Photoexcited Ru single-atomic sites for efficient biomimetic redox catalysis.

The unsatisfactory catalytic activity of nanozymes owing to their inefficient electron transfer (ET) is the major challenge in biomimetic catalysis-related biomedical applications. Inspired by the photoelectron transfers in natural photoenzymes, we herein report a photonanozyme of single-atom Ru anchored on metal-organic frameworks (UiO-67-Ru) for achieving photoenhanced peroxidase (POD)-like activity. We demonstrate that the atomically dispersed Ru sites can realize high photoelectric conversion efficiency, superior POD-like activity (7.0-fold photoactivity enhancement relative to that of UiO-67), and good catalytic specificity. Both in situ experiments and theoretical calculations reveal that photoelectrons follow the cofactor-mediated ET process of enzymes to promote the production of active intermediates and the release of products, demonstrating more favorable thermodynamics and kinetics in H2O2 reduction. Taking advantage of the unique interaction of the Zr-O-P bond, we establish a UiO-67-Ru-based immunoassay platform for the photoenhanced detection of organophosphorus pesticides.

Amino-Ligand-Coordinated Dicopper Active Sites Enable Catechol Oxidase-Like Activity for Chiral Recognition and Catalysis.

Developing highly active and selective advanced nanozymes for enzyme-mimicking catalysis remains a long-standing challenge for basic research and practical applications. Herein, we grafted a chiral histidine- (His-) coordinated copper core onto Zr-based metal-organic framework (MOF) basic backbones to structurally mirror the bimetal active site of natural catechol oxidase. Such a biomimetic fabricated process affords MOF-His-Cu with catechol oxidase-like activity, which can catalyze dehydrogenation and oxidation of o-diphenols and then transfer electrons to O2 to generate H2O2 by the cyclic conversion of Cu(II) and Cu(I). Specifically, the elaborate incorporation of chiral His arms results in higher catalytic selectivity over the chiral catechol substrates than natural enzyme. Density functional theory calculations reveal that the binding energy and potential steric effect in active site-substrate interactions account for the high stereoselectivity. This work demonstrates efficient and selective enzyme-mimicking catalytic processes and deepens the understanding of the catalytic mechanism of nanozymes.

[Study on mechanism of Aconitum pendulum in treating rheumatoid arthritis based on toxicity efficacy evaluation and metabonomics].

The study aims to investigate the effects and potential mechanism of raw and processed Aconitum pendulum Busch on rheumatoid arthritis(RA) and analyze their toxicity attenuating and efficacy retaining effects. The bovine type Ⅱ collagen-induced arthritis(CIA) rat model was established. The weight, cardiac index, immune organ index, and arthritis index of the rats were recorded and calculated after administration. ELISA was used to measure the expressions of creatine kinase(CK), cardiac troponin T(cTnT), and multiple factors. The pathological morphological changes in heart tissue and ankle joint tissue were observed by hematoxylin-eosin staining. Connexin 43(Cx43) expression in the hearts of CIA rats was detected via immunohistochemical method. The levels of endogenous metabolites in the serum of CIA rats were detected by UPLC-Q-TOF-MS. Potential biomarkers were screened, and related metabolic pathways were analyzed. The results showed that raw A. pendulum could induce local myocardial fiber degeneration and necrosis, increase the cardiac index, decrease the average positive area of Cx43 expression significantly, and increase the expressions of CK and cTnT in cardiac tissue of rats. Meanwhile, raw A. pendulum could decrease the immune organ index, interleukin-6(IL-6), and other inflammatory cytokine contents in the serum and improve the damaged synovium and joint surface of CIA rats, with toxicity and efficacy coexisting. The Zanba stir-fired A. pendulum could reduce the index of arthritis, immune organ index, and content of IL-6 and inflammatory cytokines in serum and improve damaged synovium and joint surface of CIA rats with no obvious cardiac toxicity, showing significant toxicity attenuating and efficacy retaining effects. A total of 19 potential biomarkers of raw A. pendulum and Zanba stir-fired A. pendulum against RA were screened by serum metabolomics, including glycerophospholipid metabolism, glycine, serine, and threonine metabolism, arginine and proline metabolism, and steroid hormone synthesis. In conclusion, Xizang medicine A. pendulum is preventive and curative for RA. Raw A. pendulum has certain cardiotoxicity, and Zanba stir-fired A. pendulum has significant toxicity attenuating and efficacy retaining effects. The anti-RA mechanism may be related to the regulation of glycerophospholipid and amino acid metabolism.

