Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

Viral infections pose a persistent threat to human health. The relentless epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health problem, with millions of infections and fatalities so far. Traditional approaches such as random screening and optimization of lead compounds by organic synthesis have become extremely resource- and time-consuming. Various modern innovative methods or integrated paradigms are now being applied to drug discovery for significant resistance in order to simplify the drug process. This review provides an overview of newly emerging antiviral strategies, including proteolysis targeting chimera (PROTAC), ribonuclease targeting chimera (RIBOTAC), targeted covalent inhibitors, topology-matching design and antiviral drug delivery system. This article is dedicated to Prof. Dr. Erik De Clercq, an internationally renowned expert in the antiviral drug research field, on the occasion of his 80th anniversary.     

Simultaneous Estimation of Escitalopram and Clonazepam in Tablet Dosage Forms Using HPLC-DAD Method and Optimization of Chromatographic Conditions by Box-Behnken Design

The study aimed to develop a new reverse-phase high-performance liquid chromatography (RP-HPLC) method with diode array detection (DAD) detection for simultaneous estimation of escitalopram (EST) and clonazepam (CZP) in tablet dosage forms with a quality by design (QbD) approach. The chromatographic conditions were optimized by Box-Behnken design (BBD) and developed method was validated for the linearity, system suitability, accuracy, precision, robustness, sensitivity, and solution stability according to International Council for Harmonization (ICH) guidelines. EST and CZP standard drugs peaks were separated at retention times of 2.668 and 5.046 min by C-18 column with dimension of 4.6 × 100 mm length and particle size packing 2.5 µm. The mobile phase was methanol: 0.1% orthophosphoric acid (OPA) (25:75, v/v), with a flow rate of 0.7 mL/min at temperature of 26 °C. The sample volume injected was 20 µL and peaks were detected at 239 nm. Using the standard calibration curve, the % assay of marketed tablet was founded 98.89 and 98.76 for EST and CZP, respectively. The proposed RP-HPLC method was able to detect EST and CZP in the presence of their degradation products, indicating the stability-indicating property of the developed RP-HPLC method. The validation parameter’s results in terms of linearity, system suitability, accuracy, precision, robustness, sensitivity, and solution stability were in an acceptable range as per the ICH guidelines. The newly developed RP-HPLC method with QbD application is simple, accurate, time-saving, and economic.     

Apoptolidin: induction of apoptosis by a natural product

Apoptolidin is a natural product that selectively induces apoptosis in several cancer cell lines. Apoptosis, programmed cell death, is a biological key pathway for regulating homeostasis and morphogenesis. Apoptotic misregulations are connected with several diseases, in particular cancer. The extrinsic way to apoptosis leads through death ligands and death receptors to the activiation of the caspase cascade, which results in proteolytic degradation of the cell architecture. The intrinsic pathway transmits signals of internal cellular damage to the mitochondrion, which loses its structural integrity, and forms an apoptosome that initiates the caspase cascade. Compounds which regulate apoptosis are of high medical significance. Many natural products regulate apoptotic pathways, and apoptolidin is one of them. The known synthetic routes to apoptolidin are described and compared in this Review. Selected further natural products which regulate apoptosis are introduced briefly.     

Multi‐responses Methodology Applied in the Electroanalytical Determination of Hair Dye by Using Printed Carbon Electrode Modified with Graphene

This paper describes a rapid and sensitive method for determination of the hair dye Basic Blue 41 in wastewater samples using screen‐printed carbon electrodes modified with graphene (SPCE/Gr). The method is based on the reversible reduction of azo groups of the dye at potential of ?0.23 V/?0.26 V, where both the anodic and cathodic currents increased 1,300 % when compared to screen‐printed carbon (SPCE) and glassy carbon electrodes (GCE). The optimization of a square wave voltammetric method was performed by means of 2³ factorial design, Doehlert matrix and multi‐response assays, and the best parameters were: frequency (54.8 Hz), step potential (6 mV), pulse amplitude (43.7 mV) and pH 4.5. The analytical curve was constructed from 3.00×10^?8 to 2.01×10^?6 mol L^?1, with detection and quantification limits of 5.00×10^?9 and 1.70×10^?8 mol L^?1, respectively. The repeatability of the method evaluated for 10 consecutive measurements at concentrations of 1.70×10^?7 mol L^?1 and 1.70×10^?6 mol L^?1, showed relative standard deviation of 3.56 and 0.57 %, respectively. The sensor based in SPCE/Gr was successfully applied in wastewater samples collected from a drinking water treatment plant and validated by comparison with HPLC‐DAD method with good accuracy.     

高锰铝青铜ZCuAl8Mn14Fe3Ni2最佳熔炼化学成分筛选

运用正交试验设计的方法,筛选出了高锰铝青铜ZCuAl8Mn14Fe3Ni2熔炼的最佳内控化学成分范围,对开发生产该合金铸件具有重要的意义.试验表明:用该高锰铝青铜材料制造冶金备件产品时,锰含量宜以中限控制,铝含量宜以下限控制,镍控制在2%左右为最佳,铁控制在3%左右为最佳.     

