Revealing the intrinsic relationship between microbial communities and physicochemical properties during ripening of Xuanwei ham.

To clarify the relationship between microorganisms and physicochemical indicators of Xuanwei ham. Six ham samples for the first, second and third year were selected, respectively. The changes of physicochemical properties, the free fatty acids and microbial communities of Xuanwei ham were investigated by GC-MS and high-throughput sequencing technology. Results showed that scores of colour, overall acceptability, texture, taste and aroma were the highest in the third year sample. With increasing ripening time, moisture content, water activity (Aw), lightness (L*), springiness, and resilience decreased continuously, and yellowness (b*) was the highest in the second year sample. 31 free fatty acids were detected, and unsaturated fatty acids such as palmitoleic acid, oleic acid, and linoleic acid were the major fatty acids. The content of palmitoleic acid, oleic acid and eicosenoic acid increased significantly during processing. At the phylum level, the dominant bacteria were Proteobacteria and Firmicutes, and fungi were Ascomycota. At the genus level, the dominant bacteria were Staphylococcus and Psychrobacter, and fungi were Aspergillus. Correlation analysis showed that water content and Aw were closely related to microorganisms, and most unsaturated fatty acids were significantly correlated with microorganisms. These findings showed that microorganisms played an important role in the quality of Xuanwei ham, and provided a scientific basis for the quality control of Xuanwei ham.

SEGCN: a subgraph encoding based graph convolutional network model for social bot detection.

Message passing neural networks such as graph convolutional networks (GCN) can jointly consider various types of features for social bot detection. However, the expressive power of GCN is upper-bounded by the 1st-order Weisfeiler-Leman isomorphism test, which limits the detection performance for the social bots. In this paper, we propose a subgraph encoding based GCN model, SEGCN, with stronger expressive power for social bot detection. Each node representation of this model is computed as the encoding of a surrounding induced subgraph rather than encoding of immediate neighbors only. Extensive experimental results on two publicly available datasets, Twibot-20 and Twibot-22, showed that the proposed model improves the accuracy of the state-of-the-art social bot detection models by around 2.4%, 3.1%, respectively.

Flavor Characteristics of Umami Peptides from Wuding Chicken Revealed by Molecular Dynamics Simulation.

Wuding chicken is famous for its delicious meat, and HLEEEIK, LDDALR, and ELY were jointly extracted from different processing stages of Wuding chicken. However, whether these peptides can be used as umami supplements is unclear. The sensory evaluation tests were used to study the taste characteristics. The secondary structure of the peptides and their interaction with T1R1/T1R3 were predicted by the circular dichroism spectrum and molecular dynamics simulation. The umami threshold was 0.03125 to 0.06250 mg/mL, all of which could increase umami, saltiness, sweetness, and mask bitterness. Compared with HLEEEIK, the frequency of umami active fragments and the improvement rate of the umami score of EEE increased by 133.35% and 40.09%, respectively. Peptides were dominated by umami taste according to sensory analysis, among which EE-3 (3.18) has the highest umami intensity followed by LR-4 (2.58), HK-7 (2.13), and EY-3 (1.82). The main secondary structure of umami peptides was ß-folding, and Tyr74, Arg323, Arg272, and Gln35 were the key amino acid residues for binding of umami peptides to the receptor. This study further elucidated that the umami intensity of the peptides could be altered by changing the sequence composition of the peptides, which enhanced our understanding of the complex flavor properties of umami peptides.

Non-enzymatic synthesis of C-methylated fluostatins: discovery and reaction mechanism.

Two C-methylated fluostatins (FSTs) B3 (1) and B4 (2) were synthesized from flavin-mediated nonenzymatic epoxide ring-opening reactions of FST C. The structures of 1 and 2 were elucidated by HRESIMS, NMR, and ECD spectroscopic analyses. A subsequent 13C labeling study demonstrated that the C-methyl groups of 1 and 2 were derived from DMSO and enabled the mechanistic proposal of a nonenzymatic C-methylation.

Meroterpenoids from the marine-derived fungus Aspergillus terreus GZU-31-1 exerts anti-liver fibrosis effects by targeting the Nrf2 signaling in vitro.

