Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19. However, RDV can only be given by intravenous route, and there is a pressing medical need for ...oral antivirals. Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated. We performed an in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) assessment to examine the potential of RDV, and particularly GS-441524, as oral drugs. In our in vitro assessments, RDV exhibited prohibitively low stability in human liver microsomes (HLMs, t1/2 = ∼1 min), with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety. This observation is poorly aligned with any potential oral use of RDV, though in the presence of cobicistat, the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH. Conversely, GS-441524 showed excellent metabolic stability in human plasma and HLMs. In further in vivo studies in CD-1 mice, GS-441524 displayed a favorable oral bioavailability of 57%. Importantly, GS-441524 produced adequate drug exposure in the mice plasma and lung, and was effectively converted to the active triphosphate, suggesting that it could be a promising oral antiviral drug for treating COVID-19.
While extensive hydrolysis and CYP-mediated metabolism in liver render remdesivir (RDV) unsuitable as an oral drug, GS-441524 exhibited favorable oral bioavailability and effective bioactivation in mice toward oral use. Display omitted
Wireless-powered communication and reconfigurable intelligent surface (RIS) can complement each other for increasing energy utilization and spectrum efficiency by reconfiguring the surrounding radio ...environment, however, which has not been sufficiently studied by the existing works. In this paper, we propose a joint radio resource and passive beamforming optimization scheme for a downlink RIS-assisted wireless-powered communication network with a harvest-then-transmit protocol to improve system energy efficiency (EE). In the considered model, the single-antenna wireless devices (WDs) harvest wireless energy from a multi-antenna dedicated power station (PS) through the RIS in the downlink and transmit their independent information to a single-antenna receiver in the uplink by a time-division-multiple-access mode. Our goal is to maximize the total EE of all WDs. To make full use of the beamforming gain provided by both the PS and the RIS, we jointly optimize the active beamforming of the PS and the passive beamforming of the RIS. To deal with the challenging non-convex optimization problem with multiple coupled variables, we first consider fixing the passive beamforming, and converting the remaining radio resource allocation problem into an equivalent convex problem which is solved by using Lagrange dual theory. Then, we fix the optimized resource allocation parameters and optimize the passive beamforming of the RIS by using a semidefinite programming method. Simulation results demonstrate that the proposed algorithm achieves higher EE compared to the conventional schemes.
Selective inhibition of overexpressed ATP binding cassette (ABC) transporters is an attractive approach to enhancing the efficacy of chemotherapeutics in multidrug resistant cancers. Previously, we ...reported that the cancer sensitizing effect of deazaflavin analogs, an important chemotype for developing combination treatments with topoisomerase II (TOP2) poisons, is associated with increased intracellular drug accumulation. Here we report the characterization of ZW-1226, a deazaflavin analog, as a potent inhibitor of multidrug resistance-associated protein 1 (MRP1). Specifically, ZW-1226 inhibited MRP1 with a 16-fold higher potency than the most widely used positive control MK-571 in vesicular transport assay and displayed excellent selectivity indices exceeding 100 over other major ABC transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MRP2 and MRP3. Mechanistically, we revealed that its MRP1 inhibitory action requires the participation of GSH. In chemo-sensitization test, ZW-1226 fully reversed the MRP1-mediated drug resistance to TOP2 poisons etoposide (ETP) and doxorubicin (DOX) in H69AR cells and conferred CC50s comparable to those in the sensitive parental NCI-H69 cells. The sensitization was associated with boosted intracellular accumulation of ETP and DOX and elevated endogenous GSH. Moreover, ZW-1226 showed potential to occupy the leukotriene C4 binding site in molecular docking with bovine MRP1, presumably with the help of GSH. Lastly, ZW-1226 exhibited high tissue to plasma partitions in mice but did not alter ETP distribution to normal tissues, suggesting it could be a viable lead with desirable pharmacokinetic properties to warrant further investigation.
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•Deazaflavin analog ZW-1226 is 16 times more potent than the known MRP1 inhibitor MK-571 in vesicular transport assay.•ZW-1226 showed good selectivity for MRP1 over other major ABC transporters, including P-gp, BCRP, MRP2 and MRP3.•The inhibition of MRP1 by ZW-1226 is GSH dependent.•ZW-1226 effectively reversed MRP1-mediated drug resistance to TOP2 poisons etoposide and doxorubicin in H69AR cells.•ZW-1226 exhibited high tissue to plasma partitioning in mice without altering etoposide distribution to normal tissues.
