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Electrically reconfigurable nonlinear metasurfaces provide dynamic control over nonlinear phenomena such as second-harmonic generation (SHG), unlocking novel applications in signal processing, light switching, and sensing. Previous methods, like electric-field-induced SHG in plasmonic metasurfaces and Stark-tuned nonlinearities in quantum well metasurfaces, face limitations due to weak SHG responses from metals and mid-infrared constraints of quantum wells, respectively. Addressing the need for efficient SHG control in the visible and near-infrared ranges, we present a novel approach using the electro-optic (EO) effect to modulate SHG. By leveraging the exceptional EO and SHG properties of lithium niobate (LN), we integrate the EO effect with SHG within a metasurface framework for the first time. Our LN metasurface achieves an 11.3% modulation depth in SHG amplitude under a ±50 V alternating voltage. These results open new avenues for reconfigurable photonic applications. including tunable nonlinear light sources, quantum optics, and nonlinear information processing.

This work describes the use of computational strategies to design megamolecule building blocks for the self-assembly of lattice networks. The megamolecules are prepared by attaching four Cutinase-SnapTag fusion proteins (CS fusions) to a four-armed linker, followed by functionalizing each fusion with a terpyridine linker. This functionality is designed to participate in a metal-mediated self-assembly process to give networks. This article describes a simulation-guided strategy for the design of megamolecules to optimize the peptide linker in the fusion protein to give conformations that are best suited for self-assembly and therefore streamlines the typically time-consuming and labor-intensive experimental process. We designed 11 candidate megamolecules and identified the most promising linker, (EAAAK) 2 , along with the optimal experimental conditions through a combination of all-atom molecular dynamics, enhanced sampling, and larger-scale coarse-grained molecular dynamics simulations. Our simulation findings were validated and found to be consistent with the experimental results. Significantly, this study offers valuable insight into the self-assembly of megamolecule networks and provides a novel and general strategy for large biomolecular material designs by using systematic bottom-up coarse-grained simulations.

Phosphotriesterase (PTE) biodegradation of organophosphorus pesticides (OPs) is an efficient and environmentally friendly method. However, the instability and nonreusability of free PTE become the key factors restricting its practical application. In this study, a novel cross-linked magnetic hybrid nanoflower (CLMNF) was prepared. Molecular dynamics (MD) simulations were performed to further investigate the enhanced catalytic efficiency of the enzymes. The recovery rate of enzyme activity was 298% due to the large specific surface area and metal ion activation effect. More importantly, the immobilization scheme greatly improved the stability and reuse performance of the catalyst and simplified the recovery operation. CLMNFs retained 90.32% relative activity after 5 consecutive cycles and maintained 84.8% relative activity after 30 days at 25 °C. It has a good practical application prospect in the degradation and detection of OPs. Consequently, the immobilized enzyme as a biocatalyst has the characteristics of high efficiency, stability, safety, and easy separation, establishing the key step in a biodetoxification system to control organophosphorus contamination in food and the environment.

In this study, we synthesized mesoporous polydopamine nanoparticles (MPDA NPs) using an emulsion-induced interface assembly strategy and loaded epigallocatechin gallate (EGCG) into MPDA NPs via electrostatic attraction to form EGCG@MPDA NPs. In the post myocardial infarction (MI) environment, these interventions specifically aimed to eliminate reactive oxygen species (ROS) and facilitate the repair of MI. We further combined them with a thermosensitive chitosan (CS) hydrogel to construct an injectable composite hydrogel (EGCG@MPDA/CS hydrogel). Utilizing in vitro experiments, the EGCG@MPDA/CS hydrogel exhibited excellent ROS-scavenging ability of H9C2 cells under the oxidative stress environment and also could inhibit their apoptosis. The EGCG@MPDA/CS hydrogel significantly promoted left ventricular ejection fraction (LVEF) in infarcted rat models post injection for 28 days compared to the PBS group (51.25 ± 1.73% vs 29.31 ± 0.78%, P < 0.05). In comparison to the PBS group, histological analysis revealed a substantial increase in left ventricular (LV) wall thickness in the EGCG@MPDA/CS hydrogel group (from 0.58 ± 0.03 to 1.39 ± 1.11 mm, P < 0.05). This work presents a novel approach to enhance MI repair by employing the EGCG@MPDA/CS hydrogel. This hydrogel effectively reduces local oxidative stress by ROS and stimulates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.

The catalytic asymmetric synthesis of chiral phthalides has garnered considerable interest. However, the construction of phthalides with a chiral quaternary carbon stereocenter still remains challenging. In this study, we developed a new strategy toward catalytic asymmetric synthesis of chiral 3,3-disubstituted phthalides via a dirhodium(II)/phosphine-catalyzed carbonyl addition cascade, yielding phthalides with up to 97% ee values. The reaction proceeded through dirhodium(II)/phosphine-catalyzed asymmetric carbonyl addition of arylboronic acids to isoquinoline-1,3,4(2 H )-triones, followed by base-mediated ring contraction.

Luminescent thermometry affords remote measurement of temperature and shows huge potential in future technology beyond those possible with traditional methods. Strategies of temperature measurement aiming to increase thermal sensitivity in a wide temperature response window would represent a pivotal step forward, but most thermometers cannot do both of them. Herein, we propose a balancing strategy to achieve a trade-off between high Arrhenius activation energy ( E a ), which could stretch the temperature response windows, and fluorescence quantum yields (QYs) in a manner that will increase thermal sensitivity in a wide response window. In particular, a luminescent thermometer composed of AuNCs-MOF is prepared via a facile impregnation process to enhance QYs and E a , responsible for high relative sensitivity ( S r ) (15.6% K -1 ) and ultrawide temperature linearity range (from 83 to 343 K), respectively. Taking fluorescence intensity and lifetime as multiple parameters, the maximum S r can reach 22.4% K -1 by multiple linear regression. The maximum S r and temperature response range of the proposed thermometer outperform those of the most recent luminescent thermometers. The strategy of balancing S r and thermal response range by regulating E a and QYs enables the construction of ultra-accurate thermal sensors in the age of artificial intelligence.

