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OBJECTIVE: To investigate the causal association between immune cell and different types of sepsis by using Mendelian randomization (MR) method, and to find the immune cell phenotypes causally associated with sepsis. METHODS: Summary data for various circulating immune cell phenotypes were obtained from the GWAS catalog (GCST90001391-GCST90002121). Sepsis data were sourced from the UK Biobank database. Single nucleotide polymorphisms (SNP) were used as instrumental variables. The correlation threshold of P < 5×10-6 was used to identify the strongly correlated instrumental variables, and the code was used to remove the linkage disequilibrium and the instrumental variables with F-value < 10. Inverse variance weighting (IVW) was used as the main research method to evaluate the stability and reliability of the results, including Cochran's Q test, MR-Egger regression and Leave one out. Reverse MR analysis was performed based on the immunophenotypic results of the removal of horizontal pleiotropy, and the immune cell phenotype with one-way causal association was obtained. Odds ratio (OR) and 95% confidence interval (95%CI) were used to represent the effect value of the results. RESULTS: CD16 on CD14-CD16+; monocyte had horizontal pleiotropy in sepsis (OR = 0.965 4, 95%CI was 0.933 5-0.998 3, P = 0.039 6). There were five immunophenotypes that had reverse causal associations with the types associated with sepsis. After excluding immune cell phenotypes with horizontal pleiotropy and reverse causation, a total of 42 immune cell phenotypes with sepsis, 36 immune cell phenotypes with sepsis (28-day death in critical care), 32 immune cell phenotypes with sepsis (critical care), 44 immune cell phenotypes with sepsis (28-day death), and 30 immune cell phenotypes had potential causal associations with sepsis (under 75 years old). After false discovery rate (FDR) correction, the correlations between BAFF-R on IgD- CD38br and sepsis (28-day death) were negative and strong (OR = 0.737 8, 95%CI was 0.635 9-0.856 0, P = 6.05×10-5, PFDR = 0.044 2). CONCLUSIONS: A variety of immune cell phenotypes may have a protective effect on sepsis, especially BAFF-R on IgD- CD38br expression is negatively correlated with sepsis (28-day death), which provides a new idea for immune modulation therapy in sepsis.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Sepsis , Humanos , Sepsis/genética , Fenotipo , Desequilibrio de Ligamiento , Oportunidad RelativaRESUMEN
Structural health monitoring (SHM) of composite materials is of great significance in various practical applications. However, it is a challenge to accurately monitor the damage of composites without affecting their mechanical properties. In this paper, an embedded sensing layer based on carbon nanotube-coated glass fiber is designed, combined with electrical resistance tomography (ERT) for in situ damage monitoring. Multi-wall carbon nanotube-coated glass fiber (MWCNT-GF) is prepared and embedded into laminates as an in situ sensing layer. Low-velocity impact experiments demonstrate that the embedded sensing layer has high compatibility with the composite laminates and has no adverse effect on its impact response; although, the energy absorption behavior of glass fiber-reinforced polymer (GFRP) laminates containing MWCNT-GF occurs about 10% earlier than that of GFRP laminates overall. ERT technology is used to analyze the laminates after a low-velocity impact test. The results show that the in situ monitoring method with the embedded MWCNT-GF sensing layer can achieve high precision in imaging localization of impact damage, and the error of the detected damage area is only 4.5%.
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The study aimed to compare the impact of four chemical additives on fermentation characteristics, aerobic stability and in vitro digestibility of total mixed ration (TMR) silage based on soy sauce residue. The TMR (35% soy sauce residue + 45% Napier grass + 20% concentrate) was placed into silos (10 L). The experiment followed the completely random design, treated with different chemical additives: (1) distilled water (control); (2) 0.1% potassium sorbate (SP); (3) 0.1% sodium benzoate (SS); (4) 0.5% calcium propionate (SC); (5) 0.5% sodium diacetate (SD). Total of 100 silos (5 treatments × 4 aerobic exposure days × 5 replicates) were ensiled for 60 days. After exposure to the air, the samples were analyzed for the dynamic change of fermentation parameters at 4, 9 and 15 days, and the data was analyzed as repeated measures. The content of butyric acid and ammonia nitrogen was maintained at a low level. The highest (p < 0.05) lactic acid (LA) content and the lowest (p < 0.05) pH value were measured in SP. At the first 4 days of aerobic exposure, TMR silages treated with four chemical additives were more stable relative to the control, as indicated by the low pH value and yeast counts. Furthermore, the highest (p < 0.05) LA content and the lowest (p < 0.05) pH value indicated that SP performed superior aerobic stability compared with other chemical additives. The SP shows higher (p < 0.05) 72 h cumulative gas production (GP72) and in vitro neutral detergent fiber digestibility (IVNDFD) relative to the control. In conclusion, the SP performed superior in improving fermentation characteristics, aerobic stability and in vitro digestibility of TMR silages based on soy sauce residue.
