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Considering that the precise delivery of Celastrol (Cst) into mitochondria to induce mitochondrial dysfunction may be a potential approach to improve the therapeutic outcomes of Cst on TNBC, a novel tumor mitochondria dual-targeted mixed-micelle nano-system was fabricated via self-synthesized triphenylphosphonium-modified cholesterol (TPP-Chol) and hyaluronic acid (HA)-modified cholesterol (HA-Chol). The Cst-loaded mixed micelles (Cst@HA/TPP-M) exhibited the characteristics of a small particle size, negative surface potential, high drug loading of up to 22.8%, and sustained drug release behavior. Compared to Cst-loaded micelles assembled only by TPP-Chol (Cst@TPP-M), Cst@HA/TPP-M decreased the hemolysis rate and upgraded the in vivo stability and safety. In addition, a series of cell experiments using the triple-negative breast cancer cell line MDA-MB-231 as a cell model proved that Cst@HA/TPP-M effectively increased the cellular uptake of the drug through CD44-receptors-mediated endocytosis, and the uptake amount was three times that of the free Cst group. The confocal results demonstrated successful endo-lysosomal escape and effective mitochondrial transport triggered by the charge converse of Cst@HA/TPP-M after HA degradation in endo-lysosomes. Compared to the free Cst group, Cst@HA/TPP-M significantly elevated the ROS levels, reduced the mitochondrial membrane potential, and promoted tumor cell apoptosis, showing a better induction effect on mitochondrial dysfunction. In vivo imaging and antitumor experiments based on MDA-MB-231-tumor-bearing nude mice showed that Cst@HA/TPP-M facilitated drug enrichment at the tumor site, attenuated drug systemic distribution, and polished up the antitumor efficacy of Cst compared with free Cst. In general, as a target drug delivery system, mixed micelles co-constructed by TPP-Chol and HA-Chol might provide a promising strategy to ameliorate the therapeutic outcomes of Cst on TNBC. [ABSTRACT FROM AUTHOR]

Reactive astrocytes are important pathophysiologically and synthesize neurosteroids. We observed that LPS increased immunoreactive TLR4 and key steroidogenic enzymes in cortical astrocytes of rats and investigated whether corticosteroids are produced and mediate astrocytic TLR4‐dependent innate immune responses. We found that LPS increased steroidogenic acute regulatory protein (StAR) and StAR‐dependent aldosterone production in purified astrocytes. Both increases were blocked by the TLR4 antagonist TAK242. LPS also increased 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) and corticosterone production, and both were prevented by TAK242 and by siRNAs against 11β‐HSD1, StAR, or aldosterone synthase (CYP11B2). Knockdown of 11β‐HSD1, StAR, or CYP11B2 or blocking either mineralocorticoid receptors (MR) or glucocorticoid receptors (GR) prevented dephosphorylation of p‐Ser9GSK‐3β, activation of NF‐κB, and the GSK‐3β‐dependent increases of C3, IL‐1β, and TNF‐α caused by LPS. Exogenous aldosterone mimicked the MR‐ and GSK‐3β‐dependent pro‐inflammatory effects of LPS in astrocytes, but corticosterone did not. Supernatants from astrocytes treated with LPS reduced MAP2 and viability of cultured neurons except when astrocytic StAR or MR was inhibited. In adrenalectomized rats, intracerebroventricular injection of LPS increased astrocytic TLR4, StAR, CYP11B2, and 11β‐HSD1, NF‐κB, C3 and IL‐1β, decreased astrocytic p‐Ser9GSK‐3β in the cortex and was neurotoxic, except when spironolactone was co‐injected, consistent with the in vitro results. LPS also activated NF‐κB in some NeuN+ and CD11b+ cells in the cortex, and these effects were prevented by spironolactone. We conclude that intracrine aldosterone may be involved in the TLR4‐dependent innate immune responses of astrocytes and can trigger paracrine effects by activating astrocytic MR/GSK‐3β/NF‐κB signaling. [ABSTRACT FROM AUTHOR]