Brain organoids are widely used to model brain development and diseases. However, a major challenge in their application is the insufficient supply of oxygen and nutrients to the core region, restricting the size and maturation of the organoids. In order to vascularize brain organoids and enhance the nutritional supply to their core areas, two-photon polymerization (TPP) 3D printing is employed to fabricate high-resolution meshed vessels in this study. These vessels made of photoresist with densely distributed micropores with a diameter of 20 μm on the sidewall, are cocultured with brain organoids to facilitate the diffusion of culture medium into the organoids. The vascularized organoids exhibit dimensional breaking growth and enhanced proliferation, reduced hypoxia and apoptosis, suggesting that the 3D-printed meshed vessels partially mimic vascular function to promote the culture of organoids. Furthermore, cortical, striatal and medial ganglionic eminence (MGE) organoids are respectively differentiated to generate Cortico-Striatal-MGE assembloids by 3D-printed vessels. The enhanced migration, projection and excitatory signaling transduction are observed between different brain regional organoids in the assembloids. This study presents an approach using TPP 3D printing to construct vascularized brain organoids and assembloids for enhancing the development and assembly, offering a research model and platform for neurological diseases.

Increasing efforts have been made to develop proteins in circulating extracellular vesicles (EVs) as potential disease markers. It is in particular intriguing to measure post-translational modifications (PTMs) such as phosphorylation, preserved and stable in EVs. To facilitate the quantitative measurement of EV protein phosphorylation for potential clinical use, a label-free (LF) multiple reaction monitoring (MRM) strategy is introduced by utilizing a synthetic phosphopeptide set (phos-iRT) as the internal standards and a local normalization method. The quantitation method was investigated in terms of its linear dynamic range, sensitivity, accuracy, precision, and matrix effect, with a dynamic range spanning from 10 to 1000 ng/mL and an accuracy ranging from 82.4 to 116.8% for EV samples. Then, the LF-MRM-based local normalization method was utilized to evaluate and optimize our recently developed EVTOP method for the enrichment of phosphopeptides from EVs. Finally, we applied the optimized EV enrichment approach and the LF-MRM-based local normalization method to quantify phosphopeptides in urine EVs from patients with prostate cancer (PCa) and healthy individuals, showcasing the strategy's superiority in quantifying phosphopeptides without isotopic internal standards and validating that the method is generally applicable in MRM-based EV phosphopeptide quantification.

Transdermal microneedle-mediated glucose-responsive insulin delivery systems can modulate insulin release based on fluctuations in blood glucose levels, thus maintaining normoglycemia effectively in a continuous, convenient, and minimally invasive manner. However, conventional microneedles are limited by the low drug loading capacity, making it challenging to be applied on human skin at a reasonable size for a lasting glucose-controlling effect, thus hindering their clinical translation. Here, we design a microneedle patch with a solid insulin powder core to achieve a high loading capacity of insulin (>70 wt %) as well as a glucose-sensitive polymeric shell to realize glucose-responsive insulin release. Once exposed to hyperglycemia, the formation of negatively charged glucose-boronate complexes increases the charge density of the shell matrix, leading to swelling of the shell and accelerating insulin release from the core. We have demonstrated that this glucose-responsive microneedle patch could achieve long-term regulation of blood glucose levels in both type 1 diabetic mice and minipigs (up to 48 h with patches of ∼3.5 cm 2 for minipigs >25 kg).

With the continuous exploitation of petroleum resources, the distribution and displacement of residual oils have become key issues in enhancing oil recovery. In a reservoir, there are various forms of residual oils caused by the capillary force, viscous force, and some other hydrodynamic effects, which lead to the Jamin effect, and they restrict the oil displacement process. In this study, the morphologies of oil droplets in a capillary tube laden with water and sodium dodecyl sulfate (SDS) solutions are experimentally investigated. The pinning behavior of the oil droplet is observed in the waterflood with a lower velocity, while depinning and rupturing behaviors occur at a higher velocity. Hereto, we build a mechanics model to analyze the evolution of the Jamin effect in a capillary tube with varying cross sections. Using this theoretical model, we obtain the two critical velocities for the depinning and rupture of the oil droplet, which agree with the experimental results. Moreover, we find that oil droplets can more easily pass through the entire capillary tube in SDS solutions compared with water. The time required for oil droplets to pass through the pore throat becomes shorter with the increase of SDS concentration. Therefore, a theoretical model is established to determine the total pressure difference and the minimum applied pressure difference. These findings are beneficial to obtain a deep insight into the detailed oil displacement and achieve a higher oil recovery rate.

