124,595 research outputs found

    Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein

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    Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis in most cases. We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing.Comment: 25 pages, 9 figures, plus Supplementary Material including Supplementary Text S1-S7, Supplementary Tables S1-S2, and Supplementary Figures S1-2. Version that appears in PLoS Genetic

    A refined estimate for the topological degree

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    We sharpen an estimate of Bourgain, Brezis, and Nguyen for the topological degree of continuous maps from a sphere Sd\mathbb{S}^d into itself in the case d≄2d \ge 2. This provides the answer for d≄2d \ge 2 to a question raised by Brezis. The problem is still open for d=1d=1

    Ecological host fitting of Trypanosoma cruzi TcI in Bolivia: mosaic population structure, hybridization and a role for humans in Andean parasite dispersal.

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    An improved understanding of how a parasite species exploits its genetic repertoire to colonize novel hosts and environmental niches is crucial to establish the epidemiological risk associated with emergent pathogenic genotypes. Trypanosoma cruzi, a genetically heterogeneous, multi-host zoonosis, provides an ideal system to examine the sylvatic diversification of parasitic protozoa. In Bolivia, T. cruzi I, the oldest and most widespread genetic lineage, is pervasive across a range of ecological clines. High-resolution nuclear (26 loci) and mitochondrial (10 loci) genotyping of 199 contemporaneous sylvatic TcI clones was undertaken to provide insights into the biogeographical basis of T. cruzi evolution. Three distinct sylvatic parasite transmission cycles were identified: one highland population among terrestrial rodent and triatomine species, composed of genetically homogenous strains (Ar = 2.95; PA/L = 0.61; DAS = 0.151), and two highly diverse, parasite assemblages circulating among predominantly arboreal mammals and vectors in the lowlands (Ar = 3.40 and 3.93; PA/L = 1.12 and 0.60; DAS = 0.425 and 0.311, respectively). Very limited gene flow between neighbouring terrestrial highland and arboreal lowland areas (distance ~220 km; FST = 0.42 and 0.35) but strong connectivity between ecologically similar but geographically disparate terrestrial highland ecotopes (distance >465 km; FST = 0.016-0.084) strongly supports ecological host fitting as the predominant mechanism of parasite diversification. Dissimilar heterozygosity estimates (excess in highlands, deficit in lowlands) and mitochondrial introgression among lowland strains may indicate fundamental differences in mating strategies between populations. Finally, accelerated parasite dissemination between densely populated, highland areas, compared to uninhabited lowland foci, likely reflects passive, long-range anthroponotic dispersal. The impact of humans on the risk of epizootic Chagas disease transmission in Bolivia is discussed

    Protocol-Dependence and State Variables in the Force-Moment Ensemble

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    Stress-based ensembles incorporating temperature-like variables have been proposed as a route to an equation of state for granular materials. To test the efficacy of this approach, we perform experiments on a two-dimensional photoelastic granular system under three loading conditions: uniaxial compression, biaxial compression, and simple shear. From the interparticle forces, we find that the distributions of the normal component of the coarse-grained force-moment tensor are exponential-tailed, while the deviatoric component is Gaussian-distributed. This implies that the correct stress-based statistical mechanics conserves both the force-moment tensor and the Maxwell-Cremona force-tiling area. As such, two variables of state arise: the tensorial angoricity (α^\hat{\alpha}) and a new temperature-like quantity associated with the force-tile area which we name {\it keramicity} (Îș\kappa). Each quantity is observed to be inversely proportional to the global confining pressure; however only Îș\kappa exhibits the protocol-independence expected of a state variable, while α^\hat{\alpha} behaves as a variable of process

    Interactive Music Generation with Positional Constraints using Anticipation-RNNs

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    Recurrent Neural Networks (RNNS) are now widely used on sequence generation tasks due to their ability to learn long-range dependencies and to generate sequences of arbitrary length. However, their left-to-right generation procedure only allows a limited control from a potential user which makes them unsuitable for interactive and creative usages such as interactive music generation. This paper introduces a novel architecture called Anticipation-RNN which possesses the assets of the RNN-based generative models while allowing to enforce user-defined positional constraints. We demonstrate its efficiency on the task of generating melodies satisfying positional constraints in the style of the soprano parts of the J.S. Bach chorale harmonizations. Sampling using the Anticipation-RNN is of the same order of complexity than sampling from the traditional RNN model. This fast and interactive generation of musical sequences opens ways to devise real-time systems that could be used for creative purposes.Comment: 9 pages, 7 figure

    The Evolution of Male-Biased Dispersal under the Joint Selective Forces of Inbreeding Load and Demographic and Environmental Stochasticity

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    Acknowledgments We thank G. Bocedi, S. Palmer, and three anonymous reviewers for helpful comments on earlier drafts. R.C.H. was funded by the Natural Environment Research Council (1271380). Simulations were performed on the University of Aberdeen’s Maxwell high performance computing cluster.Peer reviewedPublisher PD

    Adaptation of the State Trait Anxiety Inventory in Arabic: A Comparison with the American STAI