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Chemotherapy-based combination regimens are recommended as first-line treatment for colorectal cancer. However, multidrug resistance (MDR) and limited drug infiltration in tumor microenvironment remain critical challenges. Herein, a pH/redox dual activated supramolecular DAS@CD-OxPt (IV) nanoparticles (NPs) via host-guest molecular recognition to achieve relay drugs delivery of active oxaliplatin (OxPt (IV)) and Src inhibitor dasatinib (DAS) between tumor cells is developed. DAS@CD-OxPt (IV) NPs exhibit prolonged circulation in the blood and intra-tumoral retention. Triggered by the endo/lysosome (pH 5.0), flexible DAS@CD-OxPt (IV) NPs exhibited proton-driven in situ assembly to form nanofiber in tumor cells. Dual chemotherapeutic agents released from DAS@CD-OxPt (IV) NPs synergistically cause irreversible DNA damage by blocking p53-mediated DNA repair. Supramolecular nanofibers can further serve as the "ammunition depot" to continuously release drugs from dying cells and transport them into neighboring tumor cells, leading to domino-like cell death and enhanced immunogenicity. Furthermore, DAS@CD-OxPt (IV) NPs combined with immune checkpoint blockade (ICB) therapy strikingly suppress CT26 tumor growth and pulmonary metastasis.
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Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1ß levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury.
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Lesión Pulmonar Aguda , Caspasa 3 , Modelos Animales de Enfermedad , Piroptosis , Sepsis , Animales , Piroptosis/efectos de los fármacos , Sepsis/complicaciones , Ratones , Caspasa 3/metabolismo , Lesión Pulmonar Aguda/patología , Masculino , Ratones Endogámicos C57BL , Interleucina-6/metabolismo , Inhibidores de Caspasas/farmacología , Pulmón/patología , Pulmón/metabolismo , Oligopéptidos/farmacología , GasderminasRESUMEN
PURPOSE: Gastric cancer (GC) is among the deadliest malignancies and the third leading cause of cancer-related deaths worldwide. Galectin-1 (Gal-1) is a primary protein secreted by cancer-associated fibroblasts (CAFs); however, its role and mechanisms of action of Gal-1 in GC remain unclear. In this study, we stimulated GC cells with exogenous human recombinant galectin-1 protein (rhGal-1) to investigate its effects on the proliferation, migration, and resistance to cisplatin. MATERIALS AND METHODS: We used simulated rhGal-1 protein as a paracrine factor produced by CAFs to induce GC cells and investigated its promotional effects and mechanisms in GC progression and cisplatin resistance. Immunohistochemical (IHC) assay confirmed that Gal-1 expression was associated with clinicopathological parameters and correlated with the expression of neuropilin-1 (NRP-1), c-JUN, and Wee1. RESULTS: Our study reveals Gal-1 expression was significantly associated with poor outcomes. Gal-1 boosts the proliferation and metastasis of GC cells by activating the NRP-1/C-JUN/Wee1 pathway. Gal-1 notably increases GC cell resistance to cisplatin The NRP-1 inhibitor, EG00229, effectively counteracts these effects. CONCLUSIONS: These findings revealed a potential mechanism by which Gal-1 promotes GC growth and contributes to chemoresistance, offering new therapeutic targets for the treatment of GC.
