Abstract
The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M
pro
), critical for viral replication, is a key target for therapeutic ...development. An organoselenium drug called ebselen has been demonstrated to have potent M
pro
inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M
pro
via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M
pro
inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of M
pro
with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic
beta
-corona viruses.
Precise and robust localization in a large-scale outdoor environment is essential for an autonomous vehicle. In order to improve the performance of the fusion of GNSS (Global Navigation Satellite ...System)/IMU (Inertial Measurement Unit)/DMI (Distance-Measuring Instruments), a multi-constraint fault detection approach is proposed to smooth the vehicle locations in spite of GNSS jumps. Furthermore, the lateral localization error is compensated by the point cloud-based lateral localization method proposed in this paper. Experiment results have verified the algorithms proposed in this paper, which shows that the algorithms proposed in this paper are capable of providing precise and robust vehicle localization.
An improved nondominated sorting genetic algorithm-II (INSGA-II) has been proposed for optimal planning of multiple distributed generation (DG) units in this paper. First, multiobjective functions ...that take minimum line loss, minimum voltage deviation, and maximal voltage stability margin into consideration have been formed. Then, using the proposed INSGA-II algorithm to solve the multiobjective planning problem has been described in detail. The improved sorting strategy and the novel truncation strategy based on hierarchical agglomerative clustering are utilized to keep the diversity of population. In order to strengthen the global optimal searching capability, the mutation and recombination strategies in differential evolution are introduced to replace the original one. In addition, a tradeoff method based on fuzzy set theory is used to obtain the best compromise solution from the Pareto-optimal set. Finally, several experiments have been made on the IEEE 33-bus test case and multiple actual test cases with the consideration of multiple DG units. The feasibility and effectiveness of the proposed algorithm for optimal placement and sizing of DG in distribution systems have been proved.
In this study, a new pinning-based distributed cooperative control scheme is proposed for multi-agent system (MAS)-based autonomous microgrids. By pinning parts of selected agents, only a small ...fraction of the pinned agents are controlled by simple feedback controllers, while the other DGAs in the MAS synchronize through the communication coupling among the pinned agents in a distributed manner. The main contributions of this study are as follows: 1) the proposal of a fully distributed control for autonomous microgrids where each agent shares its operation information only with its neighbors, which obviates the requirement for a central controller and complex communication topology; 2) the proposal of a pinning-based control scheme, which reduces the number of controllers, for a predefined consensus can be reached if a small fraction of the pinned agents is controlled; and 3) the proposal of the pinning consensus under uncertain communication topologies that can meet the requirements of line switches and plug-and-play operation. Simulation results are demonstrated to verify the effectiveness and adaptability of the proposed scheme.
Mitigating the risk of drug hypersensitivity reactions is an important facet of a given pharmaceutical, with poor performance in this area of safety often leading to warnings, restrictions and ...withdrawals. In the last 50 years, efforts to diagnose, manage, and circumvent these obscure, iatrogenic diseases have resulted in the development of assays at all stages of a drugs lifespan. Indeed, this begins with intelligent lead compound selection/design to minimize the existence of deleterious chemical reactivity through exclusion of ominous structural moieties. Preclinical studies then investigate how compounds interact with biological systems, with emphasis placed on modeling immunological/toxicological liabilities. During clinical use, competent and accurate diagnoses are sought to effectively manage patients with such ailments, and pharmacovigilance datasets can be used for stratification of patient populations in order to optimise safety profiles. Herein, an overview of some of the
approaches to predict intrinsic immunogenicity of drugs and diagnose culprit drugs in allergic patients after exposure is detailed, with current perspectives and opportunities provided.