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    The main goal of the present study was to develop an Arabic adaptation of the State Trait Anxiety Inventory (STAI, Form Y, Spielberger, 1983). In addition, cultural and linguistic influences on the experience and expression of anxiety were assessed. The American STAI and fifty initial Arabic items were administered to 286 university students at the American University of Beirut, Lebanon. The American STAI was also administered to 336 university students at the University of South Florida. Item and factor analyses were conducted on responses of the calibration sample to obtain the final set of Arabic items, which was validated using the responses of the validation sample. In conducting item selection and validation of the Arabic STAI, internal consistency coefficients for subscales, corrected item-total correlations, alpha coefficients if-item-deleted, item-factor loadings, and theoretical meaningfulness were all used as criteria for selection of the best 10 Arabic items to be included in each subscale of the STAI: S-Anxiety Absent, S-Anxiety Present, T-Anxiety Absent, T-Anxiety present. The two-factor solution for the Arabic STAI yielded a simple solution with two distinct factors: Anxiety Present and Anxiety Absent for each of S-Anxiety and T-Anxiety, lending more support to the theoretical distinction of state and trait anxiety. Lebanese students reported significantly higher anxiety levels than their American peers on S-Anxiety Present, T-Anxiety Absent, and T-Anxiety Present, S-Anxiety and T-Anxiety of the American STAI. For S-Anxiety Absent, scores for the Lebanese sample were lower than American students but did not reach significance levels. S-Anxiety Absent and T-Anxiety Absent subscales assessed lower levels of anxiety rather than the higher levels of anxiety assessed by S-Anxiety Present and T-Anxiety Present. Females tend to experience and express higher levels of mild and severe anxiety symptoms as compared to males in both samples. Factor analyses of the American STAI for the American and Lebanese samples revealed similar two and three- factor solutions. For each of the State and trait subscales, three factors emerged: Anxiety Absent, Worry, and Emotionality factors, denoting the importance of cognitions and feelings in the experience and expression of anxiety

    From Cellular Characteristics to Disease Diagnosis: Uncovering Phenotypes with Supercells

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    Cell heterogeneity and the inherent complexity due to the interplay of multiple molecular processes within the cell pose difficult challenges for current single-cell biology. We introduce an approach that identifies a disease phenotype from multiparameter single-cell measurements, which is based on the concept of ‘‘supercell statistics’’, a single-cell-based averaging procedure followed by a machine learning classification scheme. We are able to assess the optimal tradeoff between the number of single cells averaged and the number of measurements needed to capture phenotypic differences between healthy and diseased patients, as well as between different diseases that are difficult to diagnose otherwise. We apply our approach to two kinds of single-cell datasets, addressing the diagnosis of a premature aging disorder using images of cell nuclei, as well as the phenotypes of two non-infectious uveitides (the ocular manifestations of Behcžet’s disease and sarcoidosis) based on multicolor flow cytometry. In the former case, one nuclear shape measurement taken over a group of 30 cells is sufficient to classify samples as healthy or diseased, in agreement with usual laboratory practice. In the latter, our method is able to identify a minimal set of 5 markers that accurately predict Behcžet’s disease and sarcoidosis. This is the first time that a quantitative phenotypic distinction between these two diseases has been achieved. To obtain this clear phenotypic signature, about one hundred CD8+ T cells need to be measured. Although the molecular markers identified have been reported to be important players in autoimmune disorders, this is the first report pointing out that CD8+ T cells can be used to distinguish two systemic inflammatory diseases. Beyond these specific cases, the approach proposed here is applicable to datasets generated by other kinds of state-of-the-art and forthcoming single-cell technologies, such as multidimensional mass cytometry, single-cell gene expression, and single-cell full genome sequencing techniques.Fil: Candia, Julian Marcelo. University of Maryland; Estados Unidos. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Centro CientĂ­fico TecnolĂłgico Conicet - La Plata. Instituto de FĂ­sica de LĂ­quidos y Sistemas BiolĂłgicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de FĂ­sica de LĂ­quidos y Sistemas BiolĂłgicos; ArgentinaFil: Maunu, Ryan. University of Maryland; Estados UnidosFil: Driscoll, Meghan. University of Maryland; Estados UnidosFil: Biancotto, AngĂ©lique. National Institutes of Health; Estados UnidosFil: Dagur, Pradeep. National Institutes of Health; Estados UnidosFil: McCoy Jr., J Philip. National Institutes of Health; Estados UnidosFil: Nida Sen, H.. National Institutes of Health; Estados UnidosFil: Wei, Lai. National Institutes of Health; Estados UnidosFil: Maritan, Amos. UniversitĂ  di Padova; ItaliaFil: Cao, Kan. University of Maryland; Estados UnidosFil: Nussenblatt, Robert B. National Institutes of Health; Estados UnidosFil: Banavar, Jayanth R.. University of Maryland; Estados UnidosFil: Losert, Wolfgang. University of Maryland; Estados Unido

    Convocation

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    The origins of phenotypic variation within mimetic Heliconius butterflies have long fascinated biologists and naturalists. However, the evolutionary processes that have generated this extraordinary diversity remain puzzling. Here we examine intraspecific variation across Heliconius cydno diversification and compare this variation to that within the closely related H. melpomene and H. timareta radiations. Our data, which consist of both mtDNA and genome scan from nearly 2250 AFLP loci, reveal a complex history of differentiation and admixture at different geographic scales. Both mtDNA and AFLP phylogenies suggest that H. timareta and H. cydno are probably geographic extremes of the same radiation that likely diverged from H. melpomene during the Pliocene-Pleistocene boundary. MtDNA suggest that this radiation originated in Central America or the Northwestern region of South America, with a subsequent colonization of the eastern and western slopes of the Andes. Our genome-scan data indicate significant admixture among sympatric H. cydno/H.timareta and H. melpomene populations across the extensive geographic ranges of the two radiations. Within H. cydno, both mtDNA and AFLP data indicate significant population structure at local scales, with strong genetic differences even among adjacent H. cydno color pattern races. These genetic patterns highlight the importance of past geoclimatic events, intraspecific gene flow, and local population differentiation in the origin and establishment of new adaptive forms
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