Optical trapping is a potent tool for achieving precise and noninvasive manipulation of small objects in a vacuum and liquids. However, due to the substantial disparity between optical forces and interfacial adhesion, target objects should be suspended in fluid environments, rendering solid contact surfaces a restricted area for conventional optical tweezers. In this work, by relying on a single continuous wave (CW) laser, we demonstrate an optical manipulation system applicable for both fluid and solid domains, namely, amphibious hybrid laser tweezers. The key to our system lies in modulating the intensity of the CW laser with duration shorter than the dynamic thermal equilibrium time within objects, wherein strong thermal gradient forces with ∼6 orders of magnitude higher than the forces in optical tweezers are produced, enabling moving and trapping micro/nano-objects on solid interfaces. Thereby, CW laser-based optical tweezers and pulsed laser-based photothermal shock tweezers are seamlessly fused with the advantages of cost-effectiveness and simplicity. Our concept breaks the stereotype that CW lasers are limited to generating tiny forces and instead achieve ultrawide force generation spanning from femto-newtons (10 -15 N) to (10 -6 N). Our work expands the horizon of optical manipulation by seamlessly bridging its applications in fluid and solid environments and holds promise for inspiring optical manipulation techniques to perform more challenging tasks, which may unearth application scenarios in diverse fields such as fundamental physical research, nanofabrication, micro/nanorobotics, biomedicine, and cytology.

In moiré crystals resulting from the stacking of twisted two-dimensional (2D) layered materials, a subtle adjustment in the twist angle surprisingly gives rise to a wide range of correlated optical and electrical properties. Herein, we report the synthesis of supertwisted WS 2 spirals and the observation of giant second harmonic generation (SHG) in these spirals. Supertwisted WS 2 spirals featuring different twist angles are synthesized on a Euclidean or step-edge particle-induced non-Euclidean surface using carefully designed water-assisted chemical vapor deposition. We observed an oscillatory dependence of SHG intensity on layer number, attributed to atomically phase-matched nonlinear dipoles within layers of supertwisted spiral crystals where inversion symmetry is restored. Through an investigation into the twist angle evolution of SHG intensity, we discovered that the stacking model between layers plays a crucial role in determining the nonlinearity, and the SHG signals in supertwisted spirals exhibit enhancements by a factor of 2 to 136 when compared with the SHG of the single-layer structure. These findings provide helpful perspectives on the rational growth of 2D twisted structures and the implementation of twist angle adjustable endowing them great potential for exploring strong coupling correlation physics and applications in the field of twistronics.

Ultrasmall metallic nanoclusters (NCs) protected by surface ligands represent the most promising catalytic materials; yet understanding the structure and catalytic activity of these NCs remains a challenge due to dynamic evolution of their active sites under reaction conditions. Herein, we employed a single-nanoparticle collision electrochemistry method for real-time monitoring of the dynamic electrocatalytic activity of a single fully ligand-protected Au 25 (PPh 3 ) 10 (SC 2 H 4 Ph) 5 Cl 2 2+ nanocluster (Au 25 2+ NC) at a cavity carbon nanoelectrode toward the oxygen reduction reaction (ORR). Our experimental results and computational simulations indicated that the reversible depassivation and passivation of ligands on the surface of the Au 25 2+ NC, combined with the dynamic conformation evolution of the Au 25 9+ core, led to a characteristic current signal that involves "ON-OFF" switches and "ON" fluctuations during the ORR process of a single Au 25 2+ NC. Our findings reinvent the new perception and comprehension of the structure-activity correlation of NCs at the atomic level.

Exploring a novel natural cryoprotectant and understanding its antifreeze mechanism allows the rational design of future sustainable antifreeze analogues. In this study, various antifreeze polysaccharides were isolated from wheat bran, and the antifreeze activity was comparatively studied in relation to the molecular structure. The antifreeze mechanism was further revealed based on the interactions of polysaccharides and water molecules through dynamic simulation analysis. The antifreeze polysaccharides showed distinct ice recrystallization inhibition activity, and structural analysis suggested that the polysaccharides were arabinoxylan, featuring a xylan backbone with a majority of Ara f and minor fractions of Man p , Gal p , and Glc p involved in the side chain. The antifreeze arabinoxylan, characterized by lower molecular weight, less branching, and more flexible conformation, could weaken the hydrogen bonding of the surrounding water molecules more evidently, thus retarding the transformation of water molecules into the ordered ice structure.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by the disruption of the intestinal epithelial barrier. This study described the synthesis and characterization of CCM-Co-ZIF-8, a novel composite material with enzyme-like activities similar to catalase, peroxidase, and superoxide dismutase. CCM-Co-ZIF-8 demonstrated the ability to scavenge reactive oxygen species that play a critical role in UC pathogenesis. In vitro studies using lipopolysaccharide-induced RAW264.7 cells showed that CCM-Co-ZIF-8 exhibited anti-inflammatory activity by promoting the transition of macrophages from an M1 to an M2 phenotype. In vivo experiments using a mouse model of UC demonstrated that CCM-Co-ZIF-8 suppressed the expression of proinflammatory cytokines. These findings suggested that CCM-Co-ZIF-8 might hold promise as a therapeutic strategy for the treatment of UC., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Mine tailings are extremely oligotrophic environments frequently contaminated with elevated As and Sb, making As(III) and Sb(III) oxidation potentially important energy sources for the tailing microbiome. Although they have been proposed to share similar metabolic pathways, a systemic comparison of the As(III) and Sb(III) oxidation mechanisms and energy utilization efficiencies requires further elucidation. In this study, we employed a combination of physicochemical, molecular, and bioinformatic analyses to compare the kinetic and genetic mechanisms of As(III) and Sb(III) oxidation as well as their respective energy efficiencies for fueling the key nutrient acquisition metabolisms. Thiobacillus and Rhizobium spp. were identified as functional populations for both As(III) and Sb(III) oxidation in mine tailings by DNA-stable isotope probing. However, these microorganisms mediated As(III) and Sb(III) oxidation via different metabolic pathways, resulting in preferential oxidation of Sb(III) over As(III). Notably, both As(III) and Sb(III) oxidation can facilitate nitrogen fixation and phosphate solubilization in mine tailings, with Sb(III) oxidation being more efficient in powering these processes. Thus, this study provided novel insights into the microbial As(III) and Sb(III) oxidation mechanisms and their respective nutrient acquisition efficiencies, which may be critical for the reclamation of mine tailings.

