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A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies
Oliver Stegle ,Leopold Parts ,Richard Durbin,John Winn
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000770
Abstract: Gene expression measurements are influenced by a wide range of factors, such as the state of the cell, experimental conditions and variants in the sequence of regulatory regions. To understand the effect of a variable of interest, such as the genotype of a locus, it is important to account for variation that is due to confounding causes. Here, we present VBQTL, a probabilistic approach for mapping expression quantitative trait loci (eQTLs) that jointly models contributions from genotype as well as known and hidden confounding factors. VBQTL is implemented within an efficient and flexible inference framework, making it fast and tractable on large-scale problems. We compare the performance of VBQTL with alternative methods for dealing with confounding variability on eQTL mapping datasets from simulations, yeast, mouse, and human. Employing Bayesian complexity control and joint modelling is shown to result in more precise estimates of the contribution of different confounding factors resulting in additional associations to measured transcript levels compared to alternative approaches. We present a threefold larger collection of cis eQTLs than previously found in a whole-genome eQTL scan of an outbred human population. Altogether, 27% of the tested probes show a significant genetic association in cis, and we validate that the additional eQTLs are likely to be real by replicating them in different sets of individuals. Our method is the next step in the analysis of high-dimensional phenotype data, and its application has revealed insights into genetic regulation of gene expression by demonstrating more abundant cis-acting eQTLs in human than previously shown. Our software is freely available online at http://www.sanger.ac.uk/resources/softwa?re/peer/.
Joint Genetic Analysis of Gene Expression Data with Inferred Cellular Phenotypes
Leopold Parts equal contributor ,Oliver Stegle equal contributor,John Winn,Richard Durbin
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001276
Abstract: Even within a defined cell type, the expression level of a gene differs in individual samples. The effects of genotype, measured factors such as environmental conditions, and their interactions have been explored in recent studies. Methods have also been developed to identify unmeasured intermediate factors that coherently influence transcript levels of multiple genes. Here, we show how to bring these two approaches together and analyse genetic effects in the context of inferred determinants of gene expression. We use a sparse factor analysis model to infer hidden factors, which we treat as intermediate cellular phenotypes that in turn affect gene expression in a yeast dataset. We find that the inferred phenotypes are associated with locus genotypes and environmental conditions and can explain genetic associations to genes in trans. For the first time, we consider and find interactions between genotype and intermediate phenotypes inferred from gene expression levels, complementing and extending established results.
Inferring Genome-Wide Recombination Landscapes from Advanced Intercross Lines: Application to Yeast Crosses
Christopher J. R. Illingworth, Leopold Parts, Anders Bergstr?m, Gianni Liti, Ville Mustonen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062266
Abstract: Accurate estimates of recombination rates are of great importance for understanding evolution. In an experimental genetic cross, recombination breaks apart and rejoins genetic material, such that the genomes of the resulting isolates are comprised of distinct blocks of differing parental origin. We here describe a method exploiting this fact to infer genome-wide recombination profiles from sequenced isolates from an advanced intercross line (AIL). We verified the accuracy of the method against simulated data. Next, we sequenced 192 isolates from a twelve-generation cross between West African and North American yeast Saccharomyces cerevisiae strains and inferred the underlying recombination landscape at a fine genomic resolution (mean segregating site distance 0.22 kb). Comparison was made with landscapes inferred for a similar cross between four yeast strains, and with a previous single-generation, intra-strain cross (Mancera et al., Nature 2008). Moderate congruence was identified between landscapes (correlation 0.58–0.77 at 5 kb resolution), albeit with variance between mean genome-wide recombination rates. The multiple generations of mating undergone in the AILs gave more precise inference of recombination rates than could be achieved from a single-generation cross, in particular in identifying recombination cold-spots. The recombination landscapes we describe have particular utility; both AILs are part of a resource to study complex yeast traits (see e.g. Parts et al., Genome Res 2011). Our results will enable future applications of this resource to take better account of local linkage structure heterogeneities. Our method has general applicability to other crossing experiments, including a variety of experimental designs.
