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Abstract Covalent probes coupled with chemical proteomics represent a powerful method for investigating small molecule and protein interactions. However, the creation of a reactive warhead within various ligands to form covalent probes has been a major obstacle. Herein, we report a convenient and robust process to assemble a unique electrophile, an α-acyloxyenamide, through a one-step late-stage coupling reaction. This procedure demonstrates remarkable tolerance towards other functional groups and facilitates ligand-directed labeling in proteins of interest. The reactive group has been successfully incorporated into a clinical drug targeting the EGFR L858R mutant, erlotinib, and a pan-kinase inhibitor. The resulting probes have been shown to be able to covalently engage a lysine residue proximal to the ATP-binding pocket of the EGFR L858R mutant. A series of active sites, and Mg2+, ATP-binding sites of kinases, such as K33 of CDK1, CDK2, CDK5 were detected. This is the first report of engaging these conserved catalytic lysine residues in kinases with covalent inhibition. Further application of this methodology to natural products has demonstrated its success in profiling ligandable conserved lysine residues in whole proteome. These findings offer insights for the development of new targeted covalent inhibitors (TCIs).

This study aims to alleviate the serious deformation of surrounding rock (SR) in an extremely soft and fragile fully mechanized caving face roadway (ESFFMCFR, the 8# coal seam, Huaibei mining area) under a conventional support. Laboratory tests of roadway SR were conducted. The results show that in this coal seam, the extremely soft and fragile coal body has a high clay mineral content, so it is of low strength and breaks and softens easily. With reference to the mechanical tests on coal and rock mass around the coal seam and the monitoring results of roadway deformation, the roadway deformation is mainly caused by the development of fractures in the roadway SR, the separation of the support body and SR and the loose supporting structure. Considering the engineering environment and deformation characteristics of SR in the ESFFMCFR (the 8# coal seam, Huaibei mining area), this study proposed a synergistic support system of “lowering, drilling, anchoring, grouting and flatting (LDAGF)” for the ESFFMCFR based on the synergistic mechanism of support and SR under the basic principles of synergetics. Specifically, the synergistic support system of “LDAGF” includes the following measures: floor breaking and side lowering, bolt advance support, anchor cable support, advance water injection and grouting and flat-roof U-shaped steel shed support. Furthermore, this synergistic support system was applied on the ESFFMCFR in the 8# coal seam of Xinhu and Guobei coal mines, Huaibei mining area. The on-site application results reveal that when the synergistic support system is adopted, the maximum subsidence values in the above roadway roofs are 117 mm and 121 mm and the maximum displacement values of the two sides are 66 mm and 74 mm, respectively, which proves an excellent support effect. The synergistic support system, which can effectively control the serious deformation of the SR in ESFFMCFRs and ensure long-term stability and safety of the roadways, is suitable for the support of ESFFMCFRs and is of great guiding significance for roadways of the same type.

Different levels of EspP2 expression are seen in strains of Glaesserella parasuis with high and low pathogenicity. As a potential virulence factor for G. parasuis, the pathogenic mechanism of EspP2 in infection of host cells is not clear. To begin to elucidate the effect of EspP2 on virulence, we used G. parasuis SC1401 in its wild-type form and SC1401, which was made EspP2-deficient. We demonstrated that EspP2 causes up-regulation of claudin-1 and occludin expression, thereby promoting the adhesion of G. parasuis to host cells; EspP2-deficiency resulted in significantly reduced adhesion of G. parasuis to cells. Transcriptome sequencing analysis of EspP2-treated PK15 cells revealed that the Rap1 signaling pathway is stimulated by EspP2. Blocking this pathway diminished occludin expression and adhesion. These results indicated that EspP2 regulates the adhesion of Glaesserella parasuis via Rap1 signaling pathway.

Optical anisotropy offers a heightened degree of flexibility in shaping optical properties and designing cutting-edge devices. Quasi-one-dimensional Ta2NiS5, with giant optical anisotropy, has been used in the development of new lasers and sensors. In this research endeavor, we successfully acquired the complete dielectric tensor of Ta2NiS5, utilizing the advanced technique of Mueller matrix spectroscopic ellipsometry, enabling a rigorous quantitative assessment of its optical anisotropy. The results indicate that Ta2NiS5 demonstrates giant birefringence and dichroism, with Δnmax = 1.54 and Δkmax = 1.80. This pursuit also delves into the fundamental underpinnings of this optical anisotropy, drawing upon a fusion of first-principles calculations and critical points analysis. The anisotropy of Ta2NiS5 arises from differences in optical transitions in different directions and is shown to be due to van Hove singularities without exciton effects. Its giant optical anisotropy is expected to be useful in the design of novel optical devices, and the revelation of the physical mechanism facilitates the modulation of its optical properties.