Six undescribed meroterpenoids aspertermeroterpenes A-F and four known analogues were isolated from the marine-derived fungus Aspergillus terreus GZU-31-1. Their structures were elucidated based on spectroscopic methods and electronic circular dichroism calculations. All meroterpenoids possessed the unique acetyl group at C-11, and also aspertermeroterpene A featured the rare C-14 decarboxylated in DMOA meroterpenoids. In the bioassays, aspermeroterpene B exhibited a potent inhibitory effect on the activation of hepatic stellate cells at the concentration of 5 µM via targeting the Nrf2 signaling. This is the first time reported that aspermeroterpene B as a previously undescribed carbon skeleton of meroterpenoid possessed anti-liver fibrosis effect.

A decade of liver organoids: Advances in disease modeling.

Liver organoids are three-dimensional cellular tissue models in which cells interact to form unique structures in culture. During the past 10 years, liver organoids with various cellular compositions, structural features, and functional properties have been described. Methods to create these advanced human cell models range from simple tissue culture techniques to complex bioengineering approaches. Liver organoid culture platforms have been used in various research fields, from modeling liver diseases to regenerative therapy. This review discusses how liver organoids are used to model disease, including hereditary liver diseases, primary liver cancer, viral hepatitis, and nonalcoholic fatty liver disease. Specifically, we focus on studies that used either of two widely adopted approaches: differentiation from pluripotent stem cells or epithelial organoids cultured from patient tissues. These approaches have enabled the generation of advanced human liver models and, more importantly, the establishment of patient-tailored models for evaluating disease phenotypes and therapeutic responses at the individual level.

Bioinspired and Inflammation-Modulatory Glycopeptide Hydrogels for Radiation-Induced Chronic Skin Injury Repair.

Clinical wound management of radiation-induced skin injury (RSI) remains a great challenge due to acute injuries induced by excessive reactive oxygen species (ROS), and the concomitant repetitive inflammatory microenvironment caused by an imbalance in macrophage homeostasis. Herein, a cutaneous extracellular matrix (ECM)-inspired glycopeptide hydrogel (GK@TAgel ) is rationally designed for accelerating wound healing through modulating the chronic inflammation in RSI. The glycopeptide hydrogel not only replicates ECM-like glycoprotein components and nanofibrous architecture, but also displays effective ROS scavenging and radioprotective capability that can reduce the acute injuries after exposure to irradiation. Importantly, the mannose receptor (MR) in GK@TAgel exhibits high affinity and bioactivity to drive the M2 macrophage polarization, thereby overcoming the persistent inflammatory microenvironment in chronic RSI. The repair of RSI in mice demonstrates that GK@TAgel significantly reduces the hyperplasia of epithelial, promotes appendage regeneration and angiogenesis, and decreased the proinflammatory cytokine expression, which is superior to the treatment of commercial radioprotective drug amifostine. Collectively, the ECM-mimetic hydrogel dressing can protect the tissue from irradiation and heal the chronic wound in RSI, holding great potential in clinical wound management and tissue regeneration.

Are Socialized Services of Agricultural Green Production Conducive to the Reduction in Fertilizer Input? Empirical Evidence from Rural China.

Reducing the use of chemical fertilizers in agricultural production is an inevitable requirement for achieving carbon neutrality and coping with global warming, and it is also an important measure for achieving green and sustainable agricultural development. Furthermore, the development of socialized services of green production provides a new approach to effectively reducing the use of fertilizers. Based on the survey data of 2202 rice growers in Jiangsu Province in 2021, this paper empirically analyzed the effects of socialized services of green production and social network on the reduction in fertilizer application by farmers. The results showed that both the socialized services of green production and social networks could significantly promote the reduction in fertilizer application by farmers. Social networks have a moderating effect between socialized services of green production and reduction in fertilizer application and can enhance the promotion of farmers' adoption of socialized services of green production to reduce the application of fertilizers. With consideration of the potential endogenous problems of the model and the robustness test by replacing the key explanatory variables and the explained variables, all of the results were stable. Therefore, it is emphasized that the government should cultivate the main body of agricultural socialized services, improve the socialized service system of green production, and promote the green development of agriculture by service scale operation. Equally, it is necessary to strengthen the construction of rural social networks for the exchange of fertilization experience and give full play to the positive role of social networks in the reduction in fertilizer application by farmers.

Discovery of a novel anti-obesity meroterpenoid agent targeted subcutaneous adipose tissue.

