PIAS3 acts as a zinc sensor under zinc deficiency and plays an important role in myocardial ischemia/reperfusion injury.

Alterations in zinc transporter expression in response to zinc loss protect cardiac cells from ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms how cardiac cells sense zinc loss remains unclear. Here, we found that zinc deficiency induced ubiquitination and degradation of the protein inhibitor of activated STAT3 (PIAS3), which can alleviate myocardial I/R injury by activating STAT3 to promote the expression of ZIP family zinc transporter genes. The RING finger domain within PIAS3 is vital for PIAS3 degradation, as PIAS3-dRing (missing the RING domain) and PIAS3-Mut (zinc-binding site mutation) were resistant to degradation in the setting of zinc deficiency. Meanwhile, the RING finger domain within PIAS3 is critical for the inhibition of STAT3 activation. Moreover, PIAS3 knockdown increased cardiac Zn2+ levels and reduced myocardial infarction in mouse hearts subjected to I/R, whereas wild-type PIAS3 overexpression, but not PIAS3-Mut, reduced cardiac Zn2+ levels, and exacerbated myocardial infarction. These findings elucidate a unique mechanism of zinc sensing, showing that fast degradation of the zinc-binding regulatory protein PIAS3 during zinc deficiency can correct zinc dyshomeostasis and alleviate reperfusion injury.

NaRbB10O14(OH)4 and Na3CsB10O16(OH)2: Two Cases of Hydroxyborates with [B5Om(OH)n] Units and Deep Ultraviolet Cutoff Edges.

Two deep ultraviolet (DUV) hydroxylated-alkali-metal borates, NaRbB10O14(OH)4 (I) and Na3CsB10O16(OH)2 (II), have been successfully synthesized by a high-temperature solution and solvothermal method. Both of them feature [B5Om(OH)n] units, which form chains for (I) and bilayers with nine-membered boron rings for (II). It is worth noting that both compounds exhibit very wide theoretical band gaps of 7.33 and 6.55 eV for (I) and (II), respectively, which denotes that they should have desirable DUV transmittance ability. Moreover, the title compounds have moderate birefringence owing to the π-conjugated [BO3], [BO2(OH)] groups, corresponding to 0.070 for (I) and 0.054 for (II) at 1064 nm. The structure characteristics and optical properties were also investigated and discussed. The results make it beneficial for exploring novel DUV hydroxylated borate optical crystals.

Discovery of the potential biomarkers for early diagnosis of endometrial cancer via integrating metabolomics and transcriptomics.

Endometrial cancer (EC) is one of the most common malignant tumors in women, and the increasing incidence and mortality pose a serious threat to the public health. Early diagnosis of EC could prolong the survival period and optimize the survivorship, greatly alleviating patients' suffering and social medical pressure. In this study, we collected urine and serum samples from the recruited patients, analyzed the samples using LC-MS approach, and identified the differential metabolites through metabolomic analysis. Then, the differentially expressed genes were identified through the systematic transcriptomic analysis of EC-related dataset from Gene Expression Omnibus (GEO), followed by network profiling of metabolic-reaction-enzyme-gene. In this experiment, a total of 83 differential metabolites and 19 hub genes were discovered, of which 10 different metabolites and 3 hub genes were further evaluated as more potential biomarkers based on network analysis. According to the KEGG enrichment analysis, the potential biomarkers and gene-encoded proteins were found to be involved in the arginine and proline metabolism, histidine metabolism, and pyrimidine metabolism, which was of significance for the early diagnosis of EC. In particular, the combination of metabolites (histamine, 1-methylhistamine, and methylimidazole acetaldehyde) as well as the combination of RRM2, TYMS and TK1 exerted more accurate discrimination abilities between EC and healthy groups, providing more criteria for the early diagnosis of EC.

VDR and deubiquitination control neuronal oxidative stress and microglial inflammation in Parkinson's disease.