In this paper, the effects of surface roughness and wettability on the leakage performance of static seals were highlighted. The results show that the leakage rate is negatively correlated with the contact pressure and positively correlated with surface roughness. Surface wettability affects leakage performance. Leakage retardation is achieved by modifying the roughness and wettability at the interface. The seal interface consists of two oleophobicity surfaces and exhibits an excellent seal performance, of which the leakage reduction is approximately 64%. A theoretical model based on wettability is established to predict the leakage rates under varying wettability conditions, and its validity is confirmed. This research result is expected to be applied in the field of seals and predict the leakage performance of interfaces with different wettabilities to minimize and reduce the leakage of oil in static sealing systems.

More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound LH2-051 with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for LH2-051 , and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of Aβ aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds 37 and 45 are promising preclinical drug candidates for the treatment of AD.

Radiotherapy commonly causes damage to healthy tissues, particularly radiation-induced skin injury (RISI) that affects a significant majority of patients undergoing radiotherapy. Effective treatments for RISI are lacking. This study focuses on the pathogenesis of RISI, which primarily involves oxidative stress. Excessive reactive oxygen species (ROS) generation during radiation induces damage to biological macromolecules, triggering oxidative stress and inflammation. To address this, ergothioneine (EGT), a natural and biocompatibile thiol compound with excellent antioxidant activity, is explored as a potential radiation-protective agent. By utilizing its specific transport and absorption in the skin tissue, as well as its efficient and stable clearance of radiation-induced "ROS storm", EGT is combined with sodium hyaluronate (NaHA) to develop a novel radiation protective dressing suitable for the skin. This EGT-NaHA dressing demonstrates an effective ability to scavenge free radicals and reduce oxidative stress in vitro and in vivo, reducing cellular apoptosis and inflammation. These results demonstrate the protective properties of EGT against RISI, with far-reaching implications for research and development in the field of radioprotection.

This study discovered the impact of high-tunnel (i.e., unheated greenhouse) and open-field production on two industrial hemp cultivars (SB1 and CJ2) over their yield parameters, cannabinoid development, and volatile profiles. Development of neutral cannabinoids (CBD, THC, and CBC), acidic cannabinoids (CBDA, THCA, and CBCA), and total cannabinoids during floral maturation were investigated. The volatile profiles of hemp flowers were holistically compared via HS-SPME-GC/MS. Findings indicated a high tunnel as an efficient practice for achieving greater total weight, stem number, and caliper, especially in the SB1 cultivar. Harvesting high-tunnel-grown SB1 cultivars during early flower maturation could obtain a high CBD yield while complying with THC regulations. Considering the volatile profiles, hemp flowers mainly consisted of mono- and sesquiterpenoids, as well as oxygenated mono- and sesquiterpenoids. Volatile analysis revealed the substantial impact of cultivars on the volatile profile compared to the production systems.

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (T H 1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8 + T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.

Poly(levodopa) nanoparticles (P(l-DOPA) NPs) are another kind of melanin mimetic besides well-established polydopamine nanoparticles (PDA NPs). Due to the presence of carboxyl groups, the oxidative polymerization of l-DOPA to obtain particles was not as efficient as that of dopamine. Several established methods toward P(l-DOPA) NP fabrication do not combine convenience, morphological regularity, size controllability, low cost, and adaptability to metal-free application scenarios. In this work, P(l-DOPA) NPs were successfully prepared in hot water with the assistant of organic quaternary ammonium, due to the extra physical cross-linking mediated by cations. The employed physical interactions could also be affected by quaternary ammonium structure ( i.e. , number of cation heads, length of alkyl chain) to achieve different polymerization acceleration effects. The obtained P(l-DOPA) NPs retained superior photothermal properties and outperformed PDA-based melanin materials. Furthermore, P(l-DOPA) NPs were used in photothermal tumor therapy and showed better efficacy. This study offers new insights into the synthesis of melanin-like materials, as well as new understanding of the interaction between quaternary ammonium and bioinspired polyphenolic materials.

Helicenes represent a class of inherently chiral structures that lack conventional chiral elements, such as stereogenic centers, chiral axes, or plane. The asymmetric synthesis of these helical compounds can be particularly challenging as a result of their pronounced molecular strain. In this study, we report a palladium-catalyzed atroposelective carbon-carbon bond cleavage reaction of helical tertiary alcohols. Because the helical alcohols are configurationally stable, the reaction proceeded through a kinetic resolution pathway, resulting in achieving optically active helicenols alongside the sterically hindered axially chiral products.

Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can function in a coordinated manner to regulate diverse biological processes including insulin and leptin signaling, T-cell activation, and tumor antigen presentation, which makes them potential targets for several therapeutic applications. We have previously demonstrated that the lipidated BimBH3 peptide analogues were a new class of promising PTP1B inhibitors with once-weekly antidiabetic potency. Herein, we chemically synthesized two series of BimBH3 analogues via site-specific modification and studied their structure-activity relationship. The screened analogues S2 , S6 , A2-14 , A2-17 , A2-20 , and A2-21 exhibited an improved PTP1B/TC-PTP dual inhibitory activity and achieved good stability in the plasma of mice and dogs, which indicated long-acting potential. In mouse models of type 2 diabetes mellitus (T2DM), the selected analogues S6 , S7 , A2-20 , and A2-21 with an excellent target activity and plasma stability generated once-weekly therapeutic potency for T2DM at lower dosage (0.5 μmol/kg). In addition, evidence was provided to confirm the cell permeability and targeted enrichment of the BimBH3 analogues. In summary, we report here that site-specific modification and long fatty acid conjugation afforded cell-permeable peptidomimetic analogues of BimBH3 with enhanced stability, in vivo activity, and long-acting pharmacokinetic profile. Our findings could guide the further optimization of BimBH3 analogues and provide a proof-of-concept for PTP1B/TC-PTP targeting as a new therapeutic approach for T2DM, which may facilitate the discovery and development of alternative once-weekly anti-T2DM drug candidates., Competing Interests: The authors declare the following competing financial interest(s): C. L. Zhang is the principal inventor on a series of granted patents covering the BimBH3 analogues reported here., (© 2024 American Chemical Society.)

The complex resonance of dielectric quality factor Q , combined with a capacitance tunability n higher than 3:1 without any dispersion, was achieved in the voltage-tunable interdigital capacitors (IDCs) based on epitaxial Ba 0.8 Sr 0.2 TiO 3 ferroelectric thin films across the microwave L (1-2 GHz), S (2-4 GHz), and C (4-8 GHz) bands at room temperature. The resonant Q and n features were driven by the microwave responses of the ferroelectric nanodomains engineered in the films. To promote their application in space radiation environments, the evolutions of Q and n both as functions of frequency f (1-8 GHz) and applied electric field E (0-240 kV/cm) were systematically investigated under a series of gamma-ray irradiations up to 100 kGy. The robust capacitance tunability was accompanied by the emergence of an additional Q resonance at 2.3 GHz in most post-irradiated devices, which is ascribed to extra polar nanoregions of expanded surface lattices associated with oxygen vacancies induced by irradiations.

Covalent drugs exhibit advantages in that noncovalent drugs cannot match, and covalent docking is an important method for screening covalent lead compounds. However, it is difficult for covalent docking to screen covalent compounds on a large scale because covalent docking requires determination of the covalent reaction type of the compound. Here, we propose to use deep learning of a lateral interactions spiking neural network to construct a covalent lead compound screening model to quickly screen covalent lead compounds. We used the 3CL protease (3CL Pro) of SARS-CoV-2 as the screen target and constructed two classification models based on LISNN to predict the covalent binding and inhibitory activity of compounds. The two classification models were trained on the covalent complex data set targeting cysteine (Cys) and the compound inhibitory activity data set targeting 3CL Pro, respected, with good prediction accuracy (ACC > 0.9). We then screened the screening compound library with 6 covalent binding screening models and 12 inhibitory activity screening models. We tested the inhibitory activity of the 32 compounds, and the best compound inhibited SARS-CoV-2 3CL Pro with an IC 50 value of 369.5 nM. Further assay implied that dithiothreitol can affect the inhibitory activity of the compound to 3CL Pro, indicating that the compound may covalently bind 3CL Pro. The selectivity test showed that the compound had good target selectivity to 3CL Pro over cathepsin L. These correlation assays can prove the rationality of the covalent lead compound screening model. Finally, covalent docking was performed to demonstrate the binding conformation of the compound with 3CL Pro. The source code can be obtained from the GitHub repository (https://github.com/guzh970630/Screen&#95;Covalent&#95;Compound&#95;by&#95;LISNN).

Cartilage repair has been a significant challenge in orthopedics that has not yet been fully resolved. Due to the absence of blood vessels and the almost cell-free nature of mature cartilage tissue, the limited ability to repair cartilage has resulted in significant socioeconomic pressures. Polysaccharide materials have recently been widely used for cartilage tissue repair due to their excellent cell loading, biocompatibility, and chemical modifiability. They also provide a suitable microenvironment for cartilage repair and regeneration. In this Review, we summarize the techniques used clinically for cartilage repair, focusing on polysaccharides, polysaccharides for cartilage repair, and the differences between these and other materials. In addition, we summarize the techniques of tissue engineering strategies for cartilage repair and provide an outlook on developing next-generation cartilage repair and regeneration materials from polysaccharides. This Review will provide theoretical guidance for developing polysaccharide-based cartilage repair and regeneration materials with clinical applications for cartilage tissue repair and regeneration.

In the current years, polydopamine nanoparticles (PDA NPs) have been extensively investigated as an eumelanin mimic. However, unlike natural eumelanin, PDA NPs contain no 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-derived units and may be limited in certain intrinsic properties; superior eumelanin-like nanomaterials are still actively being sought. Levodopa ( l -DOPA) is a natural eumelanin precursor and expected to convert into DHICA and further remain within the final product through covalent or physical interactions. Herein, poly(levodopa) nanoparticles [P( l -DOPA) NPs] were synthesized with the assistance of zinc oxide as a supplement to synthetic eumelanin. This study found that P( l -DOPA) NPs had ∼90% DHICA-derived subunits on their surface and exhibited superior antioxidant activity compared to PDA NPs due to their looser polymeric microstructure. Benefitting from a stronger ROS scavenging ability, P( l -DOPA) NPs outperformed PDA NPs in treating cellular oxidative stress and acute inflammation. This research opens up new possibilities for the development and application of novel melanin-like materials.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Efficient production of cyclodextrins (CDs) has always been challenging. CDs are primarily produced from starch via cyclodextrin glycosyltransferase (CGTase), which acts on α-1,4 glucosidic bonds; however, α-1,6 glucosidic bonds in starch suppress the enzymatic production of CDs. In this study, a glycogen debranching enzyme from Saccharolobus solfataricus STB09 (SsGDE) was utilized to promote the production of β-CD by hydrolyzing α-1,6 glucosidic bonds. The addition of SsGDE (750 U/g of starch) at the liquefaction stage remarkably improved the β-CD yield, with a 43.9% increase. Further mechanism exploration revealed that SsGDE addition could hydrolyze specific branches with less generation of byproducts, thereby promoting CD production. The chain segments of a degree of polymerization ≥13 produced by SsGDE debranching could also be utilized by β-CGTase to convert into CDs. Overall, these findings proposed a new approach of combining SsGDE with β-CGTase to enhance the CD yield.

