Integrated multi-omics analyses reveal microbial community resilience to fluctuating low oxygen in the East China sea.

Climate change and eutrophication are accelerating ocean deoxygenation, leading to a global decline in oxygen levels. The East China Sea, frequently experiencing deoxygenation events, harbors diverse microbial communities. However, the response of these communities to the changing deoxygenation dynamics remains poorly understood. Here, we explored the composition and function of microbial communities inhabiting seawaters of the Changjiang Estuary and offshore areas. Our findings suggested that neutral processes significantly influenced the assembly of these communities. The overall bacterial composition demonstrated remarkable high stability across the oxygen gradient. Salinity exhibited a significantly stronger correlation with bacterial community structure than dissolved oxygen. Both metagenomics and metaproteomics revealed that all of the samples exhibited similar functional community structures. Heterotrophic metabolism dominated these sites, as evidenced by a diverse array of transporters and metabolic enzymes for organic matter uptake and utilization, which constituted a significant portion of the expressed proteins. O2 was the primary electron acceptor in bacteria even under hypoxic conditions, evidenced by expression of low- and high-affinity cytochrome oxidases. Proteins associated with anaerobic processes, such as dissimilatory sulfite reductases, were virtually undetectable. Untargeted liquid chromatography with tandem mass spectrometry analysis of seawater samples revealed a diverse range of dissolved organic matter (DOM) components in amino acids, lipids, organic acids, peptides, and carbohydrates, potentially fueling dominant taxa growth. Despite fluctuations in the abundance of specific genera, the remarkable similarity in community structure, function, and DOM suggests that this ecosystem possesses robust adaptive mechanisms that buffer against abrupt changes, even below the well-defined hypoxic threshold in marine ecosystem.

Research on Residual Gas Adsorption on Surface of Hexagonal Boron Nitride-Based Memristor.

As a promising nonvolatile memory device with two ends, the memristor has received extensive attention for its industrial manufacture. Density functional theory was used to analyze the adsorption properties of residual gas on hexagonal boron nitride (h-BN)-based memristor model surfaces with Stone-Wales-5577 grain boundary defects [h-BN(SW)]. First, by calculating the adsorption energy, geometric parameters, and charge transfer, we identified the most stable adsorption sites for hydrogen atoms (H-TB1) and H2 molecules (H2-TN2). We observed a tendency toward chemisorption for hydrogen atoms and physical adsorption for H2 molecules at these sites. Furthermore, two coadsorption configurations were formed by introducing H2 molecules and hydrogen atoms into single adsorption configurations: namely H-TB1_H2-TN1TN2 and H2-TN2_H-TB1TN1TN3. In the case of hydrogen-based configuration, there is weak dissociation of the H2 molecule, which does not facilitate hydrogen atom adsorption. However, adjacent hydrogen atoms tend to form stable dimers, while excess hydrogen atoms have a tendency to weakly chemisorb in the case of H2-based configuration. The pristine h-BN surface is more favorable for hydrogen atom migration compared to the h-BN(SW) surface due to its higher adsorption energy. On the h-BN(SW) surface, hydrogen atoms tend to migrate inward from the center of adjacent heptagonal boron nitride rings while coadsorption has a minimal impact on their vertical migration as well as that of H2 molecules. This work provides theoretical insights into the H/H2 trace gas interaction during h-BN wafer-level fabrication for memristor devices.

Idiopathic Subglottic Stenosis in Non-Caucasian Women.