The tumor microenvironment plays a critical role in tumor progression and immune regulation. As one of the most important components of the tumor microenvironment, macrophages have become a new therapeutic target for inhibiting tumor progression. Despite the well-documented anticancer activity of cucurbitacin I, its effect on macrophages remains unclear. In this study, we established a coculture system of macrophages and cancer cells under hypoxic conditions to simulate the tumor-promoting environment mediated by M2-like macrophages. We determined whether cucurbitacin I modulates M2-like polarization in macrophages in vitro and conducted RNA sequencing to identify gene expression changes induced by cucurbitacin I in macrophages. The results indicated a remarkable inhibition of the M2-like polarization phenotype in macrophages following treatment with cucurbitacin I, which was accompanied by the significant downregulation of heme oxygenase-1. Moreover, we found that cucurbitacin I-treated macrophages reduced the migration of cancer cells by inhibiting the M2 polarization in vitro. These findings highlight the potential of cucurbitacin I as a therapeutic agent that targets M2-like macrophages to inhibit cancer cell metastasis. Our study provides novel insights into the intricate interplay among macrophage polarization, cucurbitacin I, and heme oxygenase-1, thereby opening new avenues for cancer treatment.

Various studies have shown that the cell-cycle-related regulatory proteins UBE2C, PLK1, and BIRC5 promote cell proliferation and migration in different types of cancer. However, there is a lack of in-depth and systematic research on the mechanism of these three as therapeutic targets. In this study, we found a positive correlation between the expression of UBE2C and PLK1/BIRC5 in the Cancer Genome Atlas (TCGA) database, revealing a potential combination therapy candidate for pan-cancer. Quantitative real-time PCR (qRT-PCR), Western blotting (WB), cell phenotype detection, and RNA-seq techniques were used to evidence the effectiveness of the combination candidate. We found that combined interference of UBE2C with PLK1 and UBE2C with BIRC5 affected metabolic pathways by significantly downregulating the mRNA expression of IDH1 and ACLY, which was related to the synthesis of acetyl-CoA. By combining the PLK1 inhibitor volasertib and the ACLY inhibitor bempedoic acid, it showed a higher synergistic inhibition of cell viability and higher synergy scores in seven cell lines, compared with those of other combination treatments. Our study reveals the potential mechanisms through which cell-cycle-related genes regulate metabolism and proposes a potential combined targeted therapy for patients with higher PLK1 and ACLY expression in pan-cancer.

Taking the roadway peripheral rock anchoring unit as the research object, the rock compression test containing the anchor solid was carried out to analyze the influence of the degree of peripheral rock fragmentation and the anchor support method on the mechanical properties of the rock body. The test results showed that the smaller the size of the structural surface, the more a greater number of anchor rods were needed, which in turn provided better support. With the increase in the size of the structural surface, the uniaxial compressive strength and modulus of elasticity of the specimen showed a gradual decrease. Numerical tests of the uniaxial compression of rock containing cohesive units showed that the deformation of the specimen near the anchor bar was significantly reduced, while the main rupture surface was blocked, and an obvious reinforcement zone was formed near the anchor bar. Under the double-anchor condition, the anchor tension stress was more obvious, the reinforcement zone was wider, and the rock rupture surface was strongly blocked, all of which made its reinforcement effect the more obvious. This double-anchor condition showed that the anchoring effect of the anchor rods on the specimens was reflected in two aspects of reinforcement and crack stopping. The denser the anchor rods, the wider the reinforcement zone and hence the more likely that the superposition effect will occur, which allowed the anchor rods to play a greater supporting role in stabilizing the rock. The research results can provide a theoretical basis for the design of anchor support and early warning prediction of destabilization damage in the fractured surrounding rock of coal mine roadways.

