Biochar alleviates inhibition effects of humic acid on anaerobic digestion: Insights to performances and mechanisms.

To recover methane from waste activated sludge through anaerobic digestion (AD) is one promising alternative to achieve carbon neutrality for wastewater treatment plants. However, humic acids (HAs) are one of the major compositions in waste activated sludge, and their accumulation performs inhibition effects on AD. This study investigated the potentials of biochar (BC) in alleviating inhibition effects of HAs on AD. Results showed that although the accumulated HAs reduced methane yield by 9.37% compared to control, the highest methane yield, 132.6 mL CH4/g VSS, was obtained after adding BC, which was 45.9% higher than that in HA group. Mechanism analysis showed that BC promoted the activities of hydrolase such as protease and α-glucosidase, which were 69.7% and 29.7% higher than those in HA group, respectively. The conversion of short-chain fatty acids was accelerated. In addition, the evolutions of electroactive microorganisms like Clostridium_sensu_stricto_13 and Methanosaeta were consistent with the activitiies of electron transfer and the contents of cytochrome c. Furthermore, parts of HAs rather than all of them were adsorbed by BC, and the remaining free HAs and BC formed synergistic effects on methanogenesis, then both CO2 reduction and acetoclastic methanogenesis pathways were improved. The findings may provide some solutions to alleviate inhibition effects of HAs on AD.

Roles of quorum-sensing molecules in methane production from anaerobic digestion aided by biochar.

Biochar has been used to enhance methane generation from anaerobic digestion through establishing direct interspecific electron transfer between microorganisms. However, the microbial communication is still inadequate, thereby limiting further methane production improvement contributed by biochar. This study investigated the roles of quorum-sensing molecules, acylated homoserine lactone (AHL), in anaerobic digestion of waste activated sludge aided by biochar. Results showed that the co-addition of separated biochar and AHL achieved best methane production performance, with the maximal methane yield of 154.7 mL/g volatile suspended solids, which increased by 51.9%, 47.2%, 17.9%, and 39.4% respectively compared to that of control, AHL-loaded biochar, sole AHL, and sole biochar groups. The reason was that the co-addition of separated biochar and AHL promoted the stages of hydrolysis and acidification, promoting the conversion of organic matters and short-chain fatty acids, and optimizing the accumulation of acetate acid. Moreover, the methanogenesis stage also performed best among experimental groups. Correspondingly, the highest activities of electron transfer and coenzyme F420 were obtained, with increase ratios of 33.2% and 27.2% respectively compared to that of control. Furthermore, biochar did more significant effects on the evolution of microbial communities than AHL, and the direct interspecific electron transfer between fermentative bacteria and methanogens were possibly promoted.

[Regulatory effect of Tingli Dazao Xiefei Decoction on asthmatic rats by urine metabolomics].

Urine metabolomics based on ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS) was utilized to investigate the metabolic regulation mechanism of Tingli Dazao Xiefei Decoction(TLDZ) in rats with allergic asthma. SD male rats were divided into a normal group, a model group, a dexamethasone group, and a TLDZ group. The allergic asthma model was established by intraperitoneal injection of ovalbumin(OVA) to induce allergy, combined with atomization excitation. Urine metabolites from all rats were collected by UHPLC-Q-TOF-MS. The metabolic profiles of rats in each group were built by principal component analysis(PCA). Besides, the differential metabolites between the model group and the TLDZ group were selected by orthogonal partial least squares discriminant analysis(OPLS-DA), t-test(P<0.05), and variable importance in the projection(VIP) values of more than 3. The differential metabolites were identified through HMDB, METLIN, and other online databa-ses. Heat maps and clustering analysis for relative quantitative information of biomarkers in each group were drawn by MeV 4.8.0 software. Finally, MetaboAnalyst, MBRole, and KEGG databases were used to enrich related metabolic pathways and construct metabolic networks. The result demonstrated that TLDZ could effectively regulate the disordered urine metabolic profiles of asthmatic rats. Combined with multivariate statistical analysis and online databases, a total of 45 differential metabolites with significant changes(P<0.05) between the model group and the TLDZ group were screened out. Metabolic pathways including histidine metabolism, tryptophan metabolism, and arginine and proline metabolism were enriched. TLDZ could improve asthma by regulating related metabolic pathways and interfering with pathological processes such as immune homeostasis airway inflammation. The study investigates the molecular mechanism of anti-asthma of TLDZ from the perspective of urine metabolomics, and combined with previous pharmacological studies, it provides a scientific basis for the clinical development and application of TLDZ in the treatment of asthma.

