The mechanism of water oxidation using transition metal-based heterogeneous electrocatalysts.

The water oxidation reaction, a crucial process for solar energy conversion, has garnered significant research attention. Achieving efficient energy conversion requires the development of cost-effective and durable water oxidation catalysts. To design effective catalysts, it is essential to have a fundamental understanding of the reaction mechanisms. This review presents a comprehensive overview of recent advancements in the understanding of the mechanisms of water oxidation using transition metal-based heterogeneous electrocatalysts, including Mn, Fe, Co, Ni, and Cu-based catalysts. It highlights the catalytic mechanisms of different transition metals and emphasizes the importance of monitoring of key intermediates to explore the reaction pathway. In addition, advanced techniques for physical characterization of water oxidation intermediates are also introduced, for the purpose of providing information for establishing reliable methodologies in water oxidation research. The study of transition metal-based water oxidation electrocatalysts is instrumental in providing novel insights into understanding both natural and artificial energy conversion processes.

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition.

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

Effects of coated sodium butyrate on the growth performance, serum biochemistry, antioxidant capacity, intestinal morphology, and intestinal microbiota of broiler chickens.

Introduction: This study examined the impact of adding coated sodium butyrate (CSB) to the diet on the growth performance, serum biochemistry, antioxidant capacity, intestinal morphology, and cecal microbiota of yellow-feathered broiler chickens. Methods: In this study, 240 yellow-feathered broiler chickens at 26 days old were divided into two groups: the control group (CON group) received a standard diet, and the experimental group (CSB group) received a diet with 0.5 g/kg of a supplement called CSB. Each group had 6 replicates, with 20 chickens in each replicate, and the experiment lasted for 36 days. Results: Compared to the CON group, the CSB group showed a slight but insignificant increase in average daily weight gain during the 26-62 day period, while feed intake significantly decreased. The CSB group exhibited significant increases in serum superoxide dismutase, catalase, and total antioxidant capacity. Additionally, the CSB group had significant increases in total protein and albumin content, as well as a significant decrease in blood ammonia levels. Compared to the CON group, the CSB group had significantly increased small intestine villus height and significantly decreased jejunal crypt depth. The abundance of Bacteroidetes and Bacteroides in the cecal microbiota of the CSB group was significantly higher than that of the CON group, while the abundance of Proteobacteria, Deferribacteres, and Epsilonbacteraeota was significantly lower than that of the CON group. Conclusion: These results suggest that adding CSB to the diet can improve the growth performance and antioxidant capacity of yellow-feathered broiler chickens while maintaining intestinal health.

Cascade Reactions Catalyzed by Gold Hybrid Nanoparticles Generate CO Gas Against Periodontitis in Diabetes.

The treatment of diabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN-Au@CO). The Glucose-like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase-like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti-inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2-related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa-B signaling to diminish inflammatory response. Importantly, the antibacterial and anti-inflammation effects of MSN-Au@CO are validated in diabetic rats with ligature-induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN-Au@CO is fabricate to utilize glucose-activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.

Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation.

OBJECTIVES: Gamete and embryo-foetal origins of adult diseases hypothesis proposes that adulthood chronic disorders are associated with adverse foetal and early life traits. Our study aimed to characterise developmental changes and underlying mechanisms of metabolic disorders in offspring of pre-eclampsia (PE) programmed pregnancy. METHODS: Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME) induced pre-eclampsia-like C57BL/6J mouse model was used. Lipid profiling, histological morphology, indirect calorimetry, mRNA sequencing, and pyrosequencing were performed on PE offspring of both young and elderly ages. RESULTS: PE offspring exhibited increased postnatal weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance that continued to adulthood. Integrated RNA sequencing of foetal and 52-week-old livers revealed that the differentially expressed genes were mainly enriched in lipid metabolism, including glycerol-3-phosphate acyl-transferase 3 (Gpat3), a key enzyme for de novo synthesis of triglycerides (TG), and carnitine palmitoyltransferase-1a (Cpt1a), a key transmembrane enzyme that mediates fatty acid degradation. Pyrosequencing of livers from PE offspring identified hypomethylated and hypermethylated regions in Gpat3 and Cpt1a promoters, which were associated with upregulated and downregulated expressions of Gpat3 and Cpt1a, respectively. These epigenetic alterations are persistent and consistent from the foetal stage to adulthood in PE offspring. CONCLUSION: These findings suggest a methylation-mediated epigenetic mechanism for PE-induced intergenerational lipid accumulation, impaired energy balance and obesity in offspring, and indicate the potential benefits of early interventions in offspring exposed to maternal PE to reduce their susceptibility to metabolic disorder in their later life.

