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With the rapid global spread of COVID-19 and the continuous emergence of variants, there is an urgent need to develop safe and effective vaccines. Here, we developed a novel mRNA vaccine, HC009, based on new formulation by the QTsome delivery platform. Immunogenicity results showed that the prime-boost immunization strategy with HC009 was able to induce robust and durable humoral immunity, as well as Th1-biased cellular responses in rodents or non-human primates (NHPs). After further challenge with live SARS-CoV-2 virus, HC009 provided adequate protection against virus infection in hACE2 transgenic mice. Therefore, HC009 could provide significant immune protection against SARS-CoV-2.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunogenicidad Vacunal , Ratones Transgénicos , SARS-CoV-2 , Vacunas de ARNm , Animales , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Ratones , Vacunas de ARNm/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Humanos , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Inmunidad Humoral , Femenino , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Ratones Endogámicos BALB C , Eficacia de las VacunasRESUMEN
CONTEXT: The cyclopropane skeleton plays a significant role in bioactive molecules due to its distinctive structural properties. This has sparked keen interest and in-depth exploration in the field of stereoselective synthesis of cyclopropane derivatives. In the present study, the mechanism and the origin of stereoselectivity of diastereodivergent synthesis of cyclopropane derivatives via the catalyst-free [2 + 1]-cyclopropanation reactions of 3-diazo-N-methylindole (R1) with two types of electron-deficient olefins (R2 and R3) in both aqueous and toluene media have been studied using the DFT calculations. The findings indicate that these [2 + 1] cycloaddition reactions proceed in two stages, where the first step is not only the rate-determining step but also critically dictates the stereoselectivity of the product. The calculated diastereomeric ratios are in agreement with the experimental results. Furthermore, by utilizing non-covalent interaction (NCI) analysis and energy decomposition analysis based on molecular force fields (EDA-FF), we elucidated that the electrostatic interactions between reactant fragments in the transition state TS1s for the first step are the predominant factors determining the stereoselectivity, as opposed to the experimentally hypothesized steric hindrance and π-π stacking interactions. METHODS: The geometrical structures of all minima and transition states on the potential energy surface (PES) in solvents water and toluene were fully optimized using the DFT method at the M06-2X(D3)/SMD/6-31 + G(d,p) level of theory. Single-point energy calculations were carried out based on the optimized geometries in the solution at the M06-2X(D3)/6-311 + G(d,p) level. All the DFT calculations were performed using the Gaussian 09 software. The optimized molecular structures were visualized using CYLview software. NCI analysis was performed using the Multiwfn and VMD softwares. The Multiwfn program was also used for CDFT and EDA-FF analyses.
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Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by synovitis and cartilage destruction. The active compound, icariin (ICA), derived from the herb Epimedium, exhibits potent anti-inflammatory properties. However, its clinical utility is limited by its water insolubility, poor permeability, and low bioavailability. To address these challenges, we developed a multifunctional drug delivery system-adipose-derived stem cells-exosomes (ADSCs-EXO)-ICA to target active macrophages in synovial tissue and modulate macrophage polarization from M1 to M2. High-performance liquid chromatography analysis confirmed a 92.4 ± 0.008% loading efficiency for ADSCs-EXO-ICA. In vitro studies utilizing cellular immunofluorescence (IF) and flow cytometry demonstrated significant inhibition of M1 macrophage proliferation by ADSCs-EXO-ICA. Enzyme-linked immunosorbent assay, cellular transcriptomics, and real-time quantitative PCR indicated that ADSCs-EXO-ICA promotes an M1-to-M2 phenotypic transition by reducing glycolysis through the inhibition of the ERK/HIF-1α/GLUT1 pathway. In vivo, ADSCs-EXO-ICA effectively accumulated in the joints. Pharmacodynamic assessments revealed that ADSCs-EXO-ICA decreased cytokine levels and mitigated arthritis symptoms in collagen-induced arthritis (CIA) rats. Histological analysis and micro computed tomography confirmed that ADSCs-EXO-ICA markedly ameliorated synovitis and preserved cartilage. Further in vivo studies indicated that ADSCs-EXO-ICA suppresses arthritis by promoting an M1-to-M2 switch and suppressing glycolysis. Western blotting supported the therapeutic efficacy of ADSCs-EXO-ICA in RA, confirming its role in modulating macrophage function through energy metabolism regulation. Thus, this study not only introduces a drug delivery system that significantly enhances the anti-RA efficacy of ADSCs-EXO-ICA but also elucidates its mechanism of action in macrophage function inhibition.