Lighting up endogenous H2O2 in the tumor microenvironment using a dual-mode nanoprobe for long afterglow and MR bioimaging.

Persistent luminescent nanoparticles (PLNPs) are excellent luminescent materials, and near-infrared PLNPs are efficiently applied for biosensing and bioimaging due to their advantages of no excitation, excellent light stability and long afterglow. However, due to interference from the complex environment within organisms, single-mode imaging methods often face limitations in selectivity, sensitivity, and accuracy. Therefore, it is desirable to construct a dual-mode imaging probe strategy with higher specificity and sensitivity for bioimaging. Magnetic resonance imaging (MRI) has been widely used in the field of bioimaging due to its advantages of high resolution, non-radiation and non-invasiveness. Here, by combining near-infrared PLNPs and manganese dioxide (MnO2) nanosheets, a sensitive and convenient dual-mode "turn on" bioimaging nanoprobe ZGC@MnO2 has been developed for long afterglow imaging and MRI of endogenous hydrogen peroxide (H2O2) in the tumor microenvironment (TME). The monitoring of H2O2 has garnered significant attention due to its crucial role in human pathologies. For the dual-mode "turn on" bioimaging nanoprobe, the near-infrared PLNPs of quasi-spherical ZnGa2O4:Cr (ZGC) nanoparticles were synthesized as luminophores, and MnO2 nanosheets were utilized as a fluorescence quencher, carrier and H2O2 recognizer. H2O2 in the TME could reduce MnO2 nanosheets to Mn2+ for MRI, and ZGC nanoparticles were released for long afterglow imaging. Finally, the ZGC@MnO2 nanoprobe exhibited a rapid response, an excellent signal-to-noise ratio and a limit of detection of 3.67 nM for endogenous H2O2 in the TME. This dual-mode approach enhances the detection sensitivity for endogenous H2O2, thereby facilitating the research of endogenous H2O2-associated diseases and clinical diagnostics.

Enhancing thromboprophylaxis after colorectal cancer surgery in China: Bridging the gap between evidence and implementation through pathway optimization.

BACKGROUND: The CRC-VTE trial conducted in China revealed a significant occurrence of venous thromboembolism (VTE) in patients following colorectal cancer (CRC) surgery, raising concerns about implementing thromboprophylaxis measures. The present study aimed to identify and analyze inappropriate aspects of current thromboprophylaxis practices. METHODS: This study performed an analysis of the CRC-VTE trial, a prospective multicenter study that enrolled 1836 patients who underwent CRC surgery. The primary objective was to identify independent risk factors for VTE after CRC surgery using multivariate logistic regression analysis. Furthermore, among the cases in which VTE occurred, the appropriateness of thromboprophylaxis was assessed based on several factors, including pharmacologic prophylaxis, time to initiate prophylaxis, drug selection, drug dosage, and duration of pharmacologic prophylaxis. Based on the analysis of the current state of thromboprophylaxis and relevant clinical guidelines, a modified Delphi method was used to develop a clinical pathway for VTE prophylaxis after CRC surgery. RESULTS: In this analysis of 1836 patients, 205 (11.2%) were diagnosed with VTE during follow-up. The multifactorial analysis identified several independent risk factors for VTE, including age (≥70 years), female sex, varicose veins in the lower extremities, intraoperative blood transfusion, and the duration of immobilization exceeding 24 h. None of the patients diagnosed with VTE in the CRC trial received adequate thromboprophylaxis. The main reasons for this inappropriate practice were the omission of thromboprophylaxis, delayed initiation, and insufficient duration of thromboprophylaxis. We developed a specialized clinical pathway for thromboprophylaxis after CRC surgery to address these issues. CONCLUSIONS: This study offers a comprehensive nationwide evaluation of existing thromboprophylaxis practices in patients after CRC surgery in China. A specialized clinical pathway was developed to address the identified gaps and improve the quality of care. This clinical pathway incorporates explicit, tailored, detailed recommendations for thromboprophylaxis after CRC surgery.

A Multicomponent Workplace Environmental Intervention to Promote Physical Activity among the Staff of Universiti Malaysia Sarawak.