Collagen plays a crucial role in cancer development and migration. However, the impact of changes in the collagen molecular structure on its interaction with cancer cells remains unclear. In this study, natural bovine tendon collagen was heat-treated to obtain collagen samples with different triple helix dissociation degrees. Three methods, including cell adhesion assay, fluorescence labeling assay, and cancer cell capture assay, were employed to compare the binding efficiency of collagen samples to both breast cancer cells (MCF-7) and human umbilicus vein endothelial cells (HUVECs). The results demonstrated that collagen samples exhibited stronger binding efficiency to cancer cells than to normal cells. Additionally, untreated collagen samples showed higher cell binding efficiency compared to heat-treated collagen samples. Furthermore, by comparing the differences in the binding efficiency of collagen samples with different triple helix dissociation degrees to cancer cells and normal cells, it was confirmed that untreated collagen samples exhibited the greatest disparity in binding efficiency with both cell types. Moreover, a strong linear relationship was observed between the triple helix dissociation degree of collagen and the capture rate of cancer cells in the co-culture system. These findings provide important insights into the role of collagen in cancer development. [ABSTRACT FROM AUTHOR]

In order to precisely deliver celastrol into mitochondria of tumor cells, improve antitumor efficacy of celastrol and overcome its troublesome problems in clinical application, a novel multistage-targeted celastrol delivery system (C-TL/HA) was developed via electrostatic binding of hyaluronic acid (HA) to celastrol-loaded cationic liposomes composed of natural soybean phosphatidylcholine and cholesterol modified with mitochondrial targeting molecular TPP. Study results in this article showed that C-TL/HA successfully transported celastrol into mitochondria, effectively activated apoptosis of mitochondrial pathway, exerted higher tumor inhibition efficiency and lower toxic side effects compared with free celastrol. More importantly, HA coating not only enabled this delivery system to have good stability and safety in vivo, but also increased drug uptake and facilitated tumor targeting through recognizing CD44 receptors rich on the surface of tumor cells. Conclusively, this HA-coated mitochondrial targeting liposomes may provide a prospect for the clinical application of celastrol in tumor therapy. [ABSTRACT FROM AUTHOR]

High-quality ontologies are critical to ontology-based applications, such as natural language understanding and information extraction, but logical conflicts naturally occur in the lifecycle of ontology development. To deal with such conflicts, conflict detection and ontology repair become two critical tasks, and we focus on repairing ontologies. Most existing approaches for ontology repair rely on the syntax of axioms or logical consequences but ignore the semantics of axioms. In this paper, we propose an embedding-based approach by considering sentence embeddings of axioms, which translates axioms into semantic vectors and provides facilities to compute semantic similarities among axioms. A threshold-based algorithm and a signature-based algorithm are designed to repair ontologies with the help of detected conflicts and axiom embeddings. In the experiments, our proposed algorithms are compared with existing ones over 20 real-life incoherent ontologies. The threshold-based algorithm with different distance metrics is further evaluated with 10 distinct thresholds and 3 pre-trained models. The experimental results show that the embedding-based algorithms could achieve promising performances. [ABSTRACT FROM AUTHOR]

Experiencing nature can induce the perception of happiness because of mental stress alleviation and well-being restoration. The largeness of green space may not always mean the frequency of experiencing greenery. It is arguing about the probability of positive sentiments in response to an experience of interacting with green nature. In this study, 38 green spaces were investigated in Nanchang City, China, where the green space area was evaluated by the largeness of the landscape metrics of the Normalized Vegetation Index (NDVI), and Green View Index (GVI) data were further obtained using Open Street Maps (OSM). The semantic segmentation method was used by machine learning to analyze a total of 1549 panoramic photos taken in field surveys to assess the Panoramic Green View Index (PGVI) proportion. The photos of 2400 people's facial expressions were obtained from social networks at their check-in visits in green spaces and rated for happy and sad scores using FireFACE software. Split-plot analysis of variance suggested that different categories of NDVI largeness had a significant positive effect on posted positive sentiments. Multivariate linear regression indicated that PGVI was estimated to have a significant contribution to facial expression. Increasing the amount of PGVI promoted happy and PRI scores, while at the same time, neutral sentiments decreased with increasing PGVI. Overall, increasing the PGVI in green spaces, especially in parks with smaller green spaces, can be effective in promoting positive emotions in the visitor experience. [ABSTRACT FROM AUTHOR]

