarely occurring tri-allelic pattern in the vWA locus (16, 18, 19) was identified only in the DNA of one identical twin, which could help to exonerate the innocent twin in a murder charge. This mutation was defined as primary through genotyping of the family and could be detected in blood, buccal and semen samples from the individual; however, two alternative allele-balanced di-allelic patterns (16, 18 or 16, 19) were detected in hair root sheath cells. Such a kind of segregation indicates a one-step mutation occurs in cell mitosis, which is after embryonic zygote formation and during the early development of the individual after the division of the blastocyte. Sequencing revealed the insertion between the allele 18 and 19 is a repeat unit of TAGA/TCTA (plus/minus strand), which belongs to "AGAT/ATCT"-based core repeats identified from all tri-allelic pattern reports recorded in the STR base and a detailed model was proposed for STR repeat length variation caused by false priming during DNA synthesis. Our model illustrates the possible origination of allele-balanced and unbalanced tri-allelic pattern, clarifies that the genotypes of parent-child mismatches, aberrant di-allelic patterns, and type 1 or 2 tri-allelic patterns should be considered as independent, but interconnected forms of STR mutation. PMID:25732248

  12. DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia.

    PubMed

    Ding, Qi; Bramble, Lori; Yuzbasiyan-Gurkan, Vilma; Bell, Thomas; Meek, Katheryn

    2002-01-23

    Previously, spontaneous genetic immunodeficiencies in mice, Arabian foals, and recently in Jack Russell terriers have been ascribed to defects in DNA-PKcs (catalytic subunit of the DNA dependent protein kinase) expression. In severe combined immunodeficiency (SCID) foals, a 5 bp deletion at codon 9480 results in a frameshift and a 967 amino acid deletion from the C terminus (including the entire PI3 kinase domain) and an unstable mutant protein. In SCID mice, a single base pair mutation results in a premature stop codon and deletion of 83 amino acids; as in SCID foals, the mutant protein is unstable. Here, we define the mutation within the canine DNA-PKcs gene that results in SCID. In this case, a point mutation results in a stop codon at nucleotide 10,828 and premature termination at a position 517 amino acids before the normal C terminus resulting in a functionally null allele. Thus, this is the third documentation of a spontaneous germline mutation in the C terminus of DNA-PKcs. Emerging data implicate DNA repair factors as potential tumor suppressors. Here, we have ascertained the carrier frequency of the defective DNA-PKcs genes in Arabian horses and in Jack Russell terriers. Our data indicate (in good agreement with a previous report) that the carrier frequency of the equine SCID allele is approximately 8%; in contrast, the carrier frequency of the canine SCID allele is less than 1.1%. We also assessed the frequency of the equine SCID allele in a series of 295 tumors from Arabian horses. We find a statistically significant correlation between the development of a virally induced tumor (sarcoid) and heterozygosity for the equine SCID allele. These data provide further support for an emerging consensus: that DNA-PK may normally act as a tumor suppressor through its caretaker role in maintaining chromosomal stability. PMID:11867233

  13. Behavioral Contrast in Infants.

    ERIC Educational Resources Information Center

    Fagen, Jeffrey W.

    This study used the behavioral contrast paradigm to assess the excitatory and inhibitory capabilities of young infants. Behavioral contrast is described as the phenomenon whereby the rates of responding in the presence of two stimuli, both of which were previously associated with reinforcement, change in opposite directions when only one of them…

  14. A Mutant Ahr Allele Protects the Embryonic Kidney from Hydrocarbon-Induced Deficits in Fetal Programming

    PubMed Central

    Nanez, Adrian

    2011-01-01

    Background: The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis. Objectives: We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP). Methods: We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahrb-1 allele and B6.D2N-Ahrd/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahrd) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis. Results: Hydrocarbon challenge of metanephri from C57 mice altered Wilms’ tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10–13. Conclusions: These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease. PMID:21803694