Lipid nanoparticles (LNPs), a nonviral nucleic acid delivery system, have shown vast potential for vaccine development and disease treatment. LNPs assist mRNA to cross physiological barriers such as cell membranes and endosomes/lysosomes, promoting the intracellular presentation of mRNA. However, the endosome escape efficiency and biosafety of currently commercialized LNPs are still unsatisfactory, resulting in underutilization of mRNA. Herein, we report that fluorinated modification of the 1,2-distearoyl- sn -glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (PEG-DSPE), termed as FPD, in the LNPs can improve the delivery efficiency of mRNA. FPD accounts for only 1.5% of lipids in LNPs but could mediate a 5-fold and nearly 2-fold enhancement of mRNA expression efficiency in B16F10 tumor cells and primary dendritic cells, respectively. Mechanism studies reveal that FPD promotes the cellular internalization of LNPs as well as endosome escape. In vivo studies substantiate that FPD can augment overall mRNA expression at least 3-fold, either by intravenous or intraperitoneal injection, compared to LNPs prepared with nonfluorinated PEG-lipids at a relatively low mRNA dose. Besides, with the introduction of FPD, mRNA expression in the spleen augmented compared to that of the DMG-PEG commercial formulations. Benefiting from a prudent dosage of fluorine, the fluorinated LNPs display favorable biosafety profiles at cellular and zoological levels.

Dityrosine (Dityr) has been detected in commercial food as a product of protein oxidation and has been shown to pose a threat to human health. This study aims to investigate whether Dityr causes a decrease in lactic acid metabolism in the gastrocnemius muscle during endurance exercise. C57BL/6 mice were administered Dityr or saline by gavage for 13 weeks and underwent an endurance exercise test on a treadmill. Dityr caused a severe reduction in motion displacement and endurance time, along with a significant increase in lactic acid accumulation in the blood and gastrocnemius muscle in mice after exercise. Dityr induced significant mitochondrial defects in the gastrocnemius muscle of mice. Additionally, Dityr induced serious oxidative stress in the gastrocnemius muscle, accompanied by inflammation, which might be one of the causes of mitochondrial dysfunction. Moreover, significant apoptosis in the gastrocnemius muscle increased after exposure to Dityr. This study confirmed that Dityr induced oxidative stress in the gastrocnemius muscle, which further caused significant mitochondrial damage in the gastrocnemius muscle cell, resulting in decreased capacity of lactic acid metabolism and finally affected performance in endurance exercise. This may be one of the possible mechanisms by which highly oxidized foods cause a decreased muscle energy metabolism.

The use of Paenibacillus polymyxa as an industrial producer is limited by the lack of suitable synthetic biology tools. In this study, we identified a native sucrose operon in P. polymyxa . Its structural and functional relationship analysis revealed the presence of multiple regulatory elements, including four ScrR-binding sites and a catabolite-responsive element (CRE). In P. polymyxa , we established a cascade T7 expression system involving an integrated T7 RNA polymerase ( T7P ) regulated by the sucrose operon and a T7 promoter. It enables controllable gene expression by sucrose and regulatory elements, and a 5-fold increase in expression efficiency compared with the original sucrose operon was achieved. Further deletion of SacB in P. polymyxa resulted in a 38.95% increase in the level of thermophilic lipase (TrLip) production using the cascade T7 induction system. The results highlight the effectiveness of sucrose regulation as a novel synthetic biology tool, which facilitates exploring gene circuits and enables their dynamic regulation.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H 2 O 2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

Long noncoding RNA (lncRNA) has been shown to participate in adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). In this study, we aimed to investigate the role of lncRNA-LOC646762 in adipogenic differentiation of BMSCs. Transcriptome sequencing revealed a positive correlation between LOC646762 transcription and expression of adipogenic marker genes in adipogenic differentiation. Moreover, LOC646762 overexpression did not negatively impact the cell proliferation of BMSCs. Besides, LOC646762 plays a crucial role in adipogenic differentiation, as evidenced by its positive correlation with adipogenic marker gene expression. Its possible interaction with its proposed target C/EBPβ suggests its involvement in essential pathways governing adipogenesis. Collectively, our study outcomes provide valuable insights into the molecular mechanisms underlying the adipogenic differentiation of BMSCs and lay a strong foundation for further research in regenerative medicine., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Enzymes are an important tool used for signal amplification in biosensing. However, traditional amplification methods based on enzymes are always dependent on their catalytic activities, so their signals fluctuate with the change of microenvironment (e.g., pH and temperature). In this work, we communicate an activity-independent enzyme-powered (AIEP) amplification strategy for biosensing to improve signal stability and fidelity. To verify this hypothesis, the monitoring of oxidative stress during drug-induced liver injury was carried out. Carboxylesterase (CEs), highly expressed in hepatic tissue, was selected as the amplification tool. A CEs configuration-matching fluorophore (CMF) was designed and screened, and a nanobeacon was fabricated by loading CMF within an O 2 •- -responsive polymeric micelle. Since the degradation of the nanobeacon was triggered by O 2 •- , CMF was released to bind with CEs, and the fluorescence was lit by CEs-CMF configuration matching but not catalytic reaction. Results demonstrated that the oxidative stress during drug-induced liver injury could be successfully monitored, and the hepatoprotective effects of repair drugs could be evaluated by cell and in vivo imaging. This strategy is flexible for bioactive molecules by altering the responsive unit and generally accessible for pharmacological evaluation., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by Nanjing University and American Chemical Society.)