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Tejido Adiposo , Artritis Reumatoide , Exosomas , Flavonoides , Macrófagos , Animales , Flavonoides/farmacología , Flavonoides/química , Exosomas/metabolismo , Ratas , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Tejido Adiposo/citología , Masculino , Artritis Experimental/tratamiento farmacológico , Ratas Sprague-Dawley , Sistemas de Liberación de Medicamentos/métodos , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacosRESUMEN
Biodiversity conservation amidst the uncertainty of climate change presents unique challenges that necessitate precise management strategies. The study reported here was aimed at refining understanding of these challenges and to propose specific, actionable management strategies. Employing a quantitative literature analysis, we meticulously examined 1268 research articles from the Web of Science database between 2005 and 2023. Through Cite Spaces and VOS viewer software, we conducted a bibliometric analysis and thematic synthesis to pinpoint emerging trends, key themes, and the geographical distribution of research efforts. Our methodology involved identifying patterns within the data, such as frequency of keywords, co-authorship networks, and citation analysis, to discern the primary focus areas within the field. This approach allowed us to distinguish between research concentration areas, specifically highlighting a predominant interest in Environmental Sciences Ecology (67.59 %) and Biodiversity Conservation (22.63 %). The identification of adaptive management practices and ecosystem services maintenance are central themes in the research from 2005 to 2023. Moreover, challenges such as understanding phenological shifts, invasive species dynamics, and anthropogenic pressures critically impact biodiversity conservation efforts. Our findings underscore the urgent need for precise, data-driven decision-making processes in the face of these challenges. Addressing the gaps identified, our study proposes targeted solutions, including the establishment of germplasm banks for at-risk species, the development of advanced genomic and microclimate models, and scenario analysis to predict and mitigate future conservation challenges. These strategies are aimed at enhancing the resilience of biodiversity against the backdrop of climate change through integrated, evidence-based approaches. By leveraging the compiled and analyzed data, this study offers a foundational framework for future research and practical action in biodiversity conservation strategies, demonstrating a path forward through detailed analysis and specified solutions.
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Biodiversidad , Cambio Climático , Conservación de los Recursos Naturales , Conservación de los Recursos Naturales/métodos , EcosistemaRESUMEN
Intelligent diagnosis of bearing faults is fundamental to machinery automation and their intelligent operation. Deep learning-based analysis of bearing vibration data has emerged as one research mainstream for fault diagnosis. To enhance the quality of feature extraction from bearing vibration signals and the robustness of the model, we construct a fault diagnostic model based on convolutional neural network (CNN) and long short-term memory (LSTM) parallel network to extract their temporal and spatial features from two perspectives. First, via resampling, vibration signal is split into equal-sized slices which are then converted into time-frequency images by continuous wavelet transform (CWT). Second, LSTM extracts the time-correlation features of 1D signals as one path, and 2D-CNN extracts the local frequency distribution features of time-frequency images as another path. Third, 1D-CNN further extracts integrated features from the fusion features yielded by former parallel paths. Finally, these categories are calculated through the softmax function. According to experimental results, the proposed model has satisfactory diagnostic accuracy and robustness in different contexts on two different datasets.