  15. Allele-specific locus binding and genome editing by CRISPR at the p16INK4a locus

    PubMed Central

    Fujita, Toshitsugu; Yuno, Miyuki; Fujii, Hodaka

    2016-01-01

    The clustered regularly interspaced short palindromic repeats (CRISPR) system has been adopted for a wide range of biological applications including genome editing. In some cases, dissection of genome functions requires allele-specific genome editing, but the use of CRISPR for this purpose has not been studied in detail. In this study, using the p16INK4a gene in HCT116 as a model locus, we investigated whether chromatin states, such as CpG methylation, or a single-nucleotide gap form in a target site can be exploited for allele-specific locus binding and genome editing by CRISPR in vivo. First, we showed that allele-specific locus binding and genome editing could be achieved by targeting allele-specific CpG-methylated regions, which was successful for one, but not all guide RNAs. In this regard, molecular basis underlying the success remains elusive at this stage. Next, we demonstrated that an allele-specific single-nucleotide gap form could be employed for allele-specific locus binding and genome editing by CRISPR, although it was important to avoid CRISPR tolerance of a single nucleotide mismatch brought about by mismatched base skipping. Our results provide information that might be useful for applications of CRISPR in studies of allele-specific functions in the genomes. PMID:27465215

  16. Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern.

    PubMed

    Picanço, Juliane Bentes; Raimann, Paulo Eduardo; da Motta, Carlos Henrique Ares Silveira; Rodenbusch, Rodrigo; Gusmão, Leonor; Alho, Clarice Sampaio

    2015-05-01

    Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications. PMID:25549886

  17. Comparative in vivo expression of beta(+)-thalassemia alleles.

    PubMed

    Marwan, M M; Scerri, C A; Zarroag, S O; Cao, A; Kyrri, A; Kalogirou, E; Kleanthous, M; Ioannou, P; Angastiniotis, M; Felice, A E

    1999-08-01

    Double heterozygotes who inherit one abnormal though stable beta-globin variant in association with a molecularly identified beta(+)-thalassaemia allele provide unique opportunities to quantify the in vivo expression of particular beta(+)-thalassemia alleles. The globin products of the two alleles can be separated, quantified and the output of the beta(+)-thalassaemia allele expressed as the MCH-beta(A) in pg beta(A)-globin/beta(+)-thalassemia allele/RBC = 0.5 MCH x Hb A%. In this communication we provide new quantitative data on the expression of five mutations as follows: the beta(+)-87 (C-->G) = 3.8 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 1); the beta(+) IVS-I-1 (G-->A) = 0.2 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 1); the beta(+) IVS-I-6 (T-->C) = 2.9 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 7); the beta(+) IVS-I-110 (G-->A) = 1.1 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 13), and the beta(+) IVS-II-745 (C-->G) = 1.74 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 2). The values obtained are compared with those of other beta(+)-thalassemia alleles from the literature. It can be seen that the MCH-beta(A) value may be a correct index of thalassemia severity useful for the correlation of genotype with phenotype, and for understanding the effects of mutations in beta-globin genes on pathophysiologically meaningful beta-globin gene expression. PMID:10490134

  18. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots

    PubMed Central

    Baker, Christopher L.; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M.; Paigen, Kenneth

    2015-01-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9 +/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. PMID:26368021

  19. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.

    PubMed

    Baker, Christopher L; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M; Paigen, Kenneth

    2015-09-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. PMID:26368021

  20. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.

    PubMed

    Baker, Christopher L; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M; Paigen, Kenneth

    2015-09-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape.

  1. Exploring the Interactions of the Dietary Plant Flavonoids Fisetin and Naringenin with G-Quadruplex and Duplex DNA, Showing Contrasting Binding Behavior: Spectroscopic and Molecular Modeling Approaches.

    PubMed

    Bhattacharjee, Snehasish; Chakraborty, Sandipan; Sengupta, Pradeep K; Bhowmik, Sudipta

    2016-09-01

    Guanine-rich sequences have the propensity to fold into a four-stranded DNA structure known as a G-quadruplex (G4). G4 forming sequences are abundant in the promoter region of several oncogenes and become a key target for anticancer drug binding. Here we have studied the interactions of two structurally similar dietary plant flavonoids fisetin and naringenin with G4 as well as double stranded (duplex) DNA by using different spectroscopic and modeling techniques. Our study demonstrates the differential binding ability of the two flavonoids with G4 and duplex DNA. Fisetin more strongly interacts with parallel G4 structure than duplex DNA, whereas naringenin shows stronger binding affinity to duplex rather than G4 DNA. Molecular docking results also corroborate our spectroscopic results, and it was found that both of the ligands are stacked externally in the G4 DNA structure. C-ring planarity of the flavonoid structure appears to be a crucial factor for preferential G4 DNA recognition of flavonoids. The goal of this study is to explore the critical effects of small differences in the structure of closely similar chemical classes of such small molecules (flavonoids) which lead to the contrasting binding properties with the two different forms of DNA. The resulting insights may be expected to facilitate the designing of the highly selective G4 DNA binders based on flavonoid scaffolds.