Overproduction of reactive oxygen species by damaged mitochondria after ischemia is a key factor in the subsequent cascade of damage. Delivery of therapeutic agents to the mitochondria of damaged neurons in the brain is a potentially promising targeted therapeutic strategy for the treatment of ischemic stroke. In this study, we developed a ceria nanoenzymes synergistic drug-carrying nanosystem targeting mitochondria to address multiple factors of ischemic stroke. Each component of this nanosystem works individually as well as synergistically, resulting in a comprehensive therapy. Alleviation of oxidative stress and modulation of the mitochondrial microenvironment into a favorable state for ischemic tolerance are combined to restore the ischemic microenvironment by bridging mitochondrial and multiple injuries. This work also revealed the detailed mechanisms by which the proposed nanodelivery system protects the brain, which represents a paradigm shift in ischemic stroke treatment.

Oral squamous cell carcinoma (OSCC) has become a global health problem due to its increasing incidence and high mortality rate. Early intervention through monitoring of the diagnostic biomarker levels during OSCC treatment is critical. Extracellular vesicles (EVs) are emerging surrogates in intercellular communication through transporting biomolecule cargo and have recently been identified as a potential source of biomarkers such as phosphoproteins for many diseases. Here, we developed a multiple reaction monitoring cubed (MRM 3 ) method coupled with a novel sample preparation strategy, extracellular vesicles to phosphoproteins (EVTOP), to quantify phosphoproteins using a minimal amount of saliva (50 μL) samples from OSCC patients with high specificity and sensitivity. Our results established differential patterns in the phosphopeptide content of healthy, presurgery, and postsurgery OSCC patient groups. Notably, we discovered significantly increased salivary phosphorylated alpha-amylase (AMY) in the postsurgery group compared to the presurgery group. We hereby present the first targeted MS method with extremely high sensitivity for measuring endogenous phosphoproteins in human saliva EVs.

The combination of immune checkpoint blockade (ICB) and chemotherapy has shown significant potential in the clinical treatment of various cancers. However, circulating regeneration of PD-L1 within tumor cells greatly limits the efficiency of chemo-immunotherapy and consequent patient response rates. Herein, we report the synthesis of a nanoparticle-based PD-L1 inhibitor (FRS) with a rational design for effective endogenous PD-L1 suppression. The nanoinhibitor is achieved through self-assembly of fluoroalkylated competitive peptides that target PD-L1 palmitoylation. The FRS nanoparticles provide efficient protection and delivery of functional peptides to the cytoplasm of tumors, showing greater inhibition of PD-L1 than nonfluorinated peptidic inhibitors. Moreover, we demonstrate that FRS synergizes with chemotherapeutic doxorubicin (DOX) to boost the antitumor activities via simultaneous reduction of PD-L1 abundance and induction of immunogenic cell death in murine colon tumor models. The nano strategy of PD-L1 regulation present in this study is expected to advance the development of ICB inhibitors and overcome the limitations of conventional ICB-assisted chemo-immunotherapy.

Pd/C catalysts have been widely applied in the debenzylation process due to their excellent ability of hydrogenolysis. However, they have been suffering from the problems of agglomeration and loss of active components, which lead to decreased and unstable activity. Thus, it is still a challenge to achieve Pd/C catalysts with high activity and stability. Herein, we propose a strategy for preparing Pd/C catalysts on porous carbon hollow spheres by a microwave discharge method. Due to the high-temperature property and reducibility of microwave discharge, Pd precursors can be rapidly reduced, resulting in well-dispersed Pd nanoparticles with a small size on the carbon carrier. Besides, the matched mesopores in the carbon hollow spheres can anchor Pd nanoparticles and effectively reduce the agglomeration and loss of Pd nanoparticles during the catalytic reaction. As a result, the as-prepared Pd/mesoporous carbon hollow spheres exhibit high and stable activity in the debenzylation reaction.

An atomic-scale understanding of the role of nonperiodic features is essential to the rational design of highly Li-ion-conductive solid electrolytes. Unfortunately, most solid electrolytes are easily damaged by the intense electron beam needed for atomic-resolution electron microscopy observation, so the reported in-depth atomic-scale studies are limited to Li 0.33 La 0.56 TiO 3 - and Li 7 La 3 Zr 2 O 12 -based materials. Here, we observe on an atomic scale a third type of solid electrolyte, Li 1.3 Al 0.3 Ti 1.7 (PO 4 ) 3 (LATP), through minimization of damage induced by specimen preparation. With this capability, LATP is found to contain large amounts of twin boundaries with an unusual asymmetric atomic configuration. On the basis of the experimentally determined structure, the theoretical calculations suggest that such asymmetric twin boundaries may considerably promote Li-ion transport. This discovery identifies a new entry point for optimizing ionic conductivity, and the method presented here will also greatly benefit the mechanistic study of solid electrolytes.