Picture Fuzzy Threshold Graphs with Application in Medicine Replenishment

In this study, a novel concept of picture fuzzy threshold graph (PFTG) is introduced. It has been shown that PFTGs are free from alternating 4-cycle and it can be constructed by repeatedly adding a dominating or an isolated node. Several properties about PFTGs are discussed and obtained the results that every picture fuzzy graph (PFG) is equivalent to a PFTG under certain conditions. Also, the underlying crisp graph (UCG) of PFTG is a split graph (SG), and conversely, a given SG can be applied to constitute a PFTG. A PFTG can be decomposed in a unique way and it generates three distinct fuzzy threshold graphs (FTGs). Furthermore, two important parameters i.e., picture fuzzy (PF) threshold dimension (TD) and PF partition number (PN) of PFGs are defined. Several properties on TD and PN have also been discussed. Lastly, an application of these developed results are presented in controlling medicine resources.     

An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method

A rapid and reproducible hydrophilic liquid chromatography (HILIC) process was established for concomitant determination of remogliflozin etabonate (RE), vildagliptin (VD), and metformin (MF) in a formulation. A face-centered central composite experimental design was employed to optimize and predict the chromatographic condition by statistically studying the surface response model and design space with desirability close to one. A HILIC column with a simple mobile phase of acetonitrile (65% v/v) and 20 mM phosphate buffer (35% v/v, pH 6, controlled with orthophosphoric acid) was used to separate RE, VD, and MF. RE, VD, and MF were separated in 3.6 min using an isocratic mode mobile phase flow at a flow rate of 1.4 mL at room temperature, and the analytes were examined by recording the absorption at 210 nm. The developed HILIC method was thoroughly validated for all parameters recommended by ICH, and linearity was observed in the ranges 20–150 µg/mL, 10–75 µg/mL, and 50–750 µg/mL for RE, VD, and MF, respectively, along with excellent regression coefficients (r² > 0.999). The calculated percentage relative deviation and relative error ascertained the precision and accuracy of the method. The selectivity and accuracy were further confirmed by the high percentage recovery of added standard drugs to the formulation using the standard addition technique. The robustness of the HILIC processes was confirmed by developing a half-normal probability plot and Pareto chart, as the slight variation of a single factor had no significant influence on the assay outcomes. Utilization of the optimized HILIC procedure for concurrent quantification of RE, VD, and MF in solid dosage forms showed accurate and reproducible results. Hence, the fast HILIC method can be regularly employed for the quality assurance of pharmaceutical preparations comprising RE, VD, and MF.     

A Bregman-Split-Based Compressive Sensing Method for Dynamic Harmonic Estimation

In order to overcome the spectral interference of the conventional Fourier transform in the International Electrotechnical Commission framework, this paper introduces a Bregman-split-based compressive sensing (BSCS) method to estimate the Taylor–Fourier coefficients in a multi-frequency dynamic phasor model. Considering the DDC component estimation, this paper transforms the phasor problem into a compressive sensing model based on the regularity and sparsity of the dynamic harmonic signal distribution. It then derives an optimized hybrid regularization algorithm with the Bregman split method to reconstruct the dynamic phasor estimation. The accuracy of the model was verified by using the cross entropy to measure the distribution differences of values. Composite tests derived from the dynamic phasor test conditions were then used to verify the potentialities of the BSCS method. Simulation results show that the algorithm can alleviate the impact of dynamic signals on phasor estimation and significantly improve the estimation accuracy, which provides a theoretical basis for P-class phasor measurement units (PMUs).     

Novel Design of RNA Aptamers as Cancer Inhibitors and Diagnosis Targeting the Tyrosine Kinase Domain of the NT-3 Growth Factor Receptor Using a Computational Sequence-Based Approach

Aptamers, the nucleic acid analogs of antibodies, bind to their target molecules with remarkable specificity and sensitivity, making them promising diagnostic and therapeutic tools. The systematic evolution of ligands by exponential enrichment (SELEX) is time-consuming and expensive. However, regardless of those issues, it is the most used in vitro method for selecting aptamers. Therefore, recent studies have used computational approaches to reduce the time and cost associated with the synthesis and selection of aptamers. In an effort to present the potential of computational techniques in aptamer selection, a simple sequence-based method was used to design a 69-nucleotide long aptamer (mod_09) with a relatively stable structure (with a minimum free energy of −32.2 kcal/mol) and investigate its binding properties to the tyrosine kinase domain of the NT-3 growth factor receptor, for the first time, by employing computational modeling and docking tools.     

教学质量要素及测控探讨

教学质量是教学对学生达到预期教育结果的促进程度,是社会和学生对这种程度的认定.在构成教学系统的各基本要素中,教师和学生是两个最活跃的因素,其中课堂教学和实验教学是教学的主要环节.教学质量测控包括对教师教学设计及教学实施的测控,也包括对学生学习质量的测控.