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Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip. Regression analyses of paired tumour and adjacent benign samples identified 2,386 significant dmCpGs (Bonferroni p < 0.01; delta-ß ≥ 40%), with LASSO regression selecting 16 dmCpGs that distinguished tumour samples in the full Australian diagnostic dataset (AUC = 0.99). Results were validated in independent North American (npaired = 19; AUC = 0.87) and The Cancer Genome Atlas (TCGA; npaired = 50; AUC = 0.94) RP datasets. Two of the 16 dmCpGs were in genes that were significantly down-regulated in Australian tumour samples (Bonferroni p < 0.01; GSTM2 and PRKCB). Ten additional dmCpGs distinguished low (n = 34) and high Gleason (n = 88) score tumours in the diagnostic Australian dataset (AUC = 0.95), but these performed poorly when applied to the RP datasets (North American: AUC = 0.66; TCGA: AUC = 0.62). The DNA methylation marks identified here could augment and improve current diagnostic tests and/or form the basis of future prognostic tests.
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Islas de CpG , Metilación de ADN , Neoplasias de la Próstata , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/metabolismo , Masculino , Islas de CpG/genética , Anciano , Persona de Mediana Edad , Prostatectomía , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Australia , PronósticoRESUMEN
Chronic obstructive pulmonary disease (COPD) is a complex syndrome with poorly understood mechanisms driving its early progression (GOLD stages 1-2). Elucidating the genetic factors that influence early-stage COPD, particularly those related to airway inflammation and remodeling, is crucial. This study analyzed lung tissue sequencing data from patients with early-stage COPD (GSE47460) and smoke-exposed mice. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning to identify potentially pathogenic genes. Further analyses included single-cell sequencing from both mice and COPD patients to pinpoint gene expression in specific cell types. Cell-cell communication and pseudotemporal analyses were conducted, with findings validated in smoke-exposed mice. Additionally, Mendelian randomization (MR) was used to confirm the association between candidate genes and lung function/COPD. Finally, functional validation was performed in vitro using cell cultures. Machine learning analysis of 30 differentially expressed genes identified 8 key genes, with CLEC5A emerging as a potential pathogenic factor in early-stage COPD. Bioinformatics analyses suggested a role for CLEC5A in macrophage-mediated inflammation during COPD. Two-sample Mendelian randomization linked CLEC5A single nucleotide polymorphisms (SNPs) with Forced Expiratory Volume in One Second (FEV1), FEV1/Forced Vital Capacity (FVC) and early/later on COPD. In vitro, the knockdown of CLEC5A led to a reduction in inflammatory markers within macrophages. Our study identifies CLEC5A as a critical gene in early-stage COPD, contributing to its pathogenesis through pro-inflammatory mechanisms. This discovery offers valuable insights for developing early diagnosis and treatment strategies for COPD and highlights CLEC5A as a promising target for further investigation.
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Progresión de la Enfermedad , Inflamación , Lectinas Tipo C , Macrófagos , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica , Receptores de Superficie Celular , Animales , Humanos , Masculino , Ratones , Inflamación/genética , Inflamación/patología , Inflamación/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Pulmón/patología , Pulmón/metabolismo , Aprendizaje Automático , Macrófagos/metabolismo , Macrófagos/patología , Análisis de la Aleatorización Mendeliana , Ratones Endogámicos C57BL , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismoRESUMEN
A cascade Nazarov cyclization/dicycloexpansions reaction was developed for the precise synthesis of the angularly fused M/5/N (M = 5, 6; N = 4-9, 13) tricyclic skeletons. The prioritized expansion of the first ring played a critical role in the transformations, due to the release of ring strain, and the nature of the substituents present on the substrate is another influencing factor. This pioneering cascade reaction features broad substrates scope (33 examples), short reaction time, exceptional yields (up to 95%), and remarkable regioselectivities (> 20:1). Exploiting the synthetic application of this cascade reaction, we successfully executed a succinct total synthesis of nominal madreporanone for the first time.
