Photouranium-Catalyzed C-F Activation Hydroxylation via Water Splitting.

The C-F bond is the strongest covalent single bond (126 kcal/mol) in carbon-centered bonds, in which the highest electronegativity of fluorine (χ = 4) gives rise to the shortest bond length (1.38 Å) and the smallest van der Waals radius (rw = 1.47 Å), resulting in enormous challenges for activation and transformation. Herein, C-F conversion was realized via photouranium-catalyzed hydroxylation of unactivated aryl fluorides using water as a hydroxyl source to deliver multifunctional phenols under ambient conditions. The activation featured cascade sequences of single electron transfer (SET)/hydrogen atom transfer (HAT)/oxygen atom transfer (OAT), highly integrated from the excited uranyl cation. The *UO22+ prompted water splitting under mild photoexcitation, caging the active oxygen in a peroxo-bridged manner for the critical OAT process and releasing hydrogen via the HAT process.

Stabilizing axin leads to optic nerve hypoplasia in a mouse model of autism.

Autism spectrum disorder (ASD) is a group of neurodevelopment disorders characterized by deficits in social interaction and communication, and repetitive or stereotyped behavior. Autistic children are more likely to have vision problems, and ASD is unusually common among blind people. However, the mechanisms behind the vision disorders in autism are unclear. Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice. In this study, we investigated the relationship between vision abnormality and autism using an XAV939-induced mouse model of autism. We found that the mice receiving XAV939 had decreased amplitude of bright light-adaptive ERG. The amplitudes and latency of flash visual evoked potential recorded from XAV939-treated mice were lower and longer, respectively than in the control mice, suggesting that XAV939 inhibits visual signal processing and conductance. Anatomically, the diameters of RGC axons were reduced when Axin2 was stabilized during the development, and the optic fibers had defective myelin sheaths and reduced oligodendrocytes. The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

Zwitterion-Modified MXene Quantum Dot as a Nanocarrier for Traditional Chinese Medicine Sanguinarine Delivery and Its Application for Photothermal-Chemotherapy Synergistic Antibacterial and Wound Healing.

The nanomaterialization of traditional Chinese medicine (TCM) has aroused widespread interest among researchers. Sanguinarine (SAN) is a kind of TCM with good antibacterial properties, which has important applications in anti-infection of wounds. Additionally, the combination of photothermal therapy and chemotherapy can overcome bacterial resistance, further improving bactericidal and wound healing efficiency. In this paper, we prepared an antibacterial agent by loading SAN on the zwitterion-modified MXene quantum dot nanocarrier (SAN@AHEP@Ta4C3), realizing pH/NIR controlled drug release and photothermal/chemotherapy synergistic antibacterial and wound healing. The particle size of SAN@AHEP@Ta4C3 is about 120 nm, and it has a good water solubility and stability. In addition, it also has excellent photothermal conversion performance (η = 39.2%), which can effectively convert light energy into heat energy under near-infrared (NIR) laser irradiation, further promoting drug release and achieving bactericidal effects by synergistic chemotherapy and photothermal therapy. The in vitro and in vivo experiments show that SAN@AHEP@Ta4C3 exhibits an excellent antibacterial effect against Staphylococcus aureus and Escherichia coli, and it can effectively promote the wound healing of mice. Moreover, the SAN@AHEP@Ta4C3 also has good biocompatibility and has no side effects on normal tissue and organs. This work introduces a multifunctional antibacterial agent based on TCM and hot-spot material MXene, which will have considerable application prospects in biomedical fields.

Graphene Oxide-Based Antifungal Pesticide Delivery System for Tobacco Fungal Disease (Tobacco Target Spot) Control.

In recent years, nanocarrier-based pesticide delivery systems have provided new possibilities for the efficient utilization of pesticides. In this research, we developed a hydroxypropyl-ß-cyclodextrin-modified graphene oxide (GO-HP-ß-CD) nanocarrier for pyraclostrobin (Pyr) delivery and studied its application for tobacco target spot disease control. GO-HP-ß-CD has excellent pesticide-loading performance for Pyr (adsorption capacity of 1562.5 mg/g) and good water dispersibility and stability. Besides, GO-HP-ß-CD shows pH-responsive release performance. In addition, GO-HP-ß-CD also has better leaf affinity than Pyr, and it can effectively adhere to the leaf surface after simulated washing. The results of antifungal experiments indicate that GO-HP-ß-CD-Pyr has a good preventive effect on tobacco target spot disease, and its EC50 value is 0.384 mg/L, which is lower than Pyr. Specifically, this nanopesticide formulation does not contain toxic organic solvent or additive, so it has good environmental friendliness. Therefore, we believe that the GO-HP-ß-CD-Pyr nanopesticide has brilliant potential in the prevention and control of tobacco diseases.