Segregating YKU80 and TLC1 Alleles Underlying Natural Variation in Telomere Properties in Wild Yeast
Gianni Liti ,Svasti Haricharan,Francisco A. Cubillos,Anna L. Tierney,Sarah Sharp,Alison A. Bertuch,Leopold Parts,Elizabeth Bailes,Edward J. Louis
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000659
Abstract: In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (<150 bp), whereas American isolates had telomeres approximately three times as long (>400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80) resulting in very short telomeres.
Climate Change at Northern Latitudes: Rising Atmospheric Humidity Decreases Transpiration, N-Uptake and Growth Rate of Hybrid Aspen
Arvo Tullus, Priit Kupper, Arne Sellin, Leopold Parts, Jaak S?ber, Tea Tullus, Krista L?hmus, Anu S?ber, Hardi Tullus
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042648
Abstract: At northern latitudes a rise in atmospheric humidity and precipitation is predicted as a consequence of global climate change. We studied several growth and functional traits of hybrid aspen (Populus tremula L.×P. tremuloides Michx.) in response to elevated atmospheric humidity (on average 7% over the ambient level) in a free air experimental facility during three growing seasons (2008–2010) in Estonia, which represents northern temperate climate (boreo-nemoral zone). Data were collected from three humidified (H) and three control (C) plots, and analysed using nested linear models. Elevated air humidity significantly reduced height, stem diameter and stem volume increments and transpiration of the trees whereas these effects remained highly significant also after considering the side effects from soil-related confounders within the 2.7 ha study area. Tree leaves were smaller, lighter and had lower leaf mass per area (LMA) in H plots. The magnitude and significance of the humidity treatment effect – inhibition of above-ground growth rate – was more pronounced in larger trees. The lower growth rate in the humidified plots can be partly explained by a decrease in transpiration-driven mass flow of NO3? in soil, resulting in a significant reduction in the measured uptake of N to foliage in the H plots. The results suggest that the potential growth improvement of fast-growing trees like aspens, due to increasing temperature and atmospheric CO2 concentration, might be smaller than expected at high latitudes if a rise in atmospheric humidity simultaneously takes place.
The miRNA Profile of Human Pancreatic Islets and Beta-Cells and Relationship to Type 2 Diabetes Pathogenesis
Martijn van de Bunt, Kyle J. Gaulton, Leopold Parts, Ignasi Moran, Paul R. Johnson, Cecilia M. Lindgren, Jorge Ferrer, Anna L. Gloyn, Mark I. McCarthy
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055272
Abstract: Recent advances in the understanding of the genetics of type 2 diabetes (T2D) susceptibility have focused attention on the regulation of transcriptional activity within the pancreatic beta-cell. MicroRNAs (miRNAs) represent an important component of regulatory control, and have proven roles in the development of human disease and control of glucose homeostasis. We set out to establish the miRNA profile of human pancreatic islets and of enriched beta-cell populations, and to explore their potential involvement in T2D susceptibility. We used Illumina small RNA sequencing to profile the miRNA fraction in three preparations each of primary human islets and of enriched beta-cells generated by fluorescence-activated cell sorting. In total, 366 miRNAs were found to be expressed (i.e. >100 cumulative reads) in islets and 346 in beta-cells; of the total of 384 unique miRNAs, 328 were shared. A comparison of the islet-cell miRNA profile with those of 15 other human tissues identified 40 miRNAs predominantly expressed (i.e. >50% of all reads seen across the tissues) in islets. Several highly-expressed islet miRNAs, such as miR-375, have established roles in the regulation of islet function, but others (e.g. miR-27b-3p, miR-192-5p) have not previously been described in the context of islet biology. As a first step towards exploring the role of islet-expressed miRNAs and their predicted mRNA targets in T2D pathogenesis, we looked at published T2D association signals across these sites. We found evidence that predicted mRNA targets of islet-expressed miRNAs were globally enriched for signals of T2D association (p-values <0.01, q-values <0.1). At six loci with genome-wide evidence for T2D association (AP3S2, KCNK16, NOTCH2, SCL30A8, VPS26A, and WFS1) predicted mRNA target sites for islet-expressed miRNAs overlapped potentially causal variants. In conclusion, we have described the miRNA profile of human islets and beta-cells and provide evidence linking islet miRNAs to T2D pathogenesis.