Objective: To characterize presentation, disease course, and treatment of idiopathic subglottic stenosis (iSGS) in non-Caucasian women and compare this cohort to the predominantly female, Caucasian patient cohorts identified in the literature. Study Design: Retrospective review. Results are compared to systematic review of demographics. Setting: Multiple California institutions from 2008 to 2021. Methods: Patients with intubation within 2 years of disease or who met exclusion criteria listed in prior publications were excluded. A systematic review of iSGS patient demographics was also completed for comparison. Results: Of 421 patients with iSGS, 58 self-identified as non-Caucasian women, with 50 ultimately included. Mean age of onset was 45.1 years old (95% confidence interval [CI], 41.5-48.8), and mean age at diagnosis was 47.2 years (95% CI, 43.6-50.7). Mean Charlson comorbidity index was 1.06 (n = 49, 95% CI, 0.69-1.44). At diagnosis, Cotton-Meyer severity scores (documented in n = 45) were Cotton-Myer (CM) I (28.9%), CM II (40%), and CM III (31.1%). Mean age at first endoscopic surgery was 47.7 (95% CI, 44.2-51.3) years. 64% experienced disease recurrence with a median of 11 months between their first and second surgery. Our systematic review identified 60 studies that reported demographic features in patients with iSGS. 95% of pooled patients were Caucasian, while other demographic features were similar to the current cohort. Conclusion: The non-Caucasian population, almost 14% of this Californian cohort, does not differ from the majority Caucasian population detailed in contemporary literature. This cohort supports the presence of some racial and ethnic heterogeneity in this disease population.

A comprehensive adsorption and desorption study on the interaction of DNA oligonucleotides with TiO2 nanolayers.

The utilization of TiO2 nanolayers that possess excellent biocompatibility and physical properties in DNA sensing and sequencing remains largely to be explored. To examine their applicability in gene sequencing, a comprehensive study on the interaction of DNA oligonucleotides with TiO2 nanolayers was performed through adsorption and desorption experiments. TiO2 nanolayers with 10 nm thickness were fabricated via magnetron sputtering onto a 6-inch silicon wafer. A simple chip block method, validated via quartz crystal microbalance experiments with dissipation monitoring (QCM-D), was proposed to study the adsorption behaviors and interaction mechanisms under a variety of critical influencing factors, including DNA concentration, length, and type, adsorption time, pH, and metal ions. It is determined that the adsorption takes 2 h to reach saturation in the MES solution and the adsorption capacity is significantly enhanced by lowering the pH due to the isoelectric point being pH = 6 for TiO2. The adsorption percentages of nucleobases are largely similar in the MES solution while following 5T = 5G > 5C > 5A in HEPES buffer for an adsorption duration of 2.5 h. Through pre-adsorption experiments, it is deduced that DNA oligonucleotides are horizontally adsorbed on the nanolayer. This further demonstrates that mono-, di-, and tri-valent metal ions promote the adsorption, whereas Zn2+ has strong adsorption by inducing DNA condensation. Based on the desorption experiments, it is revealed that electrostatic force dominates the adsorption over van der Waals force and hydrogen bonds. The phosphate group is the main functional group for adsorption, and the adsorption strength increases with the length of the oligonucleotide. This study provides comprehensive data on the adsorption of DNA oligonucleotides onto TiO2 nanolayers and clarifies the interaction mechanisms therein, which will be valuable for applications of TiO2 in DNA-related applications.

[Correlation of anti-C1q antibodies with active systemic lupus erythematosus and lupus nephritis in children]. / 抗C1qæŠ—ä½“ä¸Žå„¿ç«¥æ´»åŠ¨æ€§ç³»ç»Ÿæ€§çº¢æ–‘ç‹¼ç–®å’Œæ´»åŠ¨æ€§ç‹¼ç–®æ€§è‚¾ç‚Žçš„ç›¸å ³æ€§åˆ†æž.