Transcriptomic analysis and carbohydrate metabolism-related enzyme expression across different pH values in Rhizopus delemar.

Introduction: pH is one of the important factors affecting the growth and performance of microorganisms. Methods: We studied the pH response and plant growth-promoting (PGP) ability of Rhizopus delemar using cultivation experiments and transcriptomics, and verified the expression profiles using quantitative real-time PCR. Results: pH affected the growth and PGP properties of R. delemar. At pH 7, the growth rate of R. delemar was rapid, whereas pH 4 and 8 inhibited mycelial growth and PGP ability, respectively. In the pot experiment, the plant height was the highest at pH 7, 56 cm, and the lowest at pH 4 and pH 5, 46.6 cm and 47 cm, respectively. Enzyme activities were highest at pH 6 to pH 7. Enzyme activities were highest at pH 6 to pH 7. Among the 1,629 differentially expressed genes (DEGs), 1,033 genes were up-regulated and 596 were down-regulated. A total of 1,623 DEGs were annotated to carbohydrate-active enzyme coding genes. Discussion: The PGP characteristics, e.g., Phosphorus solubilization ability, of R. delemar were strongest at pH 7. The results provide useful information regarding the molecular mechanism of R. delemar pH response.

EvoVis: A Visual Analytics Method to Understand the Labeling Iterations in Data Programming.

Obtaining high-quality labeled training data poses a significant bottleneck in the domain of machine learning. Data programming has emerged as a new paradigm to address this issue by converting human knowledge into labeling functions(LFs) to quickly produce low-cost probabilistic labels. To ensure the quality of labeled data, data programmers commonly iterate LFs for many rounds until satisfactory performance is achieved. However, the challenge in understanding the labeling iterations stems from interpreting the intricate relationships between data programming elements, exacerbated by their many-to-many and directed characteristics, inconsistent formats, and the large scale of data typically involved in labeling tasks. These complexities may impede the evaluation of label quality, identification of areas for improvement, and the effective optimization of LFs for acquiring high-quality labeled data. In this paper, we introduce EvoVis, a visual analytics method for multi-class text labeling tasks. It seamlessly integrates relationship analysis and temporal overview to display contextual and historical information on a single screen, aiding in explaining the labeling iterations in data programming. We assessed its utility and effectiveness through case studies and user studies. The results indicate that EvoVis can effectively assist data programmers in understanding labeling iterations and improving the quality of labeled data, as evidenced by an increase of 0.16 in the average F1 score when compared to the default analysis tool.

Electrocatalytic water oxidation with manganese phosphates.

As inspired by the Mn4CaO5 oxygen evolution center in nature, Mn-based electrocatalysts have received overwhelming attention for water oxidation. However, the understanding of the detailed reaction mechanism has been a long-standing problem. Herein, homologous KMnPO4 and KMnPO4•H2O with 4-coordinated and 6-coordinated Mn centers, respectively, are prepared. The two catalysts constitute an ideal platform to study the structure-performance correlation. The presence of Mn(III), Mn(IV), and Mn(V) intermediate species are identified during water oxidation. The Mn(V)=O species is demonstrated to be the substance for O-O bond formation. In KMnPO4•H2O, the Mn coordination structure did not change significantly during water oxidation. In KMnPO4, the Mn coordination structure changed from 4-coordinated [MnO4] to 5-coordinated [MnO5] motif, which displays a triangular biconical configuration. The structure flexibility of [MnO5] is thermodynamically favored in retaining Mn(III)-OH and generating Mn(V)=O. The Mn(V)=O species is at equilibrium with Mn(IV)=O, the concentration of which determines the intrinsic activity of water oxidation. This study provides a clear picture of water oxidation mechanism on Mn-based systems.

