A composite structure containing a metallic skeleton and polyurea elastomer interpenetrating phase was fabricated, and its anti-penetration performance for low-velocity large mass fragments was experimentally studied. The protection capacity of three polyurea was compared based on the penetration resistance force measurement. Results show that the polyurea coating layer at the backside improves the performance of the polyurea-filled spherical cell porous aluminum (SCPA) plate due to its backside support effect and phase transition effect, which are accompanied by a large amount of energy absorption. The frontal-side-coated polyurea layer failed to shear and provided a very limited strengthening effect on the penetration resistance of the interpenetrating phase composite panel. The filling polyurea in SCPA increased the damage area and formed a compression cone for the backside coating layer, leading to a significant stress diffusion effect. The anti-penetration performance was synergistically improved by the plug block effect of the interpenetrating phase composite and the backside support effect of the PU coating layer. Compared with SCPA, the initial impact failure strength and the average resistance force of the composite plate were improved by 120-200% and 108-274%, respectively.

The identification of an effective inhibitor is an important starting step in drug development. Unfortunately, many issues such as the characterization of protein binding sites, the screening library, materials for assays, etc., make drug screening a difficult proposition. As the size of screening libraries increases, more resources will be inefficiently consumed. Thus, new strategies are needed to preprocess and focus a screening library towards a targeted protein. Herein, we report an ensemble machine learning (ML) model to generate a CDK8-focused screening library. The ensemble model consists of six different algorithms optimized for CDK8 inhibitor classification. The models were trained using a CDK8-specific fragment library along with molecules containing CDK8 activity. The optimized ensemble model processed a commercial library containing 1.6 million molecules. This resulted in a CDK8-focused screening library containing 1,672 molecules, a reduction of more than 99.90%. The CDK8-focused library was then subjected to molecular docking, and 25 candidate compounds were selected. Enzymatic assays confirmed six CDK8 inhibitors, with one compound producing an IC50 value of ≤100 nM. Analysis of the ensemble ML model reveals the role of the CDK8 fragment library during training. Structural analysis of molecules reveals the hit compounds to be structurally novel CDK8 inhibitors. Together, the results highlight a pipeline for curating a focused library for a specific protein target, such as CDK8.

It is of extreme importance to develop a reliable numerical prediction technique to simulate the ballistic response of ceramic armor subjected to high-velocity impact (HVI) to economize the test cost and shorten the design period. In the present manuscript, a series of experiments on tungsten heavy alloy (WHA) fragment\'s penetration into 99.5% alumina (AD995) armors are systematically simulated by employing the FE-converting-SPH technique. The numerical results are compared with the experimental counterparts to find that the FE-converting-SPH method is fairly efficient in predicting the depth of penetration, the residual velocity, length and mass of fragment, and reproducing the crack forms of ceramic. The applicability and accuracy of the numerical model in terms of the algorithm, material model parameters and contact definitions are validated. Then, the relevant parameters of the calibrated numerical model are incorporated to explore the influence of cover-layer thickness on the armor performance. A few mechanisms regarding the cover plate have been identified to act on the armor performance, such as the alteration of fracture cone half-angle, proportion of energy absorbed by ceramic, mushrooming deformation of fragment, etc. The result of multi-mechanism superposition is that the best ballistic performance is endued with 1 mm cover-layer armor, which demonstrates a 24.6% improvement over the bi-layer armor with 4.96 g/cm2 area density, only at the cost of 15.7% increase in areal density, when back-plate thickness is held as 2 mm; for a constant area density of 4.96 g/cm2, a 1 mm cover-layer is also expected to be the best choice, with 10.7% improvement in armor performance.

The identification of drug-target interaction (DTI) is significant in drug discovery and development, which is usually of high cost in time and money due to large amount of molecule and protein space. The application of deep learning in predicting DTI pairs can overcome these limitations through feature engineering. However, most works do the features extraction using the whole drug and target, which do not take the theoretical basis of pharmacological reaction that the interaction is closely related to some substructure of molecule and protein into consideration, thus poor in performance. On the other hand, some substructure-oriented studies only consider a single type of fragment, e.g., functional group. To address these issues, we propose an end-to-end predicting framework for drug-target interaction named BCM-DTI that takes diverse fragment types into account, including branch chain, common substructure and motif/fragments, and applies a feature learning module based on CNN to learn the synergistic effect between these fragments. We implement BCM-DTI on four public datasets, and the results show that BCM-DTI outperforms state-of-the-art approaches and requires lower training cost.

Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound isothiazolone fragment of PGM as targeting a cysteine residue not conserved in the human ortholog. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC50 of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation.