Nanomaterials and Nanotechnology in Agricultural Pesticide Delivery: A Review.

Pesticides play a crucial role in ensuring food production and food security. Conventional pesticide formulations can not meet the current needs of social and economic development, and they also can not meet the requirements of green agriculture. Therefore, there is an urgent need to develop efficient, stable, safe, and environmentally friendly pesticide formulations to gradually replace old formulations which have high pollution and low efficacy. The rise of nanotechnology provides new possibilities for innovation in pesticide formulations. Through reasonable design and construction of an environmentally friendly pesticide delivery system (PDS) based on multifunctional nanocarriers, the drawbacks of conventional pesticides can be effectively solved, realizing a water-based, nanosized, targeted, efficient, and safe pesticide system. In the past five years, researchers in chemistry, materials science, botany, entomology, plant protection, and other fields are paying close attention to the research of nanomaterials based PDSs and nanopesticide formulations and have made certain research achievements. These explorations provide useful references for promoting the innovation of nanopesticides and developing a new generation of green and environmentally friendly pesticide formulations. This Perspective summarizes the recent advances of nanomaterials in PDSs and nanopesticide innovation, aiming to provide useful guidance for carrier selection, surface engineering, controlled release conditions, and application in agriculture.

Bilateral Unsymmetrical Disulfurating Reagent Design for Polysulfide Construction.

Polysulfides are significant compounds in life science, pharmaceutical science, and materials science. Therefore, polysulfide construction is in great demand. The controllable sequential installation of groups on both ends of a S-S motif faces an enormous challenge owing to the reversible nature of the covalent S-S bond. A library was established with two divergent mask groups for bilateral unsymmetrical disulfurating reagents (R1O-SS-SO2R2). Sequential coupling with preferential activation of the S-SO2 bond (37.6 kcal/mol) and controllable activation of the S-O bond (54.8 kcal/mol) in the presence of the S-S bond (62.0 kcal/mol) enabled successive reactions at each end of the S-S motif to afford unsymmetrical disulfides and trisulfides, even for the cross-linkage of natural products, pharmaceuticals, peptides, and a protein (bovine serum albumin).

C-SuFEx linkage of sulfonimidoyl fluorides and organotrifluoroborates.

Sulfur(VI) fluoride exchange, a new type of linkage reaction, has excellent potential for application in functional molecule linkage to prepare pharmaceuticals, biomolecules, and polymers. Herein, a C-SuFEx reaction is established to achieve fast (in minutes) linkage between sulfonimidoyl fluorides and aryl/alkyl organotrifluoroborates. Potassium organotrifluoroborates are instantaneously activated via a substoichiometric amount of trimethylsilyl triflate to afford organodifluoroboranes, releasing BF3 as an activating reagent in situ. This sulfur(VI) fluoride exchange technique is capable of forming S(VI)-C(alkyl), S(VI)-C(alkenyl) and S(VI)-C(aryl) bonds, demonstrating its broad scope. Natural products and pharmaceuticals with sensitive functional groups, such as valdecoxib, celecoxib and diacetonefructose, are compatible with this protocol, allowing the formation of diverse sulfoximines.

Exploring the substrate stereoselectivity and catalytic mechanism of nonribosomal peptide macrocyclization in surugamides biosynthesis.

SurE, the first reported penicillin-binding protein-like thioesterase (PBP-like TE), is known as a new off-loading cyclase, which catalyzes heterochiral coupling in nonribosomal peptides (NRPs). However, the structural rationale for substrate stereoselectivity and enzymatic mechanism remains mysterious. Here, computational models, integrating MD simulations and QM/MM methods, unveiled SurE's substrate recognition and catalytic process. An oxyanion hole stabilized the C-terminal D-residue during recognition. Residue R446 anchored the substrate for macrocyclization. A vital hydrogen-bonding network (Y154, K66, N156), verified by mutation results, was responsible for the recognition of N-terminal L-residue and involvement in catalytic process with a calculated 19.4 kcal/mol energy barrier. Four novel-designed peptide precursors were effectively cyclized into cyclopeptides by SurE based on computational analysis. Our results provide a comprehensive understanding of SurE's catalytic mechanism and guiding design of versatile PBP-like TEs for novel macrocyclic NRPs.

