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The presence of low-dose radiation (LDR) in the environment has become more prevalent. However, the effect of LDR exposure on the immune system remains elusive. Here, we interestingly found that LDR specifically elevated the percentage of CD4 + IFNγ + Th1 splenocytes, both in vitro and in vivo, without affecting the percentage of CD8 + IFNγ + Tc1 cells and regulatory T cells. A similar phenomenon was found in T cells from peripheral blood. Mechanistically, we found that LDR can induce mitochondrial damage, which stimulated the STING signaling pathway, leading to the enhanced expression of T-bet, the master transcriptional factor of Th1-cell differentiation. The specific STING signal inhibitor can abrogate the effect of LDR on Th1 differentiation, confirming the central role of the STING pathway. To further validate the immunoregulatory role of LDR, we exposed mice with whole body LDR and evaluated if LDR could protect mice against triple-negative breast cancer through enhanced antitumor immunity. As expected, LDR significantly delayed tumor development and promoted cell death. Meanwhile, LDR resulted in increased tumor-infiltrating Th1 cells, while the proportion of Tc1 and Treg cells remained unchanged. Furthermore, the infiltration of antitumor macrophages was also increased. In summary, we revealed that environmental LDR could specifically regulate Th1 T-cell activities, providing critical information for the potential application of LDR in both clinical and nonclinical settings.

Triphenyl phosphate (TPhP) is a widely used organophosphate flame retardant, the health risks of TPhP are a global concern. In this study, we found that prenatal TPhP exposure at human relevant concentration induced hyperlipidemia in male offspring, it increased serum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Placental trophoblast-derived extracellular vesicles (T-EVs) could transport to the fetus through maternal-fetal circulation. TPhP significantly upregulated the protein level of peroxisome proliferator activated receptor γ (PPARγ) in T-EVs. Similar to TPhP, gestational exposure to T-EVs isolated from TPhP exposed mice placentae induced the same effects. While, gestational intervention with GW9662 (PPARγ inhibitor) or GW4869 (EVs secretion inhibitor) would alleviate the disturbed lipid metabolism induced by TPhP. Meanwhile, in vitro experiments verified that TPhP upregulated PPARγ in HTR8/SVneo cells derived EVs, and these EVs promoted adipogenesis in preadipocyte 3T3-L1 cells. Knock down of PPARγ in HTR8/SVneo could alleviate the adipogenensis effects of EVs derived from TPhP exposed HTR8/SVneo cells. These results demonstrate that TPhP exposure induces hyperlipidemia in male offspring by upregulating PPARγ in T-EVs. Our study provides new insights into the metabolic disruptive effects of TPhP, and emphasizes the mediating effects of placental T-EVs on gestational environmental stress in fetal development.

Early childhood caries (ECC) significantly impacts the physical and mental health of children. Saliva stands as a critical model for investigating the pathogenesis of caries disease since it reflects both host and microbial dynamics. However, the specific contributions of salivary host factors to ECC have not been fully understood. In this study, we monitored a prospective cohort of 3-4 year-old healthy children for 12 months, who either stayed caries-free or developed caries. Deep quantitative proteomics analysis of saliva was conducted at both recruitment and end point of the cohort to investigate the molecular mechanisms underlying ECC etiology and identify potential biomarkers for caries prediction. Proteomics analysis identified a total of 2873 proteins and revealed involvement of immune response, dental structure repair, and regeneration, as well as interactions with microorganisms during caries pathogenesis. Characteristic salivary proteins were identified in caries-susceptible children prior to caries development. An ECC prediction panel of proteins keratin 3 (KRT3) and mucin 21 (MUC21) was established and further validated through another independent cohort. This study illuminated the role of the complex salivary microenvironment in caries etiology and offered a prognostic tool for early ECC prediction, thus facilitating the precise prevention and control of ECC to ultimately reduce its incidence.

Type I collagen, a crucial component maintaining the structural integrity and physiological function of various tissues, is widely regarded as one of the most suitable biomaterials for healthcare applications. In this study, shad scales, used for treating ulcers, scalds, and burns in traditional Chinese medicine, were exploited for type I collagen extraction. After self-assembly into hydrogels, the extracted collagen was subsequently freeze-dried to form collagen sponges. The collagen sponge promoted rapid hemostasis, neovascularization, and immune regulation. Additionally, it accelerated the formation of granulation tissue, re-epithelialization, and collagen remodeling at the wound site in full-thickness skin wound rat models. Consequently, the shad scale collagen sponge holds great promise for the treatment of chronic wounds and skin regeneration. Notably, the shad was sourced from sustainably recirculating aquaculture systems (RAS) farms that adhere to the Traceable Management of Animal Products Safety, ensuring that the derived collagen possesses potential in the medical apparatus market.

Due to the inherent challenges posed by the linear coordination of gold(I) complexes, asymmetric gold-catalyzed processes remain challenging, particularly in the atroposelective synthesis of axially chiral skeletons. Except for extremely few examples of intramolecular annulations, the construction of axial chirality via asymmetric gold-catalyzed intermolecular alkyne transformation is still undeveloped. Herein, a gold/HNTf 2 -cocatalyzed asymmetric diazo-alkyne annulation is developed, allowing the atroposelective and divergent synthesis of chiral non- C 2 -symmetric biaryls and arylquinones in generally good to excellent yield (up to 93% yield) and enantioselectivity (up to 99% ee), with broad substrate scope. Notably, this work represents the first gold-catalyzed atroposelective construction in an intermolecular manner. More interestingly, this strategy is successfully extended to the first asymmetric construction of seven-membered-ring atropisomers bearing one carbon-centered chirality in excellent diastereoselectivity and high enantioselectivity (up to 93% ee and 50:1 dr). Remarkably, the utility of this methodology is further illustrated by the successful application of a representative axially chiral ligand in a series of enantioselective reactions. Importantly, the Brønsted acid as a proton-shuttle cocatalyst significantly promotes this asymmetric annulation. Additionally, the origin of enantioselectivity of this annulation and the role of HNTf 2 are disclosed by density functional calculations and control experiments.