Synthetic cannabinoids (SCs) are new psychoactive substances that function as endocannabinoid CB1 and CB2 receptor agonists. Abuse of SCs can lead to symptoms such as confusion, dizziness, and even death. At present, Synthetic cannabinoids constitute one of the largest groups of new psychoactive substances and become popular recreational drugs of abuse for their psychoactive properties. The continuous transformation of SCs also leads to an endless emergence of new types. An efficient, high-throughput screening method is therefore very important for their identification. This paper describes a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for simultaneously screening 179 SCs and 80 SC metabolites in blood and urine. Simple acetonitrile was used to precipitate the blood and urine proteins, and the supernatants obtained after centrifugation were analyzed. The LC-HRMS run time was 20 min. The mass spectrometer used an ESI source with a scanning range of m/z 100-1000. LC-HRMS provided accurate mass, retention time, and fragment ions for qualitative analysis. The method validation results showed that the limits of detection (LODs) for over 80% compounds were 5 ng/mL in blood and urine samples. At low concentrations (50 ng/mL), 229 compounds (95.8%) in the blood showed recoveries of more than 50%, and 232 compounds (97.1%) had matrix effects greater than 80%. In the urine, 219 compounds (91.6%) had recoveries above 50%, and the matrix effects of 234 compounds (97.9%) were greater than 80%. This method was successfully applied to actual forensic cases.

As an efficient tool for functional genomics, VIGS (virus-induced gene silencing) has been widely used in reverse and forward genetics to identify genes involved in various biology processes in many plant species. Up to now, at least 50 VIGS vectors based on RNA viruses, DNA viruses or satellites have been developed for either dicots or monocots or both. Silencing specific genes using VIGS vector involves five major steps including, first, choosing an appropriate VIGS vector for the plant; second, selecting a fragment of targeted host gene; third, cloning the fragment into viral VIGS vector; forth, inoculating and infecting the appropriate plant; and fifth, quantifying silencing effects including recording silencing phenotypes and determining silencing efficiency of the target gene. In this chapter, we introduce these steps for VIGS assay in dicots and monocots, by taking a cucumber mosaic virus-based VIGS vector for Nicotiana benthamiana and maize plants as an example. Moreover, we list available VIGS vectors for monocots.

Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the N1-ribosylated, Ca2+-mobilizing, second messenger cyclic adenosine 5\'-diphosphoribose (cADPR). N1-Inosine 5\'-monophosphate (N1-IMP) is a fragment directly related to cADPR. 8-Substituted-N1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the N1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5\'-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH2-N1-IMP is the most potent inhibitor (IC50 = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach.

A series of new oxadiazole sulfone derivatives containing an amide moiety was synthesized based on fragment virtual screening to screen high-efficiency antibacterial agents for rice bacterial diseases. All target compounds showed greater bactericidal activity than commercial bactericides. 3-(4-fluorophenyl)-N-((5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)methyl)acrylamide (10) showed excellent antibacterial activity against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola, with EC50 values of 0.36 and 0.53 mg/L, respectively, which were superior to thiodiazole copper (113.38 and 131.54 mg/L) and bismerthiazol (83.07 and 105.90 mg/L). The protective activity of compound 10 against rice bacterial leaf blight and rice bacterial leaf streak was 43.2% and 53.6%, respectively, which was superior to that of JHXJZ (34.1% and 26.4%) and thiodiazole copper (33.0% and 30.2%). The curative activity of compound 10 against rice bacterial leaf blight and rice bacterial leaf streak was 44.5% and 51.7%, respectively, which was superior to that of JHXJZ (32.6% and 24.4%) and thiodiazole copper (27.1% and 28.6%). Moreover, compound 10 might inhibit the growth of Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola by affecting the extracellular polysaccharides, destroying cell membranes, and inhibiting the enzyme activity of dihydrolipoamide S-succinyltransferase.

Microplastics (MPs) in marine and terrestrial environments have been intensively studied, but the dynamics of airborne MPs remains limited. Existing studies on atmospheric MPs are mostly derived from collection of atmospheric deposition, whereas direct measurements of airborne MPs are scarce. However, the abundance of airborne MPs is more relevant for evaluating human inhalation exposure risk. Herein, airborne MPs in indoor and outdoor environments from urban and rural areas of a coastal city in eastern China were investigated. MP concentrations (mean±SD) in indoor air (1583 ± 1180 n/m3) were an order of magnitude higher than outdoor air (189 ± 85 n/m3), and airborne MP concentrations in urban areas (224 ± 70 n/m3) were higher than rural areas (101 ± 47 n/m3). MPs smaller than 100 µm dominated airborne MPs, and the predominant shape of airborne MPs was fragments, as opposed to fibers. The larger MP size fractions contained a higher proportion of fibers, whereas the smaller size fractions were nearly exclusively composed of fragments. The health risk caused by ubiquitous airborne MPs should not be discounted as the maximum annual outdoor exposure of airborne MPs can reach 1 million/year, while indoor exposure may be even higher due to higher indoor airborne MP concentrations.