Close correlation between vitamin D (VitD) deficiency and Parkinson's Disease (PD) risk, VitD as an adjuvant treatment promising to improve PD progression. However, VitD excessive intake could induce hypercalcemia and renal damage. Therefore, upregulation of vitD receptor (VDR) is considered a compensatory strategy to overcome VitD insufficiency and alleviate PD symptoms. In this study, we discovered that VDR played antioxidative roles in dopaminergic neurons by decreasing reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. Further, we newly identified VDR downstream events in C. elegans, including glutathione S-transferase (gst) and forkhead box transcription factor class O (daf-16) mediated oxidative stress resistance. VDR upregulation also mitigated microglial activation through inhibition of NLRP3/caspase-1-mediated inflammation and membrane permeabilization. These findings highlight the multifaceted protective effects of VDR in both neurons and microglia against the development of PD. Importantly, we discovered a novel deubiquitinase DUB3, whose N-terminal catalytic domain interacted with the C-terminal ligand-binding domain of VDR to reduce VDR ubiquitination. Identification of DUB3 as an essential player in the deubiquitinating mechanism of VDR provides valuable insights into VDR regulation and its potential as a therapeutic target for PD.

A new method for vascular age estimation based on relative risk difference in vascular aging.

OBJECTIVE: The current models of estimating vascular age (VA) primarily rely on the regression label expressed with chronological age (CA), which does not account individual differences in vascular aging (IDVA) that are difficult to describe by CA. This may lead to inaccuracies in assessing the risk of cardiovascular disease based on VA. To address this limitation, this work aims to develop a new method for estimating VA by considering IDVA. This method will provide a more accurate assessment of cardiovascular disease risk. METHODS: Relative risk difference in vascular aging (RRDVA) is proposed to replace IDVA, which is represented as the numerical difference between individual predicted age (PA) and the corresponding mean PA of healthy population. RRDVA and CA are regard as the influence factors to acquire VA. In order to acquire PA of all samples, this work takes CA as the dependent variable, and mines the two most representative indicators from arteriosclerosis data as the independent variables, to establish a regression model for obtaining PA. RESULTS: The proposed VA based on RRDVA is significantly correlated with 27 indirect indicators for vascular aging evaluation. Moreover, VA is better than CA by comparing the correlation coefficients between VA, CA and 27 indirect indicators, and RRDVA greater than zero presents a higher risk of disease. CONCLUSION: The proposed VA overcomes the limitation of CA in characterizing IDVA, which may help young groups with high disease risk to promote healthy behaviors.

A new methodology to reveal potential nucleic acid modifications associated with the risk of endometrial cancer through dispersive solid-phase extraction coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV.

Nucleic acid modifications have attracted increasing attention in recent years since they have been found to be related to a number of diseases including cancer. Previous studies have shown that the early development of endometrial cancer (EC) is often accompanied by changes in methylation levels of related genes, and the expression of related proteins that regulate reactive oxygen species (ROS) shows significant differences in EC cells and tissues. However, it has not been reported whether nucleic acid modifications related to methylation or ROS can serve as biomarkers for EC. Accurate quantification of these nucleic acid modifications still has challenges because their amounts in urine are very low and the interferences in urine are complicated. In this study, a novel dispersive solid-phase extraction (DSPE) method based on chitosan-carbon nanotube-Al2O3 (CS-CNT-Al2O3) has been established for the analysis of 5-hydroxymethyluracil (5 mU), 5-methyl-2'-deoxycytidine (5-mdC), 5-hydroxymethyl-2'-deoxycytidine (5-hmdC), 5-formyl-2'-deoxycytidine (5-fdC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in EC patient urine samples coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV. Firstly, the synthesis of the CS-CNT-Al2O3 nanocomposite was conducted by a sono-coprecipitation method and was characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS), and Fourier transform infrared (FTIR). Under the optimal extraction conditions of DSPE, we successfully quantified 5 mU, 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG in urine samples from 37 EC patients and 39 healthy controls. The results showed that there were significant differences in the levels of 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG in EC patients compared to the healthy control group. The receiver operator characteristic (ROC) curve analysis was carried out to evaluate the potential of 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG to distinguish EC patients from healthy volunteers. The area under the curve (AUC) for 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG was 0.7412, 0.667, 0.8438, and 0.7981, respectively. It indicated that 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG had certain potential in distinguishing between EC patients and healthy volunteers and they could act as potential non-invasive biomarkers for early diagnosis of EC. Moreover, the present study would stimulate investigations of the effects of nucleic acid modifications on the initiation and progression of EC.