BACKGROUND: Physical inactivity is a significant public health issue affecting working adults because it can increase the risk of noncommunicable diseases. OBJECTIVES: The objective is to determine the outcomes of a multi-component workplace environmental intervention that incorporated physical activity self-regulation (PASR) to promote physical activity (PA) among employees. MATERIALS AND METHODS: This was a 6-month intervention with a two-group, parallel, quasi-experimental study. A total of 11 workplaces were randomly assigned to intervention group (IG) or control group (CG) using a 1:1 allocation ratio. In each group, 84 eligible participants were recruited. The IG was exposed to the organizational support and the PA support components throughout the study. The PASR Scale, International PA Questionnaire, and pedometer were used to measure the outcome at the baseline, 3rd-month, and 6th-month follow-ups, respectively. The repeated measures-analysis of variance analysis was used to determine the changes in the PASR skills, MET-min/week, and step/week over time. RESULTS: The IG had 75 participants (51 females and 24 males) and the CG had 73 participants (52 females and 21 males) at the 6th-month follow-up. Despite there was no statistically significant difference in the outcomes between groups over time, the IG showed significant improvements in total PASR (ηp2 = 0.021), goal setting (ηp2 = 0.024), total MET-min/week (ηp2 = 0.031), housework-related PA (ηp2 = 0.101), and step/week (ηp2 = 0.827) throughout this intervention. CONCLUSION: This intervention was found to be effective in improving the PASR skills, MET-min/week, and step/week of IG participants. Meanwhile, because some effect sizes were small, these findings should be interpreted with caution.

Factors influencing recurrence and model development for recurrence of minimally invasive percutaneous transhepatic lithotripsy: a single-center retrospective study.

OBJECTIVE: To identify factors influencing recurrence after percutaneous transhepatic choledochoscopic lithotripsy (PTCSL) and to develop a predictive model. METHODS: We retrospectively analyzed clinical data from 354 patients with intrahepatic and extrahepatic bile duct stones treated with PTCSL at Qinzhou First People's Hospital between February 2018 and January 2020. Patients were followed for three years and categorized into non-recurrence and recurrence groups based on postoperative outcome. Univariate analysis identified possible predictors of stone recurrence. Data were split using the gradient boosting machine (GBM) algorithm, assigning 70% as the training set and 30% as the test set. The predictive performance of the GBM model was assessed using the receiver operating characteristic (ROC) curve and calibration curve, and compared with a logistic regression model. RESULTS: Six factors were identified as significant predictors of recurrence: age, diabetes, total bilirubin, biliary stricture, number of stones, and stone diameter. The GBM model, developed based on these factors, showed high predictive accuracy. The area under the ROC curve (AUC) was 0.763 (95% CI: 0.695-0.830) for the training set and 0.709 (95% CI: 0.596-0.822) for the test set. Optimal cutoff values were 0.286 and 0.264, with sensitivities of 62.30% and 66.70%, and specificities of 77.20% and 68.50%, respectively. Calibration curves indicated good agreement between predicted probabilities and observed recurrence rates in both sets. DeLong's test revealed no significant differences between the GBM and logistic regression models in predictive performance (training set: D = 0.003, P = 0.997 > 0.05; test set: D = 0.075, P = 0.940 > 0.05). CONCLUSION: Biliary stricture, stone diameter, diabetes, stone number, age, and total bilirubin significantly influence stone recurrence after PTCSL. The GBM model, based on these factors, demonstrates robust accuracy and discrimination. Both GBM and logistic regression models effectively predicted stone recurrence post-PTCSL.

Genotype-phenotype Correlations of Ocular Posterior Segment Abnormalities in Marfan Syndrome.

