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  1. Article ; Online: Recombination and mutational robustness in neutral fitness landscapes.

    Alexander Klug / Su-Chan Park / Joachim Krug

    PLoS Computational Biology, Vol 15, Iss 8, p e

    2019  Volume 1006884

    Abstract: Mutational robustness quantifies the effect of random mutations on fitness. When mutational robustness is high, most mutations do not change fitness or have only a minor effect on it. From the point of view of fitness landscapes, robust genotypes form ... ...

    Abstract Mutational robustness quantifies the effect of random mutations on fitness. When mutational robustness is high, most mutations do not change fitness or have only a minor effect on it. From the point of view of fitness landscapes, robust genotypes form neutral networks of almost equal fitness. Using deterministic population models it has been shown that selection favors genotypes inside such networks, which results in increased mutational robustness. Here we demonstrate that this effect is massively enhanced by recombination. Our results are based on a detailed analysis of mesa-shaped fitness landscapes, where we derive precise expressions for the dependence of the robustness on the landscape parameters for recombining and non-recombining populations. In addition, we carry out numerical simulations on different types of random holey landscapes as well as on an empirical fitness landscape. We show that the mutational robustness of a genotype generally correlates with its recombination weight, a new measure that quantifies the likelihood for the genotype to arise from recombination. We argue that the favorable effect of recombination on mutational robustness is a highly universal feature that may have played an important role in the emergence and maintenance of mechanisms of genetic exchange.
    Keywords Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Predictable properties of fitness landscapes induced by adaptational tradeoffs

    Suman G Das / Susana OL Direito / Bartlomiej Waclaw / Rosalind J Allen / Joachim Krug

    eLife, Vol

    2020  Volume 9

    Abstract: Fitness effects of mutations depend on environmental parameters. For example, mutations that increase fitness of bacteria at high antibiotic concentration often decrease fitness in the absence of antibiotic, exemplifying a tradeoff between adaptation to ... ...

    Abstract Fitness effects of mutations depend on environmental parameters. For example, mutations that increase fitness of bacteria at high antibiotic concentration often decrease fitness in the absence of antibiotic, exemplifying a tradeoff between adaptation to environmental extremes. We develop a mathematical model for fitness landscapes generated by such tradeoffs, based on experiments that determine the antibiotic dose-response curves of Escherichia coli strains, and previous observations on antibiotic resistance mutations. Our model generates a succession of landscapes with predictable properties as antibiotic concentration is varied. The landscape is nearly smooth at low and high concentrations, but the tradeoff induces a high ruggedness at intermediate antibiotic concentrations. Despite this high ruggedness, however, all the fitness maxima in the landscapes are evolutionarily accessible from the wild type. This implies that selection for antibiotic resistance in multiple mutational steps is relatively facile despite the complexity of the underlying landscape.
    Keywords antibiotic resistance ; epistasis ; tradeoff ; fitness landscape ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Interaction Analysis of Longevity Interventions Using Survival Curves

    Stefan Nowak / Johannes Neidhart / Ivan G. Szendro / Jonas Rzezonka / Rahul Marathe / Joachim Krug

    Biology, Vol 7, Iss 1, p

    2018  Volume 6

    Abstract: A long-standing problem in ageing research is to understand how different factors contributing to longevity should be expected to act in combination under the assumption that they are independent. Standard interaction analysis compares the extension of ... ...

    Abstract A long-standing problem in ageing research is to understand how different factors contributing to longevity should be expected to act in combination under the assumption that they are independent. Standard interaction analysis compares the extension of mean lifespan achieved by a combination of interventions to the prediction under an additive or multiplicative null model, but neither model is fundamentally justified. Moreover, the target of longevity interventions is not mean life span but the entire survival curve. Here we formulate a mathematical approach for predicting the survival curve resulting from a combination of two independent interventions based on the survival curves of the individual treatments, and quantify interaction between interventions as the deviation from this prediction. We test the method on a published data set comprising survival curves for all combinations of four different longevity interventions in Caenorhabditis elegans. We find that interactions are generally weak even when the standard analysis indicates otherwise.
    Keywords models of ageing ; longevity interventions ; epistasis ; survival curves ; failure time analysis ; Caenorhabditis elegans ; Biology (General) ; QH301-705.5
    Subject code 519
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Book ; Online ; Thesis: Modeling Primary Hemostasis

