The pharmacokinetics and drug-drug interactions of ivermectin in Aedes aegypti mosquitoes

Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01–1 μg/ml ivermectin without showing saturation (R²: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI_90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI_90%: 5.1–5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI_90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods.     

Enhancing the power of two choices load balancing algorithm using round robin policy

Cluster Computing - This paper proposes a new version of the power of two choices, SQ(d), load balancing algorithm. This new algorithm improves the performance of the classical model based on the...     

A Highlights from MBoC Selection: Motion of variable-length MreB filaments at the bacterial cell membrane influences cell morphology

The maintenance of rod-cell shape in many bacteria depends on actin-like MreB proteins and several membrane proteins that interact with MreB. Using superresolution microscopy, we show that at 50-nm resolution, Bacillus subtilis MreB forms filamentous structures of length up to 3.4 μm underneath the cell membrane, which run at angles diverging up to 40° relative to the cell circumference. MreB from Escherichia coli forms at least 1.4-μm-long filaments. MreB filaments move along various tracks with a maximal speed of 85 nm/s, and the loss of ATPase activity leads to the formation of extended and static filaments. Suboptimal growth conditions lead to formation of patch-like structures rather than extended filaments. Coexpression of wild-type MreB with MreB mutated in the subunit interface leads to formation of shorter MreB filaments and a strong effect on cell shape, revealing a link between filament length and cell morphology. Thus MreB has an extended-filament architecture with the potential to position membrane proteins over long distances, whose localization in turn may affect the shape of the cell wall.     

Desulfurization of dibenzothiophene using the 4S enzymatic route: Influence of operational conditions on initial reaction rates

The influence of operational conditions (pH, temperature and oxygen transfer rate) on the initial reaction rates of the four reactions involved in the 4S biodesulfurization route of dibenzothiophenes (DBT) has been studied. The bioprocess was carried out using a genetically modified organism, Pseudomonas putida CECT 5279. The rates of the four reactions were calculated from the rates of production of different compounds involved in the 4S pathway, by matrix manipulation. The initial (zero time) reaction rates showed a slight dependence on oxygen transfer rate. Temperature and pH were optimal at 30°C and 9, respectively, temperature being the most important variable. This study also identifies the last reaction as the limiting step in the pathway.     

An affine micro-sphere-based constitutive model,accounting for junctional sliding,can capture F-actin network mechanics

Actin filaments are a major component of the cytoskeleton and play a crucial role in cell mechanotransduction. F-actin networks can be reconstituted in vitro and their mechanical behaviour has been studied experimentally. Constitutive models that assume an idealised network structure, in combination with a non-affine network deformation, have been successful in capturing the elastic response of the network. In this study, an affine network deformation is assumed, in which we propose an alternative 3D finite strain constitutive model. The model makes use of a micro-sphere to calculate the strain energy density of the network, which is represented as a continuous distribution of filament orientations in space. By incorporating a simplified sliding mechanism at the filament-to-filament junctions, premature filament locking, inherent to affine network deformation, could be avoided. The model could successfully fit experimental shear data for a specific cross-linked F-actin network, demonstrating the potential of the novel model.     

Characterization of an alpine tree line using airborne LiDAR data and physiological modeling

Understanding what environmental drivers control the position of the alpine tree line is important for refining our understanding of plant stress and tree development, as well as for climate change studies. However, monitoring the location of the tree line position and potential movement is difficult due to cost and technical challenges, as well as a lack of a clear boundary. Advanced remote sensing technologies such as Light Detection and Ranging (LiDAR) offer significant potential to map short individual tree crowns within the transition zone despite the lack of predictive capacity. Process‐based forest growth models offer a complementary approach by quantifying the environmental stresses trees experience at the tree line, allowing transition zones to be defined and ultimately mapped. In this study, we investigate the role remote sensing and physiological, ecosystem‐based modeling can play in the delineation of the alpine tree line. To do so, we utilize airborne LiDAR data to map tree height and stand density across a series of altitudinal gradients from below to above the tree line within the Swiss National Park (SNP), Switzerland. We then utilize a simple process‐based model to assess the importance of seasonal variations on four climatically related variables that impose non‐linear constraints on photosynthesis. Our results indicate that all methods predict the tree line to within a 50 m altitudinal zone and indicate that aspect is not a driver of significant variations in tree line position in the region. Tree cover, rather than tree height is the main discriminator of the tree line at higher elevations. Temperatures in fall and spring are responsible for the major differences along altitudinal zones, however, changes in evaporative demand also control plant growth at lower altitudes. Our results indicate that the two methods provide complementary information on tree line location and, when combined, provide additional insights into potentially endangered forest/grassland transition zones.     

Apodemia mormo in Canada: population genetic data support prior conservation ranking

Like many species, the Mormon Metalmark butterfly (Apodemia mormo) has been given conservation ranking in Canada based on limited data. This species is widespread across western North America, but has only two populations in Canada: an “endangered” population in the Similkameen valley of British Columbia, and a “threatened” population in Grasslands National Park (GNP) in Saskatchewan. Here we present genetic data from 1498 base pairs of the cytochrome oxidase I gene sequence and six novel microsatellite loci in order to assess (1) whether the two populations are related, (2) the degree to which they are genetically diverse and demographically stable, and (3) what their relationships are to the nearest unranked populations of A. mormo across the Canada-United States border. Our principal conclusion is that the two populations are not closely related genetically. We also found that the British Columbia population is genetically depauperate and, with the exception of the nearest neighboring populations across the border, not recently genetically connected to other populations in the Pacific Northwest. In comparison, the Saskatchewan population is genetically diverse, and gene flow occurs with several other eastern populations. Population structure was not detected within either the British Columbia or the Saskatchewan populations. This research supports the prior conservation rankings of both populations and provides new insight that will help to inform future management decisions for the Canadian populations of this charismatic butterfly.     

Extending the scope of the controlled logical clock

Event traces are helpful in understanding the performance behavior of parallel applications since they allow the in-depth analysis of communication and synchronization patterns. However, the absence of synchronized clocks on most cluster systems may render the analysis ineffective because inaccurate relative event timings may misrepresent the logical event order and lead to errors when quantifying the impact of certain behaviors or confuse the users of time-line visualization tools by showing messages flowing backward in time. In our earlier work, we have developed a scalable algorithm called the controlled logical clock that eliminates inconsistent inter-process timings postmortem in traces of pure MPI applications, potentially running on large processor configurations. In this paper, we first demonstrate that our algorithm also proves beneficial in computational grids, where a single application is executed using the combined computational power of several geographically dispersed clusters. Second, we present an extended version of the algorithm that—in addition to message-passing event semantics—also preserves and restores shared-memory event semantics, enabling the correction of traces from hybrid applications.