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Proliferación Celular , Cisplatino , Resistencia a Antineoplásicos , Galectina 1 , Neuropilina-1 , Neoplasias Gástricas , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Humanos , Galectina 1/genética , Galectina 1/metabolismo , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Neuropilina-1/metabolismo , Neuropilina-1/genética , Proliferación Celular/efectos de los fármacos , Masculino , Femenino , Progresión de la Enfermedad , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Persona de Mediana Edad , Ratones , Animales , Movimiento Celular/efectos de los fármacos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patologíaRESUMEN
Carbon-fiber-reinforced polymer (CFRP) composites are widely used in lightweight structures because of their high specific strength, specific modulus, and low coefficient of thermal expansion. Additionally, the unidirectionally arrayed chopped strand (UACS) laminates have excellent mechanical properties and flowability, making them suitable for fabricating structures with complex geometry. In this paper, the damage process of UACS quasi-isotropic laminates under tensile load was tested using acoustic emission detection technology. The mechanical properties and damage failure mechanism of UACS laminates were studied combined with finite element calculation. By comparing and analyzing the characteristic parameters of acoustic emission signals such as amplitude, relative energy, and impact event, it is found that acoustic emission behavior can accurately describe the damage evolution of specimens during loading. The results show that the high-amplitude signals representing fiber fracture in continuous fiber laminates are concentrated in the last 41%, while in UACS laminates they are concentrated in the last 30%. In UACS laminates, more of the damage is caused by matrix cracks and delamination with medium- and low-amplitude signals, which indicates that UACS laminates have a good suppression effect on damage propagation. The stress-strain curves obtained from finite element analysis agree well with the experiment results, showing the same damage sequence, which confirms that the model described in this research is reliable.
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Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.
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Hipertermia Inducida , Enfermedades Mitocondriales , Nanopartículas , Neoplasias , Humanos , Verde de Indocianina/farmacología , Cobre/farmacología , Fototerapia , Terapia Fototérmica , Flavonoides , Línea Celular TumoralRESUMEN
BACKGROUND: Sepsis is characterized by severe inflammation and organ dysfunction resulting from a dysregulated organismal response to infection. Although pyroptosis has been presumably shown to be a major cause of multiple organ failure and septic death, whether gasdermin E (GSDME)-mediated pyroptosis occurs in septic liver injury and whether inhibiting apoptosis and GSDME-mediated pyroptosis can attenuate septic liver injury remain unclear. This study investigated the role of apoptosis and GSDME-mediated pyroptosis in septic liver injury. METHODS: Adult male C57BL/6 mice were randomly divided into four groups: sham, cecal ligation puncture (CLP), CLP + Z-DEVD-FMK (a caspase-3 inhibitor, 5 mg/kg), and CLP + Ac-DMLD-CMK (a GSDME inhibitor, 5 mg/kg). Sepsis severity was assessed using the murine sepsis score (MSS). Hepatic tissue damage was observed by the hematoxylin-eosin staining method, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the levels of malondialdehyde (MDA), the concentrations of interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were measured according to the related kits, and the changes in the hepatic tissue reactive oxygen species (ROS) levels were detected by immunofluorescence (IF). The protein expression levels of cleaved caspase-3, GSDME-N, IL-1ß, B-cell lymphoma-2 (Bcl-2), cytochrome C (Cyt-c), and acetaldehyde dehydrogenase 2 (ALDH2) were detected using western blotting. GSDME expression was detected by immunohistochemistry. RESULTS: Compared with the Sham group, CLP mice showed high sepsis scores and obvious liver damage. However, in the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups, the sepsis scores were reduced and liver injury was alleviated. Compared with the Sham group, the serum ALT and AST activities, MDA and ROS levels, and IL-1ß and TNF-α concentrations were increased in the CLP group, as well as the protein expression of cleaved caspase-3, GSDME-N, IL-1ß, Cyt-c, and GSDME positive cells (P < 0.05). However, the expression levels of Bcl-2 and ALDH2 protein were decreased (P < 0.05). Compared with the CLP group, the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups showed low sepsis scores, ALT and AST activities, MDA and ROS levels, decreased IL-1ß and TNF-α concentrations, and decreased expression of cleaved caspase-3, GSDME-N, IL-1ß protein expression, and GSDME positive cells (P < 0.05). The expression levels of Bcl-2 and ALDH2 protein were increased (P < 0.05). CONCLUSION: Apoptosis and GSDME-mediated pyroptosis are involved in the development of sepsis-induced hepatic injury. Inhibition of apoptosis and GSDME-mediated pyroptosis attenuates injury. ALDH2 plays a protective role by inhibiting apoptosis and pyroptosis.