Cluster of Donor-Derived Cryptococcosis after Liver and Kidney Transplantation.

Cryptococcosis infection after transplantation is easily overlooked or misdiagnosed. We report a cluster of donor-derived cryptococcosis infection in liver and kidney transplant recipients from the same donor in China. Infections occurred within 1 month after transplantation, and were confirmed by using biopsies and blood tests.

Ultrathin Ruthenium Nanosheets with Crystallinity-Modulated Peroxidase-like Activity for Protein Discrimination.

Noble-metal-based nanozymes have attracted great interest as enzyme mimics because of their unique properties. To modulate the performance and meet the requirements of practical biosensing applications, phase engineering is promising for the design of novel noble-metal-based nanomaterials. Herein, a simple salt-assist strategy was employed for the synthesis of Ru nanosheets (NSs) with the controlled crystalline degree. The crystalline degree plays a significant role in tuning peroxidase-like activity by optimizing the affinity toward the catalytic substrate. Furthermore, the inhibition effect of mercapto molecules on the peroxidase-like activity of Ru NSs was investigated. As a proof-of-concept, the Ru NSs-based colorimetric sensing arrays were developed to distinguish mercapto molecules, and five model molecules were well classified according to the different inhibition effects. Given the complexity of practical conditions, the sensing array was further applied to discriminate proteins possessing rich mercapto groups. This work not only provides an effective strategy for the design of highly active nanozymes but also achieves promising sensing arrays for practical needs.

Tuning the Ratio of Pt(0)/Pt(II) in Well-Defined Pt Clusters Enables Enhanced Electrocatalytic Reduction/Oxidation of Hydrogen Peroxide for Sensitive Biosensing.

Rational design and construction of advanced sensing platforms for sensitive detection of H2O2 released from living cells is one of the challenges in the field of physiology and pathology. Noble metal clusters are a kind of nanomaterials with well-defined chemical composition and special atomic structures, which have been widely explored in catalysis, biosensing, and therapy. Compared with noble metal nanoparticles, noble metal clusters exhibit great potential in electrochemical biosensing due to their high atom utilization efficiency and abundant reactive active sites. Herein, Pt nanoclusters anchored on hollow carbon spheres (PtNCS/HCS) were successfully prepared for sensitive detection of H2O2. By tuning the ratio of Pt(0)/Pt(II) at different annealing temperatures, the optimized PtNCS/HCS-550 showed higher H2O2 reduction and oxidation catalytic activities than other control samples. Density functional theory calculations revealed that H2O2*can be better activated and dissociated in the Pt0II model featured with the co-existence of Pt(0)/Pt(II) and the key intermediates OOH*/OH* have a stronger interaction with the Pt0II model. As a concept application, the electrochemical biosensing platform was successfully applied to sensitive detection of H2O2 released from the cells.

Direct and indirect effects of fenoxycarb on freshwater systems dominated by Neocaridina palmata (Decapoda: Atyidae) and macrophyte Ceratophyllum demersum.

Few studies have been conducted with regard to the effects of insecticides on population dynamics of shrimps and associated groups such as macrophytes, phytoplankton, microorganisms etc. In the present study, effects of a single application of fenoxycarb were tested using indoor freshwater systems dominated by Neocaridina palmata and Ceratophyllum demersum (Dicotyledons: Ceratophyllales). The no observed effect concentration (NOEC) and lowest observed effect concentration (LOEC) for the N. palmata, as scaled by liberated chitobiase, were 6.48 µg/L and 27.76 µg/L, and the dose-related effect lasted for 14 days. Results of principal components analysis (PCA) and that of principal response curves (PRC) method showed that the biomass of C. demersum and concentrations of chlorophyll-a were suppressed, while the concentrations of phycocyanin were promoted. Illumina high-throughput sequencing was adopted to determine the diversity of bacteria and fungi in the media. Result of PCA and PRC showed that the fenoxycarb promoted photosynthetic bacteria (e.g. Cyanobacteria and Rhodobacterales) and suppressed groups involved in nitrogen and sulfur the transformation (e.g. Flavobacterium, hgcI_clade, Cystobasidium, Rhodotorula and Rhizobiales). Promotion in pathogen such as Pseudomonas and Cercozoa and suppression in beneficial taxa such as Novosphingobium and Rhodotorula were also sighted. Result of study suggested a water quality deterioration due to fenoxycarb applications.