Distinct genetic clusters in HIV-1 CRF01_AE-infected patients induced variable degrees of CD4+ T-cell loss.

CRF01_AE strains have been shown to form multiple transmission clusters in China, and some clusters have disparate pathogenicity in Chinese men who have sex with men. This study focused on other CRF01_AE clusters prevalent in heterosexual populations. The CD4+ T-cell counts from both cross-section data in National HIV Molecular Epidemiology Survey and seropositive cohort data were used to evaluate the pathogenicity of the CRF01_AE clusters and other HIV-1 sub-types. Their mechanisms of pathogenicity were evaluated by co-receptor tropisms, predicted by genotyping and confirmed with virus isolate phenotyping, as well as inflammation parameters. Our research elucidated that individuals infected with CRF01_AE clusters 1 and 2 exhibited significantly lower baseline CD4+ T-cell counts and greater CD4+ T-cell loss in cohort follow-up, compared with other HIV-1 sub-types and CRF01_AE clusters. The increased pathogenesis of cluster 1 or 2 was associated with higher CXCR4 tropisms, higher inflammation/immune activation, and increased pyroptosis. The protein structure modeling analysis revealed that the envelope V3 loop of clusters 1 and 2 viruses is favorable for CXCR4 co-receptor usage. Imbedded with the most mutating reverse transcriptase, HIV-1 is one of the most variable viruses. CRF01_AE clusters 1 and 2 have been found to have evolved into more virulent strains in regions with predominant heterosexual infections. The virulent strains increased the pressure for early diagnosis and treatment in HIV patients. To save more lives, HIV-1 surveillance systems should be upgraded from serology and genotyping to phenotyping, which could support precision interventions for those infected by virulent viruses. IMPORTANCE: Retroviruses swiftly adapt, employing error-prone enzymes for genetic and phenotypic evolution, optimizing survival strategies, and enhancing virulence levels. HIV-1 CRF01_AE has persistently undergone adaptive selection, and cluster 1 and 2 infections display lower counts and fast loss of CD4+ T cells than other HIV-1 sub-types and CRF01_AE clusters. Its mechanisms are associated with increased CXCR4 tropism due to an envelope structure change favoring a tropism shift from CCR5 to CXCR4, thereby shaping viral phenotype features and impacting pathogenicity. This underscores the significance of consistently monitoring HIV-1 genetic evolution and phenotypic transfer to see whether selection bias across risk groups alters the delicate balance of transmissible versus toxic trade-offs, since virulent strains such as CRF01_AE clusters 1 and 2 could seriously compromise the efficacy of antiviral treatment. Only through such early warning and diagnostic services can precise antiviral treatments be administered to those infected with more virulent HIV-1 strains.

Diagnostic efficacy of tract-specific diffusion tensor imaging in cervical spondylotic myelopathy with electrophysiological examination validation.