Background Obesity is a major health problem worldwide, and non-alcoholic fatty pancreas disease (NAFPD) and non-alcoholic fatty liver disease (NAFLD) are obesity-associated complications. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has been approved for treatment of obesity. We aimed to evaluate the therapeutic effects of liraglutide on the complications through its regulation of endoplasmic reticulum (ER) stress. Methods A high-fat diet mouse model was established in C57BL/6J mice. Two groups of mice were fed a high-fat diet with 60% fat for 16 weeks and control mice were fed standard chow. A four-week 0.6 mg/kg/day liraglutide treatment was started in one high-fat diet group after 12 weeks of the high-fat diet. After sacrificing the mice, pancreatic and hepatic tissues were prepared for western blot and immunohistochemistry for ER stress proteins, including activating transcription factor 4 (ATF4), caspase 12, C/EBP homologous protein (CHOP) eukaryotic initiation factor 2 α (eIF2α), glucose regulated protein (GRP) 78 and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Results Liraglutide significantly decreased body weight gained by mice consuming a high-fat diet (27.6 g vs. 34.5 g, P<0.001), and levels of all ER proteins increased significantly in both the pancreas and liver (all P<0.05). Expression of most ER stress proteins in pancreatic tissue correlated with disease scores of NAFLD (all P<0.05). However, no significant differences were found in pancreatic ATF 4 expression between mice without NAFLD, and those with early non-alcoholic steatohepatitis (NASH) and fibrotic NASH (P=0.122). Conclusion Liraglutide may reduce the severity of NAFPD and NAFLD through regulating the ER stress pathway and downstream apoptosis signaling. [ABSTRACT FROM AUTHOR]

The migration and deposition processes of fine particles under the influence of temperature gradients and fluid flow are widely prevalent. Investigating the mechanisms of particle interactions in these processes contributes to the development of efficient dust removal techniques. In this work, experimental and numerical studies of particle motion in temperature gradient fields are conducted. The research encompasses both qualitative and quantitative analyses of particle motion influenced by thermophoresis and particle diameter. Qualitative analysis reveals that the motion characteristics of particles are jointly determined by gravity, drag force, and thermophoretic force, and the diameter range that exhibiting a notable influence of the thermophoretic force is 20–30 μm. Quantitative analysis shows that the manifestations of deposition and diffusion become more evident with an increasing temperature gradient. For instance, in comparison to the working condition with Δ T = 0 K and d p = 20 μm, the deposition mass increases by approximately 23% when Δ T = -15 K; conversely, it diminishes by about 11% when Δ T = 15 K. Additionally, the Discrete Phase Model (DPM) is employed to simulate the motion of gas-solid flow. This study presents a novel visualization system to observe particle motion in gas-solid systems to elucidate the mechanisms underlying the thermophoretic effect and establish a robust theoretical foundation for thermophoretic dust removal technology. [ABSTRACT FROM AUTHOR]

Magnetic skyrmions can be created and annihilated in ferromagnetic multilayers using single femtosecond infrared laser pulses above a material-dependent fluence threshold. From the perspective of applications, optical control of skyrmions offers a route to a faster and, potentially, more energy-efficient new class of information-technology devices. Here, we investigate laser-induced skyrmion generation in two different materials, mapping out the dependence of the process on the applied field and the laser fluence. We observe that sample properties like strength of the Dzyaloshinskii–Moriya interaction and pinning do not considerably influence the initial step of optical creation. In contrast, the number of skyrmions created can be directly and robustly controlled via the applied field and the laser fluence. Based on our findings, we propose concepts for applications, such as all-optical writing and deletion, an ultrafast skyrmion reshuffling device for probabilistic computing, and a combined optical and spin–orbit torque-controlled racetrack. [ABSTRACT FROM AUTHOR]

