Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.

The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer's disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of the Wnt/ß-catenin pathway to promote BBB formation during development. Here, we found that brain endothelial DR6 levels were significantly reduced in a murine model of AD (APPswe/PS1dE9 mice) at the onset of amyloid-ß (Aß) accumulation. Toxic Aß25-35 oligomer treatment recapitulated the reduced DR6 in cultured BECs. We further showed that suppressing DR6 resulted in BBB malfunction in the presence of Aß25-35 oligomers. In contrast, overexpressing DR6 increased the level of BBB functional proteins through the activation of the Wnt/ß-catenin and JNK pathways. More importantly, DR6 overexpression in BECs was sufficient to rescue BBB dysfunction in vitro. In conclusion, our findings provide new insight into the role of endothelial DR6 in AD pathogenesis, highlighting its potential as a therapeutic target to tackle BBB dysfunction in early-stage AD progression.

The Epstein-Barr virus-miRNA-BART6-5p regulates TGF-ß/SMAD4 pathway to induce glycolysis and enhance proliferation and metastasis of gastric cancer cells.

Background: EBV-miR-BARTs exhibit significant relevance in epithelial tumors, particularly in EBV-associated gastric and nasopharyngeal cancers. However, their specific mechanisms in the initiation and progression of gastric cancer remain insufficiently explored. Material and Methods: Initially, EBV-miRNA-BART6-5p and its target gene SMAD4 expression were assessed in EBV-associated gastric cancer tissues and cell lines. Subsequent transfection induced overexpression of EBV-miRNA-BART6-5p in AGS and MKN-45, and downregulation in EBV-positive cells (SUN-719). The subsequent evaluation aimed to observe their impact on gastric cancer cell proliferation, migration, and glycolytic processes, with the TGF-ß/SMAD4 signaling pathway value clarified using a TGF-ß inhibitor. Results: EBV-miRNA-BART6-5p exhibits pronounced upregulation in EBV-associated gastric cancer tissues and EBV-positive cells, while its target gene SMAD4 demonstrates downregulated expression. Upregulation of it can promote the proliferation and migration of gastric cancer cells. Additionally, We found EBV-miRNA-BART6-5p promotes glycolysis of gastric cancer cells. Inhibition of the TGF-ß/SMAD4 signaling pathway resulted in suppressed proliferation and migration of gastric cancer cells, concomitant with a diminished glycolytic capacity. Conclusion: In this study, we found that EBV-miRNA-BART6-5p can target SMAD4, effectively increasing glycolysis in gastric cancer cells by regulating the TGF-ß/SMAD4 signaling pathway, thereby enhancing the proliferation and metastasis of gastric cancer cells. Our findings may offer new insights into the metabolic aspects of gastric cancer.

Exploring the Anticancer Potential of Traditional Thai Medicinal Plants: A Focus on Dracaena loureiri and Its Effects on Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) is renowned for its aggressive and highly metastatic nature. In recent years, there has been a surge in interest regarding the therapeutic potential of traditional medicinal plants. Dracaena loureirin (D. loureirin), Ficus racemosa Linn. (F. racemosa), and Harrisonia perforata (Blanco) Merr. (H. perforata) are prominent traditional medicinal herbs in Thailand, recognized for their diverse biological activities, including antipyretic and anti-inflammatory effects. However, their prospective anti-cancer properties against NSCLC remain largely unexplored. This study aimed to evaluate the anti-cancer attributes of ethanolic extracts obtained from D. loureiri (DLEE), F. racemosa (FREE), and H. perforata (HPEE) against the A549 lung adenocarcinoma cell lines. Sulforhodamine B (SRB) assay results revealed that only DLEE exhibited cytotoxic effects on A549 cells, whereas FREE and HPEE showed no such cytotoxicity. To elucidate the anti-cancer mechanisms of DLEE, cell cycle and apoptosis assays were performed. The findings demonstrated that DLEE inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase in A549 cells through the downregulation of key cell cycle regulator proteins, including cyclin D1, CDK-2, and CDK-4. Furthermore, DLEE treatment facilitated apoptosis in A549 cells by suppressing anti-apoptotic proteins (Bcl-2, Bcl-xl, and survivin) and enhancing apoptotic proteins (cleaved-caspase-3 and cleaved-PARP-1). In summary, our study provides novel insights into the significant anti-cancer properties of DLEE against A549 cells. This work represents the first report suggesting that DLEE has the capability to impede the growth of A549 lung adenocarcinoma cells through the induction of apoptosis.

