Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors

NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors

Insights of Oxygen Reduction Selectivity and Fe Leaching from Fe-N-C Nanozyme in Ascorbate Oxidation

Ascorbic acid (H2A) is a well-known antioxidant to protect cellular components from free radical damage, meanwhile it is also emerged as pro-oxidant in cancer therapy. However, such contradictory mechanisms underlying H2A oxidation are not well understood. Here, we report the discovery of Fe leaching during catalytic H2A oxidation using Fe-N-C nanozyme as a ferritin mimic and its influence in selectivity of oxygen reduction reaction (ORR). Owing to the heterogeneity, Fe-Nx sites in Fe-N-C primarily catalyzed the H2A oxidation and 4e ORR via an iron-oxo intermediate; meanwhile marginal N-C sites catalyzed the 2e ORR via an O2 intermediate with H2O2 production, although which was less favorable in kinetics and hardly observable in the early stage. Nonetheless, trace O2 accumulated and attacked Fe-Nx sites, leading to a linear leakage of unstable Fe ions up to 420 ppb when the concentration of H2A increased. As a result, a substantial fraction (~40%) of N-C sites on Fe-N-C were activated, and a new path for Fenton-type H2A oxidation was finally enabled. After Fe ions diffused into the bulk solution, the ORR at the N-C sites stopped at H2O2 production, which was the origin for the pro-oxidant effect by H2A. This work highlights the Fe-leakage occurring on Fe-N-C nanozymes and uncovers the multifaceted insights of ORR selectivity in H2A oxidation under realistic conditions

Perceptions about respiratory syncytial virus (RSV) and attitudes toward the RSV vaccine among the general public in China: A cross-sectional survey

ABSTRACTOur study aims to assess the public’s perceptions of respiratory syncytial virus (RSV) and attitudes toward the RSV vaccine and to identify associated factors in China. A nationwide cross-sectional survey conducted using an online platform between August 16 and September 14, 2023. Questions related to socio-demographics, awareness, knowledge, perceptions of susceptibility and severity of RSV, and attitudes toward the RSV vaccine were included in the questionnaire. We used the chi-square test and logistic regression model to explore the associated factors. Overall, 2133 individuals were included in this study. Nearly a quarter of participants (24.3%) indicated that they had never heard of RSV. The proportion of individuals aged over 50 years reporting never having heard of RSV (36.5%) and having a low knowledge level of RSV (55.3%) was significantly higher that of other younger age groups. More than half of individuals (55.7%) exhibited low level of perceptions of susceptibility concerning RSV infection. A total of 68.4% of the participants expressed willingness to receive the RSV vaccine. Younger age was positively associated with a higher willingness to be vaccinated. The most frequent reason for declining the vaccine was “Concern about vaccine’s safety or side effects.” About 60% of individuals considered a price of RSV vaccine below 200 CNY (28 USD) as acceptable. The awareness and perceived susceptibility to RSV infection were limited to the Chinese public. It is necessary to take measures to address the low awareness and knowledge of RSV and acceptability of the RSV vaccine among older adults

Decoupling of Confused Complex in Oxidation of 3,3’,5,5’-Tetramethylbenzidine Enhancing Reliability of Chromogenic Bioassay

Pathway regulation of chemical reactions is an important means of precision chemistry. As an extremely important chromogenic substrate, 3,3’,5,5’-tetramethylbenzidine (TMB) generally undertakes one-electron oxidation, but the reaction product (TMBox1), a confused complex, is unstable, which significantly hampers the practical applications, such as clinic enzyme-linked immunosorbent assay (ELISA). Herein, we report that sodium dodecyl sulfate (SDS)-based micelles could promote the direct two-electron oxidation pathway of TMB into more stable TMBox2. Different to the common processes of one-electron TMB oxidation by homogeneous peroxidase (POD) or other emerging heterogeneous nanocatalysts, the confused complex consisted of TMB and TMBox1 was successfully decoupled by SDS micelles via spatial isolation and electrostatic effect. As a proof-of-concept application, glucose oxidase and SDS micelles were cascaded for glucose detection, and the selective two-electron oxidation of TMB endowed enhanced reliability and broader detection range of glucose chromogenic bioassays without any conventional strong acid termination

Construction of Cascade Nanozymatic Networks for Cell Mimic with Highly Selective Recognition and Linear Perception to H2O2

A single stimulus leading to multiple responses is an essential function of many biological enzymatic reaction networks, which enable complex life activities. Owing to the lack of allosteric regulation of natural enzymes, it is challenging to duplicate a similar network using non-living chemicals. Herein, we report a nanozymatic cascade reaction network that demonstrates multiple responses of different modes and intensities upon a single H2O2 stimulus based on a single-atom nanozyme (Co-N-CNTs). Taking the two-electron cascade oxidation of 3,3’,5,5’-tetramethylbenzidine (TMB) as an example, the endogenous product H2O2 competitively inhibited substrates in the first one-electron oxidation at the Co-N4 active site on Co-N-CNTs, while accelerated the second one-electron oxidation under a micellar nanozyme. Using such a nanozymatic network, the feedback and feedforward regulation of product transformation were further applied to microfluidic flow reactors as a cell mimic. Owing to the unique varieties of response in intensities and modes, the proposed cell mimic demonstrated highly selective recognition and linear perception of H2O2 against over 20 interferences in a wide range of concentrations (0.01-100 mM), reminiscent of a primordial life-like process in mutable and harsh conditions

