3D-QSAR and Molecular Docking Analysis for Natural Aurone Derivatives as Anti-Malarial Agents

Three-dimensional quantitative structure-activity relationships were studied on 35 natural aurone derivatives by the Topomer CoMFA method to establish the 3 D-QSAR models, and exerting potent affections as Qo site inhibitors in cytochrome b activity for anti-malaria. The cross-validated q2 value of the Topmer CoMFA model = 0.539, the non-cross-validated r2 = 0.793, rpred2 = 0.960, which revealed the model has good stability and predictability. The steric and electrostatic field visualization provided by the Topomer CoMFA model intuitively revealed the effects of different substituent structures. Using this information for molecule design, we theoretically obtained some new aurone derivatives as antimalarial drugs with higher activity. Furthermore, molecular docking was employed to explore the binding requirements between the ligands and the receptor protein. We obtained space relations by hydrogen bonds and hydrophobic interactions between aurone derivatives and the active site residues. The observations from these QSAR and molecular docking studies can be further used to design promising antimalarial drugs.</p

3D Printing of Bi₂Te₃‑Based Thermoelectric Materials with High Performance and Shape Controllability

Thermoelectric (TE) energy conversion technology provides a promising way to improve the efficiency of fossil energy by generating electricity from low-grade waste heat. With regard to these applications, thermoelectric generators (TEGs) should be designed from system integration perspectives to simultaneously improve heat transfer efficiency and system simplification as well as the robust mechanical properties. However, typical TEGs fabricated by conventional methods barely accomplish such requirements. Herein, high-quality TEGs were assembled by combining the well-flowable spherical bismuth telluride (BT) powdered precursors and selective laser melting (SLM) technology. By optimizing the electronic and phonon transport properties through defect engineering driven by 3D printing, a high figure of merit was accomplished for 1.27 (p-type) and 1.13 (n-type) in BT. This achievement is primarily attributed to the nonequilibrium solidification mechanism, which leads to the formation of multiscale defects during the 3D printing process. The introduction of these multiscale defects enables the effective scattering of wide frequency phonons, leading to a substantial reduction in lattice thermal conductivity. Meanwhile, robust mechanical properties were obtained in the printed p-type/n-type BT TE materials parallel to the building direction (BD) with a compressive strength reaching 257/250 MPa by employing the fine grain structure and the high density of nanotwins introduced during the SLM process. A well shape-controllable and high-performance TEG was designed using 3D-printed BT half-rings, and an output power of 134 mW was achieved at a temperature gradient of 38.9 °C. Our study opens a new route for the great potential of TE materials based on standard commercial SLM 3D printing technology for low-grade waste heat emitted from structures with heterogeneous shapes

Enhancing Generalizability in Protein–Ligand Binding Affinity Prediction with Multimodal Contrastive Learning

Improving the generalization ability of scoring functions remains a major challenge in protein–ligand binding affinity prediction. Many machine learning methods are limited by their reliance on single-modal representations, hindering a comprehensive understanding of protein–ligand interactions. We introduce a graph-neural-network-based scoring function that utilizes a triplet contrastive learning loss to improve protein–ligand representations. In this model, three-dimensional complex representations and the fusion of two-dimensional ligand and coarse-grained pocket representations converge while distancing from decoy representations in latent space. After rigorous validation on multiple external data sets, our model exhibits commendable generalization capabilities compared to those of other deep learning-based scoring functions, marking it as a promising tool in the realm of drug discovery. In the future, our training framework can be extended to other biophysical- and biochemical-related problems such as protein–protein interaction and protein mutation prediction

Stepwise Functionalization of Two Alkyne Moieties in a Dialkynylphosphine Complex Leading to the Formation of a Bifunctionalized Phosphine Complex Bearing a Stereogenic Center at Phosphorus

Stepwise functionalization of the two alkyne moieties in a dialkynylphosphine complex has been studied. The two alkynyl groups underwent stepwise hydrophosphination and insertion to yield two different substituents on the stereogenic phosphorus. Coordination of the dialkynylphosphine ligand PPh(CCCH3)2 to the ruthenium center generated the complex [Ru(η6-benzene){PPh(CCCH3)2}Cl2]. Removal of one Cl atom by AgPF6 followed by coordination of HPPh2 to ruthenium promoted the hydrophosphination reaction with high stereoselectivity. The hydrophosphination products then underwent insertion into the Pd−C bond of a cyclopalladated complex to give a bimetallic complex bearing a stereogenic phosphorus center with expected substituents. The product contains also a tridentate ligand chelating to palladium, which is believed to have been generated through a proton exchange process aided by palladium. Furthermore, this complex exists as two interconvertable conformations in a ratio of 3:1. The structures of complexes were confirmed by X-ray crystallographic analyses and 2D ROESY NMR studies

Water Network-Augmented Two-State Model for Protein–Ligand Binding Affinity Prediction

Water network rearrangement from the ligand-unbound state to the ligand-bound state is known to have significant effects on the protein–ligand binding interactions, but most of the current machine learning-based scoring functions overlook these effects. In this study, we endeavor to construct a comprehensive and realistic deep learning model by incorporating water network information into both ligand-unbound and -bound states. In particular, extended connectivity interaction features were integrated into graph representation, and graph transformer operator was employed to extract features of the ligand-unbound and -bound states. Through these efforts, we developed a water network-augmented two-state model called ECIFGraph::HM-Holo-Apo. Our new model exhibits satisfactory performance in terms of scoring, ranking, docking, screening, and reverse screening power tests on the CASF-2016 benchmark. In addition, it can achieve superior performance in large-scale docking-based virtual screening tests on the DEKOIS2.0 data set. Our study highlights that the use of a water network-augmented two-state model can be an effective strategy to bolster the robustness and applicability of machine learning-based scoring functions, particularly for targets with hydrophilic or solvent-exposed binding pockets