A comparison between mutational profiles in tumour tissue DNA and circulating tumour DNA in head and neck squamous cell carcinoma - A systematic review.

BACKGROUND: Head and neck cancer is the seventh most common malignancy globally. Head and neck squamous cell carcinoma (HNSCC) originates from squamous cells and 90% of HNC are HNSCC. The gold standard for diagnosing HNSCC is tissue biopsy. However, given tumour heterogeneity, biopsies may miss important cancer-associated molecular signatures, and more importantly, after the tumour is excised, there is no means of tracking response to treatment in patients. Captured under liquid biopsy, circulating tumour DNA (ctDNA), may identify in vivo molecular genotypes and complements tumour tissue analysis in cancer management. A systematic search was conducted in PubMed, Embase, Scopus and the Cochran Library between 2012 to early 2023 on ctDNA in HNSCC using publications written in English. We summarise 20 studies that compared mutational profiles between tumour tissue DNA (tDNA) and ctDNA, using a cohort of 631 HNSCC patients and 139 controls. Among these studies, the concordance rates varied greatly and the most mutated and the most concordant gene was TP53, followed by PIK3CA, CDKN2A, NOTCH1 and FAT1. Concordant variants were mainly found in Stage IV tumours, and the mutation type is mostly single nucleotide variants (SNV). We conclude that, as a biomarker for HNSCC, ctDNA demonstrates great promise as it recapitulates tumour genotypes, however additional multi-central trials are needed.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients.

BACKGROUND: Currently, the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for glucose excursion is worth investigation. AIM: To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes. METHODS: Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis. All patients were treated with metformin. We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA (group A; n = 33 and group B; n = 37). RESULTS: The degree of decrease in the levels of fasting blood glucose, mean blood glucose, mean amplitude of glycemic excursions, total cholesterol, triglycerides, tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B (P < 0.05), whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A (P < 0.001). However, there were no statistically significant differences in the levels of glycated hemoglobin, standard deviation of blood glucose, coefficient of variation, absolute mean of daily differences, percentage of time with 3.9 mmol/L < glucose < 10 mmol/L, and high- and low-density lipoproteins between the two groups (P > 0.05). The incidence of adverse reactions was significantly lower in group A than in group B (P < 0.05). CONCLUSION: The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients, suppressing inflammation, and reducing adverse reactions was significantly higher than that of the daily preparations, which is worthy of clinical promotion.

Circulating tumour DNA alterations: emerging biomarker in head and neck squamous cell carcinoma.

