Thiadiazol ligand-based laccase-like nanozymes with a high Cu+ ratio for efficient removal of tetracyclines through polymerization.

A promising water treatment technology involves inducing the polymerization of organic pollutants to form corresponding polymers, enabling rapid, efficient, and low CO2 emission removal of these pollutants. However, there is currently limited research on utilizing polymerization treatment technology for removing tetracyclines from water. In this study, we synthesized a laccase-mimic nanozyme (Cu-ATZ) with a high Cu+ ratio using 2-amino-1,3,4-thiadiazole as a ligand inspired by natural laccase. The Cu-ATZ exhibited enhanced resistance to more severe application conditions and improved stability compared to natural laccase, thereby demonstrating a broader range of potential applications. The excellent catalytic properties of Cu-ATZ enabled the nanozyme to be used in the polymerization process to remove tetracyclines from water. In order to simulate actual antibiotic pollution of water bodies, tetracyclines were added to the water from sewage treatment plants. Following Cu-ATZ treatment of the water sample, the chemical oxygen demand (COD) content was found to have decreased by over 80 %. In conclusion, this study presented a novel approach for tetracycline elimination from water.

Micro-/nano-plastics as vectors of heavy metals and stress response of ciliates using transcriptomic and metabolomic analyses.

The escalating presence of microplastics and heavy metals in marine environments significantly jeopardizes ecological stability and human health. Despite this, research on the combined effects of microplastics/nanoplastics (MPs/NPs) and heavy metals on marine organisms remains limited. This study evaluated the impact of two sizes of polystyrene beads (approximately 2 µm and 200 nm) combined with cadmium (Cd) on the ciliate species Euplotes vannus. Results demonstrated that co-exposure of MPs/NPs and Cd markedly elevated reactive oxygen species (ROS) levels in ciliates while impairing antioxidant enzyme activities, thus enhancing oxidative damage and significantly reducing carbon biomass in ciliates. Transcriptomic profiling indicated that co-exposure of MPs/NPs and Cd potentially caused severe DNA damage and protein oxidation, as evidenced by numerous differentially expressed genes (DEGs) associated with mismatch repair, DNA replication, and proteasome function. Integrated transcriptomic and metabolomic analysis revealed that DEGs and differentially accumulated metabolites (DAMs) were significantly enriched in the TCA cycle, glycolysis, tryptophan metabolism, and glutathione metabolism. This suggests that co-exposure of MPs/NPs and Cd may reduce ciliate abundance and carbon biomass by inhibiting energy metabolism and antioxidant pathways. Additionally, compared to MPs, the co-exposure of NPs and Cd exhibited more severe negative effects due to the larger specific surface area of NPs, which can carry more Cd. These findings provide novel insights into the toxic effects of MPs/NPs and heavy metals on protozoan ciliates, offering foundational data for assessing the ecological risks of heavy metals exacerbated by MPs/NPs.

Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair.

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.

EGFR-TKIs - induced cardiotoxicity in NSCLC: incidence, evaluation, and monitoring.

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors.

An informative dual ForkNet for video anomaly detection.

An autoencoder for video anomaly detection task is a type of algorithm with the primary purpose of learning an "informative" representation of the normal data that can be used for identifying the abnormal data by learning to reconstruct a set of input observations. Based on the encoding-decoding structure, we explore a novel dual ForkNet architecture that can dissociate and process the spatio-temporal representation. It is well-known in the information theory community that most autoencoders coding processes are inevitably accompanied by a certain loss of information. In this dual ForkNet, we focus on mitigating the information loss problem and propose a novel architectural recalibration approach, which we term the "Informetrics Recalibration" (IR). It can adaptively recalibrate latent feature representation by explicitly modeling the similarity between the corresponding feature maps of encoder and decoder, and retain more useful semantic information to generate greater differentiation between normal and abnormal events. Additionally, because the structure of the autoencoder itself determines the difficulty to obtain deep semantic information, we introduce a Secondary Encoder (SE) in each ForkNet, so as to recalibrate target features responses of latent feature representation. Our model is easy to be trained and robust to be applied, because it basically consists of some ResNet blocks without using complicated modules. Extensive experiments on the five publicly available benchmarks show that our model outperforms the existing state-of-the-art architectures, demonstrating our framework's effectiveness.