A recombinant inbred line population including 371 lines was developed by a high kernel number per spike (KNPS) genotype T1208 and a low KNPS genotype Chuannong18 (CN18). A genetic linkage map consisting of 11,583 markers was constructed by the Wheat55K SNP Array. The quantitative trait loci (QTLs) related to KNPS were detected in three years. Eight, twenty-seven, and four QTLs were identified using the ICIM-BIP, ICIM-MET, and ICIM-EPI methods, respectively. One QTL, QKnps.sau-2D.1, which was mapped on chromosome 2D, can explain 18.10% of the phenotypic variation (PVE) on average and be considered a major and stable QTL for KNPS. This QTL was located in a 0.89 Mb interval on chromosome 2D and flanked by the markers AX-109283238 and AX-111606890. Moreover, KASP-AX-111462389, a Kompetitive Allele-Specific PCR (KASP) marker which closely linked to QKnps.sau-2D.1, was designed. The genetic effect of QKnps.sau-2D.1 on KNPS was successfully confirmed in two RIL populations. The results also showed that the significant increase of KNPS and 1000-kernel weight (TKW) was caused by QKnps.sau-2D.1 overcoming the disadvantage due to the decrease of spike number (SN) and finally lead to a significant increase of grain yield. In addition, within the interval in which QKnps.sau-2D.1 is located in Chinese Spring reference genomes, only fifteen genes were found, and two genes that might associate with KNPS were identified. QKnps.sau-2D.1 may provide a new resource for the high-yield breeding of wheat in the future.

Glaesserella parasuis (G. parasuis.) is the etiological pathogen of Glässer’s disease, which causes high economic losses to the pig industry. The heme-binding protein A precursor (HbpA) was a putative virulence-associated factor proposed to be potential subunit vaccine candidate in G. parasuis. In this study, three monoclonal antibodies (mAb) 5D11, 2H81, and 4F2 against recombinant HbpA (rHbpA) of G. parasuis SH0165 (serotype 5) were generated by fusing SP2/0-Ag14 murine myeloma cells and spleen cells from BALB/c mice immunized with the rHbpA. Indirect enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay (IFA) demonstrated that the antibody designated 5D11 showed a strong binding affinity with the HbpA protein and was chosen for subsequent experiments. The subtypes of the 5D11 were IgG1/κ chains. Western blot analysis showed that mAb 5D11 could react with all 15 serotype reference strains of G. parasuis. None of the other bacteria tested reacted with 5D11. In addition, a linear B-cell epitope recognized by 5D11 was identified by serial truncations of HbpA protein and then a series of truncated peptides were synthesized to define the minimal region that was required for mAb 5D11 binding. The 5D11 epitope was located on amino acids 324-LPQYEFNLEKAKALLA-339 by testing the 5D11 monoclonal for reactivity with 14 truncations. The minimal epitope 325-PQYEFNLEKAKALLA-339 (designated EP-5D11) was pinpointed by testing the mAb 5D11 for reactivity with a series of synthetic peptides of this region. The epitope was highly conserved among G. parasuis strains, confirmed by alignment analysis. These results indicated that mAb 5D11 and EP-5D11 might potentially be used to develop serological diagnostic tools for G. parasuis. Three-dimensional structural analysis revealed that amino acids of EP-5D11 were in close proximity and may be exposed on the surface of the HbpA protein.

An infrared photodetector is a critical component that detects, identifies, and tracks complex targets in a detection system. Infrared photodetectors based on 3D bulk materials are widely applied in national defense, military, communications, and astronomy fields. The complex application environment requires higher performance and multi-dimensional capability. The emergence of 2D materials has brought new possibilities to develop next-generation infrared detectors. However, the inherent thickness limitations and the immature preparation of 2D materials still lead to low quantum efficiency and slow response speeds. This review summarizes 2D/3D hybrid van der Waals heterojunctions for infrared photodetection. First, the physical properties of 2D and 3D materials related to detection capability, including thickness, band gap, absorption band, quantum efficiency, and carrier mobility, are summarized. Then, the primary research progress of 2D/3D infrared detectors is reviewed from performance improvement (broadband, high-responsivity, fast response) and new functional devices (two-color detectors, polarization detectors). Importantly, combining low-doped 3D and flexible 2D materials can effectively improve the responsivity and detection speed due to a significant depletion region width. Furthermore, combining the anisotropic 2D lattice structure and high absorbance of 3D materials provides a new strategy in high-performance polarization detectors. This paper offers prospects for developing 2D/3D high-performance infrared detection technology.

Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and athletes. ACM has strong genetic determinants, and genetic variants in more than 25 genes have been identified to be associated with ACM, accounting for approximately 60% of ACM cases. Genetic studies of ACM in vertebrate animal models such as zebrafish (Danio rerio), which are highly amenable to large-scale genetic and drug screenings, offer unique opportunities to identify and functionally assess new genetic variants associated with ACM and to dissect the underlying molecular and cellular mechanisms at the whole-organism level. Here, we summarize key genes implicated in ACM. We discuss the use of zebrafish models, categorized according to gene manipulation approaches, such as gene knockdown, gene knock-out, transgenic overexpression, and CRISPR/Cas9-mediated knock-in, to study the genetic underpinning and mechanism of ACM. Information gained from genetic and pharmacogenomic studies in such animal models can not only increase our understanding of the pathophysiology of disease progression, but also guide disease diagnosis, prognosis, and the development of innovative therapeutic strategies.

To evaluate the reservoir characteristics of siliceous shale in the Dalong Formation within the late Permian intra-platform rift trough in Western Hubei (China), we studied a drill core from well ED-2 in Western Hubei. To analyze the physical characteristics, pore structure, methane adsorption performance, and their influences on the siliceous shale reservoir, we performed X-ray diffraction, total organic carbon (TOC) content, vitrinite reflectance (Ro, indicating thermal evolution), total porosity and permeability, field emission scanning electron microscopy, CO2 and N2 physical adsorption, and methane isothermal adsorption analyses, among others. Our results show that the Dalong Formation in Western Hubei is an organic-rich (2.6–14.3 wt.%), highly thermally evolved (Ro = 2.59–2.76%), siliceous shale containing mainly type-I and type-II1 organic matter. The Dalong siliceous shale has low porosity and permeability and belongs to a larger reservoir with low horizontal permeability (0.002–335.209 mD) and porosity (1.2–7.8%). Pores in the shale are mainly organic, inorganic, and microfractures; the organic pores are very developed. The pore volume and specific surface area of the shale are mainly due to micropores and mesopores and are positively correlated with TOC and clay mineral contents and weakly negatively correlated with quartz and carbonate contents. The micropores and mesopores are well developed, improving the methane adsorption capacity, which, in turn, is strongly positively correlated with TOC content. Comprehensive analysis shows that the high organic matter content of the Dalong siliceous shale has the greatest influence on its pore structure; the many organic pores generated after hydrocarbon generation have controlled the development of micropores and mesopores, which is conducive to the adsorption and storage of shale gas. The development of brittle minerals resistant to compaction, such as siliceous minerals, helps preserve organic pores. This study is informative for basin-scale petroleum system investigations, which are essential for understanding oil and gas exploration possibilities and regional petroleum systems.

DNA double-strand breaks (DSBs) are the most perilous and harmful type of DNA damage and can cause tumorigenesis or cell death if left repaired with an error or unrepaired. RadD, a member of the SF2 family, is a recently discovered DNA repair protein involved in the repair of DSBs after radiation or chemical damage. However, the function of RadD in DNA repair remains unclear. Here, we determined the crystal structures of RadD/ATPγS and RadD/ATP complexes and revealed the novel mechanism of RadD binding to DNA and ATP hydrolysis with biochemical data. In the RadD catalytic center, the Gly34 and Gly36 on the P-loop are key residues for ATP binding besides the conserved amino acids Lys37 and Arg343 in the SF2 family. If any of them mutate, then RadD loses ATPase activity. Asp117 polarizes the attacking water molecule, which then starts a nucleophilic reaction toward γ-phosphate, forming the transition state. Lys68 acts as a pocket switch to regulate substrate entry and product release. We revealed that the C-terminal peptide of single-stranded DNA-binding protein (SSB) binds the RadD C-terminal domain (CTD) and promotes the RadD ATPase activity. Our mutagenesis studies confirmed that the residues Arg428 on the zinc finger domain (ZFD) and Lys488 on the CTD of RadD are the key sites for binding branched DNA. Using the Coot software combined with molecular docking, we propose a RadD-binding DNA model for the DNA damage repair process.