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BACKGROUND: Subarachnoid hemorrhage (SAH) represents a severe stroke subtype. Our study aims to develop gender-specific prognostic prediction models derived from distinct prognostic factors observed among different-gender patients. METHODS: Inclusion comprised SAH-diagnosed patients from January 2014 to March 2016 in our institution. Collected data encompassed patients' demographics, admission severity, treatments, imaging findings, and complications. Three-month post-discharge prognoses were obtained via follow-ups. Analyses assessed gender-based differences in patient information. Key factors underwent subgroup analysis, followed by univariate and multivariate analyses to identify gender-specific prognostic factors and establish/validate gender-specific prognostic models. RESULTS: A total of 929 patients, with a median age of 57 (16) years, were analyzed; 372 (40%) were male, and 557 (60%) were female. Differences in age, smoking history, hypertension, aneurysm presence, and treatment interventions existed between genders (p < 0.01), yet no disparity in prognosis was noted. Subgroup analysis explored hypertension history, aneurysm presence, and treatment impact, revealing gender-specific variations in these factors' influence on the disease. Screening identified independent prognostic factors: age, SEBES score, admission GCS score, and complications for males; and age, admission GCS score, intraventricular hemorrhage, treatment interventions, symptomatic vasospasm, hydrocephalus, delayed cerebral ischemia, and seizures for females. Evaluation and validation of gender-specific models yielded an AUC of 0.916 (95% CI: 0.878-0.954) for males and 0.914 (95% CI: 0.885-0.944) for females in the ROC curve. Gender-specific prognostic models didn't significantly differ from the overall population-based model (model 3) but exhibited robust discriminative ability and clinical utility. CONCLUSION: Variations in baseline and treatment-related factors among genders contribute partly to gender-based prognosis differences. Independent prognostic factors vary by gender. Gender-specific prognostic models exhibit favorable prognostic performance.
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Caracteres Sexuales , Hemorragia Subaracnoidea , Humanos , Hemorragia Subaracnoidea/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , Adulto , Estudios RetrospectivosRESUMEN
Photosynthetic microorganisms, which rely on light-driven electron transfer, store solar energy in self-energy carriers and convert it into bioenergy. Although these microorganisms can operate light-induced charge separation with nearly 100% quantum efficiency, their practical applications are inherently limited by the photosynthetic energy conversion efficiency. Artificial semiconductors can induce an electronic response to photoexcitation, providing additional excited electrons for natural photosynthesis to improve solar conversion efficiency. However, challenges remain in importing exogenous electrons across cell membranes. In this work, we have developed an engineered gold nanocluster/organic semiconductor heterostructure (AuNC@OFTF) to couple the intracellular electron transport chain of living cyanobacteria. AuNC@OFTF exhibits a prolonged excited state lifetime and effective charge separation. The internalized AuNC@OFTF permits its photogenerated electrons to participate in the downstream of photosystem II and construct an oriented electronic highway, which enables a five-fold increase in photocurrent in living cyanobacteria. Moreover, the binding events of AuNC@OFTF established an abiotic-biotic electronic interface at the thylakoid membrane to enhance electron flux and finally furnished nicotinamide adenine dinucleotide phosphate. Thus, AuNC@OFTF can be exploited to spatiotemporally manipulate and enhance the solar conversion of living cyanobacteria in cells, providing an extended nanotechnology for re-engineering photosynthetic pathways.
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Aquaculture of bivalve shellfish and algae offers significant ecological benefits, yet the complex interactions between these organisms can substantially impact local carbon dynamics. This study investigated the effects of co-culturing four intertidal bivalve species Pacific oysters (Crassostrea gigas), Manila clams (Ruditapes philippinarum), Chinese clams (Cyclina sinensis), and hard clams (Mercenaria mercenaria) with microalgae (Isochrysis galbana) on specific water quality parameters, including total particulate matter (TPM), total organic matter (TOM), dissolved inorganic carbon (DIC), dissolved carbon dioxide (dCO2), dissolved oxygen (DO), and ammonium (NH4+) concentrations. The bivalves were divided into smaller and larger groups and cultured under two conditions: with algae (WP) and without (NP), along with matched controls. Total particulate matter (TPM), total organic matter (TOM), dissolved oxygen (DO), ammonium nitrogen (NH4+), dissolved inorganic carbon (DIC), and CO2 (dCO2) were measured before and after 3-h cultivation. Results revealed species-specific impacts on water chemistry. C. gigas, C. sinensis and R. philippinarum showed the strongest reduction in DIC and dCO2 in WP groups, indicating synergistic bioremediation with algae. M. mercenaria notably reduced TPM, highlighting its particle carbon sequestration potential. DO concentrations decreased in most WP or NP groups, reflecting respiration of the cultured bivalves or microalgae. NH4+ levels also declined for most species, indicating nitrogen assimilation by these creatures. Overall, the bivalve size significantly impacted carbon and nitrogen processing capacities. These findings reveal species-specific capabilities in regulating water carbon dynamics. Further research should explore integrating these bivalves in carbon-negative aquaculture systems to mitigate environmental impacts. This study provides valuable insights underlying local carbon dynamics in shallow marine ecosystems.