Head and Neck cancers (HNC) are a heterogeneous group of upper aero-digestive tract cancer and account for 931,922 new cases and 467,125 deaths worldwide. About 90% of these cancers are of squamous cell origin (HNSCC). HNSCC is associated with excessive tobacco and alcohol consumption and infection with oncogenic viruses. Genotyping tumour tissue to guide clinical decision-making is becoming common practice in modern oncology, but in the management of patients with HNSCC, cytopathology or histopathology of tumour tissue remains the mainstream for diagnosis and treatment planning. Due to tumour heterogeneity and the lack of access to tumour due to its anatomical location, alternative methods to evaluate tumour activities are urgently needed. Liquid biopsy approaches can overcome issues such as tumour heterogeneity, which is associated with the analysis of small tissue biopsy. In addition, liquid biopsy offers repeat biopsy sampling, even for patients with tumours with access limitations. Liquid biopsy refers to biomarkers found in body fluids, traditionally blood, that can be sampled to provide clinically valuable information on both the patient and their underlying malignancy. To date, the majority of liquid biopsy research has focused on blood-based biomarkers, such as circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), and circulating microRNA. In this review, we will focus on ctDNA as a biomarker in HNSCC because of its robustness, its presence in many body fluids, adaptability to existing clinical laboratory-based technology platforms, and ease of collection and transportation. We will discuss mechanisms of ctDNA release into circulation, technological advances in the analysis of ctDNA, ctDNA as a biomarker in HNSCC management, and some of the challenges associated with translating ctDNA into clinical and future perspectives. ctDNA provides a minimally invasive method for HNSCC prognosis and disease surveillance and will pave the way in the future for personalized medicine, thereby significantly improving outcomes and reducing healthcare costs.

Precision of Corneal Aberrations Measured by a New SD-OCT/Placido Topographer and Its Agreement With a Scheimpflug/Placido Topographer.

PURPOSE: To evaluate the precision of corneal aberrations measured by a new SD-OCT/Placido topographer, the MS-39 (CSO), and to compare them with those provided by a Scheimpflug/Placido device, the Sirius (CSO), in normal eyes. METHODS: This study enrolled 90 normal eyes of 90 patients. Total root mean square (RMS), higher order RMS, coma, trefoil, spherical aberration, and astigmatism II were analyzed. The within-subject standard deviation (Sw), test-retest repeatability, and intraclass correlation coefficient (ICC) were calculated to assess the precision. Bland-Altman plots and 95% limits of agreement (LoAs) were calculated to assess the agreement. RESULTS: For intraobserver repeatability of anterior and total corneal aberrations, most of the ICCs were greater than 0.869, except for trefoil and astigmatism II. Regarding the posterior corneal surface, the ICCs of total RMS, coma, and spherical aberration were higher than 0.878, whereas the ICCs of higher order RMS, trefoil, and astigmatism II were lower than 0.626. All test-retest repeatability values were 0.17 µm or less. In terms of interobserver reproducibility, the Sw values were 0.04 µm or less, Test-retest repeatability values were less than 0.11 µm, and all ICCs ranged from 0.532 to 0.996. Regarding agreement, 95% LoAs were small for all Zernike coefficients, and the mean difference was close to zero. CONCLUSIONS: The new SD-OCT/Placido device exhibited excellent repeatability and reproducibility for anterior and total surface, whereas total RMS, coma, and spherical aberrations showed high precision on the posterior surface. High agreement was confirmed between the SD-OCT/Placido and Scheimpflug/Placido devices. [J Refract Surg. 2023;39(6):405-412.].

Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders.

OBJECTIVE: To explore whether kidney deficiency (KYD) is prone to metabolic disorders may be linked to impaired mitochondrial function in thermogenesis and metabolic tissues. METHODS: A rat model of KYD was used, which was established using Sprague Dawley rat dams with warm preference subjected to herbal treatment that can improve kidney . The human relevance was confirmed by reduced serum corticosterone levels, and increased preference for warm location. RESULTS: KYD Rats were underdeveloped. Adenosine-triphosphate (ATP) production was reduced in the brown fat, but increased in the muscle. However, oxidative phosphorylated complexes to generate ATP and mitochondrial biogenesis marker were reduced in both tissues. When the second insult of high-fat diet (HFD) was introduced, KYD rats gained less weight yet developed more severe lipid and glucose metabolic disorders. This may be driven by disregulated liver gluconeogenesis marker forkhead box protein O1 and lipid metabolic regulator cholesterol 7 alpha-hydroxylase. CONCLUSION: KYD rats exhibited reduced mito-chondrial function in the brown fat, but were partially compensated by skeletal muscle, associated with the phenotype of warm preference and metabolic disorder, which was further exacerbated by additional HFD consumption. Future studies can focus on treatment targetting mitochondria function to reverse this phenotype.

