Moretti, R. | Search bioRxiv

bioRxiv2021

Increased biting rate and decreased Wolbachia density in irradiated mosquitoes: safety issues in the framework of genetic control strategies

BackgroundReleasing considerable numbers of radiation-sterilized males is a promising strategy to suppress mosquito vectors. However, releases may also include small percentages of biting females which translate to large numbers when releases are large. Currently, the effects of irradiation on the host-seeking and host-biting behaviors have not been exhaustively investigated. Information is also lacking regarding the effects of sterilizing treatment on the endosymbiotic bacterium Wolbachia, which is known to affect the vector competence of infected mosquitos. MethodsTo ascertain the effects of irradiation on females, the pupae of two Aedes albopictus strains, differing in their natural or artificial Wolbachia infection type, and Ae. aegypti--which is not infected by Wolbachia--were treated with various doses of X-rays and monitored for key fitness parameters and biting behavior over a period of two weeks. The effect of radiation on Wolbachia was investigated by qPCR and FISH analysis. ResultsPartial Ae. albopictus female sterility was achieved at 28 Gy but the number of weekly bites more than doubled compared to that of the controls. Radiation doses of 35 and 45 Gy completely inhibited progeny production but did not significantly affect the survival or flight ability of Ae. albopictus females and caused a tripling of the number of bites per female per week (compared to untreated controls). These results were also confirmed in Ae. aegypti after treatment at 50 Gy. Wolbachia density decreased significantly in 45-Gray-irradiated females, with the greatest decreases in the early irradiation group (26{+/-}2-hour-old pupae). Wolbachia density also decreased as adults aged. This trend was confirmed in ovaries but not in extra-ovarian tissues. FISH analysis showed a strongly reduced Wolbachia-specific fluorescence in the ovaries of 13{+/-}1-day-old females. ConclusionsThese results suggest that, under SIT programs, the vector capacity of a target population could increase with the frequency of the irradiated females co-released with the sterile males due to an increased biting rate. In the context of a successful suppression, the related safety issues could be generally negligible, but they should be conservatively evaluated when large scale programs relying on imperfect sexing and high overflooding release ratios are run for long time in areas endemic for arboviral diseases. Also, the effects of irradiation on the vector competence deserve further investigation.

microbiology↗

bioRxiv2020

Deep Learning for Virtual Screening: Five Reasons to Use ROC Cost Functions

Computer-aided drug discovery is an essential component of modern drug development. Therein, deep learning has become an important tool for rapid screening of billions of molecules in silico for potential hits containing desired chemical features. Despite its importance, substantial challenges persist in training these models, such as severe class imbalance, high decision thresholds, and lack of ground truth labels in some datasets. In this work we argue in favor of directly optimizing the receiver operating characteristic (ROC) in such cases, due to its robustness to class imbalance, its ability to compromise over different decision thresholds, certain freedom to influence the relative weights in this compromise, fidelity to typical benchmarking measures, and equivalence to positive/unlabeled learning. We also propose new training schemes (coherent mini-batch arrangement, and usage of out-of-batch samples) for cost functions based on the ROC, as well as a cost function based on the logAUC metric that facilitates early enrichment (i.e. improves performance at high decision thresholds, as often desired when synthesizing predicted hit compounds). We demonstrate that these approaches outperform standard deep learning approaches on a series of PubChem high-throughput screening datasets that represent realistic and diverse drug discovery campaigns on major drug target families.

pharmacology and toxicology↗