Metallic catalyst modification by organic ligands is an emerging catalyst design in enhancing the activity and selectivity of electrocatalytic carbon dioxide (CO 2 ) reactive capture and reduction to value-added fuels. However, a lack of fundamental science on how these ligand-metal interfaces interact with CO 2 and key intermediates under working conditions has resulted in a trial-and-error approach for experimental designs. With the aid of density functional theory calculations, we provided a comprehensive mechanism study of CO 2 reduction to multicarbon products over aminothiolate-coated copper (Cu) catalysts. Our results indicate that the CO 2 reduction performance was closely related to the alkyl chain length, ligand coverage, ligand configuration, and Cu facet. The aminothiolate ligand-Cu interface significantly promoted initial CO 2 activation and lowered the activation barrier of carbon-carbon coupling through the organic (nitrogen (N)) and inorganic (Cu) interfacial active sites. Experimentally, the selectivity and partial current density of the multicarbon products over aminothiolate-coated Cu increased by 1.5-fold and 2-fold, respectively, as compared to the pristine Cu at -1.16 V RHE , consistent with our theoretical findings. This work highlights the promising strategy of designing the ligand-metal interface for CO 2 reactive capture and conversion to multicarbon products.

Double emulsions are of significant practical value in protecting the core material owing to their multicomponent structure and have thus been applied in various fields, such as food, cosmetics, and drugs. However, the mechanism of double emulsion formation by native starch is not well established. Herein, we demonstrate a facile route to develop type-A, type-B, and type-C double emulsions using native starch and develop an innovative design for a carrier. Interfacial interaction, enthalpy changes of starch, and interfacial properties are key factors governing the formation of double emulsions and controlling the type of double emulsions formed. Therefore, the results of this study provide a better understanding of how and what type of starch-based double emulsions are formed.

Both ozone (O 3 ) and UV/O 3 treatment processes can effectively remove organic matter in the flocculated membrane filtration concentrate from landfill leachate, but the ozonation byproducts (OBPs) generated in the processes remain unknown. Using electrospray ionization-coupled Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS), this study investigated the molecular characteristics of unknown OBPs and their formation mechanisms during the treatment of flocculated nanofiltration concentrate (FNFC) using the O 3 and UV/O 3 processes. The results showed that after being treated by the O 3 and UV/O 3 processes, the average value of the oxygen-to-carbon ratio (O/C avg ) in the FNFC organic matter increased substantially from 0.49 to 0.61-0.64 and 0.63-0.71, respectively, with an O 3 dosage of 13.4-54.4 mg/min. The main OBPs were CHO and CHON compounds, which were mainly produced through oxygenation (+O 2 /+O 3 and -H 2 +O 2 ), oxidative deamination (-NH 3 +O 2 ), decyclopropyl (-C 3 H 4 ), and deisopropyl (-C 3 H 6 ) reactions. The hydroxyl radical ( • OH) can intensify these reactions, resulting in an abundance of OBPs with a high oxidation degree and low molecular weight. OBPs at five m / z values were fragmented and analyzed with tandem mass spectrometry, and abundant hydroxyl groups, carboxyl groups, and carbonyl groups were tentatively identified, presenting a potential toxicity to aquatic organisms. Due to the high molecular diversity of the OBPs in FNFC, their lower Δ G Cox o compared to natural fulvic acid, and potential toxicity, their impact on the water environment should be given more attention.

Efficient Auger recombination (AR) presents a significant challenge for the advancement of colloidal quantum dot (QD)-based devices involving multiexcitons. Here, the AR dynamics of near-infrared Ag 2 Se QDs were studied through transient absorption experiments. As the QD radius increases from 0.9 to 2.5 nm, the biexciton lifetime (τ 2 ) of Ag 2 Se QDs increases from 35 to 736 ps, which is approximately 10 times longer than that of comparable-sized CdSe and PbSe QDs. A qualitative analysis based on observables indicates that the slow Auger rate is primarily attributed to the low density of the final states. The biexciton lifetime and triexciton lifetime (τ 3 ) of Ag 2 Se QDs follow R 3 and R 2.6 dependence, respectively. Moreover, the ratio of τ 2 /τ 3 is ∼2.3-3.2, which is markedly lower than the value expected from statistical scaling (4.5). These findings suggest that environmentally friendly Ag 2 Se QDs can serve as excellent candidates for low-threshold lasers and third-generation photovoltaics utilizing carrier multiplication.

Immunomodulation therapies have attracted immense interest recently for the treatment of immune-related diseases, such as cancer and viral infections. This new wave of enthusiasm for immunomodulators, predominantly revolving around cytokines, has spurred emerging needs and opportunities for novel immune monitoring and diagnostic tools. Considering the highly dynamic immune status and limited window for therapeutic intervention, precise real-time detection of cytokines is critical to effectively monitor and manage the immune system and optimize the therapeutic outcome. The clinical success of such a rapid, sensitive, multiplex immunoanalytical platform further requires the system to have ease of integration and fabrication for sample sparing and large-scale production toward massive parallel analysis. In this article, we developed a nanoplasmonic bioink-based, label-free, multiplex immunosensor that can be readily "written" onto a glass substrate via one-step calligraphy patterning. This facile nanolithography technique allows programmable patterning of a minimum of 3 μL of nanoplasmonic bioink in 1 min and thus enables fabrication of a nanoplasmonic microarray immunosensor with 2 h simple incubation. The developed immunosensor was successfully applied for real-time, parallel detection of multiple cytokines (e.g., interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β)) in immunomodulated macrophage samples. This integrated platform synergistically incorporates the concepts of nanosynthesis, nanofabrication, and nanobiosensing, showing great potential in the scalable production of label-free multiplex immunosensing devices with superior analytical performance for clinical applications in immunodiagnostics and immunotherapy.