In Silico Prediction and Insights Into the Structural Basis of Drug Induced Nephrotoxicity

Drug induced nephrotoxicity is a major clinical challenge, and it is always associated with higher costs for the pharmaceutical industry and due to detection during the late stages of drug development. It is desirable for improving the health outcomes for patients to distinguish nephrotoxic structures at an early stage of drug development. In this study, we focused on in silico prediction and insights into the structural basis of drug induced nephrotoxicity, based on reliable data on human nephrotoxicity. We collected 565 diverse chemical structures, including 287 nephrotoxic drugs on humans in the real world, and 278 non-nephrotoxic approved drugs. Several different machine learning and deep learning algorithms were employed for in silico model building. Then, a consensus model was developed based on three best individual models (RFR_QNPR, XGBOOST_QNPR, and CNF). The consensus model performed much better than individual models on internal validation and it achieved prediction accuracy of 86.24% external validation. The results of analysis of molecular properties differences between nephrotoxic and non-nephrotoxic structures indicated that several key molecular properties differ significantly, including molecular weight (MW), molecular polar surface area (MPSA), AlogP, number of hydrogen bond acceptors (nHBA), molecular solubility (LogS), the number of rotatable bonds (nRotB), and the number of aromatic rings (nAR). These molecular properties may be able to play an important part in the identification of nephrotoxic chemicals. Finally, 87 structural alerts for chemical nephrotoxicity were mined with f-score and positive rate analysis of substructures from Klekota-Roth fingerprint (KRFP). These structural alerts can well identify nephrotoxic drug structures in the data set. The in silico models and the structural alerts could be freely accessed via https://ochem.eu/article/140251 and http://www.sapredictor.cn, respectively. We hope the results should provide useful tools for early nephrotoxicity estimation in drug development.

An Influence Network-Based Consensus Model for Large-Scale Group Decision Making with Linguistic Information

The vast majority of the existing social network-based group decision-making models require extra information such as trust/distrust, influence and so on. However, in practical decision-making process, it is difficult to get additional information apart from opinions of decision makers. For large-scale group decision making (LSGDM) problem in which decision makers articulate their preferences in the form of comparative linguistic expressions, this paper proposes a consensus model based on an influence network which is inferred directly from preference information. First, a modified agglomerative hierarchical clustering algorithm is developed to detect subgroups in LSGDM problem with flexible linguistic information. Meanwhile, a measure method of group consensus level is proposed and the optimal clustering level can be determined. Second, according to the preference information of group members, influence network is constructed by determining intra-cluster and inter-cluster influence relationships. Third, a two-stage feedback mechanism guided by influence network is established for the consensus reaching process, which adopts cluster adjustment strategy and individual adjustment strategy depending on the different levels of group consensus. The proposed mechanism can not only effectively improve the efficiency of consensus reaching of LSGDM, but also take individual preference adjustment into account. Finally, the feasibility and effectiveness of the proposed method are verified by the case of intelligent environmental protection project location decision.

Detecting Signatures Of Selection In Regulatory Variation

A substantial amount of phenotypic diversity results from changes in gene regulation. Understanding how regulatory diversity evolves is therefore a key priority in identifying mechanisms of adaptive change. However, in contrast to powerful models of sequence evolution, we lack a consensus model of regulatory evolution. Furthermore, recent work has shown that many of the comparative approaches used to study gene regulation are subject to biases that can lead to false signatures of selection. In this review, we first outline the main approaches for describing regulatory evolution and their inherent biases. Next, we bridge the gap between the fields of comparative phylogenetic methods and transcriptomics to reinforce the main pitfalls of inferring regulatory selection and use simulation studies to show that shifts in tissue composition can heavily bias inferences of selection. We close by highlighting the multi-dimensional nature of regulatory variation and identifying major, unanswered questions in disentangling how selection acts on the transcriptome.