Evolutionary accessibility of mutational pathways

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 pathwayexists 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 bound. We test the model predictions against an empirical 8-locus fitness landscape obtained for the filamentous fungus \textit{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 very robust, which we argue to reflect the generic topology of sequence spaces.Comment: 16 pages, 4 figures; supplementary material available on reques

Quantitative analyses of empirical fitness landscapes

The concept of a fitness landscape is a powerful metaphor that offers insight into various aspects of evolutionary processes and guidance for the study of evolution. Until recently, empirical evidence on the ruggedness of these landscapes was lacking, but since it became feasible to construct all possible genotypes containing combinations of a limited set of mutations, the number of studies has grown to a point where a classification of landscapes becomes possible. The aim of this review is to identify measures of epistasis that allow a meaningful comparison of fitness landscapes and then apply them to the empirical landscapes to discern factors that affect ruggedness. The various measures of epistasis that have been proposed in the literature appear to be equivalent. Our comparison shows that the ruggedness of the empirical landscape is affected by whether the included mutations are beneficial or deleterious and by whether intra- or intergenic epistasis is involved. Finally, the empirical landscapes are compared to landscapes generated with the Rough Mt.\ Fuji model. Despite the simplicity of this model, it captures the features of the experimental landscapes remarkably well.Comment: 24 pages, 5 figures; to appear in Journal of Statistical Mechanics: Theory and Experimen

Superconductivity in SrFe_(2-x)Co_xAs_2: Internal Doping of the Iron Arsenide Layers

In the electron doped compounds SrFe_(2-x)Co_xAs_2 superconductivity with T_c up to 20 K is observed for 0.2 < x < 0.4. Results of structure determination, magnetic susceptibility, electrical resistivity, and specific heat are reported. The observation of bulk superconductivity in all thermodynamic properties -- despite strong disorder in the Fe-As layer -- favors an itinerant picture in contrast to the cuprates and renders a p- or d-wave scenario unlikely. DFT calculations find that the substitution of Fe by Co (x > 0.3) leads to the suppression of the magnetic ordering present in SrFe_2As_2 due to a rigid down-shift of the Fe-3d_(x^2-y^2) related band edge in the density of states.Comment: 5 pages, 3 figure

Roughness correction to the Casimir force at short separations: Contact distance and extreme value statistics

So far there has been no reliable method to calculate the Casimir force at separations comparable to the root-mean-square of the height fluctuations of the surfaces. Statistical analysis of rough gold samples has revealed the presence of peaks considerably higher than the root-mean-square roughness. These peaks redefine the minimum separation distance between the bodies and can be described by extreme value statistics. Here we show that the contribution of the high peaks to the Casimir force can be calculated with a pairwise additive summation, while the contribution of asperities with normal height can be evaluated perturbatively. This method provides a reliable estimate of the Casimir force at short distances, and it solves the significant, so far unexplained discrepancy between measurements of the Casimir force between rough surfaces and the results of perturbation theory. Furthermore, we illustrate the importance of our results in a technologically relevant situation.Comment: 29 pages, 11 figures, to appear in Phys. Rev.

Alteration of Bax-to-Bcl-2 ratio modulates the anticancer activity of methanolic extract of Commelina benghalensis (Commelinaceae) in Jurkat T cells

Stem extracts of Commelina benghalensis (Linn.), although not extensively documented, are frequently used in traditional medicine for the treatment of ailments such as skin malformations and outgrowths. Accordingly, the study was aimed to investigate possible molecular mechanisms that are associated with the potential anti-carcinogenic property of this agrofield weed. Jurkat T cells were exposed to different concentrations (0-600 ug/ml) of the crude methanolic extract of C. benghalensis to evaluate their growth inhibitory and apoptosis inducing effects. The extract elicited a dose- and time-dependent inhibition of cell proliferation, followed by a concomitant decrease in cell viability. The observed cytotoxicity was linked to the induction of apoptosis as determined by morphological and biochemical features known to be associated with the advent of apoptosis. Real time quantitative RT-PCR and Western blot analyses of Bax, Bcl-2 and p53 exhibited aberrant expression profiles of these genes under various treatment conditions. Taken together, the data suggest that the crude methanolic extract of C. benghalensis contains bioactive compounds that may be beneficial in the treatment of malignant growths, and that this apparent antineoplastic activity is a consequence of dysregulated expression of apoptosis-responsive genes. These observations could provide a credible scientific justification upon which the ethnopharmacological utilisation of C. benghalensis is founded