  2. HLA-B15: a widespread and diverse family of HLA-B alleles.

    PubMed

    Hildebrand, W H; Domena, J D; Shen, S Y; Lau, M; Terasaki, P I; Bunce, M; Marsh, S G; Guttridge, M G; Bias, W B; Parham, P

    1994-04-01

    HLA-B15 embraces a multiplicity of antigenic specificities which vary in their distribution amongst human populations. To correlate B15 molecular structure with the serological picture we have sequenced alleles encoding the various subspecificities of the B15 antigen: B62, B63, B75, B76 and B77, and a number of "variants" of these antigens including the 8w66 split of B63. HLA-B63 (B*1517) and 8w66 (B*1516) heavy chains have sequence identity to B17 in the alpha 1 helix correlating with the antigenic crossreactivity of these molecules. HLA-B77(B*1513) and B75 (B*1502) heavy chains differ solely in segments determining the Bw4 and Bw6 public epitopes, consistent with the serological description of the B77 and B75 antigens. One allele encoding the B76 antigen (B*1512) appears to be the product of gene conversion between the HLA-A and -B loci and differs from B*1501 in codons 166 and 167. In contrast, a second allele encoding the B76 antigen (B*1514) differs from B*1501 by an unrelated substitution in codon 167 which confers similarily with B45, an antigen crossreactive with B76. A third allele encoding B76, B*1519, differs from B*1512 by a unique point substitution in exon 4. Three alleles encoding variant B15 and B62 antigens (B*1508, B*1511 and B*1515) differ from B*1501 by localized clusters of substitutions that probably result from interallelic conversion. The B15 sequences described in this paper, in combination with those previously determined, define a family of 22 alleles, including those encoding the B46 and B70 antigens. Within this family the patterns of allelic substitution are analogous to those of other HLA-A and -B families, in that pairwise differences almost always involve functional positions of the antigen recognition site and recombination is the major agent of diversification.

  3. Selection of allelic isozyme polymorphisms in marine organisms: pattern, theory, and application.

    PubMed

    Nevo, E; Lavie, E; Ben-Shlomo, R

    1983-01-01

    The evolutionary significance of allelic isozyme polymorphisms in several Mediterranean marine organisms was tested initially by post-hoc gene frequency analyses at 11-15 gene loci in natural populations of barnacles, Balanus amphitrite, under thermal [Nevo et al, 1977] and chemical [Nevo et al, 1978] pollutions. We next carried out pre-hoc controlled laboratory experiments to test the effects of heavy metal pollution (Hg, Zn, Cd) on genotypic frequencies of 15 phosphoglucomutase (PGM) genotypes in thousands of individuals of the shrimp Palaemon elegans [Nevo et al, 1980, 1981a, and the present study]. Similarly, we tested the effects of Hg, Zn, Cd, Pb, Cu pollutions on the genotypic and allelic frequencies of five phosphoglucose isomerase (PGI) genotypes in the two close species of marine gastropods, Monodonta turbinata and M turbiformis [Lavie and Nevo, 1982, and the present study]. In both the thermal and chemical pollution studies, we established in repeated experiments statistically significant differences of allele frequencies at 8 out of 11 (73%) and 10 out of 15 (67%) gene loci, respectively, between the contrasting environments in each. While no specific function could be singled out in the post-hoc chemical study due to the complex nature of polluted marine water, temperature could be specified as the primary selective agent in the thermal study. The strongest direct and specific evidence for significant differential survivorship among allelic isozyme genotypes was obtained in the pre-hoc studies in Palaemon and Monodonta. Their differential viability was probably associated with the different degree of heavy metal inhibition uniquely related to each specific pollutant. Furthermore, we demonstrated in the two closely related Monodonta species parallel genotypic differentiation as a response to pollution. Our results are inconsistent with the neutral theory of allelic isozyme polymorphisms and appear to reflect the adaptive nature of the allelic isozyme

