Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts.

Bench-stable 3,3-difluoroallyl sulfonium salts (DFASs), featuring tunable activity and their editable C-ß and gem-difluoroallyl group, proved to be versatile fluoroalkylating reagents for site-selective S-gem-difluoroallylation of cysteine residues in unprotected peptides. The reaction proceeds with high efficiency under mild conditions (ambient temperature and aqueous and weak basic conditions). Various protected/unprotected peptides, especially bioactive peptides, are site-selectively S-gem-difluoroallylated. The newly added gem-difluoroallyl group and other functional groups derived from C-ß of DFASs are poised for ligation with bio-functional groups through click and radical chemistry. This stepwise "doubly orthogonal" modification of peptides enables the construction of bioconjugates with enhanced complexity and functionality. This proof of principle is successfully applied to construct a peptide-saccharide-biotin chimeric bioconjugate, indicating its great potential application in medicinal chemistry and chemical biology.

Taking Advantage of Potential Coincidence Region: Insights into Gas Production Behavior in Advanced Self-Activated Hydrazine-Assisted Alkaline Seawater Electrolysis.

Water electrolysis assisted by hydrazine has emerged as a prospective energy conversion method for achieving efficient hydrogen generation. Due to the potential coincidence region (PCR) between the hydrogen evolution reaction (HER) and the electro-oxidation of hydrazine, the hydrazine oxidation reaction (HzOR) offers distinct advantages in terms of strategy amalgamation, device architecture, and the broadening of application horizons. Herein, we report a bifunctional electrocatalyst of interfacial heterogeneous Fe2P/Co2P microspheres supported on Ni foam (FeCoP/NF). Benefiting from the strong interfacial coupling effect between Fe2P and Co2P and the three-dimensional microsphere structure, FeCoP/NF exhibits outstanding bifunctional electrocatalytic performance, achieving 10 mA cm-2 with low overpotentials of 10 and 203 mV for HER and HzOR, respectively. Utilizing FeCoP/NF for both electrodes in HzOR-assisted water electrolysis results in significantly reduced potentials of 820 mV for 1 A cm-2 in contrast to the electro-oxidation of alternative chemical substrates. The presence of a potential coincidence region makes the application of self-activated seawater electrolysis realistic. The gas production behavior at different current densities in this interesting hydrogen production system is discussed, and some rules that are distinguished from conventional water electrolysis are summarized. Furthermore, a new self-powered hydrogen production system with a direct hydrazine fuel cell, rechargeable Zn-hydrazine battery, and hydrazine-assisted seawater electrolysis is proposed, emphasizing the distinct benefits of HzOR and its potential role in electrochemical energy conversion technologies powered by renewable sources.

Herb pair of Huangqi-Danggui exerts anti-tumor immunity to breast cancer by upregulating PIK3R1.

BACKGROUND: According to traditional Chinese medicine (TCM), drugs supplementing the vital energy, Qi, can eliminate tumors by restoring host immunity. The objective of this study is to investigate the underlying immune mechanisms of anti-tumor activity associated with Qi-supplementing herbs, specifically the paired use of Huangqi and Danggui. METHODS: Analysis of compatibility regularity was conducted to screen the combination of Qi-supplementing TCMs. Using the MTT assay and a transplanted tumor mice model, the anti-tumor effects of combination TCMs were investigated in vitro and in vivo. High content analysis and flow cytometry were then used to evaluate cellular immunity, followed by network pharmacology and molecular docking to dissect the significant active compounds and potential mechanisms. Finally, the anti-tumor activity and the mechanism of the active ingredients were verified by molecular experiments. RESULTS: There is an optimal combination of Huangqi and Danggui that, administered as an aqueous extract, can activate immunity to suppress tumor and is more effective than each drug on its own in vitro and in vivo. Based on network pharmacology analysis, PIK3R1 is the core target for the anti-tumor immunity activity of combined Huangqi and Danggui. Molecular docking analysis shows 6 components of the combined Danggui and Huangqi extract (quercetin, jaranol, isorhamnetin, kaempferol, calycosin, and suchilactone) that bind to PIK3R1. Jaranol is the most important component against breast cancer. The suchilactone/jaranol combination and, especially, the suchilactone/kaempferol combination are key for immunity enhancement and the anti-tumor effects of the extract. CONCLUSIONS: The combination of Huangqi and Danggui can activate immunity to suppress breast cancer and is more effective than the individual drugs alone.