Evaluation of early retinal changes in patients on long-term hydroxychloroquine using optical coherence tomography angiography.

Background: Connective tissue diseases (CTD), including systemic lupus erythematosus and rheumatoid arthritis (RA), have long been treated with hydroxychloroquine (HCQ). However, prolonged HCQ use poses a risk of adverse effects, particularly retinopathy. Objective: To detect early retinal changes assessed by optical coherence tomography angiography (OCTA) in CTD patients with long-term HCQ treatment and to explore the relationship between OCTA parameters and the concentrations of HCQ and its metabolites. Design: A cross-sectional study conducted from March 2020 to October 2021 at the First Affiliated Hospital of Anhui Medical University. Methods: The area and perimeter of the foveal avascular zone (FAZ), the thickness of the fovea and parafovea, and the vascular density of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in each area of the macula were measured by OCTA in 43 CTD patients treated with HCQ for over 6 months. Meantime, blood concentrations of HCQ and its metabolites were determined by high-performance liquid chromatography-tandem mass spectrometry, and the clinical documents of all 43 involved patients were collected. Results: There is no significant correlation between OCTA outcomes and the patient's age, disease duration, and weight-dependent dose. HCQ cumulative duration positively correlated with FAZ area and perimeter (r = 0.419, p = 0.005 and r = 0.407, p = 0.007, respectively) and negatively correlated with the foveal vessel density in DCP (r = -0.378, p = 0.012). HCQ cumulative dose had a positive correlation with FAZ area and perimeter (r = 0.445, p = 0.003 and r = 0.434, p = 0.004, respectively) and had a negative correlation with foveal vessel density in SCP and DCP (r = -0.383, p = 0.011 and r = -0.424, p = 0.005, respectively). OCTA outcomes did not correlate with HCQ and its metabolite concentrations. Conclusion: OCTA could be used to detect microvascular changes in the macula of CTD patients with long-term HCQ therapy. It was not found the concentrations of HCQ and its metabolites were associated with retinal vascular changes.

Genome-Wide Association Studies of Embryogenic Callus Induction Rate in Peanut (Arachis hypogaea L.).

The capability of embryogenic callus induction is a prerequisite for in vitro plant regeneration. However, embryogenic callus induction is strongly genotype-dependent, thus hindering the development of in vitro plant genetic engineering technology. In this study, to examine the genetic variation in embryogenic callus induction rate (CIR) in peanut (Arachis hypogaea L.) at the seventh, eighth, and ninth subcultures (T7, T8, and T9, respectively), we performed genome-wide association studies (GWAS) for CIR in a population of 353 peanut accessions. The coefficient of variation of CIR among the genotypes was high in the T7, T8, and T9 subcultures (33.06%, 34.18%, and 35.54%, respectively), and the average CIR ranged from 1.58 to 1.66. A total of 53 significant single-nucleotide polymorphisms (SNPs) were detected (based on the threshold value -log10(p) = 4.5). Among these SNPs, SNPB03-83801701 showed high phenotypic variance and neared a gene that encodes a peroxisomal ABC transporter 1. SNPA05-94095749, representing a nonsynonymous mutation, was located in the Arahy.MIX90M locus (encoding an auxin response factor 19 protein) at T8, which was associated with callus formation. These results provide guidance for future elucidation of the regulatory mechanism of embryogenic callus induction in peanut.

A novel variation of TaGW2-6B increases grain weight without penalty in grain protein content in wheat (Triticum aestivum L.).