OBJECTIVES: To study the correlation of anti-C1q antibodies with active systemic lupus erythematosus (SLE) and lupus nephritis (LN) in children, as well as their diagnostic value for active SLE and LN. METHODS: A retrospective selection of 90 hospitalized children with SLE at the Children's Medical Center of Second Xiangya Hospital, Central South University from January 2016 to March 2019 as the SLE group, all of whom were tested for anti-C1q antibodies. A control group was formed by collecting 70 hospitalized children with other autoimmune diseases (OAD) during the same period. The differences in anti-C1q antibody levels were compared between two groups.The correlation of anti-C1q antibodies with various indicators of SLE and LN was analyzed, and the diagnostic value of anti-C1q in SLE and LN was evaluated. RESULTS: The serum levels of anti-C1q antibodies in the SLE group were higher than those in the OAD group (P<0.05). The SLE disease activity index score was positively correlated with anti-C1q antibodies (rs=0.371, P<0.001) and positively correlated with anti-double-stranded DNA antibodies (rs=0.370, P<0.001). The sensitivity and specificity of anti-C1q antibodies for diagnosing active SLE were 89.90% and 53.90%, respectively, with an area under the curve of 0.720 (P<0.05) and a critical value of 5.45 U/mL. The sensitivity and specificity of anti-C1q antibody levels for diagnosing active LN were 58.50% and 85.00%, respectively, with an area under the curve of 0.675 (P<0.05) and a critical value of 22.05 U/mL. CONCLUSIONS: Anti-C1q antibodies can serve as non-invasive biomarkers for evaluating the activity of SLE or predicting the activity of LN in children.

Potassium voltage-gated channel subfamily H member 2 (KCNH2) is a promising target for incretin secretagogue therapies.

Derived from enteroendocrine cells (EECs), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are pivotal incretin hormones crucial for blood glucose regulation. Medications of GLP-1 analogs and GLP-1 receptor activators are extensively used in the treatment of type 2 diabetes (T2D) and obesity. However, there are currently no agents to stimulate endogenous incretin secretion. Here, we find the pivotal role of KCNH2 potassium channels in the regulation of incretin secretion. Co-localization of KCNH2 with incretin-secreting EECs in the intestinal epithelium of rodents highlights its significance. Gut epithelial cell-specific KCNH2 knockout in mice improves glucose tolerance and increases oral glucose-triggered GLP-1 and GIP secretion, particularly GIP. Furthermore, KCNH2-deficient primary intestinal epithelial cells exhibit heightened incretin, especially GIP secretion upon nutrient stimulation. Mechanistically, KCNH2 knockdown in EECs leads to reduced K+ currents, prolonged action potential duration, and elevated intracellular calcium levels. Finally, we found that dofetilide, a KCNH2-specific inhibitor, could promote incretin secretion in enteroendocrine STC-1 cells in vitro and in hyperglycemic mice in vivo. These findings elucidate, for the first time, the mechanism and application of KCNH2 in regulating incretin secretion by EECs. Given the therapeutic promise of GLP-1 and GIP in diabetes and obesity management, this study advances our understanding of incretin regulation, paving the way for potential incretin secretagogue therapies in the treatment of diabetes and obesity.

Hyperglycemia induced cathepsin L maturation linked to diabetic comorbidities and COVID-19 mortality.

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Leprdb/dbmice and Leprdb/+mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.

People with diabetes are at greater risk of developing severe COVID-19 and dying from the illness, which is caused by a virus known as SARS-CoV-2. The high blood sugar levels associated with diabetes appear to be a contributing factor to this heightened risk. However, diabetes is a complex condition encompassing a range of metabolic disorders, and it is therefore likely that other factors may contribute. Previous research identified a link between an enzyme called cathepsin L and more severe COVID-19 in people with diabetes. Elevated cathepsin L levels are known to contribute to diabetes complications, such as kidney damage and vision loss. It has also been shown that cathepsin L helps SARS-CoV-2 to enter and infect cells. This raised the question of whether elevated cathepsin L is responsible for the increased COVID-19 vulnerability in patients with diabetes. To investigate, He, Zhao et al. monitored disease severity and cathepsin L levels in patients with COVID-19. This confirmed that people with diabetes had more severe COVID-19 and that higher levels of cathepsin L are linked to more severe disease. Analysis also revealed that cathepsin L activity increases as blood glucose levels increase. In laboratory experiments, cells exposed to glucose or fluid from the blood of people with diabetes were more easily infected with SARS-CoV-2, with cells genetically modified to lack cathepsin L being more resistant to infection. Further experiments revealed this was due to glucose promoting maturation and migration of cathepsin L in the cells. The findings of He, Zhao et al. help to explain why people with diabetes are more likely to develop severe or fatal COVID-19. Therefore, controlling blood glucose levels in people with diabetes may help to prevent or reduce the severity of the disease. Additionally, therapies targeting cathepsin L could also potentially help to treat COVID-19, especially in patients with diabetes, although more research is needed to develop and test these treatments.