Risk factors of osimertinib-related cardiotoxicity in non-small cell lung cancer.

Objective: To investigate the risk factors associated with cardiotoxicity in patients with non-small cell lung cancer (NSCLC) treated with osimertinib. Methods: A total of 268 patients with NSCLC treated with osimertinib in our hospital from June 2019 to December 2023 were selected to observe the occurrence of cardiotoxicity and were divided into cardiotoxicity group and non-cardiotoxicity group. The differences in age, gender, body mass index (BMI), smoking, alcohol consumption, tumor stage, hypertension, diabetes, hyperlipidemia, chemotherapy, radiotherapy, antiangiogenic drugs, and osimertinib treatment time were recorded and analyzed. Logistic regression was used to analyze the risk factors for cardiotoxicity in patients with non-small cell lung cancer caused by osimertinib treatment. Results: Among the 268 patients with NSCLC treated with osimertinib, 58 patients developed cardiotoxicity, and the incidence of cardiotoxicity was 21.64%. There were statistically significant differences between the cardiotoxicity group and the non-cardiotoxicity group in terms of smoking history, hyperlipidemia history, combined chemotherapy, and combined radiotherapy (P < 0.05). Further analysis showed that patients with a smoking history were at increased risk of cardiotoxicity compared with non-smoking patients (OR = 2.569, 95% CI = 1.398-6.523). Patients with hyperlipidemia were at increased risk of cardiotoxicity compared with those without hyperlipidemia (OR = 3.412, 95% CI = 2.539-7.628). Patients with chemotherapy were at increased risk of cardiotoxicity compared with those without combination chemotherapy (OR = 2.018, 95% CI = 1.426-4.517). Patients undergoing radiotherapy to the left chest were at increased risk of cardiotoxicity compared with those without combined radiotherapy (OR = 1.629, 95% CI = 1.273-4.206). Conclusion: The incidence of cardiotoxicity in patients with NSCLC is high due to osimertinib treatment. A history of smoking, hyperlipidemia, combination chemotherapy, and radiotherapy to the left chest are independent risk factors for cardiotoxicity in patients with NSCLC treated with osimertinib.

Study of Mechanical Properties of Sand Layer Grouting Reinforcement under Seawater Erosion.

Grouting serves as an effective method for mitigating geotechnical disasters in subsea tunnels. However, current theories and designs, primarily based on terrestrial tunnel contexts, seldom address the long-term effects of seawater ion erosion on reinforcement. An improved sand permeation grouting simulation test system was employed to examine the mechanical property evolution of sand layer grouting reinforcement under seawater erosion utilizing various grout types. The mechanical properties of grouting reinforcement, under varying curing conditions, were analyzed using a uniaxial compression test, permeability test, and scanning electron microscope (SEM) test. Test results indicate that seawater curing conditions initially enhance the strength and impermeability of grouting reinforcement; however, prolonged curing diminishes these mechanical benefits. The onset of this process occurs significantly sooner in cement-sodium silicate grout (28-56 days) compared to cement grout (56d to 90d). For the cement grouting reinforcement, the deformation modulus increases over time, albeit at a decreasing rate. The deformation modulus of cement-sodium silicate grouting reinforcement follows an increase-decrease-increase pattern, correlating with the volume ratio over time. The decline in mechanical properties of grouting reinforcement during the test's mid to late stages under seawater conditions results from the interplay between erosive ions, which inhibit mechanical growth and accelerate deterioration.

Natural mineral colloids facilitated transport of EE2 in saturated porous media: Effects of humic acid and conjugate form.