Yield and quality are two crucial breeding objects of wheat therein grain weight and grain protein content (GPC) are two key relevant factors correspondingly. Investigations of their genetic mechanisms represent special significance for breeding. In this study, 199 F2 plants and corresponding F2:3 families derived from Nongda3753 (ND3753) and its EMS-generated mutant 564 (M564) were used to investigate the genetic basis of larger grain and higher GPC of M564. QTL analysis identified a total of 33 environmentally stable QTLs related to thousand grain weight (TGW), grain area (GA), grain circle (GC), grain length (GL), grain width (GW), and GPC on chromosomes 1B, 2A, 2B, 4D, 6B, and 7D, respectively, among which QGw.cau-6B.1, QTgw.cau-6B.1, QGa.cau-6B.1, and QGc.cau-6B.1 shared overlap confidence interval on chromosome 6B. This interval contained the TaGW2 gene playing the same role as the QTLs, so TaGW2-6B was cloned and sequenced. Sequence alignment revealed two G/A SNPs between two parents, among which the SNP in the seventh exon led to a premature termination in M564. A KASP marker was developed based on the SNP, and single-marker analysis on biparental populations showed that the mutant allele could significantly increase GW and TGW, but had no effect on GPC. Distribution detection of the mutant allele through KASP marker genotyping and sequence alignment against databases ascertained that no materials harbored this allele within natural populations. This allele was subsequently introduced into three different varieties through molecular marker-assisted backcrossing, and it was revealed that the allele had a significant effect on simultaneously increasing GW, TGW, and even GPC in all of three backgrounds. Summing up the above, it could be concluded that a novel elite allele of TaGW2-6B was artificially created and might play an important role in wheat breeding for high yield and quality. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01455-y.

Preparation of surface molecular imprinting fluorescent sensor based on magnetic porous silica for sensitive and selective determination of catechol.

A magnetic fluorescent molecularly imprinted sensor was successfully prepared and implemented to determine catechol (CT). Fe3O4 nanoparticles were synthesized by the solvothermal technique and mesoporous Fe3O4@SiO2@mSiO2 imprinted carriers were prepared by coating nonporous and mesoporous SiO2 shells on the surface of the Fe3O4 subsequently. The magnetic surface molecularly imprinted fluorescent sensor was created after the magnetic mesoporous carriers were modified with γ-methacryloxyl propyl trimethoxy silane to introduce double bonds on the surface of the carries and the polymerization was carried out in the presence of CT and fluorescent monomers. The magnetic mesoporous carriers were modified with γ-methacryloxyl propyl trimethoxy silane and double bonds were introduced on the surface of the carriers. After CT binding with the molecularly imprinted polymers (MIPs), the fluorescent intensity of the molecularly imprinted polymers (Ex = 400 nm, Em = 523 nm) increased significantly. The fluorescent intensity ratio (F/F0) of the sensor demonstrated a favorable linear correlation with the concentration of CT between 5 and 50 µM with a detection limit of 0.025 µM. Furthermore, the sensor was successfully applied to determine CT in actual samples with recoveries of 96.4-105% and relative standard deviations were lower than 3.5%. The results indicated that the research of our present work provided an efficient approach for swiftly and accurately determining organic pollutant in water.

Environmental stimulus-responsive mesoporous silica nanoparticles as anticancer drug delivery platforms.

Currently, cancer poses a significant health challenge in the medical community. Traditional chemotherapeutic agents are often accompanied by toxic side effects and limited therapeutic efficacy, restricting their application and advancement in cancer treatment. Therefore, there is an urgent need for developing intelligent drug release systems. Mesoporous silica nanoparticles (MSNs) have many advantages, such as a large specific surface area, substantial pore volume and size, adjustable mesoporous material pore size, excellent biocompatibility, and thermodynamic stability, making them ideal carriers for drug delivery and release. Additionally, they have been widely used to develop novel anticancer drug carriers. Recently, MSNs have been employed to design responsive systems that react to the tumor microenvironment and external stimuli for controlled release of anticancer drugs. This includes factors within the intratumor environment, such as pH, temperature, enzymes, and glutathione as well as external tumor stimuli, such as light, magnetic field, and ultrasound, among others. In this review, we discuss the research progress on environmental stimulus-responsive MSNs in anticancer drug delivery systems, including internal and external environment single stimulus-responsive release and combined stimulus-responsive release. We also summarize the current challenges associated with environmental stimulus-responsive MSNs and elucidate future directions, providing a reference for the functionalization modification and practical application of these MSNs.