Cascading effects caused by fenoxycarb in freshwater systems dominated by Daphnia carinata and Dolerocypris sinensis.

To evaluate the aquatic hazards of the insect juvenile hormone analogue fenoxycarb, a single application (0, 48.8, 156.3, 500, 1600, and 5120 µg/L) of it was done in indoor freshwater systems dominated by Daphnia carinata (daphnid) and Dolerocypris sinensis (ostracoda). The responses of zooplankton (counted by abundance and the activity and immuno-reactive content of free N-Acetyl-ß-D-glucosaminidase (NAGase)), phytoplankton (counted by chlorophyll and phycocyanin), planktonic bacteria and fungi, and some water quality parameters were investigated in a period of 35 d. Results of the study showed that the ostracoda was more sensitive than daphnid, with time-weighted average (TWA)-based no observed effect concentrations (NOECs) to be 8.45 and 12.66 µg/L in systems without humic acid addition (HA-) and to be 6.37 and 9.54 µg/L in systems with humic acid addition (HA+). The duration of treatment-related effects in the ostracoda population was longer than the daphnid population (21 vs. 14 days). Besides, the data analysis indicated that the toxicity of fenoxycarb was significantly enhanced in the HA+ systems. Owing to the reduced grazing pressure, the concentrations of chlorophyll and phycocyanin increased in the two highest treatments. The increase in photosynthesis along with a reduced animal excretion led to an increase in pH and a decrease in nutrient contents. These changes seemed to have an effect on the microbial communities. For example, the abundances of some opportunistic pathogens of aquatic animals (e.g. Aeromonas and Cladosporium) and organic-pollutant-degrading microorganisms (e.g. Ancylobacter and Azospirillum) increased significantly in microbial communities, but the abundances of Pedobacter, Candidatus Planktoluna, and Rhodobacter (photosynthetic bacteria) markedly decreased. This study provides useful information to understand the ecotoxicological impacts of fenoxycarb at the population and community levels while integrating the effects of HA on toxicity.

Tumor-associated lymphangiogenesis predicts unfavorable prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Tumor-associated lymphangiogenesis is considered significant in number of solid malignancies. However, its impact on prognosis of intrahepatic cholangiocarcinoma (ICC) after resection remains further confirmation. Herein, we conducted this study to evaluate prognostic impact of tumor-associated lymphangiogenesis in patients with ICC. METHODS: Extent of tumor-associated lymphangiogenesis of ICC was evaluated by quantifying microlymphatic vessel density (MLVD) from immunohistochemical staining of a lymphatic endothelial-specific antibody (podoplanin). Clinicopathological characteristics were comprehensively analyzed to identify MLVD-associated factors. The patients were stratified into high and low MLVD groups according to the distinctive correlation between the MLVD and overall survival using the Spearman's correlation test. Kaplan-Meier estimation was performed to confirm prognostic impact of MLVD in patients with ICC. Univariate and multivariate analyses were performed using the Cox proportional hazard model. RESULTS: The MLVD between 4 to 12 counts showed inverse proportion to the overall survival (Spearman's r = - 0.66; 95% confidence interval [CI], - 0.82 to - 0.39; p <  0.0001), which was set as a cut-off for the high MLVD group, whereas the MLVD between 13 to 25 showed no correlation to the overall survival (r = - 0.11; 95% CI, - 0.38 to 0.19; p = 0.4791). The high MLVD group showed more frequent lymph node metastasis (p <  0.001) and were more likely to suffer from recurrence of the tumor compared to the low MLVD group (p <  0.001). The high MLVD was found to be independently associated with reduced overall and recurrence-free survival. The 5-year overall survival of the patients with high MLVD was significantly lower compared to those with low MLVD (0% vs 48%). CONCLUSIONS: Our study reveals that tumor-associated lymphangiogenesis is significantly associated with increased lymphatic metastasis, recurrence of the tumor, and reduced overall survival in patients with ICC, thus providing guidance when estimating postresection prognosis.