Steroid estrogens have posed significant ecological risks to aquatic organisms due to their potent endocrine-disrupting effects. The role of natural mineral colloids in facilitating the transport of hydrophobic organic pollutants in the environment has been confirmed, but the control mechanisms of colloids on 17α-Ethinylestradiol (EE2) migration in the subsurface environment are often still not well understood. This study combined the batch sorption equilibrium experiments and dynamic transport simulations to reveal the interface interactions and co-transport characteristics between illite colloids and EE2 at both macroscopic and microscopic levels. The existing form changes of EE2 and the influence of coexisting humic acid (HA) during transport in porous media were also specifically investigated. The batch experiments demonstrated that the primary mechanisms governing EE2 sorption onto illite colloids involved surface sorption and hydrogen bonding. The coexistence of HA could load onto the surface of illite colloids, thereby enhancing the colloidal sorption capacity for EE2. Transport experiments demonstrated that the migratory ability of EE2 in silty clay was limited, but illite colloids could significantly promote its penetration, with the peak penetration content (Ct/C0) increasing from 0.64 to 0.77. In the absence of HA, EE2 primarily transported in a dissolved form, accounting for 62.86% of the total concentrations. When HA concentrations were increased to 10 mg/L and 20 mg/L, the proportion of colloidal conjugate EE2 in the effluents reached 52.13% and 54.49%, respectively. The enhanced transport of EE2 by HA was primarily attributed to the improved migration ability of illite colloids and the increased proportion of illite-EE2 conjugate, resulting in a maximum Ct/C0 value of 0.94. The validity of these results was further confirmed by employing calculations based on the Derjaguin-Landau-Verwey-Overbeek and Colloidal Filtration Theory. This study provides new insights of understanding the transport of EE2 in subsurface environment.

Rice floury endosperm26 encoding a mitochondrial single-stranded DNA-binding protein is essential for RNA-splicing of mitochondrial genes and endosperm development.

Endosperm, the major storage organ in cereal grains, determines the grain yield and quality. Mitochondria provide the energy for dry matter accumulation, in the endosperm development. Although mitochondrial single-stranded DNA-binding proteins (mtSSBs) play a canonical role in the maintenance of single-stranded mitochondrial DNA, their molecular functions in RNA processing and endosperm development remain obscure. Here, we report a defective rice endosperm mutant, floury endosperm26 (flo26), which develops abnormal starch grains in the endosperm. Map-based cloning and complementation experiments showed that FLO26 allele encodes a mitochondrial single-stranded DNA-binding protein, named as mtSSB1.1. Loss of function of mtSSB1.1 affects the transcriptional level of many mitochondrially-encoded genes and RNA splicing of nad1, a core component of respiratory chain complex I in mitochondria. As a result, dysfunctional mature nad1 led to dramatically decreased complex I activity, thereby reducing ATP production. Our results reveal that mtSSB1.1 plays an important role in the maintenance of mitochondrial function and endosperm development by stabilizing the splicing of mitochondrial RNA in rice.

Clinical Outcomes of Percutaneous Endoscopic Transforaminal Discectomy for the Treatment of Disc Herniation: A 3-Year Retrospective Study.

AIM: Percutaneous endoscopic transforaminal discectomy (PELD) is a new minimally invasive spine surgery for patients with lumbar disc herniation (LDH). Based on the 3-year follow-up data, the effect of PELD on the clinical outcomes of patients with LDH through a retrospective cohort study was analyzed in this article, so as to provide guidance for clinical selection of surgical options. METHODS: The clinical data of 150 patients with LDH admitted to our hospital from January 2019 to October 2020 were retrospectively analyzed. According to the surgical methods recorded in the medical record system, the patients were divided into the open lumbar microdiscectomy (OLM) group (n = 50) and the PELD group (n = 100). The surgical and postoperative recovery indicators of the two groups were compared after matching. These included incision length, intraoperative blood loss, operation time, postoperative ambulation time and hospital stays, recovery rate, short-term complication rate, Lumbar visual analogue scale (VAS) score, and Oswestry Disability Index (ODI) score. RESULTS: Compared with the OLM group, the PELD group had shorter incision length, shorter operation time, shorter postoperative ambulation time, shorter hospital stays, less intraoperative blood loss, lower short-term complication rate, lower lumbar pain and dysfunction scores at 3 months, 6 months, and 1 year after operation, higher short-term excellent-and-good recovery rate, and higher quality-of-life scores at 3 years after operation (p < 0.05). CONCLUSIONS: Compared with OLM, PELD in the treatment of LDH patients can reduce the operation time, blood loss, and length of hospital stays, suggesting a short-term postoperative recovery effect. Compared with OLM, PELD can also reduce the incidence of short-term complications, enhance the effect of pain control and improvement of dysfunction in the medium term, and improve the long-term quality of life.