PURPOSE: This study aimed to investigate the effectiveness of tract-specific diffusion tensor imaging (DTI) metrics in identifying the responsible segments for neurological dysfunction in cervical spondylotic myelopathy (CSM). METHODS: The study encompassed nineteen participants diagnosed with CSM, including 10 males and 9 females. Additionally, a control group consisting of ten healthy caregivers (5 males and 5 females) were recruited with no symptoms and no compressions on magnetic resonance imaging (MRI). All participants underwent a comprehensive physical examination, MRI assessment, and DTI examination conducted by a senior chief physician. Several parameters were collected from the MR images, including the aspect ratio (defined as the anteroposterior diameter / the transverse diameter of the corresponding segment's spinal cord), transverse ratio (defined as the transverse diameter of the corresponding segment's spinal cord / the transverse diameter of the spinal cord at C2/3), and T2 high signal of the spinal cord. Furthermore, quantitative DTI metrics, such as axial diffusivity (AD), mean diffusivity (MD), radial diffusivity (RD), and fractional anisotropy (FA), were calculated using automatic region-of-interest (ROI) analysis for both whole spinal cord column and dorsal column. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic efficacy of the aspect ratio, transverse ratio, and DTI parameters. The area under the curve (AUC), sensitivity, and specificity were calculated. Intraoperative spinal cord electrophysiological examination was performed as the objective measure of spinal cord function during surgery. RESULTS: As determined by electrophysiological examination, neurological dysfunction was found in 2 patients due to C3/4 compression, in 10 patients due to C4/5 compression, in 6 patients due to C5/6 compression, and in 1 patient due to C6/7 compression. The modified Japanese Orthopedic Association scale (mJOA) was 12.71 ± 1.55 in the CSM group, with 4.87 ± 0.72 for sensory nerve function and 5.05 ± 1.35 for motor nerve function. For the control group, none of the volunteers had neurological dysfunction. T2 high signal was found at the most stenotic segment in 13 patients of the CSM group. Considering all the cervical segments, the aspect ratio (AUC = 0.823, P = 0.001, Sensitivity = 68.42%, Specificity = 82.47%) was more capable of determining the responsible segment than transverse ratio (AUC = 0.661, P = 0.027, Sensitivity = 68.42%, Specificity = 67.01%). AD, MD, and RD were significantly higher while FA was significantly lower in the responsible segment than in the irresponsible segment (P < 0.05). The AUC of DTI-Dorsal column parameters (AD, MD, RD, FA) was larger than the corresponding parameters of the DTI (Whole spinal cord). AD of DTI-Dorsal Column possessed the greatest efficacy (AUC = 0.823, sensitivity = 84.21%, specificity = 77.32%) to determine the responsible segment, larger than AD of DTI-Whole spinal cord (AUC = 0.822, P = 0.001, Sensitivity = 89.47%, Specificity = 77.32%), aspect ratio (AUC = 0.823, P = 0.001, Sensitivity = 68.42%, Specificity = 82.47%) and transverse ratio (AUC = 0.661, P = 0.027, Sensitivity = 68.42%, Specificity = 67.01%). Subgroup analysis revealed that the diagnostic efficacy of DTI and MRI parameters was influenced by cervical spine segment. CONCLUSIONS: When considering all cervical segments, AD from the DTI-Dorsal Column exhibited the most significant potential in identifying responsible segments. This potential was found to be superior to that of DTI-Whole spinal cord, aspect ratio, the most stenotic segment, T2 high signals, transverse ratio, motor nerve dysfunction, and sensory nerve dysfunction. The diagnostic effectiveness of both DTI and MRI parameters was notably influenced by the specific cervical spine segment.

Application of five risk stratification tools for syncope in older adults.

OBJECTIVE: Treatment of syncope in older adults places a burden on healthcare systems. We used five risk stratification tools to predict short-term adverse outcomes in older patients with syncope. METHODS: This was a retrospective analysis of patients with syncope (age ≥60 years) in the emergency department of an urban academic hospital. The data were evaluated using the Risk Stratification of Syncope in the Emergency Department (ROSE), San Francisco Syncope Rule (SFSR), FAINT, Canadian Syncope Risk Score (CSRS), and Boston Syncope Criteria (BSC) tools. Sensitivity, specificity, accuracy, positive and negative predictive value (NPV), and positive and negative likelihood ratios of each tool were calculated and compared for adverse events within 1 month. RESULTS: In total, 221 patients (average age 75.6 years) were analyzed. Fifty-nine patients (26.7%) had experienced an adverse event within 1 month. For the ROSE, SFSR, FAINT, CSRS and BSC tools, sensitivities were 81.3%, 76.3%, 93.2%, 71.2%, and 94.9%, specificities were 88.3%, 87.7%, 56.8%, 71.6%, and 67.3%, and NPVs were 92.9%, 91.0%, 95.8%, 87.2%, and 97.3%, respectively. CONCLUSION: The five assessed tools could be useful for physicians in screening older patients with syncope for the risk of short-term adverse events, according to the patient's actual situation.

Spinal cord perfusion is associated with microstructural damage in cervical spondylotic myelopathy patients who underwent cervical laminoplasty.