Purpose: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 ( (FBN1). In addition to typical phenotypes such as ectopia lentis (EL) and aortic dilation, patients with MFS are prone to ocular posterior segment abnormalities, including retinal detachment (RD), maculopathy, and posterior staphyloma (PS). This study aims to investigate the correlations between FBN1 genotype and posterior segment abnormalities within a Chinese cohort of MFS. Design: Retrospective study. Participants: One hundred twenty-one eyes of 121 patients with confirmed FBN1 mutations between January 2015 and May 2023 were included. Methods: Comprehensive ophthalmic examination findings were reviewed, and the incidence of RD, atrophic, tractional, and neovascular maculopathy (ATN classification system), and PS was analyzed between different genotype groups. Only the more severely affected eye from each patient was included. Main Outcome Measures: Clinical features and risk factors. Results: Of 121 patients, 60 eyes (49.59%) exhibited posterior segment abnormalities, including RD (4, 3.31%), maculopathy (47, 38.84%), and PS (54, 44.63%). The mean age was 11.53 ± 11.66 years, with 79.34% of patients <20 years old. The location and region of mutations were found to be associated with the incidence of maculopathy (P = 0.013, P = 0.033) and PS (P = 0.043, P = 0.036). Mutations in the middle region had a lower incidence of maculopathy and PS (P = 0.028 and P = 0.006, respectively) than those in C-terminal region. Mutations in the transforming growth factor-ß (TGF-ß) regulating sequence exhibited a higher incidence of maculopathy and PS (P = 0.020, P = 0.040). Importantly, the location and region of mutations were also associated with the incidence of atrophic maculopathy (P = 0.013 and P = 0.033, respectively). Mutations in the middle region had a significantly lower probability of atrophic maculopathy (P = 0.006), while mutations in the TGF-ß regulating region had a higher incidence of atrophic maculopathy (P = 0.020). Conclusions: Maculopathy and PS were associated with the location and region of FBN1 mutations. Patients with mutations in the TGF-ß regulating region faced an increased risk of developing retinopathy. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Self-assembled branched polypeptides as amelogenin mimics for enamel repair.

The regeneration of demineralized enamel holds great significance in the treatment of dental caries. Amelogenin (Ame), an essential protein for mediating natural enamel growth, is no longer secreted after enamel has fully matured in childhood. Although biomimetic mineralization based on peptides or proteins has made significant progress, easily accessible, low-cost, biocompatible and highly effective Ame mimics are still lacking. Herein, we construct a series of amphiphilic branched polypeptides (CAMPs) by facile coupling of the Ame's C-terminal segment and poly(γ-benzyl-L-glutamate), which serves to simulate the Ame's hydrophobic N-terminal segment. Among them, CAMP15 is the best biomimetic mineralization template with great self-assembly performance to guide the oriented crystallization of hydroxyapatite and is capable of inhibiting the adhesion of Streptococcus mutans and Staphylococcus aureus on the enamel surfaces. This work highlights the potential application of amphiphilic branched polypeptide as Ame mimics in repairing defected enamel, providing a promising strategy for prevention and treatment of dental caries.

Prognostic models for mucinous and non-specific adeno cholangiocarcinoma: a population-based retrospective study.

Background: Clinically, the diagnosis and treatment of cholangiocarcinoma are generally different according to the location of occurrence, and the studies rarely consider the differences between different pathological types. Cholangiocarcinomas in large- and middle-sized intrahepatic bile ducts are mostly mucinous, while in small sized bile duct are not; mucinous extrahepatic cholangiocarcinomas are also more common than mucinous intrahepatic cholangiocarcinoma. However, it is unclear whether these pathological type differences are related to the prognosis. Methods: Data of total 22509 patients was analyzed from Surveillance, Epidemiology, and End Results program database out of which 22299 patients were diagnosed with common adeno cholangiocarcinoma while 210 were diagnosed with mucinous cholangiocarcinoma. Based on the propensity score matching (PSM) analysis, between these two groups' clinical, demographic, and therapeutic features were contrasted. The data were analyzed using Cox and LASSO regression analysis and Kaplan-Meier survival curves. Ultimately, overall survival (OS) and cancer specific survival (CSS) related prognostic models were established and validated in test and external datasets and nomograms were created to forecast these patients' prognosis. Results: There was no difference in prognosis between mucinous cholangiocarcinoma and adeno cholangiocarcinoma. Therefore, we constructed prognostic model and nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time. By comparing the 9 independent key characteristics i.e. Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy, risk scores were calculated for each individual. By integrating these two pathological types in OS and CSS prognostic models, effective prognosis prediction results could be achieved in multiple datasets (OS: AUC 0.70-0.87; CSS: AUC 0.74-0.89). Conclusion: Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy are the independent prognostic factors in OS or CSS of the patients with mucinous and ordinary cholangiocarcinoma. Nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time is of significance in clinical practice and management of cholangiocarcinoma.

Genotype-phenotype profile of global ASPH-associated ectopia lentis and clinical findings from a Chinese cohort.