The ability to track pedestrians without any infrastructure support is required by numerous applications in the healthcare, augmented reality, and entertainment industries. In this paper, we present ...a simple self-contained pedestrian tracking method using a foot-mounted inertial and magnetic sensor module. Traditional methods normally incorporate double integration of the measured acceleration, but such methods are susceptible to the acceleration noise and integration drift. To avoid this issue, alternative approaches which make use of walking dynamics to aggregate individual stride have been explored. The key for stride aggregating is to accurately and reliably detect stride boundary and estimate the associated heading direction for each stride, but it is still not well solved yet due to sensor noise and external disturbance. In this paper, we propose to make use of the inertial sensor and magnetometer measurements for stride detection and heading direction determination. In our method, a simple and reliable stride detection method, which is resilient to random bouncing motions and sensor noise, is designed based on gyroscope and accelerometer measurements. Heading direction is then determined from the foot's orientation which fuses all the three types of sensor information together. The proposed pedestrian tracking method has been evaluated using experiments, including both short distance walking with different patterns and long distance walking performed indoors and outdoors. The good experimental results have illustrated the effectiveness of the proposed pedestrian tracking method.
Definition of the relationship between drug protein adduct formation (haptenation) and development of immunological adverse drug reactions (drug hypersensitivity) has been an area of active research ...for over 80 years. The hapten hypothesis which states that “immunogenicity of low molecular weight organic chemicals is dependent on modification of self-proteins,” evolved from Landsteiner and Jacob’s discovery of a correlation between the reactivity of dinitro-halogenated benzenes and their sensitization potential. The hypothesis rapidly evolved to encompass drugs that often require metabolic activation to generate electrophilic, protein-reactive intermediates. As tissue culture methods advanced, the importance of drug hapten-specific T-cells in the disease pathogenesis was defined. This led to a plethora of studies describing the uptake and processing of drug(metabolite) protein adducts by antigen presenting cells, and the subsequent surface display of hapten-modified peptides in the context of MHC molecules. Although the pathway of hapten-specific T-cell activation is now well established, several questions need to be addressed: first, what is the nature of the hapten-modified peptides displayed by MHC? Second, how many of these peptides stimulate T-cells?; third, what are the critical protein modifications involved in T-cell activation; and finally, what is the role of hapten-specific T-cells in the iatrogenic disease? These questions will become increasingly important as more and more targeted covalent binding inhibitor drugs are approved for human use. In this review, we provide a brief synopsis of hapten research and then describe the approaches used by Pharma and academia to study hapten covalent binding and the role of drug protein adducts in the activation of human T-cells.
This paper investigates the coordinated voltage control problem for smart distribution grid with the integration of distributed generation (DG). By actively participating in voltage control together ...with under-load tap changer and shunt capacitors, DG can operate more effectively in the distribution network. The objective of the proposed control method is to minimize the active power loss in the distribution system and to decrease the number of switching device operations while maintaining the grid voltage within the allowable range. Nondispatchable and dispatchable DG are both considered in the control method. To solve the mixed integer nonlinear programming problem, the trust region sequential quadratic programming method is integrated with the branch and bound approach to iteratively approximate the optimization with trust region guidance. Numerical tests on a standard 10-kV distribution system, a real 10-kV distribution system in the Sichuan province of China, and the IEEE 13-bus demonstrate the applicability of the proposed coordinated voltage control method.
The covalent binding of drugs (metabolites) to proteins to form drug–protein adducts can have an adverse effect on the body. These adducts are thought to be responsible for idiosyncratic drug ...reactions including severe drug hypersensitivity reactions. Major advances in proteomics technology have allowed for the identification and quantification of target proteins for certain drugs. Human serum albumin (HSA) and Hb have been identified as accessible targets and potential biomarkers for drug–protein adducts formation, for numerous drugs (metabolites) including β-lactam antibiotics, reactive drug metabolites such as quinone imines (acetaminophen) and acyl glucuronides (diclofenac), and covalent inhibitors (neratinib). For example, MS/MS analysis of plasma samples from patients taking flucloxacillin revealed that flucloxacillin and its 5-hydroxymethyl metabolite formed covalent adducts with lysine residues on albumin via opening of the β-lactam ring. Other proteins such as P450 and keratin are also potential targets for covalent binding. However, for most drugs, the properties of these target proteins including their location, their quantity, the timing of conjugate generation, and their biological function are not well understood. In this review, currently available proteomic technologies including MS/MS analysis to identify antigens, precise location of modifications, and the immunological consequence of hapten–protein complex are illustrated. Moving forward, identification of the nature of the antigenic determinants that trigger immune responses to drug–protein adducts will increase our ability to predict idiosyncratic toxicity for a given compound.
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