Equiangular Tight Frames That Contain Regular Simplices

An equiangular tight frame (ETF) is a type of optimal packing of lines in Euclidean space. A regular simplex is a special type of ETF in which the number of vectors is one more than the dimension of the space they span. In this paper, we consider ETFs that contain a regular simplex, that is, have the property that a subset of its vectors forms a regular simplex. As we explain, such ETFs are characterized as those that achieve equality in a certain well-known bound from the theory of compressed sensing. We then consider the so-called binder of such an ETF, namely the set of all regular simplices that it contains. We provide a new algorithm for computing this binder in terms of products of entries of the ETF\u27s Gram matrix. In certain circumstances, we show this binder can be used to produce a particularly elegant Naimark complement of the corresponding ETF. Other times, an ETF is a disjoint union of regular simplices, and we show this leads to a certain type of optimal packing of subspaces known as an equichordal tight fusion frame. We conclude by considering the extent to which these ideas can be applied to numerous known constructions of ETFs, including harmonic ETFs

Is the time in therapeutic range on coumarins predicted by previous time in therapeutic range?

Background The benefit of vitamin K antagonists depends on the time within the therapeutic range (TTR). A patient's previous TTR could be a factor in the decision to change the anticoagulation regimen. However, the predictive value of a previous TTR for a future TTR is not well established, nor is it clear which TTR should prompt action. Objectives To investigate the predictive performance of a TTR and identify a threshold below which no recovery of TTR should be expected. Patients/Methods From 18 031 patients who used acenocoumarol in a first-line anticoagulation clinic, a TTR was calculated over multiple periods of 90, 180, and 365 days each. We assessed the correlation between baseline and later TTR and the separation between groups by quintile of baseline TTR. We describe the proportion of patients who obtain a TTR >= 70% conditional on baseline TTR. Results The correlation between baseline and later TTR was 0.25 (95% confidence interval [CI], 0.24-0.26), 0.27 (95% CI, 0.26-0.28) and 0.34 (95% CI, 0.32-0.35) for analyses over 90, 180, and 365 days. Corresponding c statistics for discrimination by baseline group were 0.60, 0.61, and 0.63. The probability to obtain a TTR >= 70% increased with baseline TTR: from 42% with a baseline TTR of 50%-65% when TTR was 100% (TTR calculated over 180 days). Conclusions We conclude that a current TTR hardly predicts a future TTR. Physicians and patients should deliberate together which probabilities to accept, take measures to improve TTR, and consider potential alternatives

Genome-wide SNP identification by high-throughput sequencing and selective mapping allows sequence assembly positioning using a framework genetic linkage map

Determining the position and order of contigs and scaffolds from a genome assembly within an organism’s genome remains a technical challenge in a majority of sequencing projects. In order to exploit contemporary technologies for DNA sequencing. We developed a strategy for whole genome single nucleotide polymorphism sequencing allowing the positioning of sequence contigs onto a linkage map using the bin mapping method. The strategy was tested on a draft genome of the fungal pathogen Venturia inaequalis, the causal agent of apple scab, and further validated using sequence contigs derived from the diploid plant genome Fragaria vesca. Using our novel method we were able to anchor 70% and 92% of sequences assemblies for V. inaequalis and F. vesca, respectively, to genetic linkage maps. We demonstrated the utility of this approach by accurately determining the bin map positions of the majority of the large sequence contigs from each genome sequence and validated our method by mapping single sequence repeat markers derived from sequence contigs on a full mapping population.Deciduous Fruit Producers Trust THRIP Program National Research Foundation Claude Harris Leon FoundationWeb of Scienc