The spatial variations and driving factors of C, N, P stoichiometric characteristics of plant and soil in the terrestrial ecosystem.

Carbon(C), nitrogen(N), and phosphorus(P) are crucial elements in the element cycling in the terrestrial ecosystems. In the past decades, the spatial pattern and driving mechanism of plant and soil ecological stoichiometry have been hot topics in ecological geography. So far, many studies at different spatial and ecological scales have been conducted, but systematic review has not been reported to summarize the research status. In this paper, we tried to fill this gap by reviewing both the spatial variations and driving factors of C, N, P stoichiometric characteristics of plant and soil at regional to large scale. Additionally, we synthesized researches on the relationships between plant and soil C, N and P stoichiometric characteristics. At the global scale, plant C, N, P stoichiometric characteristics exhibited some trends along latitude and temperature gradient. Plant taxonomic classification was the main factor controlling the spatial variations of plant C, N and P stoichiometric characteristics. Climate factor and soil properties showed varying impacts on the spatial variations of plant C, N, P stoichiometric characteristics across different spatial scales. Soil C, N, P stoichiometric characteristics also vary along climate gradient at large scale. Their spatial variations result from the combined effects of climate, topography, soil properties, and vegetation characteristics at regional scale. The spatial pattern of soil C, N, P stoichiometric characteristics and the driving effects from environmental factors could be notably different among different ecosystems and vegetation types. Plant C:N:P is obviously higher than that of soil, and there exists a positive correlation between plant and soil C:N:P. Their trends along longitude and latitude are similar, but this correlation varies significantly among different vegetation types. Finally, based on the issues identified in this paper, we highlighted eight potential research themes for the future studies.

Efficient Electrochemical Sensing of Chlorpromazine with a Composite of Multiwalled Carbon Nanotubes and a Thiacalix[4]arene-Based Metal-Organic Framework.

Chlorpromazine (CPMZ) is a representative drug for the treatment of psychiatric disorders. Excessive use of CPMZ could result in some serious health problems, and therefore, construction of a sensitive electrochemical sensor for CPMZ detection is greatly significant for human health. Herein, a feasible electrochemical method for the detection of CPMZ was provided. To design a suitable electrode surface modifier, a new two-dimensional (2D) thiacalix[4]arene-based metal-organic framework was designed and synthesized under solvothermal conditions, namely, [Co(TMPA)Cl2]MeOH·2EtOH·2H2O (Co-TMPA). Afterward, a series of composite materials was prepared by combining Co-TMPA with highly conductive carbon materials. Markedly, Co-TMPA/MWCNT-2@GCE (GCE = glassy carbon electrode, MWCNT = multiwalled carbon nanotube) exhibited the best electrocatalytic performance for CPMZ detection due to the synergistic effect between MWCNT and Co-TMPA. Particularly, it featured a low limit of detection (8 nM) and a wide linear range (0.05 to 1350 µM) in quantitative determination of CPMZ. Meanwhile, the sensor possessed excellent stability, selectivity, and reproducibility. Importantly, Co-TMPA/MWCNT-2@GCE was employed to analyze CPMZ in urine and serum with satisfactory recoveries (98.87-102.17%) and relative standard deviations (1.44-3.80%). Furthermore, the electrochemical detection accuracy of the Co-TMPA/MWCNT-2@GCE sensor was verified with the ultraviolet-visible spectroscopy technique. This work offers a promising sensor for the efficient analysis of drug molecules.