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Climate change plays a pivotal role in shaping the shifting patterns of plant distribution, and gaining insights into how medicinal plants in the plateau region adapt to climate change will be instrumental in safeguarding the rich biodiversity of the highlands. Gymnosia orchidis Lindl. (G. orchidis) is a valuable Tibetan medicinal resource with significant medicinal, ecological, and economic value. However, the growth of G. orchidis is severely constrained by stringent natural conditions, leading to a drastic decline in its resources. Therefore, it is crucial to study the suitable habitat areas of G. orchidis to facilitate future artificial cultivation and maintain ecological balance. In this study, we investigated the suitable zones of G. orchidis based on 79 occurrence points in the Qinghai-Tibet Plateau (QTP) and 23 major environmental variables, including climate, topography, and soil type. We employed the Maximum Entropy model (MaxEnt) to simulate and predict the spatial distribution and configuration changes in G. orchidis during different time periods, including the last interglacial (LIG), the Last Glacial Maximum (LGM), the Mid-Holocene (MH), the present, and future scenarios (2041-2060 and 2061-2080) under three different climate scenarios (SSP126, SSP370, and SSP585). Our results indicated that annual precipitation (Bio12, 613-2466 mm) and mean temperature of the coldest quarter (Bio11, -5.8-8.5 °C) were the primary factors influencing the suitable habitat of G. orchidis, with a cumulative contribution of 78.5%. The precipitation and temperature during the driest season had the most significant overall impact. Under current climate conditions, the suitable areas of G. orchidis covered approximately 63.72 × 104/km2, encompassing Yunnan, Gansu, Sichuan, and parts of Xizang provinces, with the highest suitability observed in the Hengduan, Yunlin, and Himalayan mountain regions. In the past, the suitable area of G. orchidis experienced significant changes during the Mid-Holocene, including variations in the total area and centroid migration direction. In future scenarios, the suitable habitat of G. orchidis is projected to expand significantly under SSP370 (30.33-46.19%), followed by SSP585 (1.41-22.3%), while contraction is expected under SSP126. Moreover, the centroids of suitable areas exhibited multidirectional movement, with the most extensive displacement observed under SSP585 (100.38 km2). This study provides a theoretical foundation for the conservation of biodiversity and endangered medicinal plants in the QTP.
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BACKGROUND: Carbon and water use efficiencies (CUE and WUE, respectively) are vital indicators of the adaptability of plants to environmental conditions. However, the effects of grazing and climate change on the spatiotemporal changes in CUE and WUE in Qinghai-Tibet Plateau grasslands (QTPG) are still unclear. RESULTS: Using the enhanced Biome-BGCMuSo model in combination with observed data, we estimated and analyzed the spatiotemporal variations in CUE and WUE and their responses to grazing in QTPG from 1979 to 2018. The mean annual CUE was 0.7066 in QTPG from 1979 to 2018 under the actual climate scenario. In general, the grassland CUE was low in the southeast and high in the northwest. Grazing generally decreased CUE in QTPG from 1979 to 2018, and there was an increasing trend in the difference in CUE between the grazing and nongrazing scenarios. The difference in CUE was generally greater in the northwest than in the southeast. The mean annual WUE was 0.5591 g C/kg H2O in QTPG from 1979 to 2018 under the actual climate scenario. After 2000, the grassland WUE exhibited a fluctuating upward trend. In general, the grassland WUE was greater in the southeast than in the northwest. Grazing generally decreased WUE in QTPG from 1979 to 2018, and there was an increasing trend in the difference in WUE between the grazing and nongrazing scenarios. The difference in WUE was generally greater in the northwest than in the southeast. CONCLUSIONS: The findings of this study suggested that the spatiotemporal changes in CUE and WUE in QTPG were closely related to changes in the natural environment and grazing management.