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Background: Metastasis is a complex process involving multiple factors and stages, in which tumor cells and the tumor microenvironment (TME) play significant roles. A combination of orally bioavailable therapeutic agents that target both tumor cells and TME is conducive to prevent or impede the progression of metastasis, especially when undetectable. However, sequentially overcoming intestinal barriers, ensuring biodistribution in tumors and metastatic tissues, and enhancing therapeutic effects required for efficient therapy remain challenging. Methods: Inspired by the unique chemical features of natural herbs, we propose an oral herb-nanoparticle hybrid system (HNS) formed through the self-binding of Platycodon grandiflorum-Curcuma zedoaria (HG), a herb pair/group used in clinical practice to treat breast cancer metastasis, to lipid-polymer nanoparticles (LPNs) loaded with silibinin. The molecular structure responsible for HG association with LPNs was assessed using surface-enhanced Raman spectroscopy for HNS surface chemistry characterization. Moreover, the molecular class of HG was identified using UPLC-Orbitrap-MS/MS to further confirm the surface binding. Mucus diffusion and in vivo biodistribution were evaluated using in vitro multiple-particle tracking and environment-responsive fluorescence probe in 4T1 tumor-bearing mice, respectively. The alleviation of breast cancer metastasis was assessed in 4T1 tumor-bearing mice, and the underlying mechanism was investigated. Results: The HNS reduced particle-mucus interactions by altering hydrophilicity and surface characteristics compared to LPNs. The epithelium transportation of HNS and absorption through Peyer's patch in mice were improved, promoting their biodistribution in the lung and tumor tissues. Furthermore, the HNS alleviated lung metastasis by inducing cell apoptosis and regulating the expression of MMP-9 and TGF-ß1, which altered the TME in 4T1 tumor-bearing mice. Conclusion: HNS provides an appealing system with multi-component binding of herbal medicine to facilitate both oral nanoparticle delivery efficiency and the alleviation of lung metastasis. This strategy may potentially help improve treatment for patients with breast cancer.
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Neoplasias de la Mama , Neoplasias Pulmonares , Ratones Endogámicos BALB C , Nanopartículas , Animales , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/metabolismo , Administración Oral , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Ratones , Línea Celular Tumoral , Distribución Tisular , Nanopartículas/química , Nanopartículas/administración & dosificación , Humanos , Microambiente Tumoral/efectos de los fármacosRESUMEN
OBJECTIVE: Since January 8, 2023, China has managed COVID-19 as a Class-B infectious disease, marking the epidemic's transition to a low-level stage. This study analyzes the relationship between the public's perceived a community with shared future for doctor-patient (PCSF), health self-consciousness, benefit finding, and anxiety in this stage. Additionally, it compares changes in these variables across different stages of COVID-19. METHODS: Using a repeated cross-sectional design, three surveys were conducted respectively in three different stages of COVID-19 in China. Specifically, the first survey was conducted in Beijing, Dalian, Zhengzhou, Heihe, and Shangrao from November 13 to 20, 2021 in the outbreak stage of COVID-19, yielding 1,252 valid responses out of 1,534 collected questionnaires. The second survey was conducted in Dalian, Zhengzhou, Heihe, Shangrao, and Lanzhou from December 1 to 19, 2021 in the stable stage of COVID-19, with 872 valid responses obtained from 1,075 collected questionnaires. The third survey was conducted in Beijing, Dalian, Zhengzhou, Heihe, Shangrao, Lanzhou, and Chengdu from January 29 to February 4, 2023 in the low epidemic level stage of COVID-19, achieving 2,113 valid responses from the 2,461 questionnaires collected. RESULTS: Unlike in the outbreak stage but similar to the stable stage, the public's anxiety, health self-consciousness and benefit finding decreased while PCSF was improved in the low epidemic level stage. Consistent with both the outbreak and stable stage, PCSF, health self-consciousness, benefit finding, and anxiety showed positive correlations in the low epidemic level stage, with health self-consciousness partially mediating the positive impact of PCSF on benefit finding. Unlike in the stable stage but similar to the outbreak stage, anxiety did not moderate the relationship between PCSF and health self-consciousness in the low epidemic level stage. CONCLUSIONS: The public's health self-consciousness, benefit finding, and anxiety decreased, while PCSF increased in the low epidemic level stage. Furthermore, PCSF had a greater impact on benefit finding, and anxiety's impact on health self-consciousness was significantly reduced. Across different stages of COVID-19, PCSF directly increased benefit finding and also enhanced benefit finding by improving health self-consciousness. Thus, comprehensive intervention measures are beneficial in the low epidemic level stage.