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Sepsis , Factor de Necrosis Tumoral alfa , Ratones , Animales , Masculino , Piroptosis , Caspasa 3 , Especies Reactivas de Oxígeno , Aldehído Deshidrogenasa Mitocondrial , Ratones Endogámicos C57BL , Hígado/metabolismo , Apoptosis , Sepsis/complicaciones , Sepsis/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
BACKGROUND/AIMS: Gastric cancer is a prevalent malignancy with unfavorable prognosis partially resulting from its high metastasis rate. Clarifying the molecular mechanism of gastric cancer occurrence and progression for improvement of therapeutic efficacy and prognosis is needed. The study tended to delineate the role and regulatory mechanism of aldo-keto reductase 1B10 (AKR1B10) in gastric cancer progression. MATERIALS AND METHODS: The relationship of AKR1B10 expression with survival rate in gastric cancer was analyzed through Kaplan-Meier analysis. The mRNA levels of AKR1B10 and integrin subunit alpha 5 (ITGA5) in gastric cancer tissues and cell lines were measured by real-time quantitative polymerase chain reaction. Protein levels of AKR1B10 and integrin subunit alpha 5 were assayed via western blot. The molecular relationship between AKR1B10 and ITGA5 was analyzed by co-immunoprecipitation assay. Cell viability was assayed through Cell Counting Kit-8, invasion and migration of tumor cells was assessed through wound healing and transwell assays. Transwell assay was utilized to detect invasion. The adhesion of gastric cancer cells was detected using cell adhesion assays. RESULTS: The results unveiled that integrin subunit alpha 5 was upregulated, while AKR1B10 was downregulated in gastric cancer tissues and cells. Overexpressing AKR1B10 hindered gastric cancer cell proliferation, migration, invasion and adhesion. It was striking that we certified the inhibitory effect of AKR1B10 on integrin subunit alpha 5 expression and their (AKR1B10 and ITGA5)) negative relationship via bioinformatics method, real-time quantitative polymerase chain reaction, and co-immunoprecipitation assays. Via rescue experiments, it was concluded that AKR1B10 served as tumor suppressor potentially by ITGA5 expression in gastric cancer. CONCLUSION: Our results indicated that AKR1B10 inhibited migration, invasion, and adhesion of gastric cancer cells via modulation of ITGA5.
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Aldo-Ceto Reductasas , Integrinas , Neoplasias Gástricas , Humanos , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Aldo-Ceto Reductasas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Gástricas/patologíaRESUMEN
Inflammatory bowel disease (IBD) has been closely associated with immune disorders and excessive M1 macrophage activation, which can be reversed by the M2-polarizing effect of interleukin-4 (IL-4). However, maintaining native IL-4 activity with its specific release in the inflammatory microenvironment and efficient biological performance remain a challenge. Inspired by the multilayered defense mechanism of the earth's atmosphere, we constructed a multilayered protective nanoarmor (NA) for IL-4 delivery (termed as IL-4@PEGRA NAs) into an intricate inflammatory microenvironment. The poly(ethylene glycol) (PEG)-ylated phenolic rosmarinic acid (RA)-grafted copolymer contains two protective layers-the intermediate polyphenol (RA molecules) and outermost shield (PEG) layers-to protect the biological activity of IL-4 and prolong its circulation in blood. Moreover, IL-4@PEGRA NAs scavenge reactive oxygen species with the specific release of IL-4 and maximize its biofunction at the site of inflammation, leading to M2 macrophage polarization and downregulation of inflammatory mediators. Simultaneously, gut microbiota dysbiosis can improve to amplify the M2-polarizing effect and inhibit the phosphatidylinositol 3 kinase/Akt signaling pathway, thereby attenuating inflammation and promoting colitis tissue repair. It provides a nature-inspired strategy for constructing an advanced multilayered NA delivery system with protective characteristics and potential for IBD management.