Clinical Outcomes and Prognostic Factors in Stage III C Cervical Cancer Patients Treated with Radical Radiotherapy or Radiochemotherapy.

Objective: Since the update of the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging criteria, there have been few reports on the prognosis of stage III C cervical cancer. Moreover, some studies have drawn controversial conclusions, necessitating further verification. This study aims to evaluate the clinical outcomes and determine the prognostic factors for stage III C cervical cancer patients treated with radical radiotherapy or radiochemotherapy. Methods: The data of 117 stage III C cervical cancer patients (98 III C1 and 19 III C2) who underwent radical radiotherapy or radiochemotherapy were retrospectively analyzed. We evaluated 3-year overall survival (OS) and disease-free survival (DFS) using the Kaplan-Meier method. Prognostic factors were analyzed using the Log-rank test and Cox proportional hazard regression model. The risk of para-aortic lymph node metastasis (LNM) in all patients was assessed through Chi-squared test and logistic regression analysis. Results: For stage III C1 and III C2 patients, the 3-year OS rates were 77.6% and 63.2% (P = .042), and the 3-year DFS rates were 70.4% and 47.4% (P = .003), respectively. The pretreatment location of pelvic LNM, histological type, and FIGO stage was associated with OS (P = .033, .003, .042, respectively); the number of pelvic LNM and FIGO stage were associated with DFS (P = .015, .003, respectively). The histological type was an independent prognostic indicator for OS, and the numbers of pelvic LNM and FIGO stage were independent prognostic indicators for DFS. Furthermore, a pelvic LNM largest short-axis diameter ≥ 1.5 cm and the presence of common iliac LNM were identified as high-risk factors influencing para-aortic LNM in stage III C patients (P = .046, .006, respectively). Conclusions: The results of this study validated the 2018 FIGO staging criteria for stage III C cervical cancer patients undergoing concurrent chemoradiotherapy. These findings may enhance our understanding of the updated staging criteria and contribute to better management of patients in stage III C.

Novel intelligent packaging films based on starch/PVA with Cu-ICA nanocrystal as functional compatibilizer for monitoring food freshness.

Considering public health and environmental safety, the development of reliable and efficient monitoring methods is essential to ensure food quality and safety. Herein, a new Cu-based metal organic framework (Cu-ICA) nanocrystal with ammonia-sensitive performance was built up and then introduced as a functional compatibilizer of starch/polyvinyl alcohol (STA/PVA) blend to develop high-performance intelligent packaging films for food freshness monitoring. The introduction of Cu-ICA upgraded the compatibility, mechanical strength (42.9 MPa), UV-protection (with UV transmittance of only 2.8 %), and moisture/oxygen barrier performances of STA/PVA film. Furthermore, the developed STA/PVA/Cu-ICA films presented long-term colour stability, outstanding antibacterial efficacy (over 99.5 %) toward both Escherichia coli and Staphylococcus aureus bacteria, as well as remarkable ammonia-sensitive discoloration capability. The STA/PVA/Cu-ICA films possessed visually identifiable colour change during the monitoring of shrimp spoilage. These findings indicate that the developed STA/PVA/Cu-ICA film possesses tremendous potential as an intelligent active packaging material.

Effects of Streptomyces sp. HU2014 inoculation on wheat growth and rhizosphere microbial diversity under hexavalent chromium stress.

Wheat (Triticum aestivum L.) is a major foodstuff for over 40% of the world's population. However, hexavalent chromium [Cr(VI)] in contaminated soil significantly affects wheat production and its ecological environment. Streptomyces sp. HU2014 was first used to investigate the effects of Cr (VI) stress on wheat growth. We analyzed the Cr(VI) concentration, physicochemical properties of wheat and soil, total Cr content, and microbial community structures during their interactions. HU2014 reduced the toxicity of Cr(VI) and promoted wheat growth by increasing total nitrogen, nitrate nitrogen, total phosphorus, and Olsen-phosphorus in Cr(VI)-contaminated soil. These four soil variables had strong positive effects on two bacterial taxa, Proteobacteria and Bacteroidota, in the HU2014 treatments. In addition, the level of the dominant Proteobacteria positively correlated with the total Cr content in the soil. Among the fungal communities, which had weaker correlations with soil variables compared with bacterial communities, Ascomycota was the most abundant. Our findings suggest that HU2014 can promote the phytoremediation of Cr(VI)-contaminated soil.