Changes in α-Dicarbonyl Compound Contents during Storage of Various Fruits and Juices.

α-Dicarbonyl compounds (α-DCs) are commonly present in various foods. We conducted the investigation into concentration changes of α-DCs including 3-deoxyglucosone (3-DG), glyoxal (GO), and methylglyoxal (MGO) in fresh fruits and decapped commercial juices during storage at room temperature and 4 °C, as well as in homemade juices during storage at 4 °C. The studies indicate the presence of α-DCs in all samples. The initial contents of 3-DG in the commercial juices (6.74 to 65.61 µg/mL) are higher than those in the homemade ones (1.97 to 4.65 µg/mL) as well as fruits (1.58 to 3.33 µg/g). The initial concentrations of GO and MGO are normally less than 1 µg/mL in all samples. During storage, the α-DC levels in the fruits exhibit an initial increase followed by a subsequent decrease, whereas, in all juices, they tend to accumulate continuously over time. As expected, 4 °C storage reduces the increase rates of the α-DC concentrations in most samples. From the viewpoint of the α-DC contents, fruits and homemade juices should always be the first choice for daily intake of nutrients and commercial juices ought to be mostly avoided.

Advanced optimal tracking integrating a neural critic technique for asymmetric constrained zero-sum games.

This paper investigates the optimal tracking issue for continuous-time (CT) nonlinear asymmetric constrained zero-sum games (ZSGs) by exploiting the neural critic technique. Initially, an improved algorithm is constructed to tackle the tracking control problem of nonlinear CT multiplayer ZSGs. Also, we give a novel nonquadratic function to settle the asymmetric constraints. One thing worth noting is that the method used in this paper to solve asymmetric constraints eliminates the strict restriction on the control matrix compared to the previous ones. Further, the optimal controls, the worst disturbances, and the tracking Hamilton-Jacobi-Isaacs equation are derived. Next, a single critic neural network is built to estimate the optimal cost function, thus obtaining the approximations of the optimal controls and the worst disturbances. The critic network weight is updated by the normalized steepest descent algorithm. Additionally, based on the Lyapunov method, the stability of the tracking error and the weight estimation error of the critic network is analyzed. In the end, two examples are offered to validate the theoretical results.

Gene associations of lipid traits, lipid-lowering drug-target genes and endometriosis.

RESEARCH QUESTION: Does the observed correlation between dyslipidaemia and endometriosis indicate a bidirectional causal association? DESIGN: Bidirectional Mendelian randomization was used to investigate the causal association between lipid traits and endometriosis. Drug-target Mendelian randomization was used to explore potential drug-target genes for managing endometriosis. In cases where lipid-mediated effects via specific drug targets were significant, aggregate analyses, such as summary-data-based Mendelian randomization and colocalization methods, were introduced to validate the outcomes. Mediation analyses supplemented these evaluations. RESULTS: The bidirectional Mendelian randomization results suggested that genetically predicted triglyceride (OR 1.15, 95% CI 1.08-1.23), high-density lipoprotein cholesterol (OR 0.87, 95% CI 0.81-0.94), low-density lipoprotein cholesterol (OR 1.20, 95% CI 1.06-1.34) and apolipoprotein A (OR 0.90, 95% CI 0.83-0.96) concentrations were causally associated with endometriosis. Reverse Mendelian randomization results revealed that genetically proxied endometriosis was causally associated with triglyceride concentration (OR 1.02, 95% CI 1.01-1.02). In drug-target Mendelian randomization, genetic mimicry in proprotein convertase subtilisin/kexin type 9 (PCSK9) (OR 1.40, 95% CI 1.13-1.72), apolipoprotein B (APOB) (OR 1.49, 95% CI 1.21-1.86) and angiopoietin-related protein 3 (ANGPTL3) (OR 1.57, 95% CI 1.14-2.16) was significantly associated with the risk of endometriosis stages 1-2. CONCLUSION: There is a potential bidirectional causal association between endometriosis and dyslipidaemia. Genetic mimicry of PCSK9, APOB and ANGPTL3 is associated with the risk of early-stage endometriosis. The development of lipid-lowering drugs to treat endometriosis is of potential clinical interest.

