Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold.

Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.

D3Rings: A Fast and Accurate Method for Ring System Identification and Deep Generation of Drug-Like Cyclic Compounds.

Continuous exploration of the chemical space of molecules to find ligands with high affinity and specificity for specific targets is an important topic in drug discovery. A focus on cyclic compounds, particularly natural compounds with diverse scaffolds, provides important insights into novel molecular structures for drug design. However, the complexity of their ring structures has hindered the applicability of widely accepted methods and software for the systematic identification and classification of cyclic compounds. Herein, we successfully developed a new method, D3Rings, to identify acyclic, monocyclic, spiro ring, fused and bridged ring, and cage ring compounds, as well as macrocyclic compounds. By using D3Rings, we completed the statistics of cyclic compounds in three different databases, e.g., ChEMBL, DrugBank, and COCONUT. The results demonstrated the richness of ring structures in natural products, especially spiro, macrocycles, and fused and bridged rings. Based on this, three deep generative models, namely, VAE, AAE, and CharRNN, were trained and used to construct two data sets similar to DrugBank and COCONUT but 10 times larger than them. The enlarged data sets were then used to explore the molecular chemical space, focusing on complex ring structures, for novel drug discovery and development. Docking experiments with the newly generated COCONUT-like data set against three SARS-CoV-2 target proteins revealed that an expanded compound database improves molecular docking results. Cyclic structures exhibited the best docking scores among the top-ranked docking molecules. These results suggest the importance of exploring the chemical space of structurally novel cyclic compounds and continuous expansion of the library of drug-like compounds to facilitate the discovery of potent ligands with high binding affinity to specific targets. D3Rings is now freely available at http://www.d3pharma.com/D3Rings/.

Synthesis of polydopamine modified MgAl-LDH for high efficient Cr(VI) removal from wastewater.

A highly efficient absorbent was developed in this study by modifying polydopamine film on Mg-Al layered double hydroxide (PDA/MgAl-LDH) to remove Cr(VI) from wastewater. The characterization results showed that the polydopamine film was successfully coated on the MgAl-LDH surface. The preparation ratio, pH, and adsorbent dosage influencing absorption by PDA/MgAl-LDH were systematically investigated. The absorption capacity of Cr(VI) by PDA/MgAl-LDH was 87 mg/g. The equilibrium adsorption isotherm of PDA/MgAl-LDH was in good agreement with that of the Langmuir model. Therefore, the pseudo-second-order kinetic model is suitable for describing adsorption kinetics. The interaction between PDA and Cr(VI) and Cr(III) was investigated using density generalized function theory (DFT), which demonstrated that the PDA amino group could provide electrons for Cr(VI) reduction. Hydrogen and covalent bonding were dominant during the chemisorption process of PDA absorbing Cr(VI), the nitrogen of 5,6-dihydroxyindole was the primary active site for absorbing Cr(III), and electrostatic attraction was mainly responsible for Cr(III) absorption. Therefore, PDA/MgAl-LDH has the potential to adsorb and remove Cr(VI) from wastewater.

Enhancing safety in conditionally automated driving: Can more takeover request visual information make a difference in hazard scenarios with varied hazard visibility?

Autonomous driving technology has the potential to significantly reduce the number of traffic accidents. However, before achieving full automation, drivers still need to take control of the vehicle in complex and diverse scenarios that the autonomous driving system cannot handle. Therefore, appropriate takeover request (TOR) designs are necessary to enhance takeover performance and driving safety. This study focuses on takeover tasks in hazard scenarios with varied hazard visibility, which can be categorized as overt hazards and covert hazards. Through ergonomic experiments, the impact of TOR interface visual information, including takeover warning, hazard direction, and time to collision, on takeover performance is investigated, and specific analyses are conducted using eye-tracking data. The following conclusions are drawn from the experiments: (1) The visibility of hazards significantly affects takeover performance. (2) Providing more TOR visual information in hazards with different visibility has varying effects on drivers' visual attention allocation but can improve takeover performance. (3) More TOR visual information helps reduce takeover workload and increase human-machine trust. Based on these findings, this paper proposes the following TOR visual interface design strategies: (1) In overt hazard scenarios, only takeover warning is necessary, as additional visual information may distract drivers' attention. (2) In covert hazard scenarios, the TOR visual interface should better assist drivers in understanding the current hazard situation by providing information on hazard direction and time to collision to enhance takeover performance.