  4. Segment aberration effects on contrast.

    PubMed

    Crossfield, Ian J; Troy, Mitchell

    2007-07-20

    High-contrast imaging, particularly the direct detection of extrasolar planets, is a major science driver for the next generation of telescopes. This science requires the suppression of scattered starlight at extremely high levels and that telescopes be correctly designed today to meet these stringent requirements in the future. The challenge increases in systems with complicated aperture geometries such as obscured, segmented telescopes. Such systems can also require intensive modeling and simulation efforts in order to understand the trade-offs between different optical parameters. The feasibility and development of a contrast prediction tool for use in the design and systems engineering of these telescopes is described. The performance of a particular starlight suppression system on a large segmented telescope is described analytically. These analytical results and the results of a contrast predictor are then compared with the results of a full wave-optics simulation. PMID:17609697

  5. Differential X-ray phase contrast tomography of Alzheimer plaques in mouse models: perspectives for drug development and clinical imaging techniques

    NASA Astrophysics Data System (ADS)

    Pinzer, B. R.; Cacquevel, M.; Modregger, P.; Thuering, T.; Stampanoni, M.

    2013-05-01

    Alzheimer's disease (AD) is a looming threat on an ever-ageing population, with devastating effects on the human intellect. A particular characteristic lesion — the extracellular amyloid plaque — accumulates in the brain of AD patients during the course of the disease, and could therefore be used to monitor the progression of the disease, years before the first neurological symptoms appear. In addition, strategies for drug intervention in AD are often based on amyloid reduction, since amyloid plaques are hypothesized to be involved in a chain of reactions leading to the death of neurons. Developments in both fields would benefit from a microscopic technique that is capable of single plaque imaging, ideally in 3D. While such a non-destructive, single-plaque imaging technique does not yet exist for humans, it has been recently shown that synchrotron based differential X-ray phase contrast imaging can be used to visualize individual plaques at μm resolution in mouse models of AD ex-vivo. This method, which relies on a grating interferometer to measure refraction angles induced by fluctuations in the refractive index, yields a precise three-dimensional distribution of single plaques. These data could not only improve the understanding of the evolution of AD or the effectiveness of drugs, but could also help to improve reliable markers for current and future non-invasive clinical imaging techniques. In particular, validation of PET markers with small animal models could be rapidly carried out by co-registration of PET and DPC signals.

  6. Contrast Adaptation Implies Two Spatiotemporal Channels but Three Adapting Processes

    ERIC Educational Resources Information Center

    Langley, Keith; Bex, Peter J.

    2007-01-01

    The contrast gain control model of adaptation predicts that the effects of contrast adaptation correlate with contrast sensitivity. This article reports that the effects of high contrast spatiotemporal adaptors are maximum when adapting around 19 Hz, which is a factor of two or more greater than the peak in contrast sensitivity. To explain the…

  7. Natural allelic variations of xenobiotic-metabolizing enzymes affect sexual dimorphism in Oryzias latipes.

    PubMed

    Katsumura, Takafumi; Oda, Shoji; Nakagome, Shigeki; Hanihara, Tsunehiko; Kataoka, Hiroshi; Mitani, Hiroshi; Kawamura, Shoji; Oota, Hiroki

    2014-12-22

    Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection. Interestingly, sexually selected traits show geographical variations within species despite strong directional selective pressures. This paradox has eluded many evolutionary biologists for some time, and several models have been proposed (e.g. 'indicator model' and 'trade-off model'). However, disentangling which of these theories explains empirical patterns remains difficult, because genetic polymorphisms that cause variation in sexual differences are still unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolizing enzyme, are associated with geographical differences in sexual dimorphism in the anal fin morphology of medaka fish (Oryzias latipes). Biochemical assays and genetic cross experiments show that high- and low-activity CYP1B1 alleles enhanced and declined sex differences in anal fin shapes, respectively. Behavioural and phylogenetic analyses suggest maintenance of the high-activity allele by sexual selection, whereas the low-activity allele possibly has experienced positive selection due to by-product effects of CYP1B1 in inferred ancestral populations. The present data can elucidate evolutionary mechanisms behind genetic variations in sexual dimorphism and indicate trade-off interactions between two distinct mechanisms acting on the two alleles with pleiotropic effects of xenobiotic-metabolizing enzymes.