Artificial Heterointerfaces with Regulated Charge Distribution of Ni Active Sites for Urea Oxidation Reaction.

In contrast to the thermodynamically unfavorable anodic oxygen evolution reaction, the electrocatalytic urea oxidation reaction (UOR) presents a more favorable thermodynamic potential. However, the practical application of UOR has been hindered by sluggish kinetics. In this study, hierarchical porous nanosheet arrays featuring abundant Ni-WO3 heterointerfaces on nickel foam (Ni-WO3/NF) is introduced as a monolith electrode, demonstrating exceptional activity and stability toward UOR. The Ni-WO3/NF catalyst exhibits unprecedentedly rapid UOR kinetics (200 mA cm-2 at 1.384 V vs. RHE) and a high turnover frequency (0.456 s-1), surpassing most previously reported Ni-based catalysts, with negligible activity decay observed during a durability test lasting 150 h. Ex situ X-ray photoelectron spectroscopy and density functional theory calculations elucidate that the WO3 interface significantly modulates the local charge distribution of Ni species, facilitating the generation of Ni3+ with optimal affinity for interacting with urea molecules and CO2 intermediates at heterointerfaces during UOR. This mechanism accelerates the interfacial electrocatalytic kinetics. Additionally, in situ Fourier transform infrared spectroscopy provides deep insights into the substantial contribution of interfacial Ni-WO3 sites to UOR electrocatalysis, unraveling the underlying molecular-level mechanisms. Finally, the study explores the application of a direct urea fuel cell to inspire future practical implementations.

Understanding activity-stability tradeoffs in biocatalysts by enzyme proximity sequencing.

Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.

Late-stage gem-difluoroallylation of phenol in bioactive molecules and peptides with 3,3-difluoroallyl sulfonium salts.

An efficient method for the late-stage selective O-fluoroalkylation of tyrosine residues with a stable yet highly reactive fluoroalkylating reagent, 3,3-difluoroallyl sulfonium salts (DFASs), has been developed. The reaction proceeds in a mild basic aqueous buffer (pH = 11.6) with high efficiency, high biocompatibility, and excellent regio- and chemoselectivity. Various oligopeptides and phenol-containing bioactive molecules, including carbohydrates and nucleosides, could be selectively O-fluoroalkylated. The added vinyl and other functional groups from DFASs can be valuable linkers for successive modification, significantly expanding the chemical space for further bioconjugation. The synthetic utility of this protocol has been demonstrated by the fluorescently labeled anti-cancer drug and the synthesis of O-link type 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid-tyrosine3-octreotate (DOTA-TATE), showing the prospect of the method in medicinal chemistry and chemical biology.

Learning From Human Educational Wisdom: A Student-Centered Knowledge Distillation Method.