BACKGROUND: Meroterpenoid furanasperterpene A (T2-3) with a novel 6/6/6/6/5 pentacyclic skeleton was isolated from the Aspergillus terreus GZU-31-1. Previously, we showed that T2-3 possessed significant lipid-lowering effects in 3T3-L1 adipocytes at 5 µM concentration. However, its therapeutic effect in metabolic disease and the underlying mechanisms of action remain unclear. METHODS: High fat diet-induced obesity (DIO) mouse model and 3T3-L1 cell model were used to assess the anti-obesity effects of T2-3. Lipids in the adipocytes were examined by Oil Red O staining. ß-catenin expression was examined by immunofluorescence and Western blotting, its activity was assessed by TOPflash/FOPflash assay. RESULTS: T2-3 possessed potent anti-obesity effects in DIO mice, it significantly reduced body weight and subcutaneous adipose tissue (SAT) mass. Mechanistic studies showed that T2-3 significantly inhibited 3T3-L1 preadipocyte differentiation as indicated by the reduced number of mature adipocytes. The treatments also reduced the expressions of critical adipogenic transcription factors CEBP-α and PPAR-γ in both 3T3-L1 adipocytes and SAT in DIO mice. Interestingly, T2-3 increased the cytoplasmic and nuclear expressions of ß-catenin and the transcriptional activity of ß-catenin in 3T3-L1 adipocytes; the elevated ß-catenin expression was also observed in SAT of the T2-3-treated DIO mice. Indeed, upregulation of ß-catenin activity suppressed adipogenesis, while ß-catenin inhibitor JW67 reversed the anti-adipogenic effect of T2-3. Taken together, our data suggest that T2-3 inhibits adipogenesis by upregulating ß-catenin activity. CONCLUSIONS: Our study is the first report demonstrating meroterpenoid furanasperterpene A as a novel 6/6/6/6/5 pentacyclic skeleton (T2-3) that possesses potent anti-adipogenic effect by targeting ß-catenin signaling pathway. Our findings drive new anti-obesity drug discovery and provide drug leads for chemists and pharmacologists.

Biochemical and structural insights of multifunctional flavin-dependent monooxygenase FlsO1-catalyzed unexpected xanthone formation.

Xanthone-containing natural products display diverse pharmacological properties. The biosynthetic mechanisms of the xanthone formation have not been well documented. Here we show that the flavoprotein monooxygenase FlsO1 in the biosynthesis of fluostatins not only functionally compensates for the monooxygenase FlsO2 in converting prejadomycin to dehydrorabelomycin, but also unexpectedly converts prejadomycin to xanthone-containing products by catalyzing three successive oxidations including hydroxylation, epoxidation and Baeyer-Villiger oxidation. We also provide biochemical evidence to support the physiological role of FlsO1 as the benzo[b]-fluorene C5-hydrolase by using nenestatin C as a substrate mimic. Finally, we resolve the crystal structure of FlsO1 in complex with the cofactor flavin adenine dinucleotide close to the "in" conformation to enable the construction of reactive substrate-docking models to understand the basis of a single enzyme-catalyzed multiple oxidations. This study highlights a mechanistic perspective for the enzymatic xanthone formation in actinomycetes and sets an example for the versatile functions of flavoproteins.

Flavin-enabled reductive and oxidative epoxide ring opening reactions.

Epoxide ring opening reactions are common and important in both biological processes and synthetic applications and can be catalyzed in a non-redox manner by epoxide hydrolases or reductively by oxidoreductases. Here we report that fluostatins (FSTs), a family of atypical angucyclines with a benzofluorene core, can undergo nonenzyme-catalyzed epoxide ring opening reactions in the presence of flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NADH). The 2,3-epoxide ring in FST C is shown to open reductively via a putative enol intermediate, or oxidatively via a peroxylated intermediate with molecular oxygen as the oxidant. These reactions lead to multiple products with different redox states that possess a single hydroxyl group at C-2, a 2,3-vicinal diol, a contracted five-membered A-ring, or an expanded seven-membered A-ring. Similar reactions also take place in both natural products and other organic compounds harboring an epoxide adjacent to a carbonyl group that is conjugated to an aromatic moiety. Our findings extend the repertoire of known flavin chemistry that may provide new and useful tools for organic synthesis.

ECM-mimetic immunomodulatory hydrogel for methicillin-resistant Staphylococcus aureus-infected chronic skin wound healing.

The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment-responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness diabetic and scalding skin by orchestrating a pro-regenerative response indicated by abundant M2-type macrophages, attenuated inflammation, and promoted angiogenesis. Collectively, ECM-mimetic and immunomodulatory glycopeptide hydrogel is a promising multifunctional dressing to reshape the damaged tissue environment without additional drugs, exogenous cytokines, or cells, providing an effective strategy for the repair and regeneration of chronic cutaneous wounds.