Semisynthesis of Chondroitin Sulfate E Tetrasaccharide from Hyaluronic Acid.

Chondroitin sulfate (CS) is crucial glycosaminoglycan that regulates key functions of the nervous system. CS-E is one of the key CS subtypes that modulates the biological function of CS. Herein, N-protecting-group-free semisynthesis of CS-E tetrasaccharide is reported using hyaluronic acid as a readily available starting material. The synthetic process utilizes the enzymatic degradation and selective C4 hydroxyl group conversion as key approaches for direct construction of the CS tetrasaccharide precursor, which furnishes the neuroactive CS-E tetrasaccharide in 15 steps.

Risk stratification system to predict recurrence of intrahepatic cholangiocarcinoma after hepatic resection.

BACKGROUND: Previous nomograms for intrahepatic cholangiocarcinoma (ICC) were conducted to predict overall survival, which could be influenced by various factors. Herein, we conducted our nomogram to predict recurrence of the tumor only after hepatic resection. METHODS: The nomogram was established with prognostic factors for the relapse-free survival (RFS) analyzed from our single center cohort and was evaluated by comparing with the American Joint Committee on Cancer (AJCC) staging system for the predictive accuracy. RESULTS: Seropositivity of hepatitis B surface antigen (hazard ratio [HR], 0.505; 95% confidence interval [CI], 0.279 to 0.914; P = 0.024), tumor size of larger than 5 cm (HR, 1.947; 95% CI, 1.177 to 3.219; P = 0.009), Child-Pugh score of B (HR, 3.067; 95% CI, 1.293 to 7.275; P = 0.011), and lymph node metastasis (HR, 2.790; 95% CI, 1.628 to 4.781; P < 0.001) were found to be independent prognostic factors that significantly affected RFS. The calibration curve for the prediction revealed excellent agreement between estimation by our stratification system and actual RFS. The concordance C index of the nomogram (0.71; 95% CI, 0.65 to 0.77) revealed to be significantly higher than the AJCC staging system (0.66; 95% CI, 0.60 to 0.72). In the validation cohort, our risk stratification system (C-index 0.65; 95% CI, 0.59 to 0.71) also revealed more precise prediction than the AJCC staging system (C-index, 0.57; 95% CI, 0.50 to 0.64). CONCLUSIONS: Our nomogram could more accurately predict recurrence of ICC after hepatic resection than the AJCC staging system.

[Antiplatelet aggregation bioactivity of Polygoni Multiflori Radix with chemical fingerprints and spectrum-effect correlation analysis].

To explore the active substance of antiplatelet aggregation of Polygoni Multiflori Radix by using chemical fingerprints and antiplatelet aggregation bioactivity test for spectrum-effect correlation analysis. The Polygoni Multiflori Radix was tested by antiplatelet aggregation in vitro, and the results showed that 50% aqueous ethanol extract of Polygoni Multiflori Radix had more potent antiplatelet aggregation effect than 10% or 90% aqueous ethanol extract, and ultrasonic extraction was superior to refluxing extraction in the aspect of antiplatelet aggregation. The antiplatelet aggregation bioactivity of the different Polygoni Multiflori Radix extracts was evaluated and the results showed that the inhibition rate was 32.03%-74.56%. Spectrum-effect correlation analysis indicated that trans-stilbene glucoside, cis-stilbene glucoside and catechinic acid had higher correlation coefficient and they were 0.963 (P<0.01), 0.902 (P<0.01) and 0.656 (P<0.05) respectively; furthermore, all of the above three compounds demonstrated significant antiplatelet aggregation bioactivities. Considering their content difference in Polygoni Multiflori Radix, we calculated the relative active contributions, and the results suggested that trans-stilbene glucoside was the main active substance of Polygoni Multiflori Radix in the aspect of antiplatelet aggregation in vitro.

Bifunctional enzyme-mimicking metal-organic frameworks for sensitive acetylcholine analysis.