OBJECTIVES: To investigate the association between spinal cord perfusion and microstructural damage in CSM patients who underwent cervical laminoplasty using MR dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques. METHODS: A follow-up cohort study was conducted with 53 consecutively recruited CSM patients who had undergone cervical laminoplasty 12-14 months after the surgery from April 2016 to December 2016. Twenty-one aged-matched healthy volunteers were recruited as controls. For each patient, decompressed spinal cord levels were imaged on a 3.0-T MRI scanner by diffusion and DSC sequences to quantify the degrees of microstructural damage and perfusion conditions, respectively. The diffusion data were analyzed by DTI and NODDI models to produce diffusion metrics. Classic indicator dilution model was used to quantify the DSC metrics. Mann-Whitney U test was performed for comparison of diffusion metrics between patients and healthy controls. Pearson correlation was used to explore the associations between the metrics of spinal cord perfusion and microstructural damage. RESULTS: DTI metrics, neurite density, and isotropic volume fraction had significant differences between postoperative patients and healthy controls. Pearson correlation test showed that SCBV was significantly positively correlated with RD, MD, and ODI, and negatively correlated with FA and NDI. SCBF was found to be significantly positively correlated with RD and MD, and negatively correlated with FA. CONCLUSIONS: Increased spinal cord perfusion quantified by DSC is associated with microstructural damage assessed by diffusion MRI in CSM patients who underwent cervical laminoplasty. CLINICAL RELEVANCE STATEMENT: This study found that the spinal cord perfusion is associated with microstructural damage in postoperative cervical spondylotic myelopathy patients, indicating that high perfusion may play a role in the pathophysiological process of cervical spondylotic myelopathy and deserves more attention. KEY POINTS: • Spinal cord microstructural damage can be persistent despite the compression had been relieved 12-14 months after the cervical laminoplasty in cervical spondylotic myelopathy (CSM) patients. • Spinal cord perfusion is associated with microstructural damage in CSM patients after the cervical laminoplasty. • Inflammation in the decompressed spinal cord may be a cause of increased perfusion and is associated with microstructural damage during the recovery period of CSM.

Transcriptome and proteome analyses reveal the mechanisms involved in polystyrene nanoplastics disrupt spermatogenesis in mice.

Nanoplastics have been demonstrated to be reproductively toxic to mammals. However, the mechanisms of nanoplastics induce reproductive damage in mammals, especially their effects on spermatogenesis, remain elusive. Herein, we explored the effects and underlying mechanisms of polystyrene nanoplastics (PS-NPs) on the testicular development of male mice after 28 days of exposure, representing the first systematic study of PS-NPs-induced male reproductive injury by integrating histomorphology, transcriptomics and proteomics. PS-NPs decreased the sperm concentration, sperm motility, and disrupted the structure of the seminiferous tubules of the mice. Besides, transcriptome and proteome analyses revealed that PS-NPs disrupted spermatogenesis by inhibiting the transcription of Prm3/Tnp1/Aurkc/Mea1/Mettl14 and the expression of Pmfbp1/Ggn/Fsip2. Furthermore, PS-NPs enabled Hsd3b5 protein expression to reduce dihydrotestosterone levels, and affected sperm flagellar assembly by decreasing the expression of Dnah8/Tekt5/Rsph6a. Moreover, PS-NPs induced testicular cell apoptosis by up-regulating the expression of cathepsins (B/F/H). In addition, PS-NPs destroyed tight junctions by reducing the expression of the Claudin family (3/5/15). In conclusion, PS-NPs can disrupt spermatogenesis by altering the expression patterns of transcriptome and proteome, inducing testicular cell apoptosis and destroying tight junctions.

Tetracycline inhibits tick host reproduction by modulating bacterial microbiota, gene expression and metabolism levels.