A Novel "Inside-Out" Intraocular Nanomedicine Delivery Mode for Nanomaterials' Biological Effect Enhanced Choroidal Neovascularization Occlusion and Microenvironment Regulation.

Photodynamic therapy (PDT) is commonly used in choroidal neovascularization (CNV) treatment due to the superior light transmittance of the eye. However, PDT often leads to surrounding tissue damage and further microenvironmental deterioration, including exacerbated hypoxia, inflammation, and secondary neovascularization. In this work, Pt nanoparticles (NPs) and Au NPs decorated zeolitic imidazolate framework-8 nanoplatform is developed to load indocyanine green for precise PDT and microenvironment amelioration, which can penetrate the internal limiting membrane through Müller cells endocytosis and target to CNV by surface-grafted cyclo(Arg-Gly-Asp-d-Phe-Lys) after intravitreal injection. The excessive H2 O2 in the CNV microenvironment is catalyzed by catalase-like Pt NPs for hypoxia relief and enhanced PDT occlusion of neovascular. Meanwhile, Au NPs show significant anti-inflammatory and anti-angiogenesis properties in regulating macrophages and blocking vascular endothelial growth factor (VEGF). Compared with verteporfin treatment, the mRNA expressions of hypoxia-inducible factor-1α and VEGF in the nanoplatform group are downregulated by 90.2% and 81.7%, respectively. Therefore, the nanoplatform realizes a comprehensive CNV treatment effect based on the high drug loading capacity and biosafety. The CNV treatment mode developed in this work provides a valuable reference for treating other diseases with similar physiological barriers that limit drug delivery and similar microenvironment.

Thermal Creep Behavior and Creep Crystallization of Al-Mg-Si Aluminum Alloys.

The experimental temperature is 613.15~763.15 K, and the strain rate is 0.01~10 s-1. The hot compression creep test of the 6082-T6 aluminum alloy sample is carried out by Gleeble-3500 hot compression simulation compressor, and its creep behavior is studied by scanning electron microscope. The results show that the DRX crystal has an irregular shape and that content of the Mg phase, Si phase, and Mn phase in the crystal are the main factors to change the color of DRX crystal. Temperature and strain rate are important factors affecting dynamic recrystallization. Reducing temperature and increasing strain rate will weaken dynamic recrystallization, and DRX critical condition and peak stress (strain) will increase. The constitutive equation of hot creep of 6082 aluminum alloy was established by introducing the work hardening rate-rheological stress curve, and the relationship between DRX critical condition, peak stress (strain) and parameter Z during creep was explored. Based on the Av rami equation, the prediction equation of the DRX volume fraction is established. With the increase of strain, DRX volume fraction is characterized by slow increase, then rapid increase and then slowly increase. In the hot -forming extrusion process of 6082 aluminum alloy, according to the volume fraction prediction equation, the DRX can be reduced, and the internal structure of the material can be optimized by changing the extrusion conditions and particle size.

Study on Dynamic Impact Response and Optimal Constitutive Model of Al-Mg-Si Aluminum Alloy.

Al-Mg-Si series aluminum alloy is a heat-treatment-strengthened alloy. Research on the impact resistance of Al-Mg-Si series aluminum alloy is of great significance to expand its application in engineering. Taking 6082-T6 aluminum alloy as the concrete research object, using the split Hopkinson pressure bar (SHPB) device, the dynamic mechanical response of the material under different temperatures and average strain rates was studied, and the service performance of the material under extreme conditions was determined. The absolute temperature rise was introduced to optimize the existing constitutive model. The results show that when the environment temperature is 298.15~473.15 K under high-speed impact, the internal thermal softening effect of the material is dominant in the competition with the work hardening, resulting in a decrease in the flow stress of the material. Through the analysis of the real stress-strain curve, it was found that the elastic modulus of the material was negatively correlated with the strain rate, negatively correlated with the temperature, and showed an obvious temperature-softening effect. Yield strength was negatively correlated with temperature and positively correlated with strain rate, which showed an obvious strain rate hardening effect. Based on SEM microscopic analysis, it was found that under given conditions, adiabatic shear bands appeared in some samples, and their internal structures demonstrated obvious change. It was judged that when high-speed impact occurs, cracks are induced at the shear bands, and the cracks will continue to develop along the adiabatic shear bands, resulting in many oblique cracks which will gradually become larger and eventually lead to material failure. Finally, based on the model, the strain rate and temperature softening terms were improved, and a rise in adiabatic temperature rise was introduced. The improved model can better describe the strain rate effect of the material and accurately describe its flow stress. It provides a theoretical basis for the engineering application of materials.

