Search

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]

Background: Emerging evidence has indicated a link between the gut microbiota and acute lymphoblastic leukaemia (ALL). However, the acute changes in gut microbiota during chemotherapy and the predictive value of baseline gut microbiota in infectious complication remain largely unknown. Methods: Faecal samples (n = 126) from children with ALL (n = 49) undergoing induction chemotherapy were collected at three timepoints, i.e., initiation of chemotherapy (baseline, T0), 7 days (T1) and 33 days (T2) after initiation of chemotherapy. Gut microbiome profile was performed via metagenomic shotgun sequencing. The bioBakery3 pipeline (Kneaddata, Metaphlan 3 and HUMAnN) was performed to assign taxonomy and functional annotations. Gut microbiome at T0 were used to predict infection during chemotherapy. Results: The microbial diversities and composition changed significantly during chemotherapy, with Escherichia coli, Klebsiella pneumoniae and Bifidobacterium longum being the most prominent species. The microbial metabolic pathways were also significantly altered during chemotherapy, including the pathway of pyruvate fermentation to acetate and lactate, and assimilatory sulfate reduction pathway. The receiver operating characteristic (ROC) models based on Bifidobacterium longum at T0 could predict infectious complications during the first month of chemotherapy with the area under the curve (AUC) of 0.720. Conclusions: Our study provides new insights into the acute changes in microbial and functional characteristics in children with ALL during chemotherapy. The baseline gut microbiota could be potential biomarkers for infections during chemotherapy. Trial registration: The study was approved by the Ethics Committee of Zhujiang Hospital, Southern Medical University (2021-KY-171-01) and registered on http://www.chictr.org.cn (ChiCTR2200065406, Registration Date: November 4, 2022). [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]

Metal-nitrogen-carbon catalysts with hierarchically dispersed porosity are deemed as efficient geometry for oxygen reduction reaction (ORR). However, catalytic performance determined by individual and interacting sites originating from structural heterogeneity is particularly elusive and yet remains to be understood. Here, an efficient hierarchically porous Fe single atom catalyst (Fe SAs-HP) is prepared with Fe atoms densely resided at micropores and mesopores. Fe SAs-HP exhibits robust ORR performance with half-wave potential of 0.94 V and turnover frequency of 5.99 e−1s−1site−1 at 0.80 V. Theoretical simulations unravel a structural heterogeneity induced optimization, where mesoporous Fe-N4 acts as real active centers as a result of long-range electron regulation by adjacent microporous sites, facilitating O2 activation and desorption of key intermediate *OH. Multilevel operando characterization results identify active Fe sites undergo a dynamic evolution from basic Fe-N4 to active Fe-N3 under working conditions. Our findings reveal the structural origin of enhanced intrinsic activity for hierarchically porous Fe-N4 sites.Here, authors report an inter-site structural heterogeneity induced effect of hierarchical single atom Fe catalysts for robust oxygen reduction. Dynamic evolutions and insights into structure-activity relationship are presented. [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]

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]

The pathophysiological differences between menstrually-related migraine (MRM) and pure menstrual migraine (PMM) are largely unclear. The aim of this study was to investigate the potential differences in brain structure and function between PMM and MRM. Forty-eight menstrual migraine patients (32 MRM; 16 PMM) were recruited for this study. Voxel-based morphometry (VBM) was applied on structural magnetic resonance imaging (sMRI), and the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) in resting state functional MRI (rsfMRI) were calculated. No significant between-group difference was observed in the grey matter volume (GMV). MRM patients exhibited lower ALFF values at the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (mPFC) than PMM patients. Moreover, the MRM group showed significantly higher ReHo values in the DLPFC. Higher values in the mPFC were related to higher expression of calcitonin gene-associated peptide (CGRP) in the PMM group (r = 0.5, P = 0.048). Combined ALFF and ReHo analyses revealed significantly different spontaneous neural activity in the DLPFC and mPFC, between MRM and PMM patients, and ALFF values in the mPFC were positively correlated with CGRP expression, in the PMM group. This study enhances our understanding of the relationship between neural abnormalities and CGRP expression in individuals with PMM. [ABSTRACT FROM AUTHOR]

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]