Clinical Trial Data-Driven Risk Assessment of Drug-Drug Interactions: A Rapid and Accurate Decision-Making Tool.

BACKGROUND: In clinical practice, the vast array of potential drug combinations necessitates swift and accurate assessments of pharmacokinetic drug-drug interactions (DDIs), along with recommendations for adjustments. Current methodologies for clinical DDI evaluations primarily rely on basic extrapolations from clinical trial data. However, these methods are limited in accuracy owing to their lack of a comprehensive consideration of various critical factors, including the inhibitory potency, dosage, and type of the inhibitor, as well as the metabolic fraction and intestinal availability of the substrate. OBJECTIVE: This study aims to propose an efficient and accurate clinical pharmacokinetic-mediated DDI assessment tool, which comprehensively considers the effects of inhibitory potency and dosage of inhibitors, intestinal availability and fraction metabolized of substrates on DDI outcomes. METHODS: This study focuses on DDIs caused by cytochrome P450 3A4 enzyme inhibition, utilizing extensive clinical trial data to establish a methodology to calculate the metabolic fraction and intestinal availability for substrates, as well as the concentration and inhibitory potency for inhibitors ( K i or k inact / K I ). These parameters were then used to predict the outcomes of DDIs involving 33 substrates and 20 inhibitors. We also defined the risk index for substrates and the potency index for inhibitors to establish a clinical DDI risk scale. The training set for parameter calculation consisted of 73 clinical trials. The validation set comprised 89 clinical DDI trials involving 53 drugs. which was used to evaluate the reliability of in vivo values of K i and k inact / K I , the accuracy of DDI predictions, and the false-negative rate of risk scale. RESULTS: First, the reliability of the in vivo K i and k inact / K I values calculated in this study was assessed using a basic static model. Compared with values obtained from other methods, this study values showed a lower geometric mean fold error and root mean square error. Additionally, incorporating these values into the physiologically based pharmacokinetic-DDI model facilitated a good fitting of the C-t curves when the substrate's metabolic enzymes are inhibited. Second, area under the curve ratio predictions of studied drugs were within a 1.5 × margin of error in 81% of cases compared with clinical observations in the validation set. Last, the clinical DDI risk scale developed in this study predicted the actual risks in the validation set with only a 5.6% incidence of serious false negatives. CONCLUSIONS: This study offers a rapid and accurate approach for assessing the risk of pharmacokinetic-mediated DDIs in clinical practice, providing a foundation for rational combination drug use and dosage adjustments.

Emerging nanozyme therapy incorporated into dental materials for diverse oral pathologies.

OBJECTIVE: Nanozyme materials combine the advantages of natural enzymes and artificial catalysis, and have been widely applied in new technologies for dental materials and oral disease treatment. Based on the role of reactive oxygen species (ROS) and oxidative stress pathways in the occurrence and therapy of oral diseases, a comprehensive review was conducted on the methods and mechanisms of nanozymes and their dental materials in treating different oral diseases. METHODS: This review is based on literature surveys from PubMed and Web of Science databases, as well as reviews of relevant researches and publications on nanozymes in the therapy of oral diseases and oral tumors in international peer-reviewed journals. RESULTS: Given the unique function of nanozymes in the generation and elimination of ROS, they play an important role in the occurrence, development, and treatment of different oral diseases. The application of nanozymes in dental materials and oral disease treatment was introduced, including the latest advances in their use for dental caries, pulpitis, jaw osteomyelitis, periodontitis, oral mucosal diseases, temporomandibular joint disorders, and oral tumors. Future approaches were also summarized and proposed based on the characteristics of these diseases. SIGNIFICANCE: This review will guide biomedical researchers and oral clinicians to understand the mechanisms and applications of nanozymes in the therapy of oral diseases, promoting further development in the field of dental materials within the oral medication. It is anticipated that more suitable therapeutic agents or dental materials encapsulating nanozymes, specifically designed for the oral environment and simpler for clinical utilization, will emerge in the forthcoming future.