From Polyester Plastics to Diverse Monomers via Low-Energy Upcycling.

Polyester plastics, constituting over 10% of the total plastic production, are widely used in packaging, fiber, single-use beverage bottles, etc. However, their current depolymerization processes face challenges such as non-broad spectrum recyclability, lack of diversified high-value-added depolymerization products, and crucially high energy consumption. Herein, an efficient strategy is developed for dismantling the compact structure of polyester plastics to achieve diverse monomer recovery. Polyester plastics undergo swelling and decrystallization with a low depolymerization energy barrier via synergistic effects of polyfluorine/hydrogen bonding, which is further demonstrated via density functional theory calculations. The swelling process is elucidated through scanning electron microscopy analysis. Obvious destruction of the crystalline region is demonstrated through X-ray crystal diffractometry curves. PET undergoes different aminolysis efficiently, yielding nine corresponding high-value-added monomers via low-energy upcycling. Furthermore, four types of polyester plastics and five types of blended polyester plastics are closed-loop recycled, affording diverse monomers with exceeding 90% yields. Kilogram-scale depolymerization of real polyethylene terephthalate (PET) waste plastics is successfully achieved with a 96% yield.

Integrated single-cell and bulk characterization of branched chain amino acid metabolism-related key gene BCAT1 and association with prognosis and immunogenicity of clear cell renal cell carcinoma.

BACKGROUND: The relationship between clear cell renal cell carcinoma (ccRCC) and branched-chain amino acids (BCAA) metabolism has yet to be thoroughly explored. METHODS: The BCAA metabolism-related clusters were constructed using non-negative matrix factorization (NMF). The features of BCAA metabolism in ccRCC were evaluated by building a prognostic model using least absolute shrinkage and selection operator (LASSO) regression algorithm. Real-time quantitative PCR (RT-qPCR) was employed to analyze differential expression of branched-chain amino acid transaminase 1 (BCAT1) between cancer and paracancer tissues and between different cell lines. Cell counting kit-8, wound healing and Transwell chamber assays were conducted to determine changes in proliferative and metastatic abilities of A498 and 786-O cells. RESULTS: Two BCAA metabolism-related clusters with distinct prognostic and immune infiltration characteristics were identified in ccRCC. The BCAA metabolic signature (BMS) was capable of distinguishing immune features, tumor mutation burden, responses to immunotherapy, and drug sensitivity among ccRCC patients. RT-qPCR revealed overexpression of BCAT1 in ccRCC tissues and cell lines. Additionally, single-gene RNA sequencing analysis demonstrated significant enrichment of BCAT1 in macrophages and tumor cells. BCAT1 played tumor-promoting role in ccRCC and was closely associated with immunosuppressive cells and checkpoints. BCAT1 promoted ccRCC cell proliferation and metastasis. CONCLUSIONS: The BMS played a crucial role in determining the prognosis, tumor mutation burden, responses to immunotherapy and drug sensitivity of ccRCC patients, as well as the immune cell infiltration features. BCAT1 was linked to immunosuppressive microenvironments and may offer new sights into ccRCC immunotherapeutic targets.

Nanoplatform based on carbon nanoparticles loaded with doxorubicin enhances apoptosis by generating reactive oxygen species for effective cancer therapy.

At present, due to its wide application and relatively low cost, chemotherapy remains a clinically important cancer treatment option; however, a number of chemotherapeutic drugs have important limitations, such as lack of specificity, high toxicity and side effects, and multi-drug resistance. The emergence of nanocarriers has removed numerous clinical application limitations of certain antitumor chemotherapy drugs and has been widely used in the treatment of tumors with nanodrugs. The present study used carbon nanoparticles (CNPs) as a nanocarrier for doxorubicin (DOX) to form the novel nanomedicine delivery system (CNPs@DOX)was demonstrated by UV-vis and fluorescence spectrophotometry, ζ potential and TEM characterization experiments. The results confirmed the successful preparation of CNPs@DOX nanoparticles with a particle size of 96±17 nm, a wide range of absorption and a negatively charged surface. Furthermore, CNPs@DOX produced more reactive oxygen species and induced apoptosis, and thus exhibited higher cytotoxicity than DOX, which is a small molecule anticancer drug without a nanocarrier delivery system.. The present study provides a strategy for the treatment of tumors with nanomedicine.

Epidemiological changes and molecular characteristics of Brucella strains in Ningxia, China.