Preparation and photodynamic antibacterial/anticancer effects of ultralong-lifetime room-temperature phosphorescent N-doped carbon dots.

Room-temperature phosphorescent (RTP) N-doped carbon-dots (CNDs) featuring eco-friendliness, low cost and high biocompatibility, are ideal photodynamic antibacterial and anticancer nanomaterials. However, the existing CNDs are limited by low singlet oxygen (1O2) quantum yield, which has become a bottleneck in the development of CNDs. One basic reason is the short T1-state exciton lifetime of CNDs. Herein, triethylenetetramine hexaacetic acid was used to synthesize CNDs via a one-step hydrothermal method. CNDs are characterized with low toxicity, high biocompatibility and ultralong-lifetime RTP (URTP). In addition to the URTP (average lifetime 414 ms) under solid conditions, CNDs even had URTP (average lifetime 320 ms) in a water environment. The ultralong T1 exciton lifetime largely extends the collision time between T1 state excitons and O2 and prolongs the energy transfer time, not only improving the quantum yield (0.63) of singlet oxygen (1O2) in solution, but also facilitating the photodynamic antibacterial and anticancer effects.

Maternal Cigarette Smoke Exposure Exaggerates the Behavioral Defects and Neuronal Loss Caused by Hypoxic-Ischemic Brain Injury in Female Offspring.

OBJECTIVE: Hypoxic-ischemic encephalopathy affects ∼6 in 1,000 preterm neonates, leading to significant neurological sequela (e.g., cognitive deficits and cerebral palsy). Maternal smoke exposure (SE) is one of the common causes of neurological disorders; however, female offspring seems to be less affected than males in our previous study. We also showed that maternal SE exaggerated neurological disorders caused by neonatal hypoxic-ischemic brain injury in adolescent male offspring. Here, we aimed to examine whether female littermates of these males are protected from such insult. METHODS: BALB/c dams were exposed to cigarette smoke generated from 2 cigarettes twice daily for 6 weeks before mating, during gestation and lactation. To induce hypoxic-ischemic brain injury, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen) at postnatal day (P) 10. Behavioral tests were performed at P40-44, and brain tissues were collected at P45. RESULTS: Maternal SE worsened the defects in short-term memory and motor function in females with hypoxic-ischemic injury; however, reduced anxiety due to injury was observed in the control offspring, but not the SE offspring. Both hypoxic-ischemic injury and maternal SE caused significant loss of neuronal cells and synaptic proteins, along with increased oxidative stress and inflammatory responses. CONCLUSION: Oxidative stress and inflammatory response due to maternal SE may be the mechanism of worsened neurological outcomes by hypoxic-ischemic brain injury in females, which was similar to their male littermates shown in our previous study.

Discovery of dual-target ligands binding to beta2-adrenoceptor and cysteinyl-leukotriene receptor for the potential treatment of asthma from natural products derived DNA-encoded library.