Outcomes of Surgical Treatment of Skin Cancer at Surgical Oncology Unit of Donka, Conakry University Hospital  [PDF]
Bangaly Traore, Leopold Lamah
Journal of Cancer Therapy (JCT) , 2017, DOI: 10.4236/jct.2017.812093
Abstract: Aim: The main aim of this study was to evaluate outcomes after surgical treatment of skin cancer. Methods: This retrospective cohort study concerned 46 patients who presented 43 skin cancers lesions surgically treated at surgical oncology unit, Conakry University Hospital. There were 29 (61.7%) squamous cell carcinoma, 12 (25.5%) melanoma, 4 (8.5%) sarcomas and 1 (2.1%) porocarcinoma. Surgical indications and prognosis factors were analyzed. Results: Surgical treatment included simple excision in 2 cases (3.8%), wide excision in 38 cases (71.7%) and amputation/disarticulation in 13 cases (24.5%). Inguinal lymph node dissection was performed in 16 patients (34.3%). Postoperative complications were wound suppuration (5 cases), lower limb lymphedema (4 cases), seroma (2 cases) and skin flap necrosis (1 case). Surgical margins were free in 28 (60.9%) patients, infiltrated in 3 patients (6.5%) and unspecified in 15 patients (32.6%). The median follow-up after surgery was 29 months. During the follow-up, 13 patients (28.3%) had a relapse. The relapse was influenced by surgical margins (p = 0.012) and iterative resection (p = 0.04). Overall survival was 65.2%. Factors related to survival in univariate analysis were: iterative resection (p = 0.008), fungated tumor (p = 0.037), the status of surgical margins (p = 0.002) and the occurrence of relapse (p = 0.0000). In multivariate analysis, the status of surgical margins was the only independent prognostic factor. Conclusion: The prognosis after surgical treatment of cutaneous cancers depends on the resection margins.
The Effects of Consumer Cosmopolitanism on Purchase Behavior of Foreign vs. Domestic Products
Oliver Parts,Irena Vida
Managing Global Transitions , 2011,
Abstract: The purpose of this empirical study is to investigate the effects of consumercosmopolitanism on foreign product purchase behavior in threemajor categories of consumer products (alcohol products, clothes, furniture).Based on the existing theoretical and empirical knowledge, wedevelop a conceptual model and identify two additional constructs asantecedents of foreign purchase behavior, i. e., consumer ethnocentrismand consumer knowledge of brand origins. The measurementmodel is examined using a data set of 261 adult consumers and testedvia structural equation modeling. The study results confirm the strongtotal effect of consumer cosmopolitanism in purchase behavior andindicate a strong direct effect of this phenomenon on the behavioraloutcome. The more cosmopolitan consumers have a stronger tendencyto buy foreign rather than local products. On the other hand, the directrelationship between cosmopolitanism and consumer knowledgeof brand origin was not supported in the study.
Barrel Pseudotilings
Undine Leopold
Symmetry , 2012, DOI: 10.3390/sym4030545
Abstract: This paper describes 4-valent tiling-like structures, called pseudotilings, composed of barrel tiles and apeirogonal pseudotiles in Euclidean 3-space. These (frequently face-to-face) pseudotilings naturally rise in columns above 3-valent plane tilings by?convex polygons, such that each column is occupied by stacked congruent barrel tiles or congruent apeirogonal pseudotiles. No physical space is occupied by the apeirogonal pseudotiles. Many interesting pseudotilings arise from plane tilings with high symmetry. As combinatorial structures, these are abstract polytopes of rank 4 with both finite and infinite 2-faces and facets.
The Namibian Border War: An Appraisal of the South African Strategy
Leopold Scholtz
Scientia Militaria: South African Journal of Military Studies , 2006,
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