Background: The grading and pathologic biomarkers of glioma has important guiding significance for the individual treatment. In clinical, it is often necessary to obtain tumor samples through invasive operation for pathological diagnosis. The present study aimed to use conventional machine learning algorithms to predict the tumor grades and pathologic biomarkers on magnetic resonance imaging (MRI) data. Methods: The present study retrospectively collected a dataset of 367 glioma patients, who had pathological reports and underwent MRI scans between October 2013 and March 2019. The radiomic features were extracted from enhanced MRI images, and three frequently-used machine-learning models of LC, Support Vector Machine (SVM), and Random Forests (RF) were built for four predictive tasks: (1) glioma grades, (2) Ki67 expression level, (3) GFAP expression level, and (4) S100 expression level in gliomas. Each sub dataset was split into training and testing sets at a ratio of 4:1. The training sets were used for training and tuning models. The testing sets were used for evaluating models. According to the area under curve (AUC) and accuracy, the best classifier was chosen for each task. Results: The RF algorithm was found to be stable and consistently performed better than Logistic Regression and SVM for all the tasks. The RF classifier on glioma grades achieved a predictive performance (AUC: 0.79, accuracy: 0.81). The RF classifier also achieved a predictive performance on the Ki67 expression (AUC: 0.85, accuracy: 0.80). The AUC and accuracy score for the GFAP classifier were 0.72 and 0.81. The AUC and accuracy score for S100 expression levels are 0.60 and 0.91. Conclusion: The machine-learning based radiomics approach can provide a non-invasive method for the prediction of glioma grades and expression levels of multiple pathologic biomarkers, preoperatively, with favorable predictive accuracy and stability. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest that blood lead levels are positively associated with attention deficit/hyperactivity disorder (ADHD) and ADHD-symptoms in children. However, the associations between lead exposure and ADHD subtypes are inconsistent and understudied. Objective: The objective of this study was to explore the association of low-level concurrent lead exposure with subtypes of ADHD symptoms in 578 Mexican children 6–13 years of age. Methods: We measured concurrent blood lead levels using inductively coupled plasma mass spectrometry (ICPMS). We administered the Conners’ Rating Scales-Revised (CRS-R) to mothers to evaluate their children’s ADHD symptoms. We used imputation to fill missing values in blood lead levels and used segmented regression models adjusted for relevant covariates to model the nonlinear relationship between blood lead and ADHD symptoms. Results: Mean ± SD blood lead levels were 3.4 ± 2.9 μg/dL. In adjusted models, a 1-μg/dL increase in blood lead was positively associated with Hyperactivity and Restless-Impulsivity scores on the CRS-R scale and Hyperactivity-Impulsivity scores on the CRS-R scale of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, but only in children with blood lead level ≤ 5 μg/dL. Blood lead was not associated with Inattentive symptoms or overall ADHD behavior. Conclusions: In this population of Mexican children, current blood lead level among children with low exposure (≤ 5 μg/dL) was positively associated with hyperactive/impulsive behaviors, but not with inattentiveness. These results add to the existing evidence of lead-associated neurodevelopmental deficits at low levels of exposure. Citation: Huang S, Hu H, Sánchez BN, Peterson KE, Ettinger AS, Lamadrid-Figueroa H, Schnaas L, Mercado-García A, Wright RO, Basu N, Cantonwine DE, Hernández-Avila M, Téllez-Rojo MM. 2016. Childhood blood lead levels and symptoms of attention deficit hyperactivity disorder (ADHD): a cross-sectional study of Mexican children. Environ Health Perspect 124:868–874; http://dx.doi.org/10.1289/ehp.1510067