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Ansiedad , COVID-19 , Humanos , COVID-19/psicología , COVID-19/epidemiología , Estudios Transversales , Masculino , Proyectos Piloto , Femenino , Adulto , China/epidemiología , Ansiedad/psicología , Ansiedad/epidemiología , Persona de Mediana Edad , Adulto Joven , Encuestas y Cuestionarios , Relaciones Médico-Paciente , SARS-CoV-2 , Adolescente , AncianoRESUMEN
Inhibiting O-GlcNAcase and thereby up-regulation of the O-GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC50 = 4.93 ± 2.05 nM) and cellular potency (EC50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O-GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.
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Seasonal H3N2 influenza virus, known for its rapid evolution, poses a serious threat to human health. This study focuses on analyzing the influenza virus trends in Jining City (2018-2023) and understanding the evolving nature of H3N2 strains. Data on influenza-like cases were gathered from Jining City's sentinel hospitals: Jining First People's Hospital and Rencheng Maternal and Child Health Hospital, using the Chinese Influenza Surveillance Information System. Over the period from 2018 to 2023, 7844 throat swab specimens were assessed using real-time fluorescence quantitative PCR for influenza virus nucleic acid detection. For cases positive for seasonal H3N2 influenza virus, virus isolation was followed by whole genome sequencing. Evolutionary trees were built for the eight gene segments, and protein variation analysis was performed. From 2018 to 2023, influenza-like cases in Jining City represented 6.99% (237 299/3 397 247) of outpatient visits, peaking in December and January. Influenza virus was detected in 15.67% (1229/7844) of cases, primarily from December to February. Notably, no cases were found in the 2020-2021 season. Full genome sequencing was conducted on 70 seasonal H3N2 strains, revealing distinct evolutionary branches across seasons. Significant antigenic site variations in the HA protein were noted. No resistance mutations to inhibitors were found, but some strains exhibited mutations in PA, NS1, PA-X, and PB1-F2. Influenza trends in Jining City saw significant shifts in the 2020-2021 and 2022-2023 seasons. Seasonal H3N2 exhibited rapid evolution. Sustained vigilance is imperative for vaccine updates and antiviral selection.
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Genoma Viral , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana , Filogenia , Estaciones del Año , Secuenciación Completa del Genoma , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/aislamiento & purificación , Humanos , Gripe Humana/epidemiología , Gripe Humana/virología , China/epidemiología , Epidemias , Evolución MolecularRESUMEN
Lung adenocarcinoma is the most common primary lung cancer seen in the world, and identifying genetic markers is essential for predicting the prognosis of lung adenocarcinoma and improving treatment outcomes. It is well known that alterations in circadian rhythms are associated with a higher risk of cancer. Moreover, circadian rhythms play a regulatory role in the human body. Therefore, studying the changes in circadian rhythms in cancer patients is crucial for optimizing treatment. The gene expression data and clinical data were sourced from TCGA database, and we identified the circadian clock-related genes. We used the obtained TCGA-LUAD data set to build the model, and the other 647 lung adenocarcinoma patients' data were collected from two GEO data sets for external verification. A risk score model for circadian clock-related genes was constructed, based on the identification of 8 genetically significant genes. Based on ROC analyses, the risk model demonstrated a high level of accuracy in predicting the overall survival times of lung adenocarcinoma patients in training folds, as well as external data sets. This study has successfully constructed a risk model for lung adenocarcinoma prognosis, utilizing circadian rhythm as its foundation. This model demonstrates a dependable capacity to forecast the outcome of the disease, which can further guide the relevant mechanism of lung adenocarcinoma and combine behavioral therapy with treatment to optimize treatment decision-making.