Existing studies on knowledge distillation typically focus on teacher-centered methods, in which the teacher network is trained according to its own standards before transferring the learned knowledge to a student one. However, due to differences in network structure between the teacher and the student, the knowledge learned by the former may not be desired by the latter. Inspired by human educational wisdom, this paper proposes a Student-Centered Distillation (SCD) method that enables the teacher network to adjust its knowledge transfer according to the student network's needs. We implemented SCD based on various human educational wisdom, e.g., the teacher network identified and learned the knowledge desired by the student network on the validation set, and then transferred it to the latter through the training set. To address the problems of current deficiency knowledge, hard sample learning and knowledge forgetting faced by a student network in the learning process, we introduce and improve Proportional-Integral-Derivative (PID) algorithms from automation fields to make them effective in identifying the current knowledge required by the student network. Furthermore, we propose a curriculum learning-based fuzzy strategy and apply it to the proposed PID control algorithm, such that the student network in SCD can actively pay attention to the learning of challenging samples after with certain knowledge. The overall performance of SCD is verified in multiple tasks by comparing it with state-of-the-art ones. Experimental results show that our student-centered distillation method outperforms existing teacher-centered ones.

Theoretical and experimental investigation of Al3+ ion-suppressed phase-separation structures in rare-earth-doped high-phosphorus silica glasses.

Rare-earth-doped silica-based composite glasses (Re-SCGs) are widely used as high-quality laser gain media in defense, aerospace, energy, power, and medical applications. The variable regional chemical environments of Re-SCGs can induce new photoluminescence properties of rare-earth ions but can cause the selective aggregation of rare-earth ions, limiting the application of Re-SCGs in the field of high-power lasers. Here, topological engineering is proposed to adjust the degree of cross-linking of phase-separation network chains in Re-SCGs. A combination of experimental and theoretical characterization techniques suggested that the selective aggregation of rare-earth ions originates from the formation of phase-separated structures in glasses. The decomposition of nanoscale phase separation structures to the sub-nanometer scale, enabled by incorporating Al3+ ions, not only maintains the high luminescence efficiency of rare earth ions but also increases light transmittance and reduces light scattering. Furthermore, our investigation encompassed the exploration of the inhibitory mechanism of Al3+ ions on phase-separation structures, as well as their influence on the spectral characteristics of Re-SCGs. This work provides a new design concept for composite glass materials doped with rare-earth ions and could broaden their application in the field of high-power lasers.

Minor alkaloids from an aqueous extract of the hook-bearing stem of Uncaria rhynchophylla.

Seven new monoterpene alkaloids (1 - 7), along with 16 known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis, single crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are stereoisomers belonging to a novel type of pseudoindoxyl monoterpene alkaloids, 3 is the first monoterpene furoindole alkaloid from nature, and 4 - 7 are derivatives of the known monoterpene alkaloids featuring different structures.

Self-Powered Hydrogen Production with Improved Energy Efficiency via Polysulfides Redox.

In the pursuit of efficient solar-driven electrocatalytic water splitting for hydrogen production, the intrinsic challenges posed by the sluggish kinetics of anodic oxygen evolution and intermittent sunlight have prompted the need for innovative energy systems. Here, we introduce an approach by coupling the polysulfides oxidation reaction with the hydrogen evolution reaction for energy-saving H2 production, which could be powered by an aqueous zinc-polysulfides battery to construct a self-powered energy system. This unusual hybrid water electrolyzer achieves 300 mA cm-2 at a low cell voltage of 1.14 V, saving electricity consumption by 100.4% from 5.47 to 2.73 kWh per m3 H2 compared to traditional overall water splitting. Benefiting from the favorable reaction kinetics of polysulfides oxidation/reduction, the aqueous zinc-polysulfides battery exhibits an energy efficiency of approximately 89% at 1.0 mA cm-2. Specially, the zinc-polysulfide battery effectively stores intermittent solar energy as chemical energy during light reaction by solar cells. Under an unassisted light reaction, the batteries could release energy to drive H2 production through a hybrid water electrolyzer for uninterrupted hydrogen production. Therefore, the aim of simultaneously generating H2 and eliminating the restrictions of intermittent sunlight is realized by combining the merits of polysulfides redox, an aqueous metal-polysulfide battery, and solar cells. We believe that this concept and utilization of polysulfides redox will inspire further fascinating attempts for the development of sustainable energy via electrocatalytic reactions.