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Pradera , Agua , Tibet , Carbono , EcosistemaRESUMEN
Soil contamination with heavy metals has emerged as a global environmental threat, compromising agricultural productivity, ecosystem integrity, and human health. Conventional remediation techniques often fall short due to high costs, operational complexities, and environmental drawbacks. Plant-based disposal technologies, including biochar, phytometallurgy, and phrolysis, have emerged as promising solutions in this regard. Grounded in a novel experimental framework, biochar is studied for its dual role as soil amendment and metal adsorbent, while phytometallurgy is explored for its potential in resource recovery and economic benefits derived from harvested metal-rich plant biomass. Pyrolysis, in turn, is assessed for transforming contaminated biomass into value-added products, thereby minimizing waste. These plant disposal technologies create a circular model of remediation and resource utilization that holds the potential for application in large-scale soil recovery projects, development of environmentally friendly agro-industries, and advancement in sustainable waste management practices. This review mainly discussed cutting-edge plant disposal technologies-biochar application, phytometallurgy, and pyrolysis-as revolutionary approaches to soil heavy metal remediation. The efficacy, cost-effectiveness, and environmental impact of these innovative technologies are especially evaluated in comparison with traditional methods. The success of these applications could signal a paradigm shift in how we approach both environmental remediation and resource recovery, with profound implications for sustainable development and circular economy strategies.
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Restauración y Remediación Ambiental , Metales Pesados , Contaminantes del Suelo , Humanos , Suelo , Ecosistema , Contaminantes del Suelo/análisis , Metales Pesados/análisis , Carbón Orgánico , Plantas , TecnologíaRESUMEN
BACKGROUND: Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis. Although primary prevention drugs, including non-selective ß-blockers, have effectively reduced the incidence of bleeding, their efficacy is limited due to side effects and related contraindications. With recent advances in precision medicine, precise drug treatment provides better treatment efficacy. DATA SOURCES: Literature search was conducted in PubMed, MEDLINE and Web of Science for relevant articles published up to May 2022. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS: The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs. According to the site of action, these drugs could be classified into four classes: intrahepatic, extrahepatic, both intrahepatic and extrahepatic targets and others. All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension. CONCLUSIONS: This review classified and summarized the promising drugs, which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension, demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.
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Várices Esofágicas y Gástricas , Hipertensión Portal , Várices , Humanos , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/prevención & control , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Hipertensión Portal/complicaciones , Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Prevención PrimariaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic chemotherapy, which has provided only marginal positive clinical outcomes. Currently, the first-line chemotherapeutic agent for PDAC is gemcitabine (GEM). However, the chemotherapy resistance to GEM is often overlooked in the clinical treatment of PDAC due to the lack of effective biological markers. Therefore, it is crucial to find new prognostic markers and therapeutic targets for patients with PDAC. In this study, we identified a novel regulatory mechanism in the development of resistance to GEM in PDAC. Here, we report that LINC01134 was significantly upregulated in primary tumors from PDAC patients. In vitro and in vivo functional studies revealed that LINC01134 promotes PDAC resistance to GEM through facilitating stem cell features and modulating the cell cycle. Mechanistically, LINC01134 interactes with tumor suppressor miR-497-5p in PDAC cells. Increased LINC01134 downregulates miR-140-3p to promotes the oncogenic WNT5A expression. Moreover, m6A demethylase FTO participated in the upregulation of LINC01134 by maintaining LINC01134 mRNA stability through YTHDF2. Taken together, the present study suggested FTO-mediated LINC01134 stabilization to promote chemotherapy resistance to GEM through miR-140-3p/WNT5A/WNT pathway in PDAC. Our study identified new prognostic markers and new therapeutic targets for patients with PDAC.
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Carcinoma Ductal Pancreático , MicroARNs , Neoplasias Pancreáticas , Humanos , Resistencia a Antineoplásicos/genética , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Vía de Señalización Wnt/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Gemcitabina , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , MicroARNs/metabolismo , Línea Celular Tumoral , Proteína Wnt-5a/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Neoplasias PancreáticasRESUMEN
This paper examines the linkage between Chinese stock market volatility and investor attention fluctuation. In Heterogeneous autoregressive (HAR) model, first, we analyzed the linkage between both decomposed and undecomposed stock market realized volatility and investor attention fluctuations across full-sample and two-year moving window sub-samples. Second, we compare the predictive power of four models in short-, medium-, and long-term volatility forecasting. Empirical results show large positive attention fluctuation amplified Chinese stock market volatility after the outbreak of COVID-19, and negative small attention fluctuation significantly stabilized stock market volatility before COVID-19, and the impact dwindled in after COVID-19. The model incorporating decomposed realized volatility and decomposed attention fluctuation performs better in volatility Forecasting. This research underscores a shift in the dynamics between stock market volatility and investor attention fluctuations, and investor attention fluctuation improves the volatility forecasting accuracy of the Chinese stock market.