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Adenocarcinoma del Pulmón , Relojes Circadianos , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/patología , Pronóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Relojes Circadianos/genética , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Ritmo Circadiano/genética , Persona de Mediana Edad , Bases de Datos GenéticasRESUMEN
OBJECTIVES: The combined impact of sleep quality and diet habits on ischemic stroke remains unclear, particularly in rural populations. Therefore, this study aimed to estimate the individual and joint associations of sleep quality and diet habits with nonfatal ischemic stroke among rural adults. METHODS: A total of 22â536 participants free of stroke were enrolled from the Henan Rural Cohort. Sleep quality and diet habits were evaluated with the Pittsburgh Sleep Quality Index and food frequency questionnaire, respectively. The ischemic stroke incidence was analyzed using Kaplan-Meier curves. Cox regression and restricted cubic spline were employed to estimate the correlation of sleep quality or diet habits with ischemic stroke. RESULTS: During an average 3.92 y of follow-up, 665 ischemic stroke patients were identified. The adjusted hazard ratio (95% confidence interval) of ischemic stroke risk compared with good sleep quality was 1.276 (1.057-1.542). The hazard ratio (95% confidence interval) of nonfatal ischemic stroke compared with unhealthy diet habits was 0.693 (0.589-0.814). The restricted cubic spline indicated that the risk of ischemic stroke increased with the increase of the Pittsburgh Sleep Quality Index. And the higher the diet quality score, the lower the risk of ischemic stroke. (Ptrend < 0.05). Further analysis indicated that the association of poor sleep quality with ischemic stroke was alleviated by healthy diet habits (P < 0.05). Additionally, a robust correlation remained after excluding individuals with ischemic stroke in the first year. CONCLUSIONS: Poor sleep quality was positively associated with nonfatal ischemic stroke among rural adults, and healthy diet habits attenuated this relationship. Developing healthy diet and sleep habits may have potential health implications for preventing ischemic stroke. TRIAL REGISTRATION: The Henan Rural Cohort Study has been registered at the Chinese Clinical Trial Register (registration no. ChiCTR-OOC-15006699). Date of registration: July 6, 2015.
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Background: Bulbus Fritillariae Pallidiflorae (BFP) is a traditional Chinese medicine that has long been used to treat lung diseases, but the active components and mechanism are still unclear. Objective: This study aimed to investigate the effect and mechanism of the total alkaloid extract from BFP (BFP-TA) on cigarette smoke extract (CSE)-induced Beas-2B cells injury. Design: The Beas-2B cells injury model was induced by 2% CSE, then the effect of BFP-TA on the levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and malondialdehyde (MDA) was detected according to the instructions of the T-AOC assay kit, the SOD detection kit and the MDA detection kit, and the production of ROS was detected by fluorescence microscopy. The effect of BFP-TA on Beas-2B cells apoptosis was detected by flow cytometry, and the effect of BFP-TA on related protein expression was detected by western blot. Subsequently, the effect of BFP-TA on differentially expressed genes (DEGs) in CSE-induced Beas-2B cells was studied by transcriptomic sequencing, and the expression of DEGs was verified by quantitative real-time polymerase chain reaction (qPCR). Results: The results showed that BFP-TA could attenuate CSE-induced oxidative damage in Beas-2B cells by elevating T-AOC and SOD levels while inhibiting ROS and MDA levels, and the mechanism was potentially related to the SIRT1/Nrf2/Keap1 signaling pathway. Furthermore, BFP-TA could inhibit CSE-induced apoptosis by inhibiting the protein expression of Bax, MST1 and FOXO3a, and exert anti-inflammatory effect by inhibiting the activation of MAPK signaling pathway. Subsequently, transcriptome analysis and qPCR validation showed that BFP-TA could alleviate inflammation, oxidative stress, apoptosis and lipid metabolism disorders by regulating the expression of DEGs in PPAR and PI3K-Akt signaling pathways, thereby exerting a protective effect against CSE-induced Beas-2B cell injury. Conclusion: This study is the first to demonstrate that BFP-TA could exert a protective effect on CSE-induced Beas-2B cell injury by exerting anti-inflammatory, antioxidant, anti-apoptotic and regulate lipid metabolism disorders.