The cationic surface charge critically influences the biological functions and therapeutic outcomes of the cancer nanomedicines. However, the basic correlation between the cationic group categories and their therapeutic efficacy has not been elucidated. In this study, cationic polymeric nanoparticles with amino groups (primary, tertiary, and quaternary amines) as the single variable were leveraged to investigate the various effects of amino species for enhanced antitumor chemotherapy. The nanoparticles were constructed from a series of triblock polymers with varying cationic repeating units at the hydrophilic-hydrophobic interface. Our results suggested that quaternary ammonium outperforms its primary and tertiary counterparts in destroying mitochondrial membranes to induce apoptosis, penetrating deep inside the tumor tissue, and damaging tumor vasculatures. As a result, we were able to effectively inhibit tumor growth in mice by a quaternary ammonium conjugate without causing significant toxicity. Our work demonstrated that the chemical structures played vital roles in regulating their biological functions and provided valuable information for designing cationic drug delivery systems.

Protein N-glycosylation is vital in the human liver and influences functions such as lipid metabolism, apoptosis, and inflammation. However, site-specific N-glycosylation patterns and variations in liver biopsy samples between healthy individuals and those with nonalcoholic fatty liver disease (NAFLD) remain incompletely characterized, primarily due to the limitations of current clinical glycoproteomic methods, including a large demand for clinical samples, low efficiency of tissue protein extraction, and a low recovery rate of intact N-glycopeptides (IGPs). To address this issue, we developed GlycoPCT, a quantitative glycoproteomic method based on pressure cycling technology. It enables efficient recovery of IGPs and accurate analysis of trace liver biopsy samples. Our research revealed a total of 4,459 unique IGPs and 361 glycans from 758 glycoproteins. High-mannose type, complex type, fucosylation type, and sialylation type N-glycans were significantly upregulated in the NAFLD group ( p < 0.001, t test). Notably, we also identified 182 upregulated IGPs from 67 proteins ( p < 0.05, FC > 1.50) and 108 downregulated IGPs from 44 proteins ( p < 0.05, FC < 0.67) in the NAFLD group. Furthermore, we highlighted an essential acute phase glycoprotein, alpha-1-acid glycoprotein 1 (A1TA), which is synthesized in the liver and plays a significant role in NAFLD progression. These novel glyco-signatures provide crucial clues for the diagnosis and pathogenesis of NAFLD.

Laminarin oligosaccharides (LOSs) degraded from laminarin present nutritional functions. Laminarinases with high activity and good stability are significant tools for LOS production. OUC-SaLam66, a novel GH128 laminarinase from Streptomyces albus , was heterologously expressed. OUC-SaLam66 harbored a significant activity advantage up to 2294.80 U/mg at 45 °C and pH 4.0; meanwhile, it could preserve 80% activity at 45 °C for 12 h, indicating good stability. Significantly, its residual activity was over 75% after incubating at 100 °C for 1 h. Differential scanning calorimetry and molecular dynamic modeling revealed that its melting point and RMSD average point were 114.83 °C and 0.125 nm at 100 °C, respectively, which further proved its superior stability. Its apparent K m and V max against laminarin were 6.437 mM and 2.5 μg/min/mg, respectively. Hydrolysis products were mainly composed of laminaritriose and laminaribiose. The high activity and thermostability of OUC-SaLam66 make it a promising candidate for LOS preparation.

Moiré superlattices, arising from the periodic Moiré patterns formed by two-dimensional (2D) materials stacked with a slight lattice mismatch, have attracted significant attention due to their unique electronic and optical performances. This review provides an overview of recent advances in Moiré superlattices, highlighting their formation mechanisms, structural characteristics, and emergent phenomena. First, we discuss the theoretical basis and experimental techniques employed in fabricating Moiré superlattices. Then we outline various characterization methods that enable the investigation of the structural and electronic performance of Moiré superlattices at the atomic scale. Afterward, we review the diverse range of emergent phenomena exhibited in Moiré superlattices. These phenomena include the appearance of electronic band engineering, unconventional superconductivity, and topologically nontrivial state. We explore how these phenomena arise from the interplay between the original electronic properties of the constituent materials and the Moiré pattern-induced modifications. Furthermore, we examine the potential applications of Moiré superlattices in fields such as electronics, optoelectronics, and quantum technologies. Finally, we summarize the challenges and directions in Moiré superlattice research, which include exploring more complex Moiré patterns, understanding the role of twist angle and strain engineering, and developing theoretical frameworks to describe the behaviors of Moiré systems. This review aims to provide a comprehensive understanding of the recent progress in Moiré superlattices, shedding light on their formation, performance, and potential applications. The insights gained from this research are expected to pave the way for the design and development of next-generation functional Moiré superlattices.

Piezo1 plays a pivotal role in regulating bone remodeling and homeostasis and has emerged as a promising target for chemical intervention in disuse osteoporosis. Nevertheless, the development of small-molecule Piezo1 agonists is still in its infancy, and highly efficacious Piezo1 agonists are urgently required. In this study, by shedding light on the structural novelty of the canonical Piezo1 agonist Yoda1, we initiated a structural optimization campaign based on the (thiadiazol-2-yl)pyrazine scaffold. A deuterated compound 12a was identified to be the most potent candidate against Piezo1 with an EC 50 value of 2.21 μM, which was over 20-fold more potent than the reference Yoda1. This compound effectively activated Piezo1 and initiated Ca 2+ influx in MSCs and promoted MSC osteogenesis via activating the Ca 2+ -related Erk signaling pathway. Furthermore, compound 12a was found to alleviate disuse osteoporosis with a desirable safety profile in a HU (hindlimb-unloading) rat model, thus warranting it as a potential probe for further investigation.