Viral integration promotes SV40T-induced immortalization by disturbing the expression of DNA/chromosome- and ECM-associated functional genes.

Lentivirus containing simian virus 40 large T antigen (SV40T) is routinely used to induce cell immortalization. However, the roles of viral integration itself in this progress is still controversial. Here, we transformed primary mouse embryonic fibroblasts (MEFs) with SV40T lentivirus and studied the roles of viral integration in the immortalization using RNA sequencing (RNA-seq) and whole genome sequencing (WGS). During the immortalization, differentially expressed genes (DGEs) are enriched in viral infection and several diverse activities. However, DEGs between immortalized and aging cells are significantly enriched in DNA/chromosome- and extracellular matrix (ECM)-associated activities. Gene regulatory network (GRN) analysis shows that although p53 is a key regulatory factor, many other transcription factors also play critical roles in the process, like STAT1. Of these DEGs, 32 genes have viral integration in their coding and/or regulatory regions. Our findings suggest that viral integration may promote SV40T-mediated immortalization by disturbing the expression of DNA/chromosome- and ECM-associated genes.

Dissolution-precipitation method concatenated sodium alginate/MOF-derived magnetic multistage pore carbon magnetic solid phase extraction for determination of antioxidants and ultraviolet stabilizers in polylactic acid food contact plastics.

Antioxidants and UV stabilizers have some endocrine disrupting effects and liver toxicity. Both types of additives are still widely used in food contact plastics to improve the durability of plastic products. However, efficient and rapid detection of antioxidants and UV stabilizers has been a challenge due to the complexity of the plastic matrix and the low content of antioxidants and UV stabilizers. In this study, a sodium alginate/MOF-derived magnetic multistage pore carbon material (MIL-101(Fe)/SA-CAs) was developed, having the merits of abundant multistage pore structure, large specific surface area, and good magnetic separation properties. Thus, this material was selected as the sorbent for magnetic solid-phase extraction combined with a dissolution-precipitation method for the extraction and purification of antioxidants and UV stabilizers from polylactic acid food contact plastics. The extraction parameters such as sorbent type, sorbent dosage, sample solution pH, ionic strength, sorption time, elution solution type, volume, and time were investigated. Under the optimized conditions, all the analytes determined by UPLC-MS/MS showed good linear range (r > 0.99), detection limit (0.023-3.105 ng g-1), accuracy (70.6-102.3 %), and reproducibility (RSD<9.8 %). Further, the developed method was applied to determine the antioxidants and UV stabilizers in polylactic acid lunch boxes and straws, showing excellent applicability. The results showed that the antioxidants and UV stabilizers were detected in some of the samples, with a maximum detection of antioxidant 1010 at 7297 ng g-1. This study provided a sensitive, efficient, and environmentally friendly method for antioxidants and UV stabilizers in polylactic acid food contact plastics. The ideas for the design of environmentally friendly metal-organic frameworks and biomass composite multifunctional materials would promise in the sample pretreatment field for the emerging contaminants.

Enhancing Deep-Seated Melanoma Therapy through Wearable Self-Powered Microneedle Patch.