In this paper, the neurons in the BP neural network are used to represent the skill-based talent cultivation feature vectors, and the feature vectors are trained on the network to obtain the vector ...transformation function. On the basis of the vector transformation function, after constructing the technical talent cultivation prediction model by using the backpropagation algorithm, the data indicators are determined according to the requirements of skill-based talent cultivation, and the initial data are normalized by overfitting for the technical talent cultivation prediction results. The empirical research on the synthesis of technically skilled talents in higher vocational education is designed by means of questionnaires, and the data analysis software is used to analyze the examples of skilled talent cultivation in vocational education under the background of big data technology. The results show that from 2015 to 2020, the predicted values of the number of technically skilled talents demanded in a province are 92,130, 105,396, 160,946, 225,045, 232,313 and 216,150 respectively, and the relative error values are less than 0.05 compared with the actual demand values of technically skilled talents in the same period, indicating that based on the BP neural network-based technical talent cultivation prediction model outputs a good fit between the extrapolation test prediction value and the real value. This study guides the cultivation of skilled talents in higher vocational education.
This paper investigates the price-based power control problem in the spectrum sharing cognitive radio networks. The primary user (PU) can admit secondary users (SUs) to access by pricing their ...interference power under the interference power constraint. We model the interaction between the PU and the SUs as a Stackelberg game. The revenue function of the PU is expressed as a nonconcave function of SU's transmit power by backward induction. Variable substitution is used to transform the nonconcave maximization problem into a concave maximization problem. Based on the equivalent concave maximization problem, a novel algorithm is proposed to find the optimal price for the PU to maximize its revenue. The optimal price of each SU is given as a closed-form expression with one parameter, which can be determined with the complexity of O(K), where K is the number of the SUs. Furthermore, asymptotic analysis is exploited to derive the number of the admitted SUs at low and high interference-to-noise ratio. Simulation results show the effectiveness of the proposed algorithm in comparison with the nonuniform pricing algorithm.
Nucleases are ubiquitous hydrolytic enzymes that cleave phosphodiester bond of DNA (DNases), RNA (RNases), or protein-RNA/DNA (phosphodiesterases), within the strand (endonucleases) or from the end ...(exonucleases) ....
Homocysteine (Hcy)-triggered endoplasmic reticulum (ER) stress-mediated endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury. However, whether ER stress is the ...molecular mechanism linking Hcy and cardiomyocytes death is unclear. Taurine has been reported to exert cardioprotective effects via various mechanisms. However, whether taurine protects against Hcy-induced cardiomyocyte death by attenuating ER stress is unknown. This study aimed to evaluate the opposite effects of taurine on Hcy-induced cardiomyocyte apoptosis and their underlying mechanisms. Our results demonstrated that low-dose or short-term Hcy treatment increased the expression of glucose-regulated protein 78 (GRP78) and activated protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), which in turn prevented apoptotic cell death. High-dose Hcy or prolonged Hcy treatment duration significantly up-regulated levels of C/EBP homologous protein (CHOP), cleaved caspase-12, p-c-Jun
N
-terminal kinase (JNK), and then triggered apoptotic events. High-dose Hcy also resulted in a decrease in mitochondrial membrane potential (Δψm) and an increase in cytoplasmic cytochrome C and the expression of cleaved caspase-9. Pretreatment of cardiomyocytes with sodium 4-phenylbutyric acid (an ER stress inhibitor) significantly inhibited Hcy-induced apoptosis. Furthermore, blocking the PERK pathway partly alleviated Hcy-induced ER stress-modulated cardiomyocyte apoptosis, and down-regulated the levels of Bax and cleaved caspase-3. Experimental taurine pretreatment inhibited the expression of ER stress-related proteins, and protected against apoptotic events triggered by Hcy-induced ER stress. Taken together, our results suggest that Hcy triggered ER stress in cardiomyocytes, which was the crucial molecular mechanism mediating Hcy-induced cardiomyocyte apoptosis, and the adverse effect of Hcy could be prevented by taurine.
Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In ...this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-κb. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy-induced HUVEC apoptosis and the activation of NF-κb. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-κb.
To improve the secrecy performance of cellular-enabled unmanned aerial vehicle (UAV) communication networks, this paper proposes an aerial cooperative jamming scheme and studies its optimal design to ...achieve the maximum average secrecy rate. Specifically, a base station (BS) transmits confidential messages to a UAV and meanwhile another UAV performs the role of an aerial jammer by cooperatively sending jamming signals to oppose multiple suspicious eavesdroppers on the ground. As the UAVs have the advantage of the controllable mobility, the objective is to maximize the worst-case average secrecy rate by the joint optimization of the two UAVs’ trajectories and the BS’s/UAV jammer’s transmit/jamming power over a given mission period. The objective function of the formulated problem is highly non-linear regarding the optimization variables and the problem has non-convex constraints, which is, in general, difficult to achieve a globally optimal solution. Thus, we divide the original problem into four subproblems and then solve them by applying the successive convex approximation (SCA) and block coordinate descent (BCD) methods. Numerical results demonstrate that the significantly better secrecy performance can be obtained by using the proposed algorithm in comparison with benchmark schemes.
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