Characterization and Identification of a New Daidzein Reductase Involved in (S)-Equol Biosynthesis in Clostridium sp. ZJ6.

(S)-equol (EQ) is an isoflavone with high estrogen-like activity in the human body, and is only produced by some gut bacteria in vivo. It plays an important role in maintaining individual health, however, the dearth of resources associated with (S)-EQ-producing bacteria has seriously restricted the production and application of (S)-EQ. We report here a new functional gene KEC48-07020 (K-07020) that was identified from a chick (S)-EQ-producing bacterium (Clostridium sp. ZJ6, ZJ6). We found that recombinant protein of K-07020 possessed similar function to daidzein reductase (DZNR), which can convert daidzein (DZN) into R/S-dihydrodaidzein (R/S-DHD). Interestingly, K-07020 can reversely convert (R/S)-DHD (DHD oxidase) into DZN even without cofactors under aerobic conditions. Additionally, high concentrations of (S)-EQ can directly promote DHD oxidase but inhibit DZNR activity. Molecular docking and site-directed mutagenesis revealed that the amino acid > Arg75 was the active site of DHD oxidase. Subsequently, an engineered E. coli strain based on K-07020 was constructed and showed higher yield of (S)-EQ than the engineered bacteria from our previous work. Metagenomics analysis and PCR detection surprisingly revealed that K-07020 and related bacteria may be prevalent in the gut of humans and animals. Overall, a new DZNR from ZJ6 was found and identified in this study, and its bidirectional enzyme activities and wide distribution in the gut of humans and animals provide alternative strategies for revealing the individual regulatory mechanisms of (S)-EQ-producing bacteria.

Titanium alloy composited with dual-cytokine releasing polysaccharide hydrogel to enhance osseointegration via osteogenic and macrophage polarization signaling pathways.

Titanium alloy has been widely used in orthopedic surgeries as bone defect filling. However, the regeneration of high-quality new bones is limited due to the pro-inflammatory microenvironment around implants, resulting in a high occurrence rate of implant loosening or failure in osteological therapy. In this study, extracellular matrix-mimetic polysaccharide hydrogel co-delivering BMP-2 and interleukin (IL)-4 was composited with 3D printed titanium alloy to promote the osseointegration and regulate macrophage response to create a pro-healing microenvironment in bone defect. Notably, it is discovered from the bioinformatics data that IL-4 and BMP-2 could affect each other through multiple signal pathways to achieve a synergistic effect toward osteogenesis. The composite scaffold significantly promoted the osteoblast differentiation and proliferation of human bone marrow mesenchyme stem cells (hBMSCs). The repair of large-scale femur defect in rat indicated that the dual-cytokine-delivered composite scaffold could manipulate a lower inflammatory level in situ by polarizing macrophages to M2 phenotype, resulting in superior efficacy of mature new bone regeneration over the treatment of native titanium alloy or that with an individual cytokine. Collectively, this work highlights the importance of M2-type macrophages-enriched immune-environment in bone healing. The biomimetic hydrogel-metal implant composite is a versatile and advanced scaffold for accelerating in vivo bone regeneration, holding great promise in treating orthopedic diseases.

High-Efficiency Photocatalytic Ammonia Synthesis by Facet Orientation-Supported Heterojunction Cu2O@BiOCl[100] Boosted by Double Built-In Electric Fields.

In this work, the advantages of in situ loading, heterojunction construction, and facet regulation were integrated based on the poly-facet-exposed BiOCl single crystal, and a facet-oriented supported heterojunction of Cu2O and BiOCl was fabricated (Cu2O@BiOCl[100]). The photocatalytic nitrogen reduction reaction (pNRR) activity of Cu2O@BiOCl[100] was as high as 181.9 µmol·g-1·h-1, which is 4.09, 7.13, and 1.83 times that of Cu2O, BiOCl, and Cu2O@BiOCl-ran (Cu2O randomly supported on BiOCl). Combined with the results of the photodeposition experiment, X-ray photoelectron spectroscopy characterization, and DFT calculation, the mechanism of Cu2O@BiOCl[100] for pNRR was discussed. When Cu2O directionally loaded on the [100] facet of BiOCl, electrons generated by Cu2O will be transmitted to the [100] facet of BiOCl through Z-scheme electron transmission. Due to the directional separation characteristics of charge in BiOCl, the electrons transmitted from Cu2O are enriched on the [001] facet of BiOCl, which will together with the original electrons generated by pristine BiOCl act on pNRR, thus greatly improving the activity of photocatalytic ammonia synthesis. Thus, a new construction scheme of biphasic semiconductor heterojunction was proposed, which provides a reference research idea for designing and synthesizing high-performance photocatalysts for nitrogen reduction.

