Fractional dynamics pharmacokinetics–pharmacodynamic models

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics–pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics

Species Tree Estimation for the Late Blight Pathogen, Phytophthora infestans, and Close Relatives

To better understand the evolutionary history of a group of organisms, an accurate estimate of the species phylogeny must be known. Traditionally, gene trees have served as a proxy for the species tree, although it was acknowledged early on that these trees represented different evolutionary processes. Discordances among gene trees and between the gene trees and the species tree are also expected in closely related species that have rapidly diverged, due to processes such as the incomplete sorting of ancestral polymorphisms. Recently, methods have been developed for the explicit estimation of species trees, using information from multilocus gene trees while accommodating heterogeneity among them. Here we have used three distinct approaches to estimate the species tree for five Phytophthora pathogens, including P. infestans, the causal agent of late blight disease in potato and tomato. Our concatenation-based “supergene” approach was unable to resolve relationships even with data from both the nuclear and mitochondrial genomes, and from multiple isolates per species. Our multispecies coalescent approach using both Bayesian and maximum likelihood methods was able to estimate a moderately supported species tree showing a close relationship among P. infestans, P. andina, and P. ipomoeae. The topology of the species tree was also identical to the dominant phylogenetic history estimated in our third approach, Bayesian concordance analysis. Our results support previous suggestions that P. andina is a hybrid species, with P. infestans representing one parental lineage. The other parental lineage is not known, but represents an independent evolutionary lineage more closely related to P. ipomoeae. While all five species likely originated in the New World, further study is needed to determine when and under what conditions this hybridization event may have occurred

Aphid-host plant interactions: Does aphid honeydew exactly reflect the host plant amino acid composition?

peer reviewedPlants provide aphids with unbalanced and low concentrations of amino acids. Likely, intracellular symbionts improve the aphid nutrition by participating to the synthesis of essential amino acids. To compare the aphid amino acid uptakes from the host plant and the aphids amino acid excretion into the honeydew, host plant exudates (phloem + xylem) from infested and uninfested Vicia faba L. plants were compared to the honeydew produced by two aphid species (Acyrthosiphon pisum Harris and Megoura viciae Buckton) feeding on V. faba. Our results show that an aphid infestation modifies the amino acid composition of the infested broad bean plant since the global concentration of amino acids significantly increased into the host plant in response to aphid infestations. Specifically, the concentrations of two amino acids glutamine and asparagine were strongly enhanced. The amino acid profiles from honeydews were similar for the two aphid species, but the concentrations found into the honeydews were generally lower than those measured in the exudates of infested plants (aphids uptakes). This work also highlights that aphids take large amounts of amino acids into the host plant, especially glutamine and asparagine which are converted into glutamic and aspartic acids but also into other essential amino acids. The amino acid profiles differed between the host plant exudates and the aphid excretion product. Finally, this study highlights that the pea aphid - a “specialist” for the V. faba host plant - induced more important modifications into the host plant amino acid composition than the “generalist” aphid M. viciae.Solaphi