Basic leucine zipper (bZIP) transcription factors play crucial roles in various biological processes and responses to environmental stresses. However, the functions of the bZIP family in tea plants remain largely unexplored. Here, we identified 74 bZIP genes in tea plants ( Camellia sinensis ) and classified them into 12 phylogenetic groups, supported by analyses of conserved motifs and gene structures. Cis-element analysis provided insights into the potential roles of CsbZIP genes in phytohormone signaling and stress responses. Tissue-specific expression analysis demonstrated differential expression profiles of CsbZIP genes, suggesting their tissue- and stage-specific functions. Additionally, varying expression levels under different abiotic stresses indicated functional divergence of the CsbZIP family during the long-term evolution. Notably, CsbZIP3/42/6 were identified as positive regulators of drought and salt stress responses but negative regulators in response to pathogen infection, and CsbZIP42 could interact with CsbZIP3 and CsbZIP6 in regulating these environmental stresses. This study provides valuable information on potential applications for improving stress tolerance and overall plant health of tea plants.

Many chiral carboxylic acids with α-amino, α-hydroxyl, and α-methyl groups are concurrently present in mammals establishing unique molecular phenotypes and multiple biological functions, especially host-microbiota symbiotic interactions. Their chirality-resolved simultaneous quantification is essential to reveal the biochemical details of physiology and pathophysiology, though challenging with their low abundances in some biological matrices and difficulty in enantiomer resolution. Here, we developed a method of the chirality-resolved metabolomics with sensitivity-enhanced quantitation via probe-promotion (Met-SeqPro) for analyzing these chiral carboxylic acids. We designed and synthesized a hydrazide-based novel chiral probe, ( S )-benzoyl-proline-hydrazide ( S BPH), to convert carboxylic acids into amide diastereomers to enhance their retention and chiral resolution on common C 18 columns. Using the d 5 - S BPH-labeled enantiomers as internal standards, we then developed an optimized ultrahigh-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous quantification of 60 enantiomers of 30 chiral carboxylic acids in one run. This enantiomer-resolved method showed excellent sensitivity (LOD < 4 fmol-on-column), linearity ( R 2 > 0.992), precision (CV < 15%), accuracy (|RE| < 20%), and recovery (80-120%) in multiple biological matrices. With the method, we then quantified 60 chiral carboxylic acids in human urine, plasma, feces, and A549 cells to define their metabolomic phenotypes. This provides basic data for human phenomics and a promising tool for investigating the mammal-microbiome symbiotic interactions.

The era of molecular medicine arose as we began to diagnose and treat diseases based on understanding how genes, proteins, and cells work, providing optimal therapeutic care through molecular profiling. Central to molecular medicine is molecular recognition, which is underpinned by techniques involving omics analysis, gene editing, and targeted agents. Recent advancements in these tools not only expand our understanding of biological processes but also aid in the development of diagnostic and treatment modalities at the molecular level, thus bridging the gap between medical research and clinical applications. This perspective traces the development of molecular tools, highlighting, along the way, their pivotal role in advancing molecular medicine for the global health of people.

Anion exchange in halide perovskites offers prospective approaches to band gap engineering for miniaturized and integrated optoelectronic devices. However, the band engineering at the nanoscale is uncontrollable due to the rapid and random exchange nature in the liquid or gas phase. Here, we report a source-limiting mechanism in solid-state anion exchange between low-dimensional perovskites, which readily gives access to ultralong compositional gradient nanowires (NWs) with lengths of up to 100 μm. The exchanged NWs remain single-crystalline with intact morphology, while the halogen content exhibits an apparent gradient distribution, leading to a tapered energy band profile along a NW. In the dynamic study of anion behavior, it is shown that the spatial stoichiometric composition can be precisely tuned following Fick's law of diffusion. In addition, self-powered, spectrally resolved photodetectors incorporating multiple detection units within a single gradient NW are demonstrated. This work provides a feasible strategy for the realization of perovskite-based ultracompact optoelectronics, imaging sensors, and other miniaturized semiconductor devices.

Plastic waste poses a profound threat to ecosystems and human health, necessitating novel strategies for effective degradation in nature. Here, we present a novel approach utilizing upconversion phosphors as additives to significantly accelerate plastic photodegradation in nature via enhancing ultraviolet (UV) radiation. Pr-doped Li 2 CaGeO 4 (LCGO:Pr) upconversion phosphors readily converting blue light into deep-UV radiation, dramatically improve photodegradation rates for polyethylene (PE) and polyethylene terephthalate (PET) microplastics. In situ spectroscopic studies show that upconversion fluorescence initiates the photophysical cleavage of C-C and C-O bonds in the backbones of PE and PET, resulting in plastic degradation. Moreover, incorporating LCGO:Pr into polypropylene (PP) sheets realizes markedly enhanced photodamage, with the cracking area increasing by nearly 38-fold under simulated sunlight for 10 days. This underscores the potential of employing this approach for the construction of light-driven destructible polymers. Further optimization and exploration of material compatibility hold promise for developing sustainable photodegradable plastics.

Intercalation engineering is a promising strategy to promote zinc-ion storage of layered cathodes; however, is impeded by the complex fabrication routes and inert electrochemical behaviors of intercalators. Herein, an organic imidazole intercalation strategy is proposed, where V 2 O 5 and NH 4 V 3 O 8 (NVO) model materials are adopted to verify the feasibility of the imidazole intercalator in improving the zinc storage capabilities of vanadium-based cathodes. The intercalated imidazole molecules could not only expand interlayer spacing and strengthen structural stability by serving as extra "pillars" but also provide extra coordination sites for zinc storage via the coordination reaction between Zn 2+ and the C═N group. This gives rise to a dual-mode ion storage mechanism and favorable electrochemical performances. As a result, imidazole-intercalated V 2 O 5 delivers a capacity of 179.9 mAh g -1 after 5000 cycles at 20 A g -1 , while the imidazole-intercalated NVO harvests a high capacity output of 170.2 mAh g -1 after 700 cycles at 2 A g -1 . This work is anticipated to boost the application potentials of vanadium-based cathodes in aqueous zinc-ion batteries.