  8. Compressive Phase Contrast Tomography

    SciTech Connect

    Maia, Filipe; MacDowell, Alastair; Marchesini, Stefano; Padmore, Howard A.; Parkinson, Dula Y.; Pien, Jack; Schirotzek, Andre; Yang, Chao

    2010-09-01

    When x-rays penetrate soft matter, their phase changes more rapidly than their amplitude. Interference effects visible with high brightness sources creates higher contrast, edge enhanced images. When the object is piecewise smooth (made of big blocks of a few components), such higher contrast datasets have a sparse solution. We apply basis pursuit solvers to improve SNR, remove ring artifacts, reduce the number of views and radiation dose from phase contrast datasets collected at the Hard X-Ray Micro Tomography Beamline at the Advanced Light Source. We report a GPU code for the most computationally intensive task, the gridding and inverse gridding algorithm (non uniform sampled Fourier transform).

  9. Ferrimagnetic susceptibility contrast agents.

    PubMed

    Bach-Gansmo, T

    1993-01-01

    Contrast agents based on superparamagnetic particles have been in clinical development for more than 5 years, and the complexity of their effects is still not elucidated. The relaxivities are frequently used to give an idea of their efficacy, but these parameters can only be used if they are concentration independent. For large superparamagnetic systems, the evolution of the transverse magnetization is biexponential, after an initial loss of magnetization. Both these characteristics of large superparamagnetic systems should lead to prudence in using the relaxivities as indicators of contrast medium efficacy. Susceptibility induced artefacts have been associated with the use of superparamagnetic contrast agents since the first imaging evaluation took place. The range of concentrations where good contrast effect was achieved without inducing artefacts, as well as blurring and metal artefacts were evaluated. The influence of motion on the induction of artefacts was studied, and compared to the artefacts induced by a paramagnetic agent subject to motion. With a suitable concentration of a negative contrast agent, a signal void could be achieved in the region prone to motion, and no artefacts were induced. If the concentration was too high, a displacement of the region close to the contrast agent was observed. The artefacts occurred in a volume surrounding the contrast agent, i.e., also outside the imaging plane. In comparison a positive, paramagnetic contrast agent induced heavy artefacts in the phase encoding direction, appearing as both high intensity regions and black holes, in a mosaic pattern. Clinical trials of the oral contrast agent OMP for abdominal MR imaging showed this agent to be safe and efficacious. OMP increased the diagnostic efficacy of abdominal MR imaging in 2 of 3 cases examined, with a significant decrease in motion artefacts. Susceptibility contrast agents may also be of use in the evaluation of small lesions in the liver. Particulate material

  10. Trans allele methylation and paramutation-like effects in mice

    PubMed Central

    Herman, Herry; Lu, Michael; Anggraini, Melly; Sikora, Aimee; Chang, Yanjie; Yoon, Bong June; Soloway, Paul D

    2009-01-01

    In mammals, imprinted genes have parent-of-origin–specific patterns of DNA methylation that cause allele-specific expression. At Rasgrf1 (encoding RAS protein-specific guanine nucleotide-releasing factor 1), a repeated DNA element is needed to establish methylation and expression of the active paternal allele1. At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele2,3. Here we show that replacing the Rasgrf1 repeats on the paternal allele with region 2 allows both methylation and expression of the paternal copy of Rasgrf1, indicating that sequences that control methylation can function ectopically. Paternal transmission of the mutated allele also induced methylation and expression in trans of the normally unmethylated and silent wild-type maternal allele. Once activated, the wild-type maternal Rasgrf1 allele maintained its activated state in the next generation independently of the paternal allele. These results recapitulate in mice several features in common with paramutation described in plants4. PMID:12740578

  11. CYP2D6: novel genomic structures and alleles

    PubMed Central

    Kramer, Whitney E.; Walker, Denise L.; O’Kane, Dennis J.; Mrazek, David A.; Fisher, Pamela K.; Dukek, Brian A.; Bruflat, Jamie K.; Black, John L.