BACKGROUND: Traboulsi syndrome is an under-recognized syndromic form of ectopia lentis (EL) caused by the aspartate beta-Hydroxylase (ASPH) variant. The genotype-phenotype profile of ASPH-associated disease is poorly understood due to the rarity of the condition. METHODS: We conducted targeted next-generation sequencing and bioinformatics analysis to identify potentially pathogenic ASPH variants in the cohort. Furthermore, we characterized the expression pattern of ASPH and major components of the zonules using single-cell RNA-sequencing (scRNA-seq) and evaluated the genotype-phenotype correlations by combining our data and those from the literature. RESULTS: We identified a novel missense variant c.2075G > A (p.G692D) and a recurrent nonsense variant c.1126C > G (p.R376*) of ASPH in two pedigrees from a Chinese cohort of EL. Both probands were 5-year-old boys with canonical facial dysmorphisms and bilateral anteriorly-dislocated lenses. Other ocular comorbidities included microspherophakia, shallow anterior chamber, and narrow chamber angel. No cardiac involvements or filtering blebs were identified. The single-cell expression atlas of ciliary epithelium demonstrated the coexpression of ASPH with FBN1, FBN2, and LTBP2 in the non-pigmented ciliary epithelium cells. Furthermore, molecular modeling simulation of p.G692D revealed increased affinity to the cb EGF-like domain and a subsequent destabilized calcium-binding motif. The genotype-phenotype analysis demonstrated that patients with cardiac involvements all harbored biallelic truncation variants. CONCLUSIONS: The data from this study provide new insights into the genotype-phenotype profile of ASPH-associated disease and implicate the potential role of ASPH in the pathogenesis of EL.

Effect of tocilizumab plus corticosteroid on clinical outcome in patients hospitalized with severe fever with thrombocytopenia syndrome: A randomized clinical trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with high fatality rates. The blockade of pro-inflammatory cytokines presents a promising therapeutic strategy. METHODS: We conducted a randomized clinical trial at the 154th hospital, Xinyang, Henan Province. Eligible patients with severe SFTS disease were randomly assigned in a 1:2 ratio to receive either a single intravenous infusion of tocilizumab plus usual care; or usual care only. The primary outcome was the clinical status of death/survival at day 14, while secondary outcomes included improvement from baseline in liver and kidney damage and time required for hospital discharge. The efficacy of tocilizumab plus corticosteroid was compared to those receiving corticosteroid alone. The trial is registered with the Chinese Clinical Trial Registry website (ChiCTR2300076317). RESULTS: 63 eligible patients were assigned to the tocilizumab group and 126 to the control group. The addition of tocilizumab to usual care was associated with a reduced death rate (9.5%) compared to those received only usual care (23.0%), with an adjusted hazard ratio (aHR) of 0.37 (95% confidence interval [CI], 0.15 to 0.91, P = 0.029). Combination therapy of tocilizumab and corticosteroids was associated with a significantly reduced fatality (aHR, 0.21; 95% CI, 0.08 to 0.56; P = 0.002) compared to those receiving corticosteroids alone. CONCLUSIONS: A significant benefit of reducing fatality in severe SFTS patients was observed by using tocilizumab. A combined therapy of tocilizumab plus corticosteroids was recommended for the therapy of severe SFTS.

Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion.

In the malignant progression of tumors, there is deposition and cross-linking of collagen, as well as an increase in hyaluronic acid content, which can lead to an increase in extracellular matrix stiffness. Recent research evidence have shown that the extracellular matrix plays an important role in angiogenesis, cell proliferation, migration, immunosuppression, apoptosis, metabolism, and resistance to chemotherapeutic by the alterations toward both secretion and degradation. The clinical importance of tumor-associated macrophage is increasingly recognized, and macrophage polarization plays a central role in a series of tumor immune processes through internal signal cascade, thus regulating tumor progression. Immunotherapy has gradually become a reliable potential treatment strategy for conventional chemotherapy resistance and advanced cancer patients, but the presence of immune exclusion has become a major obstacle to treatment effectiveness, and the reasons for their resistance to these approaches remain uncertain. Currently, there is a lack of exact mechanism on the regulation of extracellular matrix stiffness and tumor-associated macrophage polarization on immune exclusion. An in-depth understanding of the relationship between extracellular matrix stiffness, tumor-associated macrophage polarization, and immune exclusion will help reveal new therapeutic targets and guide the development of clinical treatment methods for advanced cancer patients. This review summarized the different pathways and potential molecular mechanisms of extracellular matrix stiffness and tumor-associated macrophage polarization involved in immune exclusion and provided available strategies to address immune exclusion.