Impact of Halogen Bonds on Protein-Peptide Binding and Protein Structural Stability Revealed by Computational Approaches.

Halogen bonds (XBs) are essential noncovalent interactions in molecular recognition and drug design. Current studies on XBs in drug design mainly focus on the interactions between halogenated ligands and target proteins, lacking a systematic study of naturally existing and artificially prepared halogenated residue XBs (hr_XBs) and their characteristics. Here, we conducted a computational study on the potential hr_XBs in proteins/peptides using database searching, quantum mechanics calculations, and molecular dynamics simulations. XBs at the protein-peptide interaction interfaces are found to enhance their binding affinity. Additionally, the formation of intramolecular XBs (intra_XBs) within proteins may significantly contribute to the structural stability of structurally flexible proteins while having a minor impact on proteins with inherently high structural rigidity. Impressively, introducing halogens without the formation of intra_XBs may lead to a decrease in the protein structural stability. This study enriches our understanding of the roles and effects of halogenated residue XBs in biological systems.

Switchable Regioselective C-H Activation/Annulation of Acrylamides with Alkynes for the Synthesis of 2-Pyridones.

A catalyst-based switchable regioselective C-H activation/annulation of acrylamides with propargyl carbonates has been developed, delivering C5 or C6 alkenyl substituted 2-pyridones. This robust protocol proceeds with a broad substrate scope and good functional group tolerance under redox-neutral reaction conditions. More significantly, this reaction is highly effective with previously challenging unsymmetrical alkynes, including unbiased alkyl-alkyl substituted alkynes, with perfect and switchable regioselectivity. Additionally, mechanistic studies and DFT calculations were performed to shed light on the switchable regioselectivity.

Direct esterification of amides by the dimethylsulfate-mediated activation of amide C-N bonds.

Amides are important intermediates in organic chemistry and the pharmaceutical industry, but their low reactivity requires catalysts and/or severe reaction conditions for esterification. Here, a novel approach was devised to convert amides into esters without the use of transition metals. The method effectively overcomes the inherent low reactivity of amides by employing dimethylsulfate-mediated reaction to activate the C-N bonds. To confirm the proposed reaction mechanism, control experiments and density functional theory (DFT) calculations were conducted. The method demonstrates a wide array of substrates, including amides with typical H/alkyl/aryl substitutions, N,N-disubstituted amides, amides derived from alkyl, aryl, or vinyl carboxylic acids, and even amino acid substrates with stereocentres. Furthermore, we have shown the effectiveness of dimethylsulfate in removing acyl protective groups in amino derivatives. This study presents a method that offers efficiency and cost-effectiveness in broadening the esterification capabilities of amides, thereby facilitating their increased utilization as synthetic compounds in diverse transformations.

Mechanistic insights into soil heavy metals desorption by biodegradable polyelectrolyte under electric field.

In this study, we firstly used alginate to enhance an electrokinetic technology to remediate soil contaminated with divalent heavy metals (Pb2+, Cu2+, Zn2+). The mechanisms of alginate-associated migration of metal ions in electric field were confirmed. Alginate resulted in a high electrical current during electrokinetic process, and soil conductivity also increased after remediation. Obvious changes in both electroosmotic flow and soil pH were observed. Moreover, these factors were affected by increasing alginate dosage. The highest Cu (95.82%) and Zn (97.33%) removal efficiencies were obtained by introducing 1 wt% alginate. Alginate can desorb Cu2+ and Zn2+ ions from soil by forming unstable gels, which could be dissociated through electrolysis. However, Pb2+ ions did not easily migrate out of the contaminated soil. The density functional theory (DFT) calculations show Pb2+ ions could form a more stable coordination sphere in metal complexes than Cu2+ and Zn2+ ions. The metal removal efficiency was decreased by increasing alginate dosage at a high level. More alginate could provide more carboxyl ligands for divalent metal ions to stabilize gels, which were difficult to dissociate by electrolysis. In summary, the results indicate it is potential for introducing alginate into an electrokinetic system to remediate Cu- and Zn- contaminated soil.