    Hoore, Masoud [Verfasser] / Gompper, Gerhard [Gutachter] / Joachim, Krug [Gutachter]

    2018  

    Author's details Masoud Hoore ; Gutachter: Gerhard Gompper, Krug Joachim
    Keywords Naturwissenschaften ; Science
    Subject code sg500
    Language English
    Publisher Universitäts- und Stadtbibliothek Köln
    Publishing place Köln
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  5. Article ; Online: Multidimensional epistasis and the transitory advantage of sex.

    Stefan Nowak / Johannes Neidhart / Ivan G Szendro / Joachim Krug

    PLoS Computational Biology, Vol 10, Iss 9, p e

    2014  Volume 1003836

    Abstract: Identifying and quantifying the benefits of sex and recombination is a long-standing problem in evolutionary theory. In particular, contradictory claims have been made about the existence of a benefit of recombination on high dimensional fitness ... ...

    Abstract Identifying and quantifying the benefits of sex and recombination is a long-standing problem in evolutionary theory. In particular, contradictory claims have been made about the existence of a benefit of recombination on high dimensional fitness landscapes in the presence of sign epistasis. Here we present a comparative numerical study of sexual and asexual evolutionary dynamics of haploids on tunably rugged model landscapes under strong selection, paying special attention to the temporal development of the evolutionary advantage of recombination and the link between population diversity and the rate of adaptation. We show that the adaptive advantage of recombination on static rugged landscapes is strictly transitory. At early times, an advantage of recombination arises through the possibility to combine individually occurring beneficial mutations, but this effect is reversed at longer times by the much more efficient trapping of recombining populations at local fitness peaks. These findings are explained by means of well-established results for a setup with only two loci. In accordance with the Red Queen hypothesis the transitory advantage can be prolonged indefinitely in fluctuating environments, and it is maximal when the environment fluctuates on the same time scale on which trapping at local optima typically occurs.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2014-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Evolutionary accessibility of mutational pathways.

    Jasper Franke / Alexander Klözer / J Arjan G M de Visser / Joachim Krug

    PLoS Computational Biology, Vol 7, Iss 8, p e

    2011  Volume 1002134

    Abstract: Functional effects of different mutations are known to combine to the total effect in highly nontrivial ways. For the trait under evolutionary selection ('fitness'), measured values over all possible combinations of a set of mutations yield a fitness ... ...

    Abstract Functional effects of different mutations are known to combine to the total effect in highly nontrivial ways. For the trait under evolutionary selection ('fitness'), measured values over all possible combinations of a set of mutations yield a fitness landscape that determines which mutational states can be reached from a given initial genotype. Understanding the accessibility properties of fitness landscapes is conceptually important in answering questions about the predictability and repeatability of evolutionary adaptation. Here we theoretically investigate accessibility of the globally optimal state on a wide variety of model landscapes, including landscapes with tunable ruggedness as well as neutral 'holey' landscapes. We define a mutational pathway to be accessible if it contains the minimal number of mutations required to reach the target genotype, and if fitness increases in each mutational step. Under this definition accessibility is high, in the sense that at least one accessible pathway exists with a substantial probability that approaches unity as the dimensionality of the fitness landscape (set by the number of mutational loci) becomes large. At the same time the number of alternative accessible pathways grows without bounds. We test the model predictions against an empirical 8-locus fitness landscape obtained for the filamentous fungus Aspergillus niger. By analyzing subgraphs of the full landscape containing different subsets of mutations, we are able to probe the mutational distance scale in the empirical data. The predicted effect of high accessibility is supported by the empirical data and is very robust, which we argue reflects the generic topology of sequence spaces. Together with the restrictive assumptions that lie in our definition of accessibility, this implies that the globally optimal configuration should be accessible to genome wide evolution, but the repeatability of evolutionary trajectories is limited owing to the presence of a large number of alternative mutational pathways.
    Keywords Biology (General) ; QH301-705.5
    Subject code 710 ; 006
    Language English
    Publishing date 2011-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Silent Cerebral Events after Atrial Fibrillation Ablation � Overview and Current Data