It is crucial to precisely construct metal-organic framework (MOF) sub-nanochannels at the tip of micro/nanopipettes for fundamental research and sensing applications. The quality of the MOF modification plays a significant role in influencing subsequent research, particularly in sensing applications. In this work, we present a precise method of constructing MOF sub-nanochannels at the tip of glass micropipettes, which serve as a universal aptamer-based sensing platform for the selective detection of proteins. In situ scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS) mapping, and fluorescence microscopy results demonstrate that the synthesized MOF (UiO-66) nanocrystals fully block the orifice of glass micropipettes (UiO-66-GMs) without forming any nanometer-scale cracks and remain confined within the geometric boundaries of the orifice. The terminal phosphate-modified aptamer readily binds to the surface of UiO-66-GMs through metal (Zr)-phosphate coordination, ultimately forming the aptamer sensor (Apt-UiO-66-GMs). The selective quantification of proteins is achieved via a decrease in current resulting from protein binding to the aptamer. Our results indicate that the precisely constructed Apt-UiO-66-GMs sensor enables highly selective and sensitive detection of SARS-CoV-2 nucleocapsid protein and holds potential for real sample detection. Furthermore, given the sharp tip of the micropipets and the external sensing interface we have constructed, our aptamer-based sensing platform also opens avenues for single-cell analysis and in vivo sensing.

Surface-enhanced Raman spectroscopy (SERS), with molecular fingerprint information and single-molecule sensitivity, has been widely used for qualitative and quantitative analysis in various fields. Plenty of nanostructured plasmonic materials have been fabricated to achieve high SERS activity. Currently, great difficulty lies in evaluating the SERS performance among substrates, making it difficult to standardize. Addressing this problem, this work proposed the SERS performance factor ( S P F = Δ I S E R S Δ C S E R S / Δ I R a m a n Δ C R a m a n ) as a practically operational parameter to evaluate the sensitivity of SERS substrates. Experimentally, SPF can be obtained by taking the ratio of the slopes (i.e., the sensitivity) for concentration-dependent SERS and normal Raman measurements in the linear range of the intensity response under identical experimental conditions. Theoretically, SPF quantitatively describes the overall contribution to the SERS performance, (i.e., the electromagnetic (EM) enhancement of the SERS substrate and the interfacial interaction between the probe and substrate). The use of SPF as the criterion for evaluating the SERS performance was validated on Au nanoparticles in colloidal and solid states, where the tendency of SPF is consistent with that of the sensitivity of the probe molecules. Derived from the typically used surface enhancement factor EF in which accurate parameters are hardly achievable and different from concentration-dependent analytical enhancement factor AEF, SPF distinguishes itself with a simpler calculation and thereby offers a convenient and reliable protocol for the evaluation of the performance of different SERS substrates, which is very important to the practical application of SERS.

Atomically dispersed catalysts anchored on nitrogen-rich substrates present promising application potential for the persulfate-based advanced oxidation process. Nevertheless, efficient activation efficiency and a clear activated mechanism of persulfate remain challenging in carbon nitride-based single-atom catalysts (SACs). To these, combined with the regulation strategy of metal-ligand section and carrier's architecture, an atomically dispersed Co single-atom catalyst anchored on regular hollow tubular carbon nitride (Co/TCN SAC) herein was devised and utilized to activate permonosulfate. As a result, Co/TCN SACs show excellent catalytic performance for the degradation of common antibiotics. Combined with X-ray absorption fine structure and theory calculation, it is confirmed that superficially anchored CoO 3 sites of the Co 2 N 2 O 2 -CoO 3 unit are the catalytic active center for peroxymonosulfate (PMS) activation. The electrochemical test and in situ electron paramagnetic resonance results demonstrate radical (SO 4 •- and • OH) and nonradical (electron transfer process and 1 O 2 ) paths contributing to the superior catalytic performance. In addition, the catalyst exhibits high reaction efficiency and structural stability considering water quality parameters. Finally, a continuous and efficient device was operated on a laboratory scale, which exhibited satisfactory efficiency in continuously removing electron-rich antibiotics such as tetracycline. This work reveals the atomic-level modulation of cobalt atomic sites on hollow tubular carbon nitride and their structure-activity relationship with persulfate activation.

The immunosuppressive nature of the tumor microenvironment (TME) contributes to radioresistance, thereby impairing the effectiveness of radiotherapy as a therapeutic intervention. Activation through the stimulator of interferon genes (STING) pathway shows potential in modulating immunogenicity. However, the therapeutic efficacy of STING agonists might be restricted by off-target effects and potential cytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous microneedles were employed for precise delivery of the STING agonist MSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration enabled by microneedles, EXOs can be continually released and accumulate within deep residual tumors. Once internalized, these EXOs release the encapsulated MSA-2, facilitating the activation of the STING pathway upon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy elevates the type I interferon level, promotes dendric cell maturation, and modulates the immunosuppressive TME, showing efficient antitumor efficacy in both primary/metastatic tumors. Furthermore, the induction of a potent immune response effectively prevented tumor recurrence. The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

Mitochondrial DNA G-quadruplexes (mtDNA G4s) play potential regulatory roles in mitochondrial functions. Fluorescent probes for imaging mtDNA G4s may provide useful information to unveil their regulating dynamics and functions. However, the existing probes for mtDNA G4s still exhibit short absorption and emission wavelengths and limited sensitivity. Here, we develop a new isaindigotone-derived near-infrared (NIR) fluorogenic probe for imaging mtDNA G4s in live cells and in vivo. Different fluorescent probes are engineered by conjugating the isaindigotone scaffold with varying electron-donating groups. It is shown that the probe ISAP using dimethylaminophenyl as the electron-donating group exhibits near-infrared absorption/emission and a high fluorescence activation fold in response to G4s. Molecular docking simulations reveal that ISAP binds to c -Myc G4 via multiple π-π stacking and hydrogen-bond interaction. Cellular studies show that ISAP exhibits an excellent mitochondrial targeting ability and allows specific imaging of mtDNA G4s. We further employed ISAP to image the dynamics of mtDNA G4s under glycolysis and oxidative stresses in live cells. Its capability to mtDNA G4s in vivo is showcased using a tumor-bearing mice model. This probe may serve as a useful tool to image mtDNA G4s and interrogate their biological roles in living systems.

Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1 H ,3 H )-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound 35j proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats ( T = 3.37 h, 1/2 = 3.37 h, F = 50.24%). Importantly, orally administered 35j significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that 35j remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that 35j is a potent CD73 inhibitor worthy of further development.

The advantages of ammonia as a hydrogen carrier have led to proposals for on-site hydrogen production through its decomposition. Rapid cold start of ammonia decomposition is crucial for applications such as ammonia-powered vehicles, but conventional heating methods are challenged by the high decomposition temperature of ammonia. In this study, we successfully achieved the rapid cold start of ammonia decomposition using Co nanoparticle catalysts driven by magnetic induction heating, demonstrating excellent catalytic performance and stability. The magnetic induction heating-driven ammonia decomposition system was integrated with a hydrogen fuel cell, proving its ability to achieve the cold start of ammonia decomposition within 10 s, as demonstrated by comparative experiments using 75% H 2 -25% N 2 from a gas cylinder as the control. This study provides a deeper understanding of hysteresis heating catalysis, promoting the practical use of ammonia as a hydrogen carrier for rapid hydrogen production in the energy industry.

Creating and unveiling chiral systems is important to the development of new materials and devices. In this study, after depositing prochiral radical molecule 3-carbamoyl-2,2,5,5-tetramethyl pyrroline-1-oxyl (CTPO) on a Au(111) substrate, 2D molecular crystals with two chiralities of CTPO molecules have been discovered. A single CTPO molecule is an achiral molecule in three-dimensional space, and it can form chiral configurations after adsorbing on the substrate. The chiralities of 2D molecular crystals originate from the chiral properties of adsorbed CTPO molecules and their assembling. Molecules with different chiralities are connected with molecular recognition through hydrogen bond interactions. Through density functional theory simulations, the hydrogen bond networks and molecular structures of this system were explored. To gain a further understanding of this system, the electronic property of CTPO/Au(111) was studied with a local density of states (LDOS) characterization. A peculiar LDOS distribution related to the vibrational excitation of the molecules was mapped at the submolecular scale. These results are useful for understanding the nature of chirality formation, 2D molecular crystal construction, and radical molecule applications.

Liquid-liquid phase separation (LLPS) of transactive response DNA-binding protein of 43 kDa (TDP-43), which exerts multiple functions in the splicing, trafficking, and stabilization of RNA, mediates the formation of membraneless condensates with crucial physiological roles, while its aberrant LLPS is linked to multiple neurodegenerative diseases. However, due to the heterogeneous and dynamic nature of LLPS, major gaps remain in understanding the precise intermolecular interactions driving LLPS and how specific mutations alter LLPS dynamics. Here, we investigated the molecular mechanisms underlying the LLPS of the TDP-43 low-complexity domain (LCD) by simulating the dimerization process using all-atom discrete molecular dynamics with microsecond-long simulations. Our results showed that the TDP-43 LCD was intrinsically disordered, with helical structures consistent with prior nuclear magnetic resonance studies. Phase separation propensity was assessed by simulating the dimerization of the TDP-43 LCD and four mutants, showing that A321G, W334G, and M337V inhibited self-association, while G335D promoted it, fully consistent with experimental reports. During the dimerization process, two peptides experienced both elastic and nonelastic collisions, and the self-associated dimer featured both high- and low-contact states. These results suggested that the dimerization process of the TDP-43 LCD was accordingly dynamic and heterogeneous. Additionally, we identified crucial regions containing hydrophobic clusters and aromatic residues in the N-terminus, central region, and C-terminus that were essential for the self-association of the TDP-43 LCD. These residues with high binding affinities can act as stickers to form peptide networks in LLPS. Together, our simulation provides a comprehensive picture of the intermolecular interactions driving the phase separation of the TDP-43 LCD, offering insights into both physiological functions and pathological mechanisms.

Sirtuin 6 (SIRT6), a member of the SIRT family, plays essential roles in the regulation of metabolism, inflammation, aging, DNA repair, and cancer development, making it a promising anticancer drug target. Herein, we present our use of proteolysis-targeting chimera (PROTAC) technology to formulate a series of highly potent and selective SIRT6 degraders. One of the degraders, SZU-B6 , induced the near-complete degradation of SIRT6 in both SK-HEP-1 and Huh-7 cell lines and more potently inhibited hepatocellular carcinoma (HCC) cell proliferation than the parental inhibitors. In preliminary mechanistic studies, SZU-B6 hampered DNA damage repair, promoting the cellular radiosensitization of cancer cells. Our SIRT6 degrader SZU-B6 displayed promising antitumor activity, particularly when combined with the well-known kinase inhibitor sorafenib or irradiation in an SK-HEP-1 xenograft mouse model. Our results suggest that these PROTACs might constitute a potent therapeutic strategy for HCC.

As emerging gain materials, lead halide perovskites have drawn considerable attention in coherent light sources. With the development of patterning and integration techniques, a perovskite laser array has been realized by distributing perovskite microcrystals periodically. Nevertheless, the packing density is limited by the crystal size and the channel gap distance. More importantly, the lasing performance for individual laser units is quite random due to variation of size and crystal quality. Herein an ultracompact perovskite nanoemitter array with uniform emission has been demonstrated. Individual emitters are formed via scattering evanescent components from a shared Fabry-Perot laser, ensuring uniform lasing emission in a unit cell with a side length of 160 nm and lattice constant of 400 nm. And the periodic silicon scatterers do not deteriorate the lasing threshold dramatically. In addition, the surface emitting efficiency increased significantly. The direct integration of a densely packed nanoemitter array with a silicon platform promises high-throughput sensing and high-capacity optical interconnects.