Elucidating Effects of Orbital Delocalization on Electrochemiluminescent Efficiency for Carbon Nitrides

Electrochemiluminescence (ECL), an emission of light excited by electrochemical reactions, has drawn attention as tools across diverse fields, ranging from clinical disease diagnosis to photo-/electro-catalysts development. Nonetheless, the ECL efficiency of most luminophores in aqueous solutions is low, which significantly hamper their broad applications; thus, understanding the intrinsic factors for ECL efficiency is highly envisioned. Herein, taking emerging carbon nitride (CN) with unique electronic structures and rigid 2D backbone as a model luminophore, we report that the orbital delocalization was a promising unifying factor for its ECL efficiency. Behind the complicated transformation of molecular structures regarding cyano-terminal groups and triazine/heptazine basal frameworks, the orbital delocalization of the as-prepared CN was found to be generally improved at an elevated condensation temperature. Such intrinsic evolution in electronic structure favored the electron injection in excitation and photon emission afterward in ECL of CN. As a result, the cathodic ECL efficiency of CN was remarkably improved to a new milestone of 170-fold greater than benchmark Ru(bpy)3Cl2

Multi-path Utilization of Earthwork in Pinglu Canal: Basic Problems and Solutions

Pinglu Canal is the backbone project of the New Western Land-Sea Corridor of China. The canal project generated a total of 3.39 × 108 m3 of earthwork that covers approximately 23 types of rocks and soil and is characterized by large amount, diverse composition, and scattered distribution. Currently, the earthwork is utilized mainly through landfill and reclamation (over 50%); however, basic problems exist, including a low high-quality utilization rate, lagging research on demand for earthwork-reused products, lack of innovative technologies for earthwork reuse, a low level of digitalization, and lack of carbon emission evaluation. To address these problems, this study proposes innovative solutions from the perspectives of resource utilization, digitization, and carbon reduction. First, it is necessary to explore the potential application demands for the canal project itself and surrounding areas and propose corresponding utilization paths according to different types of rock and soil, thus to achieve multi-scenario, multi-path utilization. Second, geological information models and information databases should be established for earthwork in excavation areas to help develop a digital excavation‒transportation‒storage‒utilization technology for earthwork. Moreover, it is recommended to conduct a lifecycle assessment to clarify the carbon emissions of multi-path utilization technologies, achieve a dynamic evaluation of carbon emissions by combining with the information from the earthwork databases, and develop modular mobile-type disposal equipment and in-situ utilization technologies to achieve the reduction of cost and carbon emissions. The organic combination of resource utilization, digitization, and carbon reduction is expected to provide a favorable support for the green construction of the Pinglu Canal Project

Economic evaluation of varicella vaccination strategies in Jiangsu province, China: a decision-tree Markov model

This study evaluated different varicella vaccination strategies in Jiangsu province, China. A decision-tree Markov model was used to evaluate the cost effectiveness of various varicella vaccination strategies for children, including direct and selective vaccination (serotesting pre-vaccination). A cohort of one-year-old children was followed through 60 one-year Markov cycles. The parameter estimation was based on field work, the literature, and statistical yearbooks. We calculated the incremental cost-utility ratio (ICUR) using the saved quality-adjusted life year (QALY). One-way and probability sensitivity analyses were performed to assess uncertainty. Among 100,000 cohort members, one-dose and two-dose direct vaccination averted 8061 and 10,701 varicella cases, respectively, compared with no vaccination. Furthermore, compared with no vaccination, one-dose and two-dose direct vaccination saved one QALY at the ICUR of USD 21,401.33 and USD 35,420.81, respectively, at less than three times the per capita gross domestic product (USD 47,626.86) of Jiangsu. The ICURs of the one-dose and two-dose selective strategies versus no vaccination were USD 42,623.62 and USD 51,406.35 per QALY gained, respectively. The cost effectiveness results were most sensitive to the QALY loss of outpatients and vaccine prices. Thus, in Jiangsu, one-dose and two-dose direct varicella vaccination in children could be cost effective at the willingness to pay threshold of three times provincial GDP per capita from a societal perspective. The findings were sensitive to the vaccine price and health utility of varicella cases

Self-Adapting Graphitic C6N6-Based Copper Single-Atom Catalyst for Smart Biosensors

Self-adaptability is highly envisioned for artificial devices such as robots with chemical noses. For this goal, seeking catalysts with multiple and modulable reaction pathways is promising but generally hampered by inconsistent reaction conditions. Herein, we report a self-adaptive CuSAC6N6 single-atom catalyst having two reactive oxygen-oriented pathways under the same reaction conditions. CuSAC6N6 consisted of coordinated peroxidase-like Cu-N coordination centers and photo-responsive donor-π-acceptor (D-π-A) units with promoted intramolecular charge separation and migration. Interestingly, it drove the basic oxidation of peroxidase substrates by the bound copper-oxo pathway, and undertook a second gain reaction triggered by light via the free hydroxyl radical pathway under the same conditions. A remarkable basic activity and a superb gain of up to 3.6 times under household lights were observed, significantly higher than that of its control systems, including solo carbon nitride-based nanozymes or photocatalysts, their mixtures, and even that under thermal stimuli to the maximum endured temperature for most lives. As an application, the self-adapting CuSAC6N6 was used to construct a glucose biosensor, which can intelligently switch the linear detection range and sensitivity to a diverse range of concentrations in vitro