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Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.
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Ferroptosis , Melatonina , Ratones Noqueados , Privación de Sueño , Animales , Ratones , Melatonina/metabolismo , Melatonina/farmacología , Privación de Sueño/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Peroxidación de Lípido , Araquidonato 15-Lipooxigenasa/metabolismo , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 12-LipooxigenasaRESUMEN
Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.
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An azeotrope is a constant boiling point mixture, and its behavior is important for fluid separation processes. Predicting azeotropes from atomistic simulations is difficult due to the complexities and convergence problems of Monte Carlo and free-energy perturbation techniques. Here, we present a methodology for predicting the azeotropes of binary mixtures, which computes the compositional dependence of chemical potentials from molecular dynamics simulations using the S0 method and employs experimental boiling point and vaporization enthalpy data. Using this methodology, we reproduce the azeotropes, or lack thereof, in five case studies, including ethanol/water, ethanol/isooctane, methanol/water, hydrazine/water, and acetone/chloroform mixtures. We find that it is crucial to use the experimental boiling point and vaporization enthalpy for reliable azeotrope predictions, as empirical force fields are not accurate enough for these quantities. Finally, we use regular solution models to rationalize the azeotropes and reveal that they tend to form when the mixture components have similar boiling points and strong interactions.
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Background: The preoperative identification of epidermal growth factor receptor (EGFR) mutations and subtypes based on magnetic resonance imaging (MRI) of brain metastases (BM) is necessary to facilitate individualized therapy. This study aimed to develop a deep learning model to preoperatively detect EGFR mutations and identify the location of EGFR mutations in patients with non-small cell lung cancer (NSCLC) and BM. Methods: We included 160 and 72 patients who underwent contrast-enhanced T1-weighted (T1w-CE) and T2-weighted (T2W) MRI at Liaoning Cancer Hospital and Institute (center 1) and Shengjing Hospital of China Medical University (center 2) to form a training cohort and an external validation cohort, respectively. A multiscale feature fusion network (MSF-Net) was developed by adaptively integrating features based on different stages of residual network (ResNet) 50 and by introducing channel and spatial attention modules. The external validation set from center 2 was used to assess the performance of MSF-Net and to compare it with that of handcrafted radiomics features. Receiver operating characteristic (ROC) curves, accuracy, precision, recall, and F1-score were used to evaluate the effectiveness of the models. Gradient-weighted class activation mapping (Grad-CAM) was used to demonstrate the attention of the MSF-Net model. Results: The developed MSF-Net generated a better diagnostic performance than did the handcrafted radiomics in terms of the microaveraged area under the curve (AUC) (MSF-Net: 0.91; radiomics: 0.80) and macroaveraged AUC (MSF-Net: 0.90; radiomics: 0.81) for predicting EGFR mutations and subtypes. Conclusions: This study provides an end-to-end and noninvasive imaging tool for the preoperative prediction of EGFR mutation status and subtypes based on BM, which may be helpful for facilitating individualized clinical treatment plans.