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Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Interleucina-4/farmacología , Inflamación/metabolismo , Macrófagos/metabolismoRESUMEN
Sensors are the key to environmental monitoring, which impart benefits to smart cities in many aspects, such as providing real-time air quality information to assist human decision-making. However, it is impractical to deploy massive sensors due to the expensive costs, resulting in sparse data collection. Therefore, how to get fine-grained data measurement has long been a pressing issue. In this article, we aim to infer values at nonsensor locations based on observations from available sensors (termed spatiotemporal inference), where capturing spatiotemporal relationships among the data plays a critical role. Our investigations reveal two significant insights that have not been explored by previous works. First, data exhibit distinct patterns at both long-and short-term temporal scales, which should be analyzed separately. Second, short-term patterns contain more delicate relations, including those across spatial and temporal dimensions simultaneously, while long-term patterns involve high-level temporal trends. Based on these observations, we propose to decouple the modeling of short-and long-term patterns. Specifically, we introduce a joint spatiotemporal graph attention network to learn the relations across space and time for short-term patterns. Furthermore, we propose a graph recurrent network with a time skip strategy to alleviate the gradient vanishing problem and model the long-term dependencies. Experimental results on four public real-world datasets demonstrate that our method effectively captures both long-and short-term relations, achieving state-of-the-art performance against existing methods.
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As a major part of global development governance, G20 countries account for 80% of global carbon emissions. In order to achieve the goal of "carbon neutrality" proposed by the United Nations, it is important to compare and analyze the drivers of carbon emissions in G20 countries and provide recommendations for their carbon emission reduction. Based on the data of 17 G20 countries in the EORA database, this paper compares the drivers of carbon emissions of each country from 1990-2021 using weighted average structural decomposition and K-mean model. This paper focuses on four drivers, including carbon emission intensity, final demand structure, export structure, and production structure. Carbon emission intensity and final demand structure are the main factors of carbon emission reduction, and the other two factors have little influence. Among the G20 countries, the UK is in the first category because it does the best job on the four factors of carbon emissions, yet Italy is in the last category because it does not take full advantage of the four factors. Therefore, improving supply energy efficiency and adjusting demand, export, and industrial structure have become important tools for countries to transform and achieve carbon neutrality.
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Dióxido de Carbono , Carbono , Carbono/análisis , Dióxido de Carbono/análisis , Industrias , Desarrollo Económico , Italia , ChinaRESUMEN
Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy.
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Neoplasias , Piroptosis , Ratones , Animales , Caspasa 3 , Nanogeles , Inmunoterapia , Verde de Indocianina/química , Línea Celular TumoralRESUMEN
Light exposure can profoundly affect neurological functions and behaviors. Here, we show that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice. This beneficial effect involves the activation of a circuit including neurons in the central amygdala (CeA), locus coeruleus (LC), and dentate gyrus (DG). Specifically, moderate light activated corticotropin-releasing hormone (CRH) positive (+) CeA neurons and induced the release of corticotropin-releasing factor (CRF) from their axon terminals ending in the LC. CRF then activated tyrosine hydroxylase-expressing LC neurons, which send projections to DG and release norepinephrine (NE). NE activated ß-adrenergic receptors on CaMKIIα-expressing DG neurons, ultimately promoting spatial memory retrieval. Our study thus demonstrated a specific light scheme that can promote spatial memory without excessive stress, and unraveled the underlying CeA-LC-DG circuit and associated neurochemical mechanisms.