Intelligent Detection and Odor Recognition of Cigarette Packaging Paper Boxes Based on a Homemade Electronic Nose.

The printing process of box packaging paper can generate volatile organic compounds, resulting in odors that impact product quality and health. An efficient, objective, and cost-effective detection method is urgently needed. We utilized a self-developed electronic nose system to test four different cigarette packaging paper samples. Employing multivariate statistical methods like Principal Component Analysis (PCA), Linear Discriminant Analysis (LDA), Statistical Quality Control (SQC), and Similarity-based Independent Modeling of Class Analogy (SIMCA), we analyzed and processed the collected data. Comprehensive evaluation and quality control models were constructed to assess sample stability and distinguish odors. Results indicate that our electronic nose system rapidly detects odors and effectively performs quality control. By establishing models for quality stability control, we successfully identified samples with acceptable quality and those with odors. To further validate the system's performance and extend its applications, we collected two types of cigarette packaging paper samples with odor data. Using data augmentation techniques, we expanded the dataset and achieved an accuracy rate of 0.9938 through classification and discrimination. This highlights the significant potential of our self-developed electronic nose system in recognizing cigarette packaging paper odors and odorous samples.

FLOURY ENDOSPERM24, a heat shock protein 101 (HSP101), is required for starch biosynthesis and endosperm development in rice.

Endosperm is the main storage organ in cereal grain and determines grain yield and quality. The molecular mechanisms of heat shock proteins in regulating starch biosynthesis and endosperm development remain obscure. Here, we report a rice floury endosperm mutant flo24 that develops abnormal starch grains in the central starchy endosperm cells. Map-based cloning and complementation test showed that FLO24 encodes a heat shock protein HSP101, which is localized in plastids. The mutated protein FLO24T296I dramatically lost its ability to hydrolyze ATP and to rescue the thermotolerance defects of the yeast hsp104 mutant. The flo24 mutant develops more severe floury endosperm when grown under high-temperature conditions than normal conditions. And the FLO24 protein was dramatically induced at high temperature. FLO24 physically interacts with several key enzymes required for starch biosynthesis, including AGPL1, AGPL3 and PHO1. Combined biochemical and genetic evidence suggests that FLO24 acts cooperatively with HSP70cp-2 to regulate starch biosynthesis and endosperm development in rice. Our results reveal that FLO24 acts as an important regulator of endosperm development, which might function in maintaining the activities of enzymes involved in starch biosynthesis in rice.

Physiological and transcriptomic responses of seawater halobios to micro/nano-scale polystyrene-cadmium exposure in a marine food web.

Micro/nano-plastics (MPs/NPs) represent an emerging contaminant, posing a significant threat to oceanic halobios. While the adverse effects of joint pollutants on marine organisms are well-documented, the potential biological impacts on the food chain transmission resulting from combinations of MPs/NPs and heavy metals (HMs) remain largely unexplored. This study exposed the microbial loop to combined contaminants (MPs/NPs + HMs) for 48h, bacteria and contaminants are washed away before feeding to the traditional food chain, employing microscopic observation, biochemical detection, and transcriptome analysis to elucidate the toxicological mechanisms of the top predator. The findings revealed that MPs/NPs combined with Cd2+ could traverse both the microbial loop and classical food chain. Acute exposure significantly affected the carbon biomass of the top predator Tigriopus japonicus (75.8% lower). Elevated antioxidant enzyme activity led to lipid peroxidation, manifesting in increased malondialdehyde levels. Transcriptome sequencing showed substantial differential gene expression levels in T. japonicus under various treatments. The upregulation of genes associated with apoptosis and inflammatory responses, highlighting the impact of co-exposure on oxidative damage and necroptosis within cells. Notably, NPs-Cd exhibited stronger toxicity than MPs-Cd. NPs-Cd led to a greater decrease in the biomass of top predators, accompanied by lower activities of GSH, SOD, CAT, and GSH-PX, resulting in increased production of lipid peroxidation product MDA and higher oxidative stress levels. This investigation provides novel insights into the potential threats of MPs/NPs combined with Cd2+ on the microbial loop across traditional food chain, contributing to a more comprehensive assessment of the ecological risks associated with micro/nano-plastics and heavy metals.