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Pueblo Asiatico , Inversiones en Salud , Humanos , China/epidemiología , COVID-19/epidemiología , Brotes de Enfermedades , Inversiones en Salud/economía , Atención , EconomíaRESUMEN
The Segmentation of infected areas from COVID-19 chest X-ray (CXR) images is of great significance for the diagnosis and treatment of patients. However, accurately and effectively segmenting infected areas of CXR images is still challenging due to the inherent ambiguity of CXR images and the cross-scale variations in infected regions. To address these issues, this article proposes a ERGPNet based on embedded residuals and global perception, to segment lesion regions in COVID-19 CXR images. First, aiming at the inherent fuzziness of CXR images, an embedded residual convolution structure is proposed to enhance the ability of internal feature extraction. Second, a global information perception module is constructed to guide the network in generating long-distance information flow, alleviating the interferences of cross-scale variations on the algorithm's discrimination ability. Finally, the network's sensitivity to target regions is improved, and the interference of noise information is suppressed through the utilization of parallel spatial and serial channel attention modules. The interactions between each module fully establish the mapping relationship between feature representation and information decision-making and improve the accuracy of lesion segmentation. Extensive experiments on three datasets of COVID-19 CXR images, and the results demonstrate that the proposed method outperforms other state-of-the-art segmentation methods of CXR images.
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Vascular smooth muscle cells (VSMCs) phenotypic switching is identified as enhanced dedifferentiation, proliferation, and migration ability of VSMCs, in which microRNAs have been identified as important regulators of the process. The present study is aimed to explore the pathophysiological effect of miR-122 on VSMC phenotypic modulation. Here, the result showed that the decreased miR-122 expression was found in VSMCs subjected to platelet-derived growth factor-BB (PDGF-BB) treatment. Next, we investigated the response of miR-122 knockdown in VSMCs with PDGF-BB stimulation. MiR-122 silencing showed increased proliferation and migration capability, whereas attenuated the differentiation markers expression. The above results were reversed by miR-122 overexpression. Finally, we further demonstrated that FOXO3 was an important target for miR-122. Collectively, we demonstrated that miR-122 silencing promoted VSMC phenotypic modulation partially through upregulated FOXO3 expression that indicated miR-122 may be a novel therapeutic target for neointimal formation.
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MicroARNs , Músculo Liso Vascular , Becaplermina/metabolismo , Becaplermina/farmacología , Proliferación Celular/genética , Células Cultivadas , MicroARNs/genética , MicroARNs/metabolismo , Miocitos del Músculo Liso/metabolismo , Movimiento CelularRESUMEN
SARS-CoV-2 main protease, Mpro, plays a crucial role in the virus replication cycle, making it an important target for antiviral research. In this study, a simplified model obtained through truncation is used to explore the reaction mechanism of aldehyde warhead compounds inhibiting Mpro at the level of density functional theory. According to the calculation results, proton transfer (P_T)-nucleophilic attack (N_A) is the rate-determining step in the entire reaction pathway. The water molecule that plays a catalytic role occupies the oxyanion hole, which is unfavorable for the aldehyde warhead to approach the Cys145 SH. Through a hypothetical study of substituting the main chain NH with methylene, it is further confirmed that the P_T-N_A is a proton transfer-dominated process accompanied by a nucleophilic attack reaction. In this process, the oxyanion hole serves only to stabilize the aldehyde oxygen anion and therefore does not have a significant impact on the activation free energy barrier of the step. Our research results provide a unique perspective for understanding the covalent inhibition reaction of the Mpro active site. This study also offers theoretical guidance for the design of new Mpro covalent inhibitors.