Enhancing User Experience of Eye-Controlled Systems: Design Recommendations on the Optimal Size, Distance and Shape of Interactive Components from the Perspective of Peripheral Vision.

For special populations with motor impairments, eye-controlled interaction may be the only way for them to communicate with the outside world. Because of the dominance of vision in the motor mechanism, eye-controlled interaction has high usability and important research value. During eye-controlled interaction, the visual channel needs to receive information from the graphical user interface (GUI) and transmit the user's eye-controlled instructions, which overburdens the visual channel and reduces the efficiency of eye-controlled interaction. This study presents an ergonomic experiment to study how to design interactive GUI components in an eye-controlled user interface. The experiments were conducted based on the shape, size, and distance (from the object to the center of the screen) of the visual interactive components. The experiment comprised three parts: (1) the pre-experiment determined the evaluation index and selected the icon material; (2) the formal experiment was a three-factor within-subjects experiment, which included a search task using participants' peripheral vision; and (3) after the experiment, subjective evaluations were conducted using a questionnaire. The results showed that the shape, size, and distance of the interactive object significantly affected the reaction time, and the size factor significantly affected the movement time of the eye-controlled interaction. Finally, combined with the results of the subjective evaluation, we concluded that the recommended sizes of the interactive components were 2.889°, 3.389°, and 3.889°, and the recommended distances were 5.966° and 8.609°. Additionally, designers should utilize components with simple concrete shapes as much as possible to improve user recognition efficiency. Our study provides enlightening recommendations on how to design components in eye-controlled interactive interfaces, and has great guiding significance for building design standards of the eye-controlled systems.

Enhanced electrokinetic remediation of heavy metals contaminated soil by biodegradable complexing agents.

In this study, an electrokinetic technique for remediation of Pb2+, Zn2+ and Cu2+ contaminated soil was explored using sodium alginate (SA) and chitosan (CTS) as promising biodegradable complexing agents. The highest Cu2+ (95.69%) and Zn2+ (95.05%) removal rates were obtained at a 2 wt% SA dosage, which demonstrated that SA significantly improved the Cu2+ and Zn2+ removal efficiency during electrokinetic process. The abundant functional groups of SA allowed metal ions desorption from soil via ion-exchange, complexation, and electrolysis. Pb2+ ions were difficult to remove from soil by SA due to the higher gelation affinity with Pb2+ than Cu2+ and Zn2+, despite the Pb2+ exchangeable fraction partially transforming to the reducible and oxidizable fractions. CTS could complex metal ions and migrate into the catholyte under the electric field to form crosslinked CTS gelations. Consequently, this study proved the suitability of biodegradable complexing agents for treating soil contaminated with heavy metals using electrokinetic remediation.

S100A8/A9 Molecular Complexes Promote Cancer Migration and Invasion via the p38 MAPK Pathway in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is one type of malignancy associated with migration and invasion through a currently unclear mechanism. We previously discovered S100A8/A9 levels were roughly elevated in the plasma of NPC patients as the promising biomarkers. However, their expressions and underlying functions in NPC tissues are still unknown. In the present study, we analyzed 49 NPC tissues and 20 chronic pharyngitis (CP) tissues. Immunohistochemical staining was performed in different tissues and analyzed by the Mann-Whitney U test statistically. Transwell migration and invasion experiments were further performed to determine S100A8/A9 effects on NPC. Our results showed that S100A8/A9 in NPC tissues were significantly higher than those in CP tissues, closely associated with NPC clinical stages. Intriguingly, exogenous S100A8/A9 protein stimulation could dramatically enhance NPC migration and invasion abilities. In addition, p38 MAPK pathway blockade could diminish the migration and invasion of NPC cells stimulated by S100A8/A9 proteins. The downstream tumor invasion and migration associated proteins (e.g., MMP7) were also elevated in NPC tissues, consistent with S100A8/A9 overexpression. Taken together, our present findings suggest that the secreted soluble inflammatory factors S100A8/A9 might promote cancer migration and invasion via the p38 MAPK signaling pathway along with invasion/migration associated proteins overexpression in the tumor microenvironment of NPC. This may shed light on the mechanism understanding of NPC prognosis and provide more novel clues for NPC diagnosis and therapy.