    Thomas Deneke / Karin Nentwich / Joachim Krug / Patrick M�ller / Peter Hubert Grewe / Andreas M�gge / Anja Schade

    Journal of Atrial Fibrillation, Vol 6, Iss 5, Pp 64-

    2014  Volume 69

    Abstract: Silent cerebral lesions (SCL) have been identified on brain magnetic resonance imaging (MRI) in apparently asymptomatic patients after cardiovascular procedures. After atrial fibrillation (AF) ablation incidences range from 1 to over 40% depending upon ... ...

    Abstract Silent cerebral lesions (SCL) have been identified on brain magnetic resonance imaging (MRI) in apparently asymptomatic patients after cardiovascular procedures. After atrial fibrillation (AF) ablation incidences range from 1 to over 40% depending upon different factors. MRI definition should include diffusion weighted imaging (DWI) to detect hyperintensities (bright spots) due to acute brain ischemia correlated with a hypointensity in the apparent diffusion coefficient mapping (ADC-map) to rule out artifacts. The genesis of SCL appears to be multifactorial and appears to be a result of embolic events either from gaseous or solid particles. The MRI pattern appears to be comparable not hinting towards a specific mechanism. One may distinguish two different MRI patterns, for one silent cerebral ischemic events not proven to be related to cell death (DWI positive but FLAIR negative) and MRI findings that are due to edema caused by cell death which will lead to glial cell scar formation (DWI positive and FLAIR positive). For ease of data interpretation, future studies should ensure that DWI and FLAIR data is acquired using identical slice thickness and orientation. Risk factors associated with increased SCL-incidences involve patient-specific, technology-associated and procedural determinants. When using a high-sensitive MRI definition differences in ischemic brain event-rates in between technologies appear to be less prominent. Further studies on the effects of different periprocedural anticoagulation regimen, different steps of the ablation procedure and new technologies are needed. For now, SCL incidence may determine the thrombogenic potential of an ablation technology and further studies to reduce or avoid SCL generation are desirable. It appears reasonable, that any cerebral ischemic event should be avoided.
    Keywords Internal medicine ; RC31-1245 ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2014-02-01T00:00:00Z
    Publisher CardioFront
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Predictors of Recurrence After Catheter Ablation of Persistent Atrial Fibrillation

    Thomas Deneke / Anja Schade / Joachim Krug / Karsten Stahl / Geza Atilla Szollosi / Dong In Shin / Clemens Nino Schukro / Mohamed El Tarahony / Enrique Murillo / Semko Aram / Gabriele Robhirt / Thomas Lawo / Andreas Mugge / Peter H. Grewe / Sebastian Kerber

    Journal of Atrial Fibrillation, Vol 4, Iss 5, Pp 8-

    2012  Volume 16

    Abstract: Catheter ablation of atrial fibrillation (AF) has been increasingly used to treat symptomatic patients.Within the last years a growing interest in ablation of persistent AF forms has evolved.Factors that may influence outcome of these procedures to treat ...

    Abstract Catheter ablation of atrial fibrillation (AF) has been increasingly used to treat symptomatic patients.Within the last years a growing interest in ablation of persistent AF forms has evolved.Factors that may influence outcome of these procedures to treat persistent AF may be patient-specific (pre-procedural),procedure-related or may involve different post-ablation followup strategies. In this review potential factors predicting recurrence of AF after ablation of persistent AF have been evaluated.In essence, data is limited mostly due to incongruent definitions of persistent AF.Left atrial dimensions, duration of continuous AF and AF cycle length may be patient-specific predictors of outcome. Intra-procedural parameters involved in recurrence prediction may be extent of ablation (effective pulmonary vein isolation appears mandatory) and termination of AF during ablation. Timing and number of cardioversion if persistent AF recurs may predict outcome, as well. Many studies have identified strators for higher recurrence rates in rather small patient groups and need to be further evaluated in larger patient collectives.
    Keywords Internal medicine ; RC31-1245 ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2012-02-01T00:00:00Z
    Publisher CardioFront
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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