Mealworms ( Tenebrio molitor ) larvae can degrade both plastics and lignocellulose through synergistic biological activities of their gut microbiota because they share similarities in chemical and physical properties. Here, a total of 428 genes encoding lignocellulose-degrading enzymes were screened from the gut microbiome of T. molitor larvae to identify poly(ethylene terephthalate) (PET)-degrading activities. Five genes were successfully expressed in E. coli , among which a feruloyl esterase-like enzyme named Tm Fae-PETase demonstrated the highest PET degradation activity, converting PET into MHET (0.7 mg MHETeq ·h -1 ·mg enzyme -1 ·h TPAeq ·h -1 ·mg enzyme -1 ) at 50 °C. Tm Fae-PETase showed a preference for the hydrolysis of ferulic acid methyl ester (MFA) in the presence of both PET and MFA. Site-directed mutagenesis and molecular dynamics simulations of Tm Fae-PETase revealed similar catalytic mechanisms for both PET and MFA. Tm Fae-PETase effectively depolymerized commercial PET, making it a promising candidate for application. Additionally, the known PET hydrolases Is PETase, FsC, and LCC also hydrolyzed MFA, indicating a potential origin of PET hydrolytic activity from its lignocellulosic-degrading abilities. This study provides an innovative strategy for screening PET-degrading enzymes identified from lignocellulose degradation-related enzymes within the gut microbiome of plastic-degrading mealworms. This discovery expands the existing pool of plastic-degrading enzymes available for resource recovery and bioremediation applications.

Two triangular prismatic cages were synthesized by combining a trishydrazide and two bisformyl precursors in strongly acidic water, where the dynamic nature of hydrazone was turned ON. An anionic guest was used as the template to drive the cage formation. Performing counterion exchange removed both the template and the Brønsted acid. The removal of the latter afforded the cages' kinetic inertness by turning OFF the reversibility of hydrazone. The cages can thus be used for recognizing various guests in water without observable degradation, driven by the hydrophobic effect. Upon being accommodated within the cage cavities, an anthracene derivative was protected from UV-stimulated oxidation, which would occur otherwise in the bulk solution without the protection from the host.

In natural environments, general plant volatiles and herbivore-induced plant volatiles (HIPVs) serve as critical clues for predatory natural enemies in the search for prey. The insect olfactory system plays a vital role in perceiving plant volatiles including HIPVs. In this study, we found that HIPV ( E , E )-4,8,12-trimethyl-1,3,7,11-tridecatetraene (TMTT) and the plant volatile geranyl acetate (GA), two structurally similar chemicals, displayed electrophysiological activities on the antennae of the ladybird Hippodamia variegata , but were only attractive to adult females in behavior. Moreover, mated female ladybirds laid a significantly higher number of eggs on TMTT-treated and GA-treated cotton leaves compared to controls. Screening of female-biased odorant receptors (ORs) from the antennal transcriptomes, performing Xenopus oocytes expression coupled with two-electrode voltage clamp recordings, suggested that HvarOR28 specifically tuned to TMTT and GA. Molecular docking and site-directed mutagenesis revealed that the amino acid residues Tyr143 and Phe81 of HvarOR28 are the key site for binding with TMTT and GA. Furthermore, RNA interference (RNAi) assay demonstrated that HvarOR28 -silenced individuals demonstrated a notable decrease in electrophysiological responses, even female adults almost lost behavioral preference for the two compounds. Thus, it could be concluded that HvarOR28 in H. variegata contributes to facilitating egg laying through the perception of TMTT and GA. These findings may help to develop new olfactory modulators based on the behaviorally active ligands of HvarOR28.

In the process of tumor metastasis, tumor cells can acquire invasion by excessive uptake of nutrients and energy and interact with the host microenvironment to shape a premetastatic niche (PMN) that facilitates their colonization and progression in the distal sites. Pyruvate is an essential nutrient that engages in both energy metabolism and remodeling of the extracellular matrix (ECM) in the lungs for PMN formation, thus providing a target for tumor metastasis treatment. There is a paucity of strategies focusing on PMN prevention, which is key to metastasis inhibition. Here, we design a bioresponsive nanoparticle (HP/GU) based on a disulfide-cross-linked hyperbranched polyethylenimine (D-PEI) core and a hyaluronic acid (HA) shell with a reactive oxygen species (ROS)-sensitive cross-linker between them to encapsulate glucose oxidase (GOX) and a mitochondrial pyruvate carrier (MPC) inhibitor via electrostatic interaction, which reinforces starvation therapy and reduces PMN formation in the lungs via inhibiting pyruvate metabolism. In tumor cells, GOX and MPC inhibitors can be rapidly released and synergistically reduce the energy supply of tumor cells by consuming glucose and inhibiting pyruvate uptake to decrease tumor cell invasion. MPC inhibitors can also reduce ECM remodeling by blocking cellular pyruvate metabolism to prevent PMN formation. Consequently, HP/GU achieves an efficient inhibition of both primary and metastatic tumors and provides an innovative strategy for the treatment of tumor metastases.

Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a series of NO-donating Netarsudil derivatives were designed, synthesized, and their activities in vitro and in vivo were evaluated. Among them, ( S )- 10e released an appropriate amount of NO in aqueous humor in vitro and displayed potent ROCK inhibition. Topical administration of ( S )- 10e significantly lowered intraocular pressure in an acute ocular hypertension rabbit model and protected retinal ganglion cells in a magnetic microbead occlusion mouse model. A metabolism investigation revealed that ( S )- 10e released 7a , a metabolite after NO releasing, and 13 , an active metabolite of ( S )-Netarsudil, in rabbit eyes. Notably, introducing an NO donor moiety attenuated ROCK inhibition-induced ocular irritation in an sGC-independent manner, suggesting that the attenuated conjunctival hyperemia effect of ( S )- 10e is related to the NO-induced protein S-nitrosation of phosphodiesterase 3A (PDE3A). Overall, ( S )- 10e is a promising candidate for glaucoma treatment.