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Aldehídos , Antivirales , Proteasas 3C de Coronavirus , SARS-CoV-2 , Humanos , Aldehídos/química , Aldehídos/farmacología , Antivirales/química , Antivirales/farmacología , Simulación del Acoplamiento Molecular , Protones , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/químicaRESUMEN
This paper investigates the prescribed-time leader-following output-feedback consensus problem for second order multiagent systems without velocity measurement. Firstly, by introducing a time-scaling function, novel prescribed-time state observers are designed to estimate the second-order states of the agents. Then, a distributed output-feedback scheme is proposed to achieve leader-following consensus, where the transient performance, including the convergence rate and the overshoot, can be offline pre-assigned. It should be noted that the singularity-like problem is solved for the system under measurement errors by adopting a form of piecewise functions. Moreover, the control strategy is modified by introducing an auxiliary system when taking the common saturation problem into account. Finally, the efficiency of the proposed schemes is illustrated by numerical simulation examples.
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The clinical applications of phototherapy nanomaterials are still limited due to concerns regarding their phototoxicity and efficacy. Herein, we report a novel type of D-π-A molecular backbone that induces type I/II photosensitivity and photodegradability by forming J-aggregates. The photodegradation rate can be regulated by changing the donor groups to regulate the photosensitivity of their aggregates because the photodegradability performance results from their oxidation by 1O2 generated by their type II photosensitivity. AID4 NPs possess faster photodegradation because of their better type I&II photosensitivity, which can also self-regulate by inhibiting type II and improving type I under hypoxic conditions. Moreover, they exhibited good photothermal and photoacoustic performance for improving their therapeutic effect by a synergistic effect and achieving photoacoustic imaging in vivo. The experimental result also showed that they can be effective for antibacterial and anti-tumor treatment and the photodegradation products of AID4 NPs possess low biological toxicity in the dark or under light. This study could provide a novel strategy for improving the safety and treatment effects of phototherapy.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Terapia Fototérmica , Nanopartículas/uso terapéutico , Fotoquimioterapia/métodos , Fototerapia/métodosRESUMEN
Introduction: The conflict between cancer cells and the host immune system shapes the immune tumour microenvironment (TME) in hepatocellular carcinoma (HCC). A deep understanding of the heterogeneity and intercellular communication network in the TME of HCC will provide promising strategies to orchestrate the immune system to target and eradicate cancers. Methods: Here, we performed single-cell RNA sequencing (scRNA-seq) and computational analysis of 35786 unselected single cells from 3 human HCC tumour and 3 matched adjacent samples to elucidate the heterogeneity and intercellular communication network of the TME. The specific lysis of HCC cell lines was examined in vitro using cytotoxicity assays. Granzyme B concentration in supernatants of cytotoxicity assays was measured by ELISA. Results: We found that VCAN+ tumour-associated macrophages (TAMs) might undergo M2-like polarization and differentiate in the tumour region. Regulatory dendritic cells (DCs) exhibited immune regulatory and tolerogenic phenotypes in the TME. Furthermore, we observed intensive potential intercellular crosstalk among C1QC+ TAMs, regulatory DCs, regulator T (Treg) cells, and exhausted CD8+ T cells that fostered an immunosuppressive niche in the HCC TME. Moreover, we identified that the TIGIT-PVR/PVRL2 axis provides a prominent coinhibitory signal in the immunosuppressive TME. In vitro, antibody blockade of PVR or PVRL2 on HCC cell lines or TIGIT blockade on immune cells increased immune cell-mediated lysis of tumour cell. This enhanced immune response is paralleled by the increased secretion of Granzyme B by immune cells. Discussion: Collectively, our study revealed the functional state, clinical significance, and intercellular communication of immunosuppressive cells in HCC at single-cell resolution. Moreover, PVR/PVRL2, interact with TIGIT act as prominent coinhibitory signals and might represent a promising, efficacious immunotherapy strategy in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Granzimas/genética , Neoplasias Hepáticas/genética , Análisis de Secuencia de ARN , Microambiente TumoralRESUMEN
BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) is used for treating depression but the efficacy and safety have not been well assessed. This study was conducted to evaluate the efficacy and safety of taVNS in depression. METHODS: The retrieval databases included English databases of PubMed, Web of Science, Embase, the Cochrane Library and PsycINFO, and Chinese databases of CNKI, Wanfang, VIP and Sino Med, and the retrieval period was from their inception to November 10, 2022. The clinical trial registers (ClinicalTrials.gov and Chinese Clinical Trial Registry) were also searched. Standardized mean difference and the risk ratio were used as the effect indicator and the effect size was represented by the 95 % confidence interval. Revised Cochrane risk-of-bias tool for randomized trials and the Grades of Recommendation, Assessment, Development and Evaluation system were used to assess the risk of bias and quality of evidence respectively. RESULTS: Totally, 12 studies of 838 participants were included. taVNS could significantly improve depression and reduce Hamilton Depression Scale scores. Low to very low evidence showed that taVNS had higher response rates than sham-taVMS and comparable response rates compared to antidepressants (ATD) and that taVNS combined with ATD had comparable efficacy to ATD with fewer side effects. LIMITATIONS: The number of studies in subgroups was small and the evidence quality was low to very low. CONCLUSIONS: taVNS is an effective and safe method for alleviating depression scores and had a comparable response rate to ATD.
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Trastorno Depresivo , Estimulación Eléctrica Transcutánea del Nervio , Estimulación del Nervio Vago , Humanos , Estimulación del Nervio Vago/efectos adversos , Estimulación del Nervio Vago/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estimulación Eléctrica Transcutánea del Nervio/métodos , Antidepresivos , Nervio Vago/fisiología , Trastorno Depresivo/terapia , Trastorno Depresivo/etiologíaRESUMEN
The current methods for evaluating the operating condition of electricity transmission lines (ETLs) and providing early warning have several problems, such as the low correlation of data, ignoring the influence of seasonal factors, and strong subjectivity. This paper analyses the sensitive factors that influence dynamic key evaluation indices such as grounding resistance, sag, and wire corrosion, establishes the evaluation criteria of the ETL operation state, and proposes five ETL status levels and seven principles for selecting evaluation indices. Nine grade I evaluation indices and twenty-nine grade II evaluation indices, including passageway and meteorological environments, are determined. The cloud model theory is embedded and used to propose a warning technology for the operation state of ETLs based on inspection defect parameters and the cloud model. Combined with the inspection defect parameters of a line in the Baicheng district of Jilin Province and the critical evaluation index data such as grounding resistance, sag, and wire corrosion, which are used to calculate the timeliness of the data, the solid line is evaluated. The research shows that the dynamic evaluation model is correct and that the ETL status evaluation and early warning method have reasonable practicability.
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Results: EA intervention and OxPAPC injection could relieve mechanical allodynia and thermal hyperalgesia caused by CIA. Paw edema and pathological damage of synovium were significantly ameliorated after EA intervention and OxPAPC injection. Furthermore, EA intervention and OxPAPC injection markedly reduced the contents of serum TNF-α, IL-1ß, and IL-6, as well as the protein expression levels of synovial TLR2, TLR4, MyD88, and NF-κB p-p65. In particular, the expression of TLR2 and TLR4 on synovial fibroblasts and macrophages in synovium was significantly reduced by EA intervention. Conclusions: Repeated EA stimulation at ST36 and SP6 can effectively relieve joint pain and synovial inflammation caused by RA in CIA rats. The analgesic and anti-inflammatory effect of EA may be closely related to the inhibition of innate immune responses driven by the TLR2/4-MyD88-NF-κB signaling pathway in the synovium.