Electronic Structure Properties of Two-Dimensional π‑Conjugated Polymers

Two-dimensional (2D) π-conjugated microporous polymers recently attracted tremendous interest due to their unique structural and electronic properties compared with 1D polymers and also graphene. In this paper, we present a comprehensive electronic structure investigation of several representative 2D conjugated polymers by virtue of first-principles density functional theory (DFT) calculations. A comparison of how spatial distribution of frontier molecular orbitals and charge carriers evolves in 1D and 2D conjugated oligomers as a function of system size is given. We also report the relationships between HOMO–LUMO gaps/ionization potential (IP)/electron affinity (EA)/structural reorganization energy upon charge doping and the oligomer size. These findings are insightful for understanding the electronic structure difference between 1D and 2D π-conjugated polymers and informative for designing new functional materials

Syntheses of Bimetallic Zwitterionic Complexes Containing Stereogenic Bifunctionalized Phosphine through Stepwise Insertion and Hydration Reactions

A class of bifunctionalized phosphine complexes bearing a stereogenic center at phosphorus have been synthesized through stepwise insertion and hydration of the two alkynyl groups of a prochiral dialkynylphosphine complex, [Ru(η6-benzene){PPh(CCCH3)2}Cl2]. One of the two alkyne moieties of this complex inserted into the Pd−C bond of cyclopalladated benzylamine complexes to yield bimetallic complexes containing two stereogenic centers at ruthenium and phosphorus with high stereoselectivity and yield. Subsequently, the remaining free alkynyl group underwent hydration in a mixed solvent system of DCM/acetone/H2O (2:10:1), which resulted in the formation of bimetallic zwitterions bearing anionic palladium(II) and cationic ruthenium(II) centers. The carbon−carbon triple bond was converted into a ketonyl group during the hydration, and the absolute configuration at phosphorus was observed to remain unchanged in the products. All structures of the insertion and hydration products have been identified by X-ray analyses or 2D ROESY NMR studies

Effects of migration and culture on phagocytosis by neutrophils.

<p>Neutrophil phagocytosis was analysed by measuring intensity of fluorescence of cells incubated with pHrodo <i>E. coli</i> BioParticles. Freshly isolated neutrophils (without or with collagenase treatment) were compared to neutrophils recovered from a gel 1h or 24 h after migrating through EC treated with 100U/ml TNF. A. Samples were incubated with bioparticles for 10, 30 or 60min before being fixed for flow cytometry. B. Confocal microscopic images of neutrophils recovered after 1h and incubated with bioparticles for 60min, imaged in the same plane for (i) bisbenzamide-stained nuclei or (ii) fluorescent intracellular bioparticles. Data are mean ± SEM from 3 experiments. ** = p<0.01compared to freshly-isolated cells by paired t test.</p

Effects of migration and culture on gene and surface protein expression by neutrophils.

<p>A. Total mRNA extracted from neutrophils (pg/cell). Freshly isolated neutrophils (Fresh) were compared to neutrophils recovered from a gel 1h, 3h or 24h after migrating through EC treated with 100U/ml TNF. B,C. mRNA and surface protein expression of β1-integrin. D,E. mRNA and surface protein expression of β2-integrin. F,G. mRNA and surface protein expression of β3-integrin. H,I. mRNA and surface protein expression of ICAM-1. In B-I, values for neutrophils recovered from a gel at 1 h, 3 h or 24 h, are expressed relative to values for freshly isolated cells. Data are mean ± SEM from 3 to 10 independent experiments. * = p<0.05, ** = p<0.01 compared to freshly-isolated cells by paired t test.</p

Open hepatic artery flow with portal vein clamping protects against bile duct injury compared to pringles maneuver

Conventional hepatic artery and portal vein clamping strategies can prevent blood loss and ischemia-reperfusion liver injury, and such preventative measures are the key to successful liver surgery. However, ischemic-induced damage to cholangiocytes is rarely considered. Here, we aimed to investigate the effect of different hepatic inflow interruption methods on bile duct injury. Forty rats were randomly grouped as sham, Pringle maneuver (PM) and hepatic arterial blood flow open (HAFO) groups. We evaluated liver histology and function in liver sections, and biliary histology, cholangiocyte apoptosis and proliferation, cytokine production, and bile composition. RNA sequencing is performed to explore possible molecular mechanisms. The Blood-biliary barrier permeability and tight junctions were analyzed by HRP injection, immunofluorescence staining and analysis of ZO-1 expression by immunoblotting. HAFO significantly attenuated ischemia-induced liver injury and decreased ALT, ALP, TBIL, and DBIL levels in serum. The histopathological observations showed that bile duct injury in the PM group was more serious than that in the HAFO group. The numbers of apoptotic biliary epithelial cells in HAFO-treated rat bile ducta were lower than those in the PM group. RNA-seq showed that tight junctions may be related to the mechanism underlying the protective effect of HAFO, as shown by the reduced HRP levels and increased ZO-1 and claudin-1/3 expression in the HAFO group compared to the PM group. Compared with PM, HAFO alleviated the ischemic injury to the biliary system, which was characterized by decreased biliary epithelial cell apoptosis, reduced inflammatory responses and decreased blood-biliary-barrier permeability.</p