    2010-01-01

    Objective CYP2D6 is a polymorphic gene. It has been observed to be deleted, to be duplicated and to undergo recombination events involving the CYP2D7 pseudogene and surrounding sequences. The objective of this study was to discover the genomic structure of CYP2D6 recombinants that interfere with clinical genotyping platforms that are available today. Methods Clinical samples containing rare homozygous CYP2D6 alleles, ambiguous readouts, and those with duplication signals and two different alleles were analyzed by long-range PCR amplification of individual genes, PCR fragment analysis, allele-specific primer extension assay, and DNA sequencing to characterize alleles and genomic structure. Results Novel alleles, genomic structures, and the DNA sequence of these structures are described. Interestingly, in 49 of 50 DNA samples that had CYP2D6 gene duplications or multiplications where two alleles were detected, the chromosome containing the duplication or multiplication had identical tandem alleles. Conclusion Several new CYP2D6 alleles and genomic structures are described which will be useful for CYP2D6 genotyping. The findings suggest that the recombination events responsible for CYP2D6 duplications and multiplications are because of mechanisms other than interchromosomal crossover during meiosis. PMID:19741566

  12. HLA-DQ association and allele competition in Chinese narcolepsy.

    PubMed

    Han, F; Lin, L; Li, J; Dong, S X; An, P; Zhao, L; Liu, N Y; Li, Q Y; Yan, H; Gao, Z C; Faraco, J; Strohl, K P; Liu, X; Miyadera, H; Mignot, E

    2012-10-01

    In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility.

  13. T Cell/Transmembrane, Ig, and Mucin-3 Allelic Variants Differentially Recognize Phosphatidylserine and Mediate Phagocytosis of Apoptotic Cells

    PubMed Central

    DeKruyff, Rosemarie H.; Bu, Xia; Ballesteros, Angela; Santiago, César; Chim, Yee-Ling E.; Lee, Hyun-Hee; Karisola, Piia; Pichavant, Muriel; Kaplan, Gerardo G.; Umetsu, Dale T.; Freeman, Gordon J.; Casasnovas, José M.

    2011-01-01

    T cell/transmembrane, Ig, and mucin (TIM) proteins, identified using a congenic mouse model of asthma, critically regulate innate and adaptive immunity. TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), exposed on the surfaces of apoptotic cells. Herein, we show with structural and biological studies that TIM-3 is also a receptor for PtdSer that binds in a pocket on the N-terminal IgV domain in coordination with a calcium ion. The TIM-3/PtdSer structure is similar to that of TIM-4/PtdSer, reflecting a conserved PtdSer binding mode by TIM family members. Fibroblastic cells expressing mouse or human TIM-3 bound and phagocytosed apoptotic cells, with the BALB/c allelic variant of mouse TIM-3 showing a higher capacity than the congenic C.D2 Es-Hba–allelic variant. These functional differences were due to structural differences in the BC loop of the IgV domain of the TIM-3 polymorphic variants. In contrast to fibroblastic cells, T or B cells expressing TIM-3 formed conjugates with but failed to engulf apoptotic cells. Together these findings indicate that TIM-3–expressing cells can respond to apoptotic cells, but the consequence of TIM-3 engagement of PtdSer depends on the polymorphic variants of and type of cell expressing TIM-3. These findings establish a new paradigm for TIM proteins as PtdSer receptors and unify the function of the TIM gene family, which has been associated with asthma and autoimmunity and shown to modulate peripheral tolerance. PMID:20083673

  14. Influence of contrast morphogenetic features of urban constructed soils on the functioning of Moscow green lawn urban ecosystems: analysis based on the field model experiment

    NASA Astrophysics Data System (ADS)

    Epikhina, Anna; Vizirskaya, Mariya; Mazirov, Ilya; Vasenev, Vyacheslav; Vasenev, Ivan; Valentini, Riccardo