A lightweight speech recognition method with target-swap knowledge distillation for Mandarin air traffic control communications.

Miscommunications between air traffic controllers (ATCOs) and pilots in air traffic control (ATC) may lead to catastrophic aviation accidents. Thanks to advances in speech and language processing, automatic speech recognition (ASR) is an appealing approach to prevent misunderstandings. To allow ATCOs and pilots sufficient time to respond instantly and effectively, the ASR systems for ATC must have both superior recognition performance and low transcription latency. However, most existing ASR works for ATC are primarily concerned with recognition performance while paying little attention to recognition speed, which motivates the research in this article. To address this issue, this article introduces knowledge distillation into the ASR for Mandarin ATC communications to enhance the generalization performance of the light model. Specifically, we propose a simple yet effective lightweight strategy, named Target-Swap Knowledge Distillation (TSKD), which swaps the logit output of the teacher and student models for the target class. It can mitigate the potential overconfidence of the teacher model regarding the target class and enable the student model to concentrate on the distillation of knowledge from non-target classes. Extensive experiments are conducted to demonstrate the effectiveness of the proposed TSKD in homogeneous and heterogeneous architectures. The experimental results reveal that the generated lightweight ASR model achieves a balance between recognition accuracy and transcription latency.

Enabling Internal Electric Field in Heterogeneous Nanosheets to Significantly Accelerate Alkaline Hydrogen Electrocatalysis.

Efficient bifunctional hydrogen electrocatalysis, encompassing both hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR), is of paramount significance in advancing hydrogen-based societies. While non-precious-metal-based catalysts, particularly those based on nickel (Ni), are essential for alkaline HER/HOR, their intrinsic catalytic activity often falls short of expectations. Herein, an internal electric field (IEF) strategy is introduced for the engineering of heterogeneous nickel-vanadium oxide nanosheet arrays grown on porous nickel foam (Ni-V2 O3 /PNF) as bifunctional electrocatalysts for hydrogen electrocatalysis. Strikingly, the Ni-V2 O3 /PNF delivers 10 mA cm-2 at an overpotential of 54 mV for HER and a mass-specific kinetic current of 19.3 A g-1 at an overpotential of 50 mV for HOR, placing it on par with the benchmark 20% Pt/C, while exhibiting enhanced stability in alkaline electrolytes. Density functional theory calculations, in conjunction with experimental characterizations, unveil that the interface IEF effect fosters asymmetrical charge distributions, which results in more thermoneutral hydrogen adsorption Gibbs free energy on the electron-deficient Ni side, thus elevating the overall efficiency of both HER and HOR. The discoveries reported herein guidance are provided for further understanding and designing efficient non-precious-metal-based electrocatalysts through the IEF strategy.

High-entropy alloys in electrocatalysis: from fundamentals to applications.

High-entropy alloys (HEAs) comprising five or more elements in near-equiatomic proportions have attracted ever increasing attention for their distinctive properties, such as exceptional strength, corrosion resistance, high hardness, and excellent ductility. The presence of multiple adjacent elements in HEAs provides unique opportunities for novel and adaptable active sites. By carefully selecting the element configuration and composition, these active sites can be optimized for specific purposes. Recently, HEAs have been shown to exhibit remarkable performance in electrocatalytic reactions. Further activity improvement of HEAs is necessary to determine their active sites, investigate the interactions between constituent elements, and understand the reaction mechanisms. Accordingly, a comprehensive review is imperative to capture the advancements in this burgeoning field. In this review, we provide a detailed account of the recent advances in synthetic methods, design principles, and characterization technologies for HEA-based electrocatalysts. Moreover, we discuss the diverse applications of HEAs in electrocatalytic energy conversion reactions, including the hydrogen evolution reaction, hydrogen oxidation reaction, oxygen reduction reaction, oxygen evolution reaction, carbon dioxide reduction reaction, nitrogen reduction reaction, and alcohol oxidation reaction. By comprehensively covering these topics, we aim to elucidate the intricacies of active sites, constituent element interactions, and reaction mechanisms associated with HEAs. Finally, we underscore the imminent challenges and emphasize the significance of both experimental and theoretical perspectives, as well as the potential applications of HEAs in catalysis. We anticipate that this review will encourage further exploration and development of HEAs in electrochemistry-related applications.