The development of nanomaterials with multi-enzyme-like activity is crucial for addressing challenges in multi-enzyme-based biosensing systems, including cross-talk between different enzymes and the complexities and costs associated with detection. In this study, Pt nanoparticles (Pt NPs) were successfully supported on a Zr-based metal-organic framework (MOF-808) to create a composite catalyst named MOF-808/Pt NPs. This composite catalyst effectively mimics the functions of acetylcholinesterase (AChE) and peroxidase (POD). Leveraging this capability, we replaced AChE and POD with MOF-808/Pt NPs and constructed a biosensor for sensitive detection of acetylcholine (ACh). The MOF-808/Pt NPs catalyze the hydrolysis of ACh, resulting in the production of acetic acid. The subsequent reduction in pH value further enhances the POD-like activity of the MOFs, enabling signal amplification through the oxidation of a colorimetric substrate. This biosensor capitalizes on pH variations during the reaction to modulate the different enzyme-like activities of the MOFs, simplifying the detection process and eliminating cross-talk between different enzymes. The developed biosensor holds great promise for clinical diagnostic analysis and offers significant application value in the field.

Development of a deep learning model for predicting recurrence of hepatocellular carcinoma after liver transplantation.

Background: Liver transplantation (LT) is one of the main curative treatments for hepatocellular carcinoma (HCC). Milan criteria has long been applied to candidate LT patients with HCC. However, the application of Milan criteria failed to precisely predict patients at risk of recurrence. As a result, we aimed to establish and validate a deep learning model comparing with Milan criteria and better guide post-LT treatment. Methods: A total of 356 HCC patients who received LT with complete follow-up data were evaluated. The entire cohort was randomly divided into training set (n = 286) and validation set (n = 70). Multi-layer-perceptron model provided by pycox library was first used to construct the recurrence prediction model. Then tabular neural network (TabNet) that combines elements of deep learning and tabular data processing techniques was utilized to compare with Milan criteria and verify the performance of the model we proposed. Results: Patients with larger tumor size over 7 cm, poorer differentiation of tumor grade and multiple tumor numbers were first classified as high risk of recurrence. We trained a classification model with TabNet and our proposed model performed better than the Milan criteria in terms of accuracy (0.95 vs. 0.86, p < 0.05). In addition, our model showed better performance results with improved AUC, NRI and hazard ratio, proving the robustness of the model. Conclusion: A prognostic model had been proposed based on the use of TabNet on various parameters from HCC patients. The model performed well in post-LT recurrence prediction and the identification of high-risk subgroups.

Evolutionary changes in metabolic dysfunction-associated steatotic liver disease and the risk of hepatocellular carcinoma: a nationwide cohort study.

Background/Aims: To determine the association between evolutionary changes in metabolic dysfunction-associated steatotic liver disease (MASLD) status and the risk of hepatocellular carcinoma (HCC) in a nationwide population-based cohort. Methods: Information on study participants were derived from the Korea National Health Insurance Service database. The study population consisted of 5,080,410 participants who underwent two consecutive biennial health screenings between 2009 and 2012. All participants were followed up until HCC, death, or 31 December 2020. Association of evolutionary changes in MASLD status as assessed by fatty liver index and cardiometabolic risk factors, including persistent non-MASLD, resolved MASLD, incident MASLD, and persistent MASLD, with HCC risk was evaluated using the multivariable-adjusted Cox proportional hazards regression. Results: Among the 5,080,410 participants with 39,910,331 person-years of follow-up, 4,801 participants developed HCC. The incidence of HCC in participants with resolved, incident, and persistent MASLD was approximately 2.2-, 2.3-, and 4.7-fold higher, respectively, than that in those with persistent non-MASLD among the Korean adult population. When stratifying the participants according to the evolutionary change in MASLD status, persistent (adjusted hazard ratio [aHR], 2.94; 95% confidence interval [CI], 2.68-3.21; P<0.001), incident (aHR, 1.85; 95% CI, 1.63-2.10; P<0.001), and resolved MASLD (aHR, 1.33; 95% CI, 1.18-1.50; P<0.001) had an increased risk of HCC than that of persistent non-MASLD. Conclusions: The evolutionary changes in MASLD were associated with the differential risk of HCC independent of metabolic risk factors and concomitant medications, providing additional information on the risk of HCC stratification in patients with MASLD.