Considering the harsh environment of deep, fully mechanized working faces and the acutely imbalanced time distribution among excavation, support and anchoring, this paper designed a new type of highly adaptable advance support for fully mechanized roadways that boasts high adaptability, great support strength and a large working space. Firstly, the structure composition and working principle of the advance support were introduced. The structures and mechanical characteristics were then emphatically discussed. Subsequently, with the geological conditions of the 8224-machine roadway in the XT Coal Mine taken as an example, the loads of the advance support were obtained and then imported into the Ansys software to obtain the stress distribution and displacement distribution of the whole advance support and its parts through calculation. Based on the distribution, the stress and strain of the advance support were analyzed. The simulation results are as follows: Under various working conditions, the maximum displacement of the advance support was 4.5 mm, which is negligible compared to the overall size of the support; the maximum stress was 72.8 MPa, which is lower than the yield strength of the material (235 MPa). Therefore, the designed support can bear the pressure from the surrounding rock in the mine. Moreover, the roof beam, which is a weak link in the support, deserves more attention in subsequent engineering designs. This method conduces to not only parallel operations of excavation, support and anchoring, but also to rapid excavation and the safe production of roadways, providing fresh ideas for the advance support for fully mechanized roadways.

Macroporous characteristics have been shown to play a key role in the osteoinductivity of hydroxyapatite ceramics, but the physics underlying the new bone formation and distribution in such scaffolds still remain elusive. The work here has emphasized the osteoinductive capacity of porous hydroxyapatite scaffolds containing different macroporous sizes (200–400 μm, 1200–1500 μm) and geometries (star shape, spherical shape). The assumption is that both the size and shape of a macropore structure may affect the microfluidic pathways in the scaffolds, which results in the different bone formations and distribution. Herein, a mathematical model and an animal experiment were proposed to support this hypothesis. The results showed that the porous scaffolds with the spherical macropores and large pore sizes (1200–1500 μm) had higher new bone production and more uniform new bone distribution than others. A finite element analysis suggested that the macropore shape affected the distribution of the medium–high velocity flow field, while the macropore size effected microfluid speed and the value of the shear stress in the scaffolds. Additionally, the result of scaffolds implanted into the dorsal muscle having a higher new bone mass than the abdominal cavity suggested that the mechanical load of the host tissue could play a key role in the microfluidic pathway mechanism. All these findings suggested that the osteoinduction of these scaffolds depends on both the microfluid velocity and shear stress generated by the macropore size and shape. This study, therefore, provides new insights into the inherent osteoinductive mechanisms of bioceramics, and may offer clues toward a rational design of bioceramic scaffolds with improved osteoinductivity.

Using a catalyst to mineralize volatile organic compounds (VOCs) in a Non-thermal Plasma (NTP) reactor is an effective method. In many kinds of catalysts for VOCs degradation, oxygen defect is a crucial factor affecting the catalytic activity. Three different methods (steaming, doping, plasma) were used to introduce possible oxygen defects into the Mn/ZSM-5 to prepare modified catalysts, which were evaluated in VOCs degradation activity using a Double Dielectric Barrier Discharge (DDBD) plasma device. Additionally, a novel Y-type ZSM-5 model was employed in the DFT simulation. The new Y-type ZSM-5 model used in this paper is a more realistic aperiodic model. It showed that introducing possible oxygen defects can substantially enhance degradation efficiency. Taking the catalyst with oxygen defects introduced by plasma as an example, the conversion (CO2 selectivity) of the methanol, acetone, and toluene could reach 100% (100%), 97.7% (99.1%), 91.2% (93.9%), respectively, at an initial concentration of 2000 ppm and specific input energy of 9 kJ/L. The results demonstrated that modification could significantly enhance the activity of the catalyst in decomposing VOCs at room temperature using non-thermal plasma catalysis. Theoretical simulation of density functional theory (DFT) revealed that the adsorption of adsorbate on the catalyst becomes easier after possible oxygen defects are introduced.