Effect of bioaugmentation on gas production and microbial community during anaerobic digestion in a low-temperature fixed-bed reactor.

Low temperature is one of the limiting factors for anaerobic digestion in cold regions. To improve the efficiency of anaerobic digestion for methane production in stationary reactors under low-temperature conditions, and to improve the structure of the microbial community for anaerobic digestion at low temperatures. We investigated the effects of different concentrations of exogenous Methanomicrobium (10, 20, 30%) and different volumes of carbon fiber carriers (0, 10, 20%) on gas production and microbial communities to improve the performance of low-temperature anaerobic digestion systems. The results show that the addition of 30% exogenous microorganisms and a 10% volume of carbon fiber carrier led to the highest daily (128.15 mL/g VS) and cumulative (576.62 mL/g VS) methane production. This treatment effectively reduced the concentrations of COD and organic acid, in addition to stabilizing the pH of the system. High-throughput sequencing analysis revealed that the dominant bacteria under these conditions were Acidobacteria and Firmicutes and the dominant archaea were Candidatus_Udaeobacter and Methanobacterium. While the abundance of microorganisms that metabolize organic acids was reduced, the functional abundance of hydrogenophilic methanogenic microorganisms was increased. Therefore, the synergistic effect of Methanomicrobium bioaugmentation with carbon fiber carriers can significantly improve the performance and efficiency of low-temperature anaerobic fermentation systems.

High glucose promotes atherosclerosis by regulating miRNA let7d-5p level.

BACKGROUND: MiRNA let7d-5p has been recently reported to be abnormally expressed in diabetes-associated atherosclerosis (AS). However, it still remains unknown how let7d-5p contributes to the process of atherosclerosis. METHODS: Twenty fresh tissues and a total of 28 wax block specimens from carotid endarterectomy procedures were obtained from the Luoyang Central Hospital affiliated to Zhengzhou University. The expression of let7d-5p was assessed using quantitative RT-PCR (qRT-PCR). A series of in vitro experiments was used to determine the roles of let7d-5p knockdown and overexpression in vascular smooth muscle cells (VSMCs). RESULTS: We discovered that the carotid plaques from diabetic patients had lower expression levels of miR let7d-5p. In VSMCs, the expression of miRNA let7d-5p was significantly lower in high glucose conditions compared with low glucose situations. The proliferation and migration of VSMCs were also inhibited by the overexpression of let7d-5p, whereas the opposite was true when let7d-5p was inhibited, according to gain and loss of function studies. Mechanically, let7d-5p might activate the GSK3ß/ß-catenin signaling pathway via binding to the high mobility group AT-Hook 2 (HMGA2) mRNA in VSMCs. Additionally, GLP-1RA liraglutide may prevent the migration and proliferation of VSMCs by raising let7d-5p levels. CONCLUSIONS: High glucose stimulated the proliferation and migration of VSMCs by regulating the let7d-5p/HMGA2/GSK3ß/ß-catenin pathway, and liraglutide may slow atherosclerosis by increasing the levels of miR let7d-5p.

Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia.

BACKGROUND: The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored. METHODS: Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms. RESULTS: We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene integrin beta 2 (ITGB2) was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine leukemia inhibitory factor (LIF). Further studies demonstrated that inhibition of cyclin-dependent kinase 7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF. We identified notoginsenoside R1 as a novel LIF inhibitor that exhibited synergistic effects in combination with temozolomide. CONCLUSIONS: Our research reveals that the epigenetic-mediated interaction of GBM cells with TAM drives the MES transition of GBM and provides a novel therapeutic avenue for patients with MES GBM.

IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/ß-catenin signaling pathway.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/ß-catenin pathway associated proteins (ß-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/ß-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/ß-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/ß-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.