    2014-05-01

    Green lawns are the key element of the urban environment. They occupy a considerable part of the city area and locate in different urban functional zones. Urban constructed soils under green lawns have a unique spatial variability in chemical and morphogenetic features. So far, there is lack of information on the influence of morphogenetic features of urban soils on the functioning of the green lawn ecosystems especially in Moscow - the biggest megalopolis in Europe. Urban lawns perform a number of principal functions including both aesthetic and environmental. The role of the green lawn ecosystems in global carbon cycle is one of their main environmental functions. It is traditionally assessed through carbon stocks and fluxes in the basic ecosystem components. So far, such a data for the urban lawn ecosystems of the Moscow megapolis is lacking. In addition to environmental functions, green lawns perform an important ornamental role, which is also a critical criterion of their optimal functioning. Considering the variability of driving factors, influencing green lawns in urban environment, we carry out the model experiment in order to analyze "pure" effect of soil morphogenetic features. The current study aimed to analyze the influence of contrast morphogenetic features of urban constructed soils on the environmental and aesthetic functions of lawn ecosystems in Moscow megapolis basing in the model experiment. We carry out the model experiment located at the experimental field of the Russian State Agrarian University. Special transparent containers developed for the experiment, provided an option to observe soil morphogenetic features dynamics, including the depth and material of the organic transformation. At the same soil body inside the containers was united with the outside environment through the system of holes in the bottom and walls. The set of urban constructed soils includ four contrast types of the top soil (turf (T), turf-sand (TSa), turf-soil (TSo) and

  15. Statistical Studies on Protein Polymorphism in Natural Populations. III. Distribution of Allele Frequencies and the Number of Alleles per Locus

    PubMed Central

    Chakraborty, Ranajit; Fuerst, Paul A.; Nei, Masatoshi

    1980-01-01

    With the aim of understanding the mechanism of maintenance of protein polymorphism, we have studied the properties of allele frequency distribution and the number of alleles per locus, using gene-frequency data from a wide range of organisms (mammals, birds, reptiles, amphibians, Drosophila and non-Drosophila invertebrates) in which 20 or more loci with at least 100 genes were sampled. The observed distribution of allele frequencies was U-shaped in all of the 138 populations (mostly species or subspecies) examined and generally agreed with the theoretical distribution expected under the mutation-drift hypothesis, though there was a significant excess of rare alleles (gene frequency, 0 ∼ 0.05) in about a quarter of the populations. The agreement between the mutation-drift theory and observed data was quite satisfactory for the numbers of polymorphic (gene frequency, 0.05 ∼ 0.95) and monomorphic (0.95 ∼ 1.0) alleles.—The observed pattern of allele-frequency distribution was incompatible with the prediction from the overdominance hypothesis. The observed correlations of the numbers of rare alleles, polymorphic alleles and monomorphic alleles with heterozygosity were of the order of magnitude that was expected under the mutation-drift hypothesis. Our results did not support the view that intracistronic recombination is an important source of genetic variation. The total number of alleles per locus was positively correlated with molecular weight in most of the species examined, and the magnitude of the correlation was consistent with the theoretical prediction from mutation-drift hypothesis. The correlation between molecular weight and the number of alleles was generally higher than the correlation between molecular weight and heterozygosity, as expected. PMID:17249018

  16. Allelic differences in a vacuolar invertase affect Arabidopsis growth at early plant development.

    PubMed

    Leskow, Carla Coluccio; Kamenetzky, Laura; Dominguez, Pia Guadalupe; Díaz Zirpolo, José Antonio; Obata, Toshihiro; Costa, Hernán; Martí, Marcelo; Taboga, Oscar; Keurentjes, Joost; Sulpice, Ronan; Ishihara, Hirofumi; Stitt, Mark; Fernie, Alisdair Robert; Carrari, Fernando