The YfeA gene, belonging to the well-conserved ABC (ATP-binding cassette) transport system Yfe, encodes the substrate-binding subunit of the iron, zinc, and manganese transport system in bacteria. As a potential vaccine candidate in Glaesserella parasuis, the functional mechanisms of YfeA in the infection process remain obscure. In this study, vaccination with YfeA effectively protected the C56BL6 mouse against the G. parasuis SC1401 challenge. Bioinformatics analysis suggests that YfeA is highly conserved in G. parasuis, and its metal-binding sites have been strictly conserved throughout evolution. Stimulation of RAW 264.7 macrophages with YfeA verified that toll-like receptors (TLR) 2 and 4 participated in the positive transcription and expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. The activation of TLR2 and TLR4 utilized the MyD88/MAL and TRIF/TRAM pairs to initiate TLRs signaling. Furthermore, YfeA was shown to stimulate nuclear translocation of NF-κB and activated diverse mitogen-activated protein (MAP) kinase signaling cascades, which are specific to the secretion of particular cytokine(s) in murine macrophages. Separate blocking TLR2, TLR4, MAPK, and RelA (p65) pathways significantly decreased YfeA-induced pro-inflammatory cytokine production. In addition, YfeA-stimulated RAW 264.7 produces the pro-inflammatory hallmark, reactive oxygen species (ROS). In conclusion, our findings indicate that YfeA is a novel pro-inflammatory mediator in G. parasuis and induces TLR2 and TLR4-dependent pro-inflammatory activity in RAW 264.7 macrophages through P38, JNK-MAPK, and NF-κB signaling pathways.

Calculation of the electrostatic double layer force (EDL force) between clay particles is relevant as it is closely related to important macroscopic mechanical behaviors of clays. The popular method to calculate the EDL force is to integrate the electric potential and Maxwell stress along the boundary enclosing a simply connected domain within which a clay particle resides. The EDL force has also been calculated by the integration of the electrostatic force density over the preceding domain. However, the subtle relation of the EDL forces calculated by the different existing methods has not yet been investigated. By means of theoretical analysis and finite element simulation, it was shown that the force calculated by the integration of Maxwell stress along the complete boundary enclosing a multiply connected domain in which the clay particle is excluded, and that along the partial boundary enclosing the preceding simply connected domain represents the electrical attractive force and osmotic repulsive force, respectively, while the integration of the potential along both the same complete and partial boundary denotes the osmotic force. Numerical results showed that the calculated EDL force deviates from its actual value significantly with the decrease in distance between the chosen integral boundary and particle surface, and the deviation varies with surface potential and angle between particles. Moreover, the recommended minimum distance was proposed to be 10 times the thickness of the particle based on the present simulation results.

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival during nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 (PC1KO) or PC2 (PC2KO), and human urine-derived proximal tubular epithelial cells (PTEC) from early-stage ADPKD patients with PC1 mutations versus healthy individuals. Basal autophagy was enhanced in PC1-deficient cells. Similarly, following starvation, autophagy was enhanced and cell death reduced when PC1 was reduced. Autophagy inhibition reduced cell death resistance in PC1KO mIMCDs to the WT level, implying that PC1 promotes autophagic cell survival. Although PC2 expression was increased in PC1KO mIMCDs, PC2 knockdown did not result in reduced autophagy. PC2KO mIMCDs displayed lower basal autophagy, but more autophagy and less cell death following chronic starvation. This could be reversed by overexpression of PC1 in PC2KO. Together, these findings indicate that PC1 levels are partially coupled to PC2 expression, and determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress.

Metal-free thermally activated delayed fluorescence (TADF) emitters have emerged as promising candidate materials for highly efficient and low-cost organic light-emitting diodes (OLEDs). Here, a novel acceptor 2-cyanopyrazine is selected for the construction of blue TADF molecules via computer-assisted molecular design. Both theoretical prediction and experimental photophysical data indicate a small S1-T1 energy gap (ΔEST) and a relative large fluorescence rate (kF) in an o-phenylene-bridged 2-cyanopyrazine/3,6-di-tert-butylcarbazole compound (TCzPZCN). The kF value of 3.7 × 107 s−1 observed in a TCzPZCN doped film is among the highest in the TADF emitters with a ΔEST smaller than 0.1 eV. Blue TADF emission is observed in a TCzPZCN doped film with a short TADF lifetime of 1.9 μs. The OLEDs using TCzPZCN as emitter exhibit a maximum external quantum efficiency (EQE) of 7.6% with low-efficiency roll-off. A sky-blue device containing a derivative of TCzPZCN achieves an improved EQE maximum of 12.2% by suppressing the non-radiative decay at T1.