The outstanding optical properties empower Sb 3+ -doped zero-dimensional hybrid metal halides as cutting-edge luminescent materials. In this research, we present an efficient hybrid tin chloride, TEA 2 SnCl 6 :Sb 3+ (TEA = tetraethylammonium), with broad dual emission bands peaking in the blue and orange regions that arise from the singlet and triplet state emissions of [SbCl 5 ] 2- , respectively. TEA 2 SnCl 6 :Sb 3+ demonstrates a high photoluminescence quantum yield (PLQY) of 83.5% under 328 nm excitation, while 358 nm light induces an orange emission with a PLQY of 92.5% and a low thermal quenching behavior (73.9% at 423 K). Benefiting from the appealing luminescence properties of TEA 2 SnCl 6 :Sb 3+ , a full spectrum white light-emitting diode (WLED) device and an anticounterfeiting model were constructed, affirming the potential use of Sb 3+ -doped TEA 2 SnCl 6 hybrid metal halide in versatile application fields.

Synthesis of PbS quantum dots (QDs) with uniform and controllable size is of great importance in realizing functionality manipulation, as well as building advanced devices, and these QDs have been normally synthesized via "bottom-up" colloidal chemistry. However, the problems of complicated techniques and the relative high cost of the "bottom-up" methods still need to be overcome. Herein, we present a facile and cost-effective "top-down" strategy for the production of PbS QDs with controllable sizes and narrow dispersions (4.8% < σ < 7%) based on the sulfuration reaction of highly active lead oxide and oxychloride intermediates. We investigated the two-step reaction mechanism of the QD synthesis. Initially, Pb(OH)Cl undergoes a reaction with oleic acid in the presence of oleylamine as an activator, leading to the formation of active lead oxide/oxychloride intermediates. Notably, this distinctive reaction induces the creation of numerous cracks within the intermediates, thereby augmenting the active sites available for the subsequent sulfuration reactions. In that, the sulfur precursor reacts with the intermediates, resulting in the rapid generation of a substantial number of PbS fragments. Over time, these small fragments undergo "ripening" until reaching the "critical" size threshold. Different from the ones obtained by the traditional "bottom-up" method, our synthesized colloidal QDs exhibit a S-rich surface and are confirmed to be N-type. In addition, size-tunable near-infrared photoluminescence renders these QDs a promising material for various applications.

Advancements in radiative cooling technology have shown significant progress in recent years. However, the limited mechanical properties of most radiative coolers greatly hinder their practical applications, particularly in the context of human cooling fabrics. In this study, we present the fabrication of facile and stretchable radiative coolers with exceptional cooling performance by utilizing the design of porous radiative coolers as guidelines for developing promising elastomer coolers. Subsequently, we employ a simple electrospinning method to fabricate these coolers, resulting in impressive solar reflectivity (∼96.1%) and infrared emissivity (over 95%). During the summer, these coolers demonstrate a maximum temperature drop of ∼9.6 °C. Additionally, the developed coolers exhibit superior hydrophobicity and mechanical properties, with a high strain capacity exceeding 700% and a stress tolerance of over 30 MPa, highlighting their potential for application in automobile textiles and cooling fabrics. Furthermore, we evaluate the radiative cooling performance of stretchable coolers using global-scale modeling, revealing their significant cooling potential across various regions worldwide.

We report a novel system consisting of a redox reaction and a highly efficient reductase-like nanozyme, silica-palladium nanoparticles (Pd@SiO 2 NPs), as a novel detection platform for fluorometric sensing. In a proof-of-concept demonstration using an oligonucleotide as the detection target, a glass fiber-based sensor is fabricated by covalently conjugating two oligo probes, which are complementary to the adjacent segments of the target oligonucleotide, on Pd@SiO 2 NPs and glass fiber, respectively. In the presence of the target oligonucleotide, the two probes are drawn together by the target through sequence-specific hybridization, bringing the Pd@SiO 2 NPs to the glass fiber. When the glass fiber is subsequently immersed in a mixture of resazurin and ammonia borane solution, the Pd@SiO 2 NPs on the glass fiber trigger the catalytic conversion of resazurin (blue, slightly fluorescent) to resorufin (pink, highly fluorescent) with massive signal amplification, indirectly signaling the presence of the target oligonucleotide. We show that the glass fiber-based fluorometric sensor can detect a target oligonucleotide associated with the BRAF mutation linearly in the concentration range of 20 to 400 pM with a detection limit (LOD) of 15 pM and the specificity to differentiate targets with single-base difference. These results demonstrate a new frontier for the development of a sensitive, specific, and inexpensive nonenzyme-based fluorometric sensing platform as an alternative to conventional enzyme-based assays.

Efficient electrochemical energy conversion technologies, such as fuel cells and water electrolyzers, require high current densities to lower the capital cost for large-scale commercialization but are often limited by mass transport. In this study, we demonstrated exceptional electrochemical performances in proton electrolyte membrane water electrolyzers (PEMWEs) creating micropatterned pore channels in the porous transport layer (MPC PTL) using a picosecond laser. This approach yielded an impressive performance of 1.82 V @ 2 A·cm -2 , which is better than commercial PTL of 1.90 V @ 2 A cm -2 . The significant performance enhancement is attributed to the micropatterned porous channel structure, facilitating the efficient expulsion of oxygen bubbles and input of reactant water. This work provides valuable insights for the design of PTL responsible for biphasic transport in electrochemical energy conversion technologies.

Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the "Design" phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.