BACKGROUND: Ticks are disease vectors that are a matter of worldwide concern. Antibiotic treatments have been used to explore the interactions between ticks and their symbiotic microorganisms. In addition to altering the host microbial community, antibiotics can have toxic effects on the host. RESULTS: In the tick Haemaphysalis longicornis, engorged females showed reproductive disruption after microinjection of tetracycline. Multi-omics approaches were implemented to unravel the mechanisms of tick reproductive inhibition in this study. There were no significant changes in bacterial density in the whole ticks on Day (D)2 or D4 after tetracycline treatment, whereas the bacterial microbial community was significantly altered, especially on D4. The relative abundances of the bacteria Staphylococcus, Bacillus and Pseudomonas decreased after tetracycline treatment, whereas the relative abundances of Coxiella and Rhodococcus increased. Ovarian transcriptional analysis revealed a cumulative effect of tetracycline treatment, as there was a significant increase in the number of differentially expressed genes with treatment time and a higher number of downregulated genes. The tick physiological pathways including lysosome, extracellular matrix (ECM)-receptor interaction, biosynthesis of ubiquinone and other terpenoids-quinones, insect hormone biosynthesis, and focal adhesion were significantly inhibited after 4 days of tetracycline treatment. Metabolite levels were altered after tetracycline treatment and the differences increased with treatment time. The differential metabolites were involved in a variety of physiological pathways; the downregulated metabolites were significantly enriched in the nicotinate and nicotinamide metabolism, galactose metabolism, and ether lipid metabolism pathways. CONCLUSIONS: These findings indicate that tetracycline inhibits tick reproduction through the regulation of tick bacterial communities, gene expression and metabolic levels. The results may provide new strategies for tick control. © 2023 Society of Chemical Industry.

A novel safer CD19CAR with shRNA interference of IFN-γ can reduce multiple cytokine levels without significantly compromising its killing efficacy.

Cytokine release syndrome (CRS) is a great challenge for the application of anti-CD19 CAR-T cell therapy. The aim of this study was to investigate the effect of knocking down interferon gamma (IFN-γ) by shRNA as a potential strategy to reduce the cytokine storms. A newly designed short hairpin interference RNA of IFN-γ (shIFN-γ) in CD19CAR gene was constructed. Several cellular model systems of approach using Nalm-6 cell lines including Nalm-6CD19pos and Nalm-6CD19neg with or without monocytes and endothelial cells were used to analyze the different levels of cytokines after shIFN-γ-anti-CD19CAR-T cell targeted therapy. The activity of this novel CD19CAR-T was evaluated both in vitro and in NSG mouse model. The killing efficacy of shIFN-γ-anti-CD19CAR-T at the E:T ratio of 2:1 was similar to that of regular anti-CD19CAR-T at the E:T ratio of 1:1. The IFN-γ level in the shIFN-γ-anti-CD19CAR-T cell group was (2673.1 ± 307.4) pg/ml at the E:T ratio of 2:1 which was significantly lower than that ((8261.5 ± 345.5) pg/ml) in the regular anti-CD19CAR-T group at the E:T ratio of 1:1. Cytotoxicity experiments in vitro showed significantly reduced concentrations of IFN-γ, IL-6 and TNFα in the shIFN-γ-anti-CD19CAR-T cell group compared to regular anti-CD19CAR-T cell group. Both regular anti-CD19CAR and shIFN-γ-CD19CAR-T exerted bystander killing effect in vitro. We conclude that shIFN-γ-anti-CD19CAR-T cells can reduce the generation of cytokine storms without significantly compromising their therapeutic efficacy in the preclinical setting. In mouse model, 3 × 106 shIFN-γ-anti-CD19CAR-T cells/mouse generated the similar killing efficacy to that with 2 × 106 regular anti-CD19CAR-T cells/mouse.

TTK inhibition activates STING signal and promotes anti-PD1 immunotherapy in breast cancer.

Despite progress in the application of checkpoint immunotherapy against various tumors, attempts to utilize immune checkpoint blockade (ICB) agents in triple negative breast cancer (TNBC) have yielded limited clinical benefits. The low overall response rate of checkpoint immunotherapy in TNBC may be attributed to the immunosuppressive tumor microenvironment (TME). In this study, we investigated the role of mitogen-associated kinase TTK in reprogramming immune microenvironment in TNBC. Notably, TTK inhibition by BAY-1217389 induced DNA damage and the formation of micronuclei containing dsDNA in the cytosol, resulting in elicition of STING signal pathway and promoted antitumor immunity via the infiltration and activation of CD8+ T cells. Moreover, TTK inhibition also upregulated the expression of PD-L1, demonstrating a synergistic effect with anti-PD1 therapy in 4T1 tumor-bearing mice. Taken together, TTK inhibition facilitated anti-tumor immunity mediated by T cells and enhanced sensitivity to PD-1 blockade, providing a rationale for the combining TTK inhibitors with immune checkpoint blockade in clinical trials.