Air traffic control (ATC) performance is important to ensure flight safety and the sustainability of aviation growth. To better evaluate the performance of ATC, this paper introduces the HFACS-BN model (HFACS: Human factors analysis and classification system; BN: Bayesian network), which can be combined with the subjective information of relevant experts and the objective data of accident reports to obtain more accurate evaluation results. The human factors of ATC in this paper are derived from screening and analysis of 142 civil and general aviation accidents/incidents related to ATC human factors worldwide from 1980 to 2019, among which the most important 25 HFs are selected to construct the evaluation model. The authors designed and implemented a questionnaire survey based on the HFACS framework and collected valid data from 26 frontline air traffic controllers (ATCO) and experts related to ATC in 2019. Combining the responses with objective data, the noisy MAX model is used to calculate the conditional probability table. The results showed that, among the four levels of human factors, unsafe acts had the greatest influence on ATC Performance (79.4%), while preconditions for safe acts contributed the least (40.3%). The sensitivity analysis indicates the order of major human factors influencing the performance of ATC. Finally, this study contributes to the literature in terms of methodological development and expert empirical analysis, providing data support for human error management intervention of ATC in aviation safety.

Interface interactions play a crucial role in determining the thermomechanical properties of carbon nanotubes (CNTs)/polymer nanocomposites. They are, however, poorly treated in the current multi-scale coarse-grained (CG) models. To develop suitable CG models of CNTs/polymer nanocomposites, we demonstrate the importance of two aspects for the first time, that is, preserving the interfacial cohesive energy and reproducing the interface load transfer behavior of all-atomistic (AA) systems. Our simulation results indicate that, for CNTs/polymer nanocomposites, the interface cohesive energy and the interface load transfer of CG models are generally inconsistent with their AA counterparts, revealing significant deviations in their predicted mechanical properties. Fortunately, such inconsistency can be “corrected” by phenomenologically adjusting the cohesive interaction strength parameter of the interface LJ potentials in conjunction with choosing a reasonable degree of coarse-graining of incorporated CNTs. We believe that the problem studied here is general for the development of the CG models of nanocomposites, and the proposed strategy used in present work may be applied to polymer nanocomposites reinforced by other nanofillers.

Enoyl acyl carrier protein (ACP) reductase (FabI) is a potential target for the development of antibacterial agents. Three-dimensional quantitative structure-activity relationships (3D-QSAR) for substituted formamides series of FabI inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore and molecular docking methods were used for construction of the molecular alignments. A training set of 36 compounds was performed to create the 3D-QSAR models and their external predictivity was proven using a test set of 11 compounds. Graphical interpretation of the results revealed important structural features of the formamides related to the active site of FabI. The results may be exploited for further optimization of the design of new potent FabI inhibitors.

NF-κB is an important transcription factor that plays critical roles in cell survival, proliferation, inflammation, and cancers. Although the majority of experimentally identified functional NF-κB binding sites (κB sites) match the consensus sequence, there are plenty of non-functional NF-κB consensus sequences in the genome. We analyzed the surrounding sequences of the known κB sites that perfectly match the GGGRNNYYCC consensus sequence and identified the nucleotide at the -1 position of κB sites as a key contributor to the binding of the κB sites by NF-κB. We demonstrated that a cytosine at the -1 position of a κB site (-1C) could be methylated, which thereafter impaired NF-κB binding and/or function. In addition, all -1C κB sites are located in CpG islands and are conserved during evolution only when they are within CpG islands. Interestingly, when there are multiple NF-κB binding possibilities, methylation of -1C might increase NF-κB binding. Our finding suggests that a single nucleotide at the -1 position of a κB site could be a critical factor in NF-κB functioning and could be exploited as an additional manner to regulate the expression of NF-κB target genes.

Lipid disorder and inflammation play critical roles in the development of atherosclerosis. Reverse cholesterol transport is a key event in lipid metabolism. Caveolae and caveolin-1 are in the center stage of cholesterol transportation and inflammation in macrophages. Here, we propose that reverse cholesterol transport and inflammation in atherosclerosis can be integrated by caveolae and caveolin-1.