Protocol for preparing patterned superlattice structures by printing assembly technology for multi-channel detection.

The transformation of superlattice structures into functional devices requires high-quality preparation. Inkjet printing is potentially a cutting-edge technology for nanofabrication. Here, we present a protocol to prepare inks for constructing patterned superlattice structures using print assembly techniques. We describe steps for preparing oleophobic substrates, optimizing ink parameters, and preparing the patterned superlattice array. We then detail procedures for preparing a multichannel surface-enhanced Raman scattering sensor and evaluating its performance. This protocol can potentially facilitate the commercialization of superlattice-related devices. For complete details regarding the use and execution of this protocol, please refer to Zhao et al.1.

MiR-337-3p improves metabolic-associated fatty liver disease through regulation of glycolipid metabolism.

Epigenetic regulations play crucial roles in the pathogenesis of metabolic-associated fatty liver disease; therefore, elucidating the biological functions of differential miRNAs helps us to understand the pathogenesis. Herein, we discovered miR-337-3p was decreased in patients with NAFLD from Gene Expression Omnibus dataset, which was replicated in various cell and mouse models with lipid disorders. Subsequently, overexpression of miR-337-3p in vivo could ameliorate hepatic lipid accumulation, reduce fasting blood glucose, and improve insulin resistance. Meanwhile, we determined miR-337-3p might influence multiple genes involved in glycolipid metabolism through mass spectrometry detection, bioinformatics analysis, and experimental verification. Finally, we selected HMGCR as a representative example to investigate the molecular mechanism of miR-337-3p regulating these genes, where the seed region of miR-337-3p bound to 3'UTR of HMGCR to inhibit HMGCR translation. In conclusion, we discovered a new function of miR-337-3p in glycolipid metabolism and that might be a new therapeutic target of MAFLD.

Bioresponsive Chimaeric Polymersomes Mediate Sustained and Liver-Specific siRNA Transfection In Vivo.

The silencing of disease-causing genes with small interfering RNA (siRNA) offers a particularly effective therapeutic strategy for different disorders; however, its clinical efficacy relies on the development of nontoxic and tissue-specific delivery vehicles. Herein, we report that bioresponsive chimaeric polymersomes (BCP) with short poly(ethylenimine) as inner shell mediate highly efficacious, sustained, and liver-specific siRNA transfection in vivo. BCP exhibited remarkable encapsulation efficiencies of siRNA (95-100%) at siRNA-feeding contents of 15-25 wt %, to afford stable, small-sized (55-64 nm), and neutral-charged BCP-siRNA. siApoB-Loaded BCP (BCP-siApoB) outperformed lipofectamine counterparts and silenced 93% of ApoB mRNA in HepG2 cells at 50 nM siApoB without inducing cytotoxicity. Intriguingly, the in vivo studies using wild-type C57BL/6 mice revealed that BCP-siApoB preferentially accumulated in the liver, and a single dose of 4.5 mg/kg achieved over 90% downregulation of ApoB mRNA for at least 10 days. The systemic administration of BCP-siApoB at 4.5 mg/kg every 2 weeks or 1.5 mg/kg weekly in diet-induced obese mice could also achieve up to 80% silencing of ApoB mRNA. The liver specificity and silencing efficacy of BCP-siApoB could further be improved by decorating it with the trivalent N-acetylgalactosamine (TriGalNAc) ligand. These bioresponsive and liver-specific chimaeric polymersomes provide an enabling technology for siRNA therapy of various liver-related diseases.