Early Developmental Characteristics and Features of a Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis.

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin (RS1) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS.

Anti-seasonal flooding drives substantial alterations in riparian plant diversity and niche characteristics in a unique hydro-fluctuation zone.

Human-induced disturbances such as dam construction and regulation have led to widespread alterations in hydrological processes and thus substantially influence plant characteristics in the hydro-fluctuation zones (HFZs). To reveal utilization of limited resources and mechanisms of inter-specific competition and species co-existence of plant communities based on niche breadth and overlap under the different HFZs of the Three Gorges Reservoir (TGR) in China, we conducted a field investigation with 368 quadrats on the effects of hydrological alterations on plant diversity and niche characteristics. The results showed anti-seasonal flooding precipitated the gradual disappearance of the original diverse niches, resulting in the reduction of plant species richness and functional diversity and more obvious competition among plant species with similar resource requirements. Annuals, perennials and shrubs accounted for 71.23%, 27.39% and 1.37%, respectively, suggesting that annuals and flood-tolerant riparian herbs were favored under such novel flooding conditions. A consistent increase in species number, Shannon-Wiener diversity index and Simpson dominance index with altitude was inconsistent with hump-shaped diversity-disturbance relationship of the intermediate disturbance hypothesis, while the opposite trend was observed for the Pielou evenness index. This species distribution pattern might be caused by several synergetic attributes (e.g., the submergence depth, plant tolerant capacity to flooding, life form, dispersal mode and inter-specific competition). Vegetation types shifted from xerophytes to mesophytes and eventually to hygrophytes with the increasing flooding time in the HFZs. Hydrological alterations proved to be the paramount driver of vegetation distribution in the different HFZs. The niche analysis provided the first insights on the mechanisms of resource utilization and inter-specific competition, of which annuals could germinate quickly after soil drainage to achieve the greatest competitive advantages and occupy a larger niche space than other plants. Vegetation was still in the early stage of primary succession in the novel riparian forests. Therefore, vegetation restoration strategies should be biased towards herbaceous plants, due to annuals with better environmental adaptability, supplemented by shrubs and small trees. To establish a complete reference system for vegetation restoration, natural vegetation monitory plots in the different succession stages should be established in the different HFZs of the TGR, and their environmental conditions, community structures and inter-specific relationships further analyzed.

Preliminary study on the active substances and cellular pathways of lactic acid bacteria for colorectal cancer treatment.

Colorectal cancer (CRC) is a common malignant tumor and is one of the three most common cancers worldwide. Traditional surgical treatment, supplemented by chemotherapy and radiotherapy, has obvious side effects on patients. Immunotherapy may lead to some unpredictable complications. Low introduction rate and high cost are some of the problems of gene therapy, so finding a safe, reliable and least toxic treatment method became the main research direction for this study. Lactic acid bacteria and their metabolites are widely used in functional foods or as adjuvant therapies for various diseases because they are safe to eat and have no adverse reactions. Research has shown that lactic acid bacteria and their metabolites play an auxiliary therapeutic role in colorectal cancer mainly by improving the intestinal flora composition, inhibiting the growth of pathogenic bacteria and inhibiting the proliferation of cancer cells. It is now widely believed that the substances that probiotics such as lactic acid bacteria exert anti-cancer effects are mainly secondary metabolites such as butyric acid. Lb. plantarum AY01 isolated from fermented food has good anti-cancer ability, and its main anti-cancer substance is 2'-deoxyinosine. Through flow cytometry detection, it was found that Lb. plantarum AY01 can block cell proliferation in the S phase. In addition, Lb. plantarum AY01 culture reduces the sensitivity of mice to colitis-associated CRC induced by azoxymethane (AOM)/dextran sulfate sodium salt (DSS) and exhibits the occurrence and promotion of tumors. According to transcriptome analysis, Lb. plantarum AY01 may induce apoptosis of colorectal cancer cells by activating the p38 MAPK pathway. This experiment provided possibilities for the treatment of CRC.