Validation of the Chinese version of the Sleep Regularity Questionnaire (SRQ) and analysis of influencing factors.

BACKGROUND: Currently, there is no instrument to measure sleep regularity in China. In this study, the Sleep Regularity Questionnaire（SRQ） was translated into Chinese, tested for reliability and validity, and analyzed for factors affecting sleep regularity. METHODS: The English version of the SRQ was translated into Chinese, and a total of 3642 individuals were included in this research. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to examine the underlying factor structure of the Chinese version of the SRQ and to measure its reliability and validity. In addition, the correlations between sleep regularity and general information, personal habits, self-control, stress, anxiety, and depression were explored. RESULTS: The Cronbach's α of the Chinese SRQ was 0.858, supporting the two-factor structure. Sleep regularity was statistically different between gender and ethnicity (p < 0.05), and personal habits (exercise, continued eating after dinner, smoking and drinking) had an effect on sleep regularity. Sleep regularity was positively associated with individual self-control and negatively associated with stress, anxiety, and depression. CONCLUSIONS: The Chinese version of the SRQ has excellent reliability and validity. There are two dimensions, namely circadian regularity and sleep continuity regularity, which can be used to assess the sleep regularity of Chinese adults. The results of this study showed that males and Han Chinese having better sleep regularity. And people with good lifestyle habits and greater self-control sleep more regularly, while stress, anxiety and depression can affect individuals' sleep regularity.

In-situ preparation of lignin/Fe3O4 magnetic spheres as bifunctional material for the efficient removal of metal ions and methylene blue.

In this paper, magnetic composite of lignin/Fe3O4 spheres were synthesized via a straightforward one-step in-situ solvothermal method showing good capacity for adsorbing heavy metal ions and dyes. The physicochemical properties of lignin/Fe3O4 spheres are analyzed using a range of techniques such as SEM, XRD, FTIR, VSM, TG, and BET. Lignin/Fe3O4 spheres exhibited high adsorption capacities of 100.00, 353.36 and 223.71 and 180.18 mg/g for Cu (II), Ni (II) and Cr (VI) metal ions and methylene blue (MB) with equilibrium attained within 60 min. After the recycling experiments, lignin/Fe3O4 spheres still possesses excellent superparamagnetic properties and displays high adsorption capacity. The lignin/Fe3O4 spheres are an efficient and continuous adsorbent to remove heavy metal ions of Cu (II), Ni (II), Cr (VI) and cationic dyes of methylene blue in wastewater, which proves the great potential in practical pollutants treatment applications for water systems.

The establishment of a multiplex fluorescent polymerase chain reaction coupled with capillary electrophoresis analysis technology enables the simultaneous detection of 16 genotypes of human papillomavirus.

BACKGROUND: The detection and accurate genotyping of human papillomavirus (HPV) infection is critical for preventing and effectively treating cervical cancer. METHODS: A multiplex fluorescent polymerase chain reaction (PCR) coupled with a capillary electrophoresis method was developed for the simultaneous detection of the 16 most prevalent HPV genotypes. Twenty-five pairs of primers were ultimately selected to ensure that both E and L regions of nine HPV genotypes, as well as the E regions of seven HPV genotypes could be accurately amplified. RESULTS: This method enables the simultaneous detection and differentiation of 16 HPV genotypes in a single closed-tube reaction, accurately distinguishing products with molecular weight differences >1 bp through capillary electrophoresis. This method demonstrated exceptional accuracy, specificity, and repeatability with a detection limit of 10 copies/µL for all 16 HPV genotypes. Furthermore, 152 cervical swab specimens were obtained to compare the disparities between this approach and Cobas 4800 HPV detection method. The concordance rate and κ value were 90.1% and 0.802, respectively, indicating a high level of agreement. The established detection method was successfully applied to cervical swab specimens for determining HPV genotypes across all levels of cervical lesions, HPV52, 56, 16, and 59 were found to be most prevalent with infection rates of 10.8%, 9.1%, 6.5%, and 6.2%, respectively. CONCLUSIONS: This study has successfully established a detection method capable of simultaneously identifying 16 HPV genotypes. This approach can be further applied to HPV vaccine research and surveillance, with the potential for broad applications.