Effective treatment of deep-seated tumors relies on enhanced drug penetration in transdermal drug delivery systems. While microneedles (MNs) and iontophoresis techniques have shown improved transdermal drug delivery efficiency, challenges such as skin elasticity, high electrical resistance of the stratum corneum, and external power supply requirements hinder their efficacy in treating deep-seated tumors. In this study, a wearable, self-powered MN patch that integrates a flexible triboelectric nanogenerator (F-TENG) is presented, aimed at advancing deep-seated tumor therapy. MNs are composed of water-soluble materials mixed with negatively charged pH-responsive nanoparticles (NPs) loaded with therapeutic drugs. The F-TENG harnesses personal mechanical movements generate electrical energy. Leveraging the advantages of both MNs and F-TENG, therapeutic NPs can penetrate deep skin locations upon MN patch insertion, releasing drugs rapidly in acidic tumor tissues. Owing to these features, a single administration of the integrated MN-patch in a mouse model with deep-seated melanoma exhibits superior therapeutic efficacy in inhibiting deep-located tumor compared to using the MN-patch alone, indicating promising potential for treating tumors at deep sites.

Treatment of Class II Malocclusion With Orthodontic Microimplant Anchorage.

INTRODUCTION: The objective of the study was to compare the effects of orthodontic microimplant anchorage (MIA) and conventional extraoral arch anchorage (EAA) on tooth structure and oral inflammatory response in patients with Class II Division I malocclusion. METHODS: A total of 104 patients with Class II malocclusion were enrolled and were randomly assigned to receive MIA or EAA treatments. Clinical efficacy was assessed at 6 months after treatment by measuring molar shift, convex distance, and hinge angle difference between maxillary and mandibular incisors. X-ray was performed for tissue evaluations. The levels of cell adhesion molecule-1 (CAM-1), matrix metalloproteinase-2 (MMP-2), and proinflammatory cytokines in gingival sulcus fluid were measured using enzyme-linked immunosorbent assay to assess inflammatory responses to the implants. RESULTS: Our study demonstrated superior efficacy of MIA compared to EAA in terms of overall efficacy, molar shift, convex distance between upper and middle incisors, as well as hinge angle difference between upper and middle incisors. MIA also showed greater efficacy in reducing tissue fix-point measurements, including saddle point-nasal root point-superior alveolar seat point (SNA), alveolar seat point-nasal root point-inferior alveolar seat point (ANB), overlying (OJ), and overbite (OB). CONCLUSIONS: MIA is a novel orthodontic treatment that showed stronger efficacy in inducing molar shift and correcting soft/hard tissue positions, whilst generating suppressed inflammatory responses. Our study could have significant implications for practice in the orthodontic treatment of Class II malocclusion.

Urine levels of estrogen and its metabolites in premenopausal middle-aged women with different degrees of obesity and their correlation with glucose and lipid metabolism.

Objectives: To determine the levels of estrogen and estrogen metabolites in the urine of premenopausal women with obesity and their correlation with glucose and lipid metabolism. Methords: 135 premenopausal women were selected from the same area. According to the body mass index (BMI), they were divided into four different groups. High performance liquid chromatography-mass spectrometry (HPLC/MS) was adopted to detect the concentrations of estrogen and estrogen metabolites in the urine. The influencing factors of BMI were analyzed, the correlation between the urinary degrees of estrogen and estrogen metabolites and glucose and lipid metabolism levels was assessed. Results: (1) The concentrations of 17ß-estradiol (E2), estrone (E1), 16α-hydroxyestrone (16α-OHE1) and 2-hydroxyestrone (2-OHE1) gradually increased with increasing BMI (p < 0.05). (2) Stepwise regression analysis displayed that the concentrations of E2, 16α-OHE1 and 2-OHE1 in urine were significantly positively correlated with BMI (p < 0.05). (3) The concentrations of E2, E1, 16α-OHE1, 2-OHE1 and 16α-OHE1/2-OHE1 in urine were greatly positively related to fasting insulin (FIN), Triglyceride (TG), Total Cholesterol (TC) and Low-density lipoprotein (LDL) (p < 0.05). And they were greatly negatively related to High-density lipoprotein (HDL) (p < 0.05). Conclusions: Early screening can reflect the degree of obesity and glucose and lipid metabolism disorders in premenopausal middle-aged women, thereby providing guidance for improving the prognosis of obese women.