Initial ribociclib plus endocrine therapy for HR+/HER2- advanced breast cancer in pre- and postmenopausal Chinese women: Primary results from a phase 2 randomized study.

BACKGROUND: The MONALEESA­7 and ­2 phase 3 randomized trials demonstrated a statistically significant progression­free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre­ and postmenopausal patients with hormone receptor­positive (HR+)/human epidermal growth factor receptor 2­negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre­ and postmenopausal patients with HR+/HER2­ ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA­7 and ­2 studies. METHODS: Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator­assessed PFS. RESULTS: As of April 25, 2022, the median follow­up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. CONCLUSIONS: These data demonstrate a favorable benefit­risk profile for ribociclib + ET in Chinese patients.

NL13, a novel curcumin analogue and polo like kinase 4 inhibitor, induces cell cycle arrest and apoptosis in prostate cancer models.

BACKGROUND AND PURPOSE: Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer. EXPERIMENTAL APPROACH: NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses. KEY RESULTS: Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC50, 3.51 µM vs. 35.45 µM) and DU145 (IC50, 2.53 µM vs. 29.35 µM) prostate cancer cells viability and PLK4 kinase activity (2.32 µM vs. 246.88 µM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3. CONCLUSION AND IMPLICATIONS: NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.

Self-Lubrication Mechanism of Surface-Textured Polymer-Matrix Composites under the Induction of Frictional Stress.

Polymer-matrix composites have been widely used in the manufacture of seals, bearings, electrical insulators, and self-lubricating films as engineering applications move toward lighter weight, higher strength, and corrosion resistance. However, the high-speed shear effect of the friction pairs in relative motion leads to localized heating of the polymer surface, resulting in deformation or softening of the device. Herein, acer mono maple and canna leaves were used as templates to construct polymer-matrix sulfonated polyether-etherketone/polytetrafluoro-wax (SPEEK/PFW) composites with a surface-textured structure. As the bionic texture reduces the level of direct contact between the friction pairs, the frictional thermosoftening of SPEEK occurs in the localized areas of the bumps and leads to the release of PFW stored in textures, resulting in the formation of a soft polymer sliding layer in the worn area and greatly enhancing the frictional stability. By investigation of the tribological properties of textured SPEEK/PFW composites under different loads and sliding speeds, the mechanisms from surface wear to matrix softening and spontaneous construction of a slipping layer are summarized. The results of scanning electron microscopy and three-dimensional profilometer characterization of the wear scars show the surface state of SPEEK/PFW after friction, revealing the friction-thermotropic deformation of the surface texture. The results of this study not only improve our understanding of the frictional heat-induced surface self-lubrication mechanism of textured polymer composites but also provide a reference for the development of multiphase hybrid polymer-matrix composites with excellent self-lubrication properties.

Access to Piperazine-Fused Pyrrolocarbazoles Enabled by Acid-Catalyzed Stereoselective Hydroarylation of Ynamide-Indoles and Subsequent Diels-Alder Reactions/Aromatizations.

Pyrrolocarbazole skeletons are well known to possess a variety of biological activities that might be therapeutically useful in the treatment of cancers. Herein, an acid-catalyzed stereoselective hydroarylation/Diels-Alder cycloaddition/aromatization of ynamide-indoles is described. We newly designed and synthesized a variety of piperazine-fused pyrrolocarbazole derivatives that could be further applied to the synthesis of potent Wee1 inhibitors.

Accumulated ß-catenin is associated with human atrial fibrosis and atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by ß-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of ß-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues . METHODS: We compared the difference of ß-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of ß-catenin in the development of AF was also explored in mice and primary cells. RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of ß-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, ß-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3ß (GSK-3ß) and Adenomatous Polyposis Coli (APC), which participated in the degradation of ß-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting ß-catenin expression in the AF model mice. CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that ß-catenin was associated with atrial fibrosis and AF progression.