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Amígdala del Cerebelo , Luz , Memoria Espacial , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/metabolismo , Animales , Ratones , Ansiedad , Giro Dentado/citología , Giro Dentado/metabolismo , Neuronas , Locus Coeruleus/citología , Locus Coeruleus/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Norepinefrina/metabolismo , Vías Nerviosas , Aprendizaje por Laberinto , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: Recent evidence indicates that hippocampus is important for conditioned fear memory (CFM). Though few studies consider the roles of various cell types' contribution to such a process, as well as the accompanying transcriptome changes during this process. The purpose of this study was to explore the transcriptional regulatory genes and the targeted cells that are altered by CFM reconsolidation. METHODS: A fear conditioning experiment was established on adult male C57 mice, after day 3 tone-cued CFM reconsolidation test, hippocampus cells were dissociated. Using single cell RNA sequencing (scRNA-seq) technique, alterations of transcriptional genes expression were detected and cell cluster analysis were performed and compared with those in sham group. RESULTS: Seven non-neuronal and eight neuronal cell clusters (including four known neurons and four newly identified neuronal subtypes) has been explored. Among them, CA subtype 1 has characteristic gene markers of Ttr and Ptgds, which is speculated to be the outcome of acute stress and promotes the production of CFM. The results of KEGG pathway enrichment indicate the differences in the expression of certain molecular protein functional subunits in long-term potentiation (LTP) pathway between two types of neurons (DG and CA1) and astrocytes, thus providing a new transcriptional perspective for the role of hippocampus in the CFM reconsolidation. More importantly, the correlation between the reconsolidation of CFM and neurodegenerative diseases-linked genes is substantiated by the results from cell-cell interactions and KEGG pathway enrichment. Further analysis shows that the reconsolidation of CFM inhibits the risk-factor genes App and ApoE in Alzheimer's Disease (AD) and activates the protective gene Lrp1. CONCLUSIONS: This study reports the transcriptional genes expression changes of hippocampal cells driven by CFM, which confirm the involvement of LTP pathway and suggest the possibility of CFM-like behavior in preventing AD. However, the current research is limited to normal C57 mice, and further studies on AD model mice are needed to prove this preliminary conclusion.
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Hipocampo , Trastornos Fóbicos , Ratones , Masculino , Animales , Hipocampo/metabolismo , Neuronas/fisiología , Señales (Psicología) , Miedo/fisiologíaRESUMEN
Short-fiber-reinforced polymers (SFRPs) based on unidirectionally arrayed chopped strands (UACSs) have excellent formability and outstanding mechanical response. The low-velocity impact response, such as the delamination, damage tolerance and energy absorption of UACS composites, are essential to guarantee the stability and safety of composite components in service. The current study investigates the low-velocity impact response of continuous carbon-fiber-reinforced polymer (CFRP) and UACS laminates with vertical slits under drop-weight impact with various impact energies (4, 7 and 11 J). The in-plane size of the studied samples is 100 mm × 100 mm, and the stacking sequence is [0/90]4s. The time-history curves of load and energy are examined during low-velocity impact experiments, as well as the nonvisible damages are obtained by ultrasound C-scan imaging technique. A user-defined subroutine VUMAT, including the Johnson-Cook material and failure model, which is used to simulate the elastic-plastic property of the slits filled with resin, is coded in ABAQUS/Explicit. According to C-scan inspections of the impact-damaged laminates, UACS specimens show more severe delamination as impact energy increases. The damaged area of continuous CFRP laminates under impact energy of 11 J is 311 mm2, while that of UACS laminates is 1230 mm2. The slits have a negative effect on the load-bearing capacity but increase the energy absorption of UACS laminates by approximately 80% compared to the continuous CFRP laminates at 7 J. According to the variables of different damage modes in numerical simulation, cracks appear at the slits and then expand along the direction perpendicular to the slits, leading to the fracture of fiber. Nevertheless, as the damage expands to the slits, the delamination confines the damage propagation. The existence of slits could guide the path of damage propagation.
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Polycyclodextrin-based supramolecular nanoplatform crosslinked by stimuli-responsive moiety shows great promise in cancer therapy owing to its superior bio-stability and feasible modification of architectures. Here, the endogenous glutathione (GSH)-responsive polycyclodextrin supramolecular nanocages (PDOP NCs) are constructed by covalent crosslinking of multiple ß-cyclodextrin (ß-CD) molecules. The polycyclodextrin provide sites for conjugation of chemotherapeutic doxorubicin (DOX). Meanwhile, the PDOP NCs are stabilized by multiple interactions including host-guest interaction between DOX and ß-CD and hydrogen bonds between ß-CD units. The supramolecular crosslinked structure endowed the nanocage with high stability and drug loading capacity. Tons of GSH-sensitive disulfide linkages in PDOP NCs were broken at tumor cells, promoting tumor-specific DOX release. Besides, the redox equilibrium in tumor microenvironment could be disturbed due to GSH depletion, which further sensitized the DOX effects and alleviated drug resistance, facilitating inducing immunogenic cell death effect for enhanced chemotherapy, thereby achieving efficient tumor suppression and prolonged survival. Thus, the versatile polycyclodextrin-based supramolecular nanocage provides a novel and efficient drug delivery strategy for cancer treatment.