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology-Based Strategy.

BACKGROUND: Yisui Qinghuang powder (YSQHP) is an effective traditional Chinese medicinal formulation used for the treatment of myelodysplastic syndromes (MDS). However, its pharmacological mechanism of action is unclear. MATERIALS AND METHODS: In this study, the active compounds of YSQHP were screened using the traditional Chinese medicine systems pharmacology (TCMSP) and HerDing databases, and the putative target genes of YSQHP were predicted using the STITCH and DrugBank databases. Then, we further screened the correlative biotargets of YSQHP and MDS. Finally, the compound-target-disease (C-T-D) network was conducted using Cytoscape, while GO and KEGG analyses were conducted using R software. Furthermore, DDI-CPI, a web molecular docking analysis tool, was used to verify potential targets and pathways. Finally, binding site analysis was performed to identify core targets using MOE software. RESULTS: Our results identified 19 active compounds and 273 putative target genes of YSQHP. The findings of the C-T-D network revealed that Rb1, CASP3, BCL2, and MAPK3 showed the most number of interactions, whereas indirubin, tryptanthrin, G-Rg1, G-Rb1, and G-Rh2 showed the most number of potential targets. The GO analysis showed that 17 proteins were related with STPK activity, PUP ligase binding, and kinase regulator activity. The KEGG analysis showed that PI3K/AKT, apoptosis, and the p53 pathways were the main pathways involved. DDI-CPI identified the top 25 proteins related with PI3K/AKT, apoptosis, and the p53 pathways. CASP8, GSK3B, PRKCA, and VEGFR2 were identified as the correlative biotargets of DDI-CPI and PPI, and their binding sites were found to be indirubin, G-Rh2, and G-Rf. CONCLUSION: Taken together, our results revealed that YSQHP likely exerts its antitumor effects by binding to CASP8, GSK3B, PRKCA, and VEGFR2 and by regulating the apoptosis, p53, and PI3K/AKT pathways.

Effects of silencing S100A8 and S100A9 with small interfering RNA on the migration of CNE1 nasopharyngeal carcinoma cells.

The calcium-binding S100 proteins are involved in functions such as cell growth, differentiation, migration, adhesion and signal transduction. S100A8 and S100A9 are highly expressed in a variety of tumor cells, and are implicated in tumor development and progression. However, the role of S100A8 and S100A9 in nasopharyngeal carcinoma (NPC) cell migration is unclear. The present study investigated the effect of S100A8 and S100A9 on migration using a NPC cell line, CNE1. The CNE1 cells were transfected with S100A8 or S100A9 small interfering RNA (siRNA). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect S100A8 and S100A9 gene expression. Following the downregulation of S100A8 or S100A9, the effects on cell migration were determined using wound-healing assays. The expression of matrix metalloproteinase-7 (MMP7), a member of the MMP family that is associated with tumor cell invasion and migration, was also detected by RT-qPCR. S100A8 and S100A9 siRNAs effectively suppressed S100A8 and S100A9 gene expression, and substantially inhibited the migration of the CNE1 cells. In addition, MMP7 expression was reduced to varying extents in S100A8 and S100A9 siRNA-treated cells compared with controls. Thus, S100A8 and S100A9 promoted the migration of CNE1 NPC cells.