The design, synthesis, and discovery of dual-target compounds are considered as a promising strategy to develop new drugs with improved safety and efficacy compared with single-target drugs. This necessitates development of the methodologies that enable us to rapidly and accurately achieve the dual-target leads. Applying rosmarinic acid, 18ß-glycyrrhetinic acid, rhein, and ferulic acid as template building blocks, we introduced the self-assembling DNA encoded technique to build the library containing 1,000 compounds. These compounds were screened by receptor chromatography with immobilized beta2-adrenoceptor (ß2-AR) and cysteinyl-leukotriene receptor (CysLT), whereby we obtained a derivative of 18ß-glycyrrhetinic acid (XC267) that specifically binds to the two receptors. In vitro assessment demonstrated the desired binding affinity of 6.57 × 104 M-1 to ß2-AR, 2.82 × 104 M-1 to CysLT, and the dissociation rate constant of 7.52 s-1 to ß2-AR, 17.2 s-1 to CysLT. Pharmacological examination with ovalbumin-induced mice demonstrated that XC267 significantly reduced the levels of IL-4, IL-13, and IgE after oral administration of 10 mg/kg. By Western blot analysis, we observed an up-regulated expression of ß2-AR and a blocked level of CysLT with a dose-dependent manner in pulmonary bronchial. Our results suggest XC627 is a potential candidate to treat asthma by simultaneously regulating the signaling pathway of the two receptors.

Successful Endovascular Treatment of a Spontaneous Rupture of the Ascending Lumbar Vein: A Case Report.

Although there have been a few case reports of spontaneous rupture of pelvic veins, such as the iliac vein, to date, there have been no reports of spontaneous rupture of the ascending lumbar vein. Here, we report a case of spontaneous rupture of the ascending lumbar vein for the first time. A 66-year-old woman visited the emergency department due to the swelling of the left lower limb for 2 hours. After admission, the patient developed symptoms of pain in the left lumbar region, as well as symptoms of shock, such as increased heart rate and decreased blood pressure. During emergency venography, it was found that the ascending lumbar vein was ruptured, which was accompanied by the compression and occlusion of the iliac vein (May-Thurner syndrome). During the endovascular surgical treatment, a covered stent was placed in the iliac vein, and the occluded common iliac vein was treated with a bare stent. Immediately after the surgical procedure, the patient's abdominal computed tomography examination showed the formation of a large retroperitoneal haematoma, and continuous routine blood parameter monitoring showed that haemoglobin was stable. Postoperative recovery was uneventful, and the patient was discharged on the ninth postoperative day.

Intrapleural treatment in patients with non-small cell lung cancer with malignant pleural effusions in the real world.

BACKGROUND: The aim of the study was to assess the efficacy and side-effects of intrapleural treatment in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). METHODS: The medical records of NSCLC patients with MPEs diagnosed in four Chinese hospitals from October 2014 to December 2019 were searched. The Kaplan-Meier method is used to calculate median overall survival (MOS) and subgroup analyses are done. RESULTS: A total of 285 patients were evaluated; 81.1% of patients received intrapleural treatment, and no patients received talc pleurodesis. MOS of the whole cohort was 21 months. Patients were divided into three groups: erythromycin group (EG; intrapleural treatment with drugs and erythromycin); intrathoracic treatment group (ITG; intrapleural treatment with drugs); control group (CG; no drug treatment in the pleural cavity). The MOS of patients in the EG, ITG and CG was 20, 22, and 19 months, respectively. Among patients who received only chemotherapy as systemic therapy, the MOS of intrathoracic administration group (IAG; i.e., EG and ITG) was longer than that of CG (12 vs. 6 months; p = 0.034), and the MOS of patients with a ratio of carcinoembryonic antigen in pleural effusion (PE-CEA): CEA in blood (B-CEA) ≤1 is worse than that of patients with a ratio >1 (4 vs. 12 months, p = 0.021) and that of CG (4 vs. 6 months, p = 0.442). CONCLUSIONS: Intrapleural treatment can prolong the survival of NSCLC patients with MPE who do not receive targeted treatment or who only receive chemotherapy. The PE-CEA: B-CEA ratio can be used to predict the efficacy if intrapleural treatment is indicated.