CDKN2A inhibited ferroptosis through activating JAK2/STAT3 pathway to modulate cisplatin resistance in cervical squamous cell carcinoma.

Cervical squamous cell carcinoma (CESC) is a significant threat to women's health. Resistance to cisplatin (DDP), a common treatment, hinders the therapeutic efficacy. Understanding the molecular basis of DDP resistance in CESC is imperative. Cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was evaluated through quantitative real-time-PCR and western blot in clinical samples from 30 CESC patients and human cervical epithelial cells and CESC cell lines (SiHa, C33A, and Caski). It was also evaluated through bioinformatics analysis in Timer, Ualcan, and GEPIA database. Cell viability was detected by CCK-8. Apoptosis was detected by Calcein AM/PI assay. Lipid reactive oxygen species (ROS), malondialdehyde, glutathione, Fe 2+ , and iron level were detected by kits. Protein level of JAK2, STAT3, p-JAK2, p-STAT3, ACSL4, GPX4, SLC7A11, and FTL were detected by western blot. In CESC, elevated CDKN2A expression was observed. Cisplatin exhibited a dual effect, inhibiting cell proliferation and inducing ferroptosis in CESC. CDKN2A knockdown in a cisplatin-resistant cell line suppressed proliferation and induced ferroptosis. Moreover, CDKN2A was identified as an inhibitor of erastin-induced ferroptosis. Additionally, targeting the JAK2/STAT3 pathway enhanced ferroptosis in cisplatin-resistant cells. CDKN2A could inhibit ferroptosis in CESC through activating JAK2/STAT3 pathway to modulate cisplatin resistance.

Differentiation and immunosuppressive function of CD19+CD24hiCD27+ regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway.

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

Identification of hyperthermophilic D-allulose 3-epimerase from Thermotoga sp. and its application as a high-performance biocatalyst for D-allulose synthesis.

D-Allulose 3-epimerase (DAE) is a vital biocatalyst for the industrial synthesis of D-allulose, an ultra-low calorie rare sugar. However, limited thermostability of DAEs hinders their use at high-temperature production. In this research, hyperthermophilic TI-DAE (Tm = 98.4 ± 0.7 ℃) from Thermotoga sp. was identified via in silico screening. A comparative study of the structure and function of site-directed saturation mutagenesis mutants pinpointed the residue I100 as pivotal in maintaining the high-temperature activity and thermostability of TI-DAE. Employing TI-DAE as a biocatalyst, D-allulose was produced from D-fructose with a conversion rate of 32.5%. Moreover, TI-DAE demonstrated excellent catalytic synergy with glucose isomerase CAGI, enabling the one-step conversion of D-glucose to D-allulose with a conversion rate of 21.6%. This study offers a promising resource for the enzyme engineering of DAEs and a high-performance biocatalyst for industrial D-allulose production.

Visible light-driven photocatalytic sulfonative oxidation of benzyl secondary amines.

A method for the α-oxidation and sulfonation of benzyl secondary amines was developed utilizing Ir(III) or Eosin Y as the photocatalyst in the presence of O2 as a green oxidant. Using commercial substrates, 37 products from cyclic and acyclic benzylamines were achieved with good functional group compatibility in 48-87% yields. Furthermore, tetrahydroisoquinoline protected by an Ac or a Boc group was oxidized under standard conditions.

Safety and efficacy of endovascular treatment for acute ischemic stroke of large-vessel occlusion beyond the time window based on imaging evaluation.