PbS quantum dots (QDs) are promising for short-wave infrared (SWIR) photodetection and imaging. Solid-state ligand exchange (SSLE) is a low-fabrication-threshold QD solid fabrication method. However, QD treatment by SSLE remains challenging in seeking refined surface passivation to achieve the desired device performance. This work investigates using NaAc in the ligand exchange process to enhance the film morphology and electronic coupling configuration of QD solids. By implementing various film and photodetector device characterization studies, we confirm that adding NaAc with a prominent adding ratio of 20 wt % NaAc with tetrabutylammonium iodide (TBAI) in the SSLE leads to an improved film morphology, reduced surface roughness, and decreased trap states in the QD solid films. Moreover, compared to the devices without NaAc treatment, those fabricated with NaAc-treated QD solids exhibit an enhanced performance, including lower dark current density (<100 nA/cm 2 ), faster response speed, higher responsivity, detectivity, and external quantum efficiency (EQE reaching 25%). The discoveries can be insightful in developing efficient, low-cost, and low-fabrication-threshold QD SWIR detection and imager applications.

As one of the least energy-efficient components in buildings, transparent building envelopes are responsible for approximately 60% of the total energy losses. Although controlling solar transmittance through electrochromic modulation is an effective method for temperature management in these structures, a dynamic control strategy for solar light on curved transparent building envelopes is still lacking. In this study, we introduce a dual-mode flexible electrochromic device based on reversible silver deposition for curved transparent building envelopes. The device operates by reversibly depositing and dissolving silver on a flexible polyethylene terephthalate-indium tin oxide (PET-ITO) substrate, controlled through the application and removal of pulsed voltage. This mechanism enables rapid switching between radiative cooling and solar heating modes, leading to modulation of solar reflectance from 89.1% to 15.7% and solar transmittance from 0.02% to 72.9%. Under approximately 700 W/m 2 of solar irradiance, the device achieves an average temperature reduction of 1.6 °C (with a maximum reduction of 4.3 °C) compared to ambient temperature in radiative cooling mode. In solar heating mode, the device achieves an average temperature increase of 17.1 °C (with a maximum increment of 23.7 °C) compared to ambient temperature. Simulation results show that the dual-mode flexible electrochromic device could offer all-season thermal regulation for curved transparent building envelopes and achieve a maximum of over 50% annual HVAC energy savings.

Exploring and developing new rechargeable halide-ion batteries plays an important role in the advancement and growth of the ion battery family. Here, we systematically explored the feasibility of single-layer MXenes and their hydrogenated derivatives as electrode materials for halide-ion batteries via first-principles theory. The calculated results indicate that halide ions (T ions) can be stably and efficiently adsorbed on the surfaces of M 2 X and M 2 XH 2 , with theoretical specific capacities ranging from 227 to 497 mAh g -1 . The diffusion barriers of the T ion on MXenes are from 0.55 to 0.10 eV, comparable to those of the Li ion in graphite and LiCoO 2 . The electronegativity of halide anions displays significant impacts on their discharge voltage plateaus on M 2 X, with the highest voltage up to 5.60 V for the F ion. As a comparison, the hydrogenation of M 2 XH 2 with less surface activity raises a 2-3 V voltage reduction. All MXene-based full cells of T x Ti 2 C|T y Ti 2 CH 2 (where x = 0-2 and y = 2-0) and T x Ti 2 N|T y Ti 2 NH 2 (where x = 0-2 and y = 2-0) demonstrated high full battery specific energies for F-, Cl-, and Br-ion batteries, up to 462 Wh kg -1 . These results demonstrate the potential of new halide-ion battery designs, paving the way for future research and innovation in battery technology.

The natural compound ( R )-(-)-mellein exhibits antiseptic and fungicidal activities. We investigated its biosynthesis using the polyketide synthase encoded by SACE&#95;5532 ( pks8 ) from Saccharopolyspora erythraea heterologously expressed in Streptomyces albus B4, a chassis chosen for its fast growth, genetic manipulability, and ample large short-chain acyl-CoA precursor supply. High-level heterologous ( R )-(-)-mellein yield was achieved by pks8 overexpression and duplication. The precursor supply pathways were strengthened by overexpression of SACE&#95;0028 (encoding acetyl-CoA carboxylase) and four genes involved in β-oxidation ( fadD , fadE , fadB , and fadA ). Cell growth inhibition by ( R )-(-)-mellein production at high concentration was relieved by in situ adsorption using Amberlite XAD16 resin. The final strain, B4mel12, produced ( R )-(-)-mellein at 6395.2 mg/L in shake-flask fermentation. Overall, this is the first report of heterologous ( R )-(-)-mellein synthesis in microorganism with a high titer. ( R )-(-)-mellein prototype in this study opens a possibility for the overproduction of valuable melleins in S. albus B4.

All-solid-state lithium-ion batteries (ASSLIBs) using sulfide electrolytes and high-capacity alloy-type anodes have attracted sizable interest due to their potential excellent safety and high energy density. Encapsulating insulating red phosphorus (P) inside nanopores of a carbon matrix can adequately activate its electrochemical alloying reaction with lithium. Therefore, the porosity of the carbon matrix plays a crucial role in the electrochemical performance of the resulting red P/carbon composites. Here, we use zeolite-templated carbon (ZTC) with monodisperse micropores and mesoporous carbon (CMK-3) with uniform mesopores as the model hosts of red P. Our results reveal that micropores enable more effective pore utilization for the red P loading, and the P@ZTC material can achieve a record-high content (65.0 wt %) of red P confined within pores. When used as an anode of ASSLIBs, the P@ZTC electrode delivers an ultrahigh capacity of 1823 mA h g -1 and a high initial Coulombic efficiency of 87.44%. After 400 deep discharge-charge cycles (running over 250 days) at 0.2 A g -1 , the P@ZTC electrode still holds a reversible capacity of 1260 mA h g -1 (99.92% capacity retention per cycle). Moreover, a P@ZTC||LiNi 0.8 Co 0.1 Mn 0.1 O 2 full cell can deliver a reversible areal capacity of over 3 mA h cm -2 at 0.1C after 100 cycles.