Research on High Temperature Stamping Forming Performance and Process Parameters Optimization of 7075 Aluminum Alloy.

The stress strain curve of 7075 aluminum alloy in the temperature range of 310 °C to 410 °C was obtained by Gleeble-3800. By Nakazima test, the isothermal thermoforming limit diagrams of 7075 aluminum alloy at different deformation temperatures and stamping speeds were acquired. Moreover, the parameters of automotive S-rail hot stamping process were optimized by GA-BP neural network. The results show that the forming limit curve of 7075 aluminum alloy increases as the deformation temperature and stamping speed increase. The predicted optimal parameters for hot stamping of automotive S-rails by GA-BP neural network are: stamping speed is 50 mm/s, friction coefficient between die and blank is 0.1, and blank holder force is 5 kN. The maximum thinning rate at this process parameter is 9.37%, which provided a reference for 7075 aluminum alloy automotive S-rail hot stamping.

Effects of 2,2',4,4'-tetrabromodiphenyl ether on the development of mouse embryonic stem cells.

2,2',4,4'-Tetrabromodiphenyl ether (BDE47) poses potential risks to reproduction and development, but the mechanism of its toxicity has not yet been elucidated. To explore the developmental toxicity of BDE47, mouse embryonic stem cells (mESCs), which are ideal models for testing the developmental toxicity of environmental contaminants in vitro, were exposed to BDE47 (0.04 µM, 1 µM, 25 µM, or 100 µM) for 24 h or 48 h in this study. Our results indicated that BDE47 treatment changed the morphology of mESCs, inhibited cell viability and increased apoptosis. In addition, alkaline phosphatase (AP) staining in mESCs was significantly decreased after BDE47 treatment (25 µM and 100 µM), indicating that BDE47 treatment affected the pluripotency of mESCs. Through a cell immunofluorescence assay, we found that the fluorescence intensities of Oct4, Sox2 and Nanog were all significantly lower in the group treated with the highest BDE47 concentration (100 µM) than in the control group, consistent with the qRT-PCR and Western blot results. The levels of miR-145 and miR-34a, which regulate genes related to cell differentiation, were significantly increased in BDE47-treated mESCs, further clarifying the potential mechanism. Overall, our findings demonstrate that BDE47 exposure upregulates the expression of miR-145 and miR-34a and in turn downregulates the expression of Oct4, Sox2 and Nanog, thereby affecting apoptosis and pluripotency and causing toxicity during embryonic development.

Pseudogene HSPB1P1 contributes to renal cell carcinoma proliferation and metastasis by targeting miR-296-5p to regulate HMGA1 expression.

With the aid of next-generation sequencing technology, pseudogenes have been widely recognized as functional regulators in the development and progression of certain diseases, especially cancer. Our present study aimed to investigate the functions and molecular mechanisms of HSPB1-associated protein 1 pseudogene 1 (HSPB1P1) in renal cell carcinoma (RCC). HSPB1P1 expression at the mRNA levels was determined by quantitative real-time polymerase chain reaction, and its clinical significance was assessed. Cell viability was detected by Cell Counting Kit-8 assay. Cell migration and invasion were detected by transwell assays. The location of HSPB1P1 in RCC cells was detected by subcellular distribution analysis. The direct relationship between HSPB1P1 and miR-296-5p/HMGA1 axis was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Our results identify the elevated expression of HSPB1P1 in RCC tissues and cell lines, which predicted advanced progression and poor prognosis in patients with RCC. Knockdown of HSPB1P1 suppressed cell proliferation, migration, and invasion, and reversed epithelial-mesenchymal transition process in RCC. HSPB1P1 was mostly enriched in the cytoplasm and functioned as a miRNA sponge for miR-296-5p and then regulated high-mobility group A1 expression. In conclusion, our study indicated that HSPB1P1 contributed to RCC progression by targeting the miR-296-5p/HMGA1 axis, and should be considered as a promising biomarker and therapeutic target for clinical applications.