A facile and efficient approach for design and synthesis of organic fluorescent nanogels has been developed by using a pre-synthesized polymeric precursor. This strategy is achieved by two key steps: (i) precise synthesis of core–shell star-shaped block copolymers with crosslinkable AIEgen-precursor (AIEgen: aggregation induced emission luminogen) as pending groups on the inner blocks; (ii) gelation of the inner blocks by coupling the AIEgen-precursor moieties to generate AIE-active spacers, and thus, fluorescent nanogel. By using this strategy, a series of star-shaped block copolymers with benzophenone groups pending on the inner blocks were synthesized by grafting from a hexafunctional initiator through atom transfer radical copolymerization (ATRP) of 4-benzoylphenyl methacrylate (BPMA) or 2-(4-benzoylphenoxy)ethyl methacrylate (BPOEMA) with methyl methacrylate (MMA) and tert-butyldimethylsilyl-protected 2-hydroxyethyl methacrylate (ProHEMA) followed by a sequential ATRP to grow PMMA or PProHEMA. The pendent benzophenone groups were coupled by McMurry reaction to generate tetraphenylethylene (TPE) groups which served as AIE-active spacers, affording a fluorescent nanogel. The nanogel showed strong emission not only at aggregated state but also in dilute solution due to the strongly restricted inter- and intramolecular movement of TPE moiety in the crosslinked polymeric network. The nanogel has been used as a fluorescent macromolecular additive to fabricate fluorescent film. [ABSTRACT FROM AUTHOR]

Semi-quantum key distribution (SQKD) allows a quantum user and a classical user to share a string of secret keys, providing support for application scenarios that cannot withstand the high cost of quantum resources. In this paper, we propose what we believe to be the first proof-of-principle experimental demonstration of free space SQKD based on the single-state protocol, which is equipped with polarization encoding scheme employing the method of selective modulation. During the half-hour test time for each operation, the overall experiment obtained the original key rate of 107.2 kbps at the repetition frequency of 100 MHz, and the average bit error rate was determined to be 1.65 % for CTRL operation and 0.64 % for SIFT operation. The experimental results indicate that our system exhibits commendable performance and stability at a low bit error rate that represents a significant initial stride toward the future practical deployment of SQKD systems within free-space channels.

Introduction: Gastrointestinal schwannomas are most commonly found in the stomach. Owing to their nonspecific clinical and endoscopic presentations, distinguishing gastric schwannomas (GS) from other gastric submucosal tumors based on typical symptoms and endoscopic features is challenging. Endoscopic full-thickness resection (EFTR) is safe and effective for GS management; however, no standard method exists for the extraction of large gastric specimens after endoscopic treatment., Case Presentation: We report the case of a 72-year-old Chinese woman who presented with abdominal distension., Diagnosis, Interventions, and Outcomes: Gastroscopy revealed a submucosal bulge on the anterior wall of the lower stomach near the greater curvature. Endoscopic ultrasonography and computed tomography suggested a stromal tumor. The patient underwent EFTR of the stomach, and the tumor was successfully removed. The surgical specimen, with a long-axis diameter of approximately 5.5 cm in vitro, was extracted using a snare. Subsequent endoscopic examination revealed longitudinal, full-thickness perforations > 2 cm at the esophageal entrance. Over 10 metal clips were used to seal the mucosa, and a gastrointestinal decompression tube was placed. Follow-up radiography performed at 1 week postoperatively revealed an esophageal mediastinal fistula, which required subsequent endoscopic intervention to close the fistula using metal clips. The patient showed improvement and was discharged at 3 weeks postoperatively. Follow-up esophageal radiography revealed no abnormalities. Postoperative immunohistochemical analysis indicated CD34 (-), CD117 (-), DOG-1 (-), Ki67 (1%), S-100 (+), SDHB (+), SOX-10 (+), and Desmin (-), confirming the diagnosis of GS. Three months postoperatively, gastroscopy showed that the esophageal perforation healed well, a white ulcer scar had formed locally, metal clips were found in the stomach body, and no recurrence was found., Conclusion: EFTR is effective for removing giant schwannomas, although the extraction of large specimens may result in iatrogenic cervical esophageal perforations. Perforations > 2 cm can be managed using endoscopic metal clip closure., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene., Objectives: This study sought to test the association between the rs9349379 genotype and SCAD., Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD., Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence., Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10 -6 ; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.