Objective: Human brucellosis causes serious public health concerns in Ningxia, China. Methods: This study employed epidemiological, bacteriological, and multiple-locus variable-number tandem repeat analysis (MLVA) methods to conduct an epidemiological investigation, which is necessary for devising tailored control strategies. Results: Between 1958 and 2022, 29,892 cases were reported, with an average annual number of cases and incidence of 467 and 7.1/100,000, respectively. The epidemic situation gradually worsened, with cases escalating from 26 cases in 2005 to 6,292 in 2022, with the incidence rate rising from 0.441 in 2005 to 86.83 in 2022. Geographically, the disease spread from a single affected county in 2004 to encompass all 22 counties in 2022. Yanchi County had the highest incidence, followed by the Hongsibao and Tongxin counties. These data suggest that Brucella infection has become a rampant regional concern in human brucellosis. Between 1958 and 2019, a total of 230 Brucella strains were identified across four studied hosts. These strains comprised four species with 12 biovars, including B. melitensis bv. 1, bv. 2, bv. 3, B. abortus bv. 1, bv. 3, bv. 4, bv. 5, bv. 6, bv. 7, B. suis bv. 1 and bv. 3, and B. canis. These data highlight the high species/biovars and host diversity of the Brucella population, posing a substantial challenge to brucellosis surveillance. There was an apparent transition from multiple species/biovars historically to the current dominance of a single species, B. melitensis, emphasizing the requirement for strengthening surveillance of B. melitensis. Genotypes 42 and 116, constituting 96.2% of the total number of genotypes, predominated in panel 1 and MLVA-11, indicating that all strains belong to the East Mediterranean lineage. MLVA cluster analysis revealed persistent transmission of dominant circulating genotypes, presenting an epidemic pattern characterized primarily by epidemiologically related cases with a few sporadic cases. Strains in this study exhibited high genetic homogeneity with strains from the Northwest, and those from Kazakhstan and Mongolia. Conclusion: The epidemic situation of human brucellosis has gradually worsened; the rampant epidemic of the disease has become a regional concern. The present study highlights that implementing the of targeted surveillance and intervention strategies is urge.

De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes.

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.

XJB-5-131 protects chondrocytes from ferroptosis to alleviate osteoarthritis progression via restoring Pebp1 expression.

Background: Osteoarthritis (OA) is the most common age-related musculoskeletal disease. However, there is still a lack of therapy that can modify OA progression due to the complex pathogenic mechanisms. The aim of the study was to explore the role and mechanism of XJB-5-131 inhibiting chondrocytes ferroptosis to alleviate OA progression. Methods: We treated tert-butyl hydroperoxide (TBHP)-induced ferroptosis of mouse primary chondrocytes with XJB-5-131 in vitro. The intracellular ferroptotic hallmarks, cartilage anabolic and catabolic markers, ferroptosis regulatory genes and proteins were detected. Then we established a mouse OA model via destabilization of the medial meniscus (DMM) surgery. The OA mice were treated with intra-articular injection of XJB-5-131 regularly (2 µM, 3 times per week). After 4 and 8 weeks, we performed micro-CT and histological examination to evaluate the protection role of XJB-5-131 in mouse OA subjects. RNA sequencing analysis was performed to unveil the key downstream gene of XJB-5-131 exerting the anti-ferroptotic effect in OA. Results: XJB-5-131 significantly suppressed TBHP-induced increases of ferroptotic hallmarks (ROS, lipid peroxidation, and Fe2+ accumulation), ferroptotic drivers (Ptgs2, Pgd, Tfrc, Atf3, Cdo1), while restored the expression of ferroptotic suppressors (Gpx4, Fth1). XJB-5-131 evidently promoted the expression of cartilage anabolic and decreased the expression of cartilage catabolic markers. Moreover, intra-articular injection of XJB-5-131 significantly inhibited the expression of Cox2 and Mmp13, while promoted the expression of Col2a1, Gpx4 and Fth1 in DMM-induced mouse articular cartilage. Further, we identified Pebp1 as a potential target of XJB-5-131 by RNA sequencing analysis. The anti-ferroptosis and chondroprotective effects of XJB-5-131 were significantly diminished by Locostatin, a specific antagonist of Pebp1. Conclusion: XJB-5-131 significantly protects chondrocytes from ferroptosis in TBHP-induced mouse primary chondrocytes and DMM surgery-induced OA mice model via restoring the expression of Pebp1. XJB-5-131 is a potential therapeutic drug in the management of OA progression.