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Background: As an autoimmune disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often affects multiple organs, including the ocular system. This study aims to investigate differences in retinal thickness (RT) and retinal superficial vascular density (SVD) between patients with AAV and healthy controls (HCs) using optical coherence tomography angiography (OCTA). Currently, these differences are not clear. Methods: A total of 16 AAV individuals (32 eyes) and 16 HCs (32 eyes) were recruited to this cross-sectional study conducted in the First Affiliated Hospital of Nanchang University from June 2023 to September 2023. The study protocol conformed with the tenets of the Declaration of Helsinki (as revised in 2013). Each image observed by OCTA was divided into 9 regions using the Early Treatment Diabetic Retinopathy Study (ETDRS) subzones as a guide. Results: In the full layer, the RT of AAV patients was found to be significantly reduced in the inner superior (IS, P<0.001), outer superior (OS, P=0.003), inner temporal (IT, P=0.003), and outer temporal (OT, P<0.001) regions; inner RT was significantly lower in the IS (P=0.006), OS (P<0.001), inner nasal (IN, P=0.005), outer nasal (ON, P<0.001), and center (C, P=0.01) regions than that in HCs. Outer RT of AAV patients showed a reduction in the IS (P<0.001), as well as IT (P=0.008), and OT (P<0.001) regions. No statistically significant differences were seen in the different subregions in other different layers (P>0.05). Only the inner inferior (II) and outer inferior (OI) regions of SVD in AAV patients did not differ significantly from controls. All other regions showed a reduction in SVD. The details are as follows: IS (P<0.001), OS (P<0.001), IT (P=0.005), OT (P<0.001), IN (P<0.001), ON (P<0.001), and C (P=0.003). According to receiver operating characteristic (ROC) curve analysis, the full IS region [area under the curve (AUC): 0.8892, 95% confidence interval (CI): 0.8041-0.9742, P<0.001] had the highest diagnostic value for AAV-induced reduction in RT. The IS (AUC: 0.9121, 95% CI: 0.8322-0.9920, P<0.001) region was also the most sensitive to changes in SVD of AAV individuals. In addition, we found that SVD in the IN region (r=-0.4224, 95% CI: -0.6779 to -0.0757, P=0.02) as well as mean visual acuity (r=-0.3922, 95% CI: -0.6579 to -0.0397, P=0.03) of AAV patients were negatively correlated with disease duration. However, we did not find an association between SVD and RT in this study. Conclusions: The findings from OCTA indicated a reduction in RT and SVD among patients with AAV. OCTA allows for the evaluation of AAV-related ocular lesions and holds promise for monitoring of disease progression through regular evaluations.
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Macrophages are plastic and play a key role in the maintenance of tissue homeostasis. In cancer progression, macrophages also take part in all processes, from initiation to progression, to final tumor metastasis. Although energy deprivation and autophagy are widely used for cancer therapy, most of these strategies do not target macrophages, resulting in undesired effects and unsatisfactory outcomes for cancer immunotherapy. Herein, we developed a lanthanum nickel oxide (LNO) nanozyme with phosphatase-like activity for ATP hydrolysis. Meanwhile, the autophagy of macrophages induced by LNO promotes the polarization of macrophages from M2-like macrophages (M2) to M1-like macrophages (M1) and reduces tumor-associated macrophages in tumor-bearing mice, exhibiting the capability of killing tumor-associated macrophages and antitumor effects in vivo. Furthermore, pre-coating the surface of LNO with a myeloid cell membrane significantly enhanced antitumor immunity. Our findings demonstrate that phosphatase-like nanozyme LNO can specifically induce macrophage autophagy, which improves therapeutic efficacy and offers valuable strategies for cancer immunotherapy.
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Three-dimensional (3D) magnetic flower-spherical Fe2O3-NiO derived from NiFe-layered double hydroxides (NiFe-LDHs) was fabricated through urea hydrothermal and calcination methods. The as-prepared materials were applied to activate PMS to degrade one of herbicide named Bensulfuron methyl (BSM). Fe2O3-NiO-1 demonstrated the highest catalytic activity and the lowest ions leaching by comparing the performance of LDHs and derivative bimetallic oxide synthesized by co-precipitation method, urea hydrothermal method and direct calcination method. Based on the results of SEM, BET and CV, the high catalytic activity of Fe2O3-NiO-1 originated from 3D morphology, lager specific area and pore size and faster electron transfer capability. The factors influencing the degradation performance were investigated and 0.1 g·L-1 Fe2O3-NiO could effectively activate PMS (1 mmol·L-1) to completely remove 10 mg·L-1 BSM within 30 min at pH 7.0. In Fe2O3-NiO/PMS system, OH, SO4- and 1O2 were produced and contributed to the BSM removal according to the results of EPR and quenching experiments. In order to expand its application range, Fe2O3-NiO/PMS system was used to degrade aniline (AN), sulfamethoxazole (SMZ), phenacetin (PNT), bisphenol A (BPA) and 2,4,6-triclofen (2,4,6-TCP) and the results showed the degradation efficiency could reach 90 % or more. Additionally, the application of catalysts in different actual water samples and the ability of reuse were tested. Based on the strategies of bimetallic synergy and morphology control, Fe-based bimetallic oxides with 3D morphology were developed in this study, which could effectively enhance the catalytic activity and inhibit the dissolution of metal ions, providing the design ideas for the construction of efficient catalysts and the removal of complex organic pollutants.