PURPOSE: Endovascular treatment (EVT) of acute ischemic stroke caused by large-vessel occlusion (AIS-LVO) over 24 h of onset remains controversial. This study was to explore the safety and efficacy of EVT for patients with AIS-LVO between 24 and 72 h of symptom onset after rigorous imaging evaluation. METHODS: Patients with AIS-LVO treated with EVT were retrospectively enrolled and divided into two groups according to the time from symptom onset to groin puncture: 64 in the over-time group (>24 h) and 257 in the within-time group (≤24 h). Outcomes included 3-month modified Rankin Scale (mRS) score, functional independence (defined as mRS 0-2), successful cerebral reperfusion, symptomatic intracranial hemorrhage (sICH), and 3-month mortality. RESULTS: Patients in the over-time group had no significant differences in the functional independence (40.6% vs 42.5%, odds ratio or OR 0.91, 95% confidence interval or CI 0.52-1.60, p = 0.753), successful reperfusion (96.7% vs 95.8%, OR 0.76, 95% CI 0.36-1.59, p = 0.467), sICH (8.3% vs 6.7%, OR 1.20, 95% CI 0.42-3.38, p = 0.735), 3-month mortality (13.3% vs 10.8%, OR 1.17, 95% CI 0.51-2.70, p = 0.716) compared with patients in the within-time group. After matching adjustment, the results did not change significantly. CONCLUSIONS: The safety and effectiveness of EVT treatment for selected AIS-LVO patients with symptom onset of 24-72 h are not inferior to those treated within 6-24 h of onset, especially in a short term based on the pre-treatment advanced neuroimaging computed tomography perfusion even though further investigations are necessary to prove this finding.

Intelligent Biogenic Missile for Two-Photon Fluorescence Imaging-Guided Combined Photodynamic Therapy and Chemotherapy in Tumors.

Photodynamic therapy (PDT) is a significant noninvasive therapeutic modality, but it is often limited in its application due to the restricted tissue penetration depth caused by the wavelength limitations of the light source. Two-photon (TP) fluorescence techniques are capable of having an excitation wavelength in the NIR region by absorbing two NIR photons simultaneously, which offers the potential to achieve higher spatial resolution for deep tissue imaging. Thus, the adoption of TP fluorescence techniques affords several discernible benefits for photodynamic therapy. Organic TP dyes possess a high fluorescence quantum yield. However, the biocompatibility of organic TP dyes is poor, and the method of coating organic TP dyes with silica can effectively overcome the limitations. Herein, based on the TP silica nanoparticles, a functionalized intelligent biogenic missile TP-SiNPs-G4(TMPyP4)-dsDNA(DOX)-Aptamer (TGTDDA) was developed for effective TP bioimaging and synergistic targeted photodynamic therapy and chemotherapy in tumors. First, the Sgc8 aptamer was used to target the PTK7 receptor on the surface of tumor cells. Under two-photon light irradiation, the intelligent biogenic missile can be activated for TP fluorescence imaging to identify tumor cells and the photosensitizer assembled on the nanoparticle surface can be activated for photodynamic therapy. Additionally, this intelligent biogenic missile enables the controlled release of doxorubicin (DOX). The innovative strategy substantially enhances the targeted therapeutic effectiveness of cancer cells. The intelligent biogenic missile provides an effective method for the early detection and treatment of tumors, which has a good application prospect in the real-time high-sensitivity diagnosis and treatment of tumors.

Phosphorylation-regulated phase separation of syndecan-4 and syntenin promotes the biogenesis of exosomes.

The biogenesis of exosomes that mediate cell-to-cell communication by transporting numerous biomolecules to neighbouring cells is an essential cellular process. The interaction between the transmembrane protein syndecan-4 (SDC4) and cytosolic protein syntenin plays a key role in the biogenesis of exosomes. However, how the relatively weak binding of syntenin to SDC4 efficiently enables syntenin sorting for packaging into exosomes remains unclear. Here, we demonstrate for the first time that SDC4 can undergo liquid-liquid phase separation (LLPS) to form condensates both in vitro and in the cell membrane and that, the SDC4 cytoplasmic domain (SDC4-CD) is a key contributor to this process. The phase separation of SDC4 greatly enhances the recruitment of syntenin to the plasma membrane (PM) despite the weak SDC4-syntenin interaction, facilitating syntenin sorting for inclusion in exosomes. Interestingly, phosphorylation at the only serine (179) in the SDC4-CD (Ser179) disrupts SDC4 LLPS, and inhibited phosphorylation or dephosphorylation restores the SDC4 LLPS to promote its recruitment of syntenin to the PM and syntenin inclusion into exosomes. This research reveals a novel phosphorylation-regulated phase separation property of SDC4 in the PM through which SDC4 efficiently recruits cytosolic syntenin and facilitates the biogenesis of exosomes, providing potential intervention targets for exosome-mediated biomedical events.