Centipeda minima: An update on its phytochemistry, pharmacology and safety.

ETHNOPHARMACOLOGICAL RELEVANCE: Centipeda minima (CM), the dried whole plant of Centipeda minima (L.) A. Braun and Aschers, has been used as a traditional Chinese medicinal herb for thousands of years for the treatments of rhinitis, sinusitis, cough and asthmatic diseases. This review aimed to evaluate the therapeutic potential of CM by summarizing its phytochemistry, pharmacology, clinical application and safety. METHODS: This review summarizes the published studies on CM in the Chinese Pharmacopoeia and literature databases including PubMed, Web of Science, Baidu Scholar, Wiley and China Knowledge Resource Integrated Database (CNKI), as well as the research articles on the phytochemistry, pharmacology, clinical application and safety of CM. RESULTS: A total of 191 compounds have been isolated and identified from CM, including terpenes, flavonoids, sterols, phenols, organic acids and volatile oils. In addition, the pharmacological effects of CM, such as anti-cancer, anti-inflammatory and anti-bacterial activities, have also been evaluated by both in vitro and in vivo studies. The signaling pathways and mechanisms of action underlying the anti-cancer effects of CM have been revealed. Clinical applications of CM mainly include rhinitis and sinusitis, gynecological inflammation, cough, as well as asthma. CONCLUSION: CM is a medicinal herb that possesses many therapeutic effects. Cutting-edge technology and system biology could provide us a more comprehensive understanding of the therapeutic effects, constituting components and toxicity of CM, which are the prerequisites for its translation into therapeutics for various disease treatments.

Polymer Composite Sponges with Inherent Antibacterial, Hemostatic, Inflammation-Modulating and Proregenerative Performances for Methicillin-Resistant Staphylococcus aureus-Infected Wound Healing.

Clinical wound management remains a major challenge due to massive bleeding, bacterial infection, and difficult wound healing after tissue trauma. To simultaneously address these issues, composite polymer sponges for accelerating drug-resistant bacterial infected wound healing are fabricated by facilely mixing sodium polyacrylate (PAAS), double quaternary ammonium salts-conjugated chitosan (QAS-CS), and collagen (COL) in aqueous solution, followed by lyophilization. Composite sponges (PAAS/QAS-CS/COL, PQC) show highly porous microstructures (porosity ≈90%) with moderate compress modulus (≈0.3 MPa), tensile strength (0.004 MPa), and high swelling ratio (≈3500%). Importantly, PQC sponge demonstrates superior hemostasis ability over commercially available CS sponge by inducing rapid hemagglutination, and exhibits significantly better antibacterial activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli by destroying cell membrane and causing the leakage of bioactive components such as potassium ion and ß-galactosidase from treated bacterial. Furthermore, PQC sponge can efficiently promote cell proliferation. Significantly, the sponge greatly expedites the regeneration of MRSA-infected full-thickness skin wound in rabbit by successfully eradicating bacterial infection, and reducing inflammation. PQC sponge also improves both early angiogenesis and blood vessel maturation at the wound site. Overall, this multifunctional sponge is a promising wound dressing for clinical use and holds great potential for rapid clinical translation.

Discovery of an Unexpected 1,4-Oxazepine-Linked seco-Fluostatin Heterodimer by Inactivation of the Oxidoreductase-Encoding Gene flsP.

Fluostatins belong to the atypical angucyclinone aromatic polyketides featuring a distinctive tetracyclic benzo[a]fluorene skeleton. To understand the formation of the heavily oxidized A-ring in fluostatins, a flavin adenine dinucleotide-binding oxidoreductase-encoding gene flsP was inactivated, leading to the production of an unprecedented 1,4-oxazepine-linked seco-fluostatin heterodimer difluostatin I (7) and five new fluostatin-related derivatives, fluostatins T-X (8-12). Their structures were elucidated by mass spectrometry, nuclear magnetic resonance, X-ray diffraction analysis, and biosynthetic considerations. Difluostatin I (7) represents the first example with an A-ring-cleaved 3',4'-seco-fluostatin skeleton. The absolute configuration of fluostatin T (8) was determined by X-ray diffraction analysis. Fluostatin W (11) contains an uncommon isoxazolinone ring. These findings highlight the structural diversity of fluostatins.