    2016-07-01

    Improving carbon fixation in order to enhance crop yield is a major goal in plant sciences. By quantitative trait locus (QTL) mapping, it has been demonstrated that a vacuolar invertase (vac-Inv) plays a key role in determining the radical length in Arabidopsis. In this model, variation in vac-Inv activity was detected in a near isogenic line (NIL) population derived from a cross between two divergent accessions: Landsberg erecta (Ler) and Cape Verde Island (CVI), with the CVI allele conferring both higher Inv activity and longer radicles. The aim of the current work is to understand the mechanism(s) underlying this QTL by analyzing structural and functional differences of vac-Inv from both accessions. Relative transcript abundance analyzed by quantitative real-time PCR (qRT-PCR) showed similar expression patterns in both accessions; however, DNA sequence analyses revealed several polymorphisms that lead to changes in the corresponding protein sequence. Moreover, activity assays revealed higher vac-Inv activity in genotypes carrying the CVI allele than in those carrying the Ler allele. Analyses of purified recombinant proteins showed a similar K m for both alleles and a slightly higher V max for that of Ler. Treatment of plant extracts with foaming to release possible interacting Inv inhibitory protein(s) led to a large increase in activity for the Ler allele, but no changes for genotypes carrying the CVI allele. qRT-PCR analyses of two vac-Inv inhibitors in seedlings from parental and NIL genotypes revealed different expression patterns. Taken together, these results demonstrate that the vac-Inv QTL affects root biomass accumulation and also carbon partitioning through a differential regulation of vac-Inv inhibitors at the mRNA level. PMID:27194734

  17. Genetic Exchange of Fimbrial Alleles Exemplifies the Adaptive Virulence Strategy of Porphyromonas gingivalis

    PubMed Central

    Kerr, Jennifer E.; Abramian, Jared R.; Dao, Doan-Hieu V.; Rigney, Todd W.; Fritz, Jamie; Pham, Tan; Gay, Isabel; Parthasarathy, Kavitha; Wang, Bing-yan; Zhang, Wenjian; Tribble, Gena D.

    2014-01-01

    Porphyromonas gingivalis is a gram–negative anaerobic bacterium, a member of the human oral microbiome, and a proposed “keystone” pathogen in the development of chronic periodontitis, an inflammatory disease of the gingiva. P. gingivalis is a genetically diverse species, and is able to exchange chromosomal DNA between strains by natural competence and conjugation. In this study, we investigate the role of horizontal DNA transfer as an adaptive process to modify behavior, using the major fimbriae as our model system, due to their critical role in mediating interactions with the host environment. We show that P. gingivalis is able to exchange fimbrial allele types I and IV into four distinct strain backgrounds via natural competence. In all recombinants, we detected a complete exchange of the entire fimA allele, and the rate of exchange varies between the different strain backgrounds. In addition, gene exchange within other regions of the fimbrial genetic locus was identified. To measure the biological implications of these allele swaps we compared three genotypes of fimA in an isogenic background, strain ATCC 33277. We demonstrate that exchange of fimbrial allele type results in profound phenotypic changes, including the quantity of fimbriae elaborated, membrane blebbing, auto-aggregation and other virulence-associated phenotypes. Replacement of the type I allele with either the type III or IV allele resulted in increased invasion of gingival fibroblast cells relative to the isogenic parent strain. While genetic variability is known to impact host-microbiome interactions, this is the first study to quantitatively assess the adaptive effect of exchanging genes within the pan genome cloud. This is significant as it presents a potential mechanism by which opportunistic pathogens may acquire the traits necessary to modify host-microbial interactions. PMID:24626479

  18. ALFRED: an allele frequency resource for research and teaching

    PubMed Central

    Rajeevan, Haseena; Soundararajan, Usha; Kidd, Judith R.; Pakstis, Andrew J.; Kidd, Kenneth K.

    2012-01-01

    ALFRED (http://alfred.med.yale.edu) is a free, web accessible, curated compilation of allele frequency data on DNA sequence polymorphisms in anthropologically defined human populations. Currently, ALFRED has allele frequency tables on over 663 400 polymorphic sites; 170 of them have frequency tables for more than 100 different population samples. In ALFRED, a population may have multiple samples with each ‘sample’ consisting of many individuals on which an allele frequency is based. There are 3566 population samples from 710 different populations with allele frequency tables on at least one polymorphism. Fifty of those population samples have allele frequency data for over 650 000 polymorphisms. Records also have active links to relevant resources (dbSNP, PharmGKB, OMIM, Ethnologue, etc.). The flexible search options and data display and download capabilities available through the web interface allow easy access to the large quantity of high-quality data in ALFRED. PMID:22039151

  19. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

  20. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Boșcaiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania.

  1. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Boșcaiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania. PMID:26711124