FBXW7 affects autophagy through MCL1 in oral squamous cell carcinoma.

BACKGROUND: Oral cancer is associated with high risk of morbidity and mortality. However, effective treatment for oral cancer is urgently required in clinics. In this study, we aimed to determine whether F-box/WD repeat-containing protein 7 (FBXW7), an essential tumor suppressor gene, can regulate autophagy and improve the prognosis in oral squamous cell carcinoma (OSCC). METHODS: mRNA levels of FBXW7 and myeloid cell leukemia 1 (MCL-1) in OSCC tissues and adjacent normal tissues were measured by qRT-PCR. FBXW7 and MCL-1 were overexpressed in OSCC cell line using lentivirus containing FBXW7 and MCL-1, respectively. Protein expression was determined by Western blot. RESULTS: The mRNA and protein levels of FBXW7 were decreased in patients with OSCC, whereas the mRNA and protein levels of MCL-1 were increased. Moreover, the mRNA coding for autophagy proteins was reduced in patients with OSCC. Additionally, it was found that overexpression of FBXW7 significantly reduced MCL-1 expression and upregulated autophagy-related proteins, including Beclin1, autophagy related 7, and microtubule-associated protein light chain 3. CONCLUSION: Our results suggest that FBXW7 affects autophagy through MCL1 in OSCC.

Intravenous Injection of Na Ions Aggravates Ang II-Induced Hypertension-Related Vascular Endothelial Injury by Increasing Transmembrane Osmotic Pressure.

Introduction: Extracellular protein nanoparticles (PNs) and ions perform synergistical functions in the control of transmembrane osmotic pressure (OP) under isotonic conditions. Intravenous injection may disrupt the ion balance and alter PN levels in blood plasma, changing transmembrane OP and damaging vascular endothelial cells. Methods: Na ions were injected into AngII-induced HUVECs to simulate cell injury in vitro, and tail vein infusion of Na ions into hypertensive rats was performed to assess vascular damage. Optical measurements using an intermediate filament (IF) tension probe were conducted to detect indicators related to transmembrane OP. Immunofluorescence, Western blotting and small interfering RNA (siRNA) transfection were employed to investigate inflammasomes and the relationship between Abl2 and inflammation. Results: Electrolyte injections with sodium ions (but not glucose and hydroxyethyl starch) induced the production of ASC and NLRP3 inflammasomes in Ang II-induced HUVECs; this in turn resulted in the disorder of calcium signals, and changes in transmembrane OP and cell permeability. Moreover, injection of Na ions into Ang II-induced HUVECs activated the mechanosensitive protein Abl2, involved in inflammation-induced transmembrane OP changes. A drug combination was identified that could induce OP recovery and block hyperpermeability induced by cytoplasmic inflammatory corpuscles in vivo and in vitro. Conclusion: Changes in extracellular PNs and ions following chemical stimuli (Ang II) participate in the regulation of transmembrane OP. Furthermore, injection of Na ions causes vascular endothelial injury in Ang II-induced cells in vitro and hypertension rats in vivo, suggesting it is not safe for hypertensive patients, and we propose a new drug combination as a solution.

Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease.

INTRODUCTION: The APOE gene is the strongest genetic risk factor for late-onset Alzheimer's Disease (LOAD). However, the gene regulatory mechanisms at this locus have not been fully characterized. METHODS: To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with RNA-seq, DNA methylation, and ChIP-seq data from human postmortem brains. RESULTS: We identified an AD-linked APOE transcript (jxn1.2.2) observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features in DLPFC. We prioritized an independent functional SNP, rs157580, significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. rs157580 is located within active chromatin regions and predicted to affect brain-related transcriptional factors binding affinity. rs157580 shared the effects on the jxn1.2.2 transcript between European and African ethnic groups. DISCUSSION: The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease's etiology.