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1.
Front Immunol ; 15: 1374763, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38596682

RESUMO

Background: Psoriasis is an immune-mediated disorder influenced by environmental factors on a genetic basis. Despite advancements, challenges persist, including the diminishing efficacy of biologics and small-molecule targeted agents, alongside managing recurrence and psoriasis-related comorbidities. Unraveling the underlying pathogenesis and identifying valuable biomarkers remain pivotal for diagnosing and treating psoriasis. Methods: We employed a series of bioinformatics (including single-cell sequencing data analysis and machine learning techniques) and statistical methods to integrate and analyze multi-level data. We observed the cellular changes in psoriatic skin tissues, screened the key genes Fatty acid binding protein 5 (FABP5) and The killer cell lectin-like receptor B1 (KLRB1), evaluated the efficacy of six widely prescribed drugs on psoriasis treatment in modulating the dendritic cell-associated pathway, and assessed their overall efficacy. Finally, RT-qPCR, immunohistochemistry, and immunofluorescence assays were used to validate. Results: The regulatory influence of dendritic cells (DCs) on T cells through the CD70/CD27 signaling pathway may emerge as a significant facet of the inflammatory response in psoriasis. Notably, FABP5 and KLRB1 exhibited up-regulation and co-localization in psoriatic skin tissues and M5-induced HaCaT cells, serving as potential biomarkers influencing psoriasis development. Conclusion: Our study analyzed the impact of DC-T cell crosstalk in psoriasis, elucidated the characterization of two biomarkers, FABP5 and KLRB1, in psoriasis, and highlighted the promise and value of tofacitinib in psoriasis therapy targeting DCs.


Assuntos
Psoríase , Humanos , Psoríase/tratamento farmacológico , Pele/patologia , Queratinócitos/metabolismo , Biomarcadores/metabolismo , Células Dendríticas/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-38578856

RESUMO

Accurate screening of cancer types is crucial for effective cancer detection and precise treatment selection. However, the association between gene expression profiles and tumors is often limited to a small number of biomarker genes. While computational methods using nature-inspired algorithms have shown promise in selecting predictive genes, existing techniques are limited by inefficient search and poor generalization across diverse datasets. This study presents a framework termed Evolutionary Optimized Diverse Ensemble Learning (EODE) to improve ensemble learning for cancer classification from gene expression data. The EODE methodology combines an intelligent grey wolf optimization algorithm for selective feature space reduction, guided random injection modeling for ensemble diversity enhancement, and subset model optimization for synergistic classifier combinations. Extensive experiments were conducted across 35 gene expression benchmark datasets encompassing varied cancer types. Results demonstrated that EODE obtained significantly improved screening accuracy over individual and conventionally aggregated models. The integrated optimization of advanced feature selection, directed specialized modeling, and cooperative classifier ensembles helps address key challenges in current nature-inspired approaches. This provides an effective framework for robust and generalized ensemble learning with gene expression biomarkers. Specifically, we have opened EODE source code on Github at https://github.com/wangxb96/EODE.

4.
Molecules ; 29(6)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38542911

RESUMO

Polygonatum cyrtonema Hua, the dried rhizome of Polygonum multiflorum from the Liliaceae family, is a widely used medicinal herb with a long history of application. Its main active ingredients are polysaccharides, which have been demonstrated in contemporary studies to effectively delay the aging process. In the present study, homogeneous polysaccharide (PCP-1) was obtained after the purification and isolation of polysaccharides from Polygonatum cyrtonema Hua (PCP). The anti-aging activities of both were compared, and the possible mechanism of action for exerting anti-aging activity was explored using Caenorhabditis elegans (C. elegans). Research has indicated that PCP and PCP-1 exhibit potent anti-oxidant and anti-aging properties. Of particular note is that PCP-1 acts better than PCP. The two were able to prolong the lifespan of nematodes, improve the stress resistance of nematodes, reduce the accumulation of lipofuscin in the intestine, decrease the content of ROS and MDA in the body, increase the activity of the antioxidant enzymes SOD and CAT, promote the nuclear translocation of DAF-16, down-regulate the mRNA levels of the age-1 and daf-2 genes of the IIS pathway in nematodes, and up-regulate the expression of the daf-16, skn-1, sod-3, and hsp-16.2 genes. Based on the aforementioned findings, it is possible that the mechanism by which PCP and PCP-1 exert anti-aging effects may be through negative regulation of the IIS pathway, activation of the transcription factor DAF-16/FOXO, and enhancement of oxidative defenses and stress resistance in nematodes. Overall, the present study illustrated the great potential of polysaccharides from Polygonatum cyrtonema Hua in anti-aging and antioxidant activities. Specifically, PCP-1 demonstrated superior characteristics, which provides a reference for the future development of Polygonatum cyrtonema Hua polysaccharides.


Assuntos
Caenorhabditis elegans , Polygonatum , Animais , Caenorhabditis elegans/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Envelhecimento , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Superóxido Dismutase/metabolismo
5.
Nature ; 628(8006): 84-92, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38538792

RESUMO

Wearable electronics with great breathability enable a comfortable wearing experience and facilitate continuous biosignal monitoring over extended periods1-3. However, current research on permeable electronics is predominantly at the stage of electrode and substrate development, which is far behind practical applications with comprehensive integration with diverse electronic components (for example, circuitry, electronics, encapsulation)4-8. Achieving permeability and multifunctionality in a singular, integrated wearable electronic system remains a formidable challenge. Here we present a general strategy for integrated moisture-permeable wearable electronics based on three-dimensional liquid diode (3D LD) configurations. By constructing spatially heterogeneous wettability, the 3D LD unidirectionally self-pumps the sweat from the skin to the outlet at a maximum flow rate of 11.6 ml cm-2 min-1, 4,000 times greater than the physiological sweat rate during exercise, presenting exceptional skin-friendliness, user comfort and stable signal-reading behaviour even under sweating conditions. A detachable design incorporating a replaceable vapour/sweat-discharging substrate enables the reuse of soft circuitry/electronics, increasing its sustainability and cost-effectiveness. We demonstrated this fundamental technology in both advanced skin-integrated electronics and textile-integrated electronics, highlighting its potential for scalable, user-friendly wearable devices.


Assuntos
Eletrônica , Dispositivos Eletrônicos Vestíveis , Pele , Têxteis , Eletrodos
6.
Biomimetics (Basel) ; 9(3)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38534875

RESUMO

Hydrodynamic pressure sensors offer an auxiliary approach for ocean exploration by unmanned underwater vehicles (UUVs). However, existing hydrodynamic pressure sensors often lack the ability to monitor subtle hydrodynamic stimuli in deep-sea environments. In this study, we present the development of a deep-sea hydrodynamic pressure sensor (DSHPS) capable of operating over a wide range of water depths while maintaining exceptional hydrodynamic sensing performance. The DSHPS device was systematically optimized by considering factors such as piezoelectric polyvinylidene fluoride-trifluoroethylene/barium titanate [P(VDF-TrFE)/BTO] nanofibers, electrode configurations, sensing element dimensions, integrated circuits, and packaging strategies. The optimized DSHPS exhibited a remarkable pressure gradient response, achieving a minimum pressure difference detection capability of approximately 0.11 Pa. Additionally, the DSHPS demonstrated outstanding performance in the spatial positioning of dipole sources, which was elucidated through theoretical charge modeling and fluid-structure interaction (FSI) simulations. Furthermore, the integration of a high Young's modulus packaging strategy inspired by fish skull morphology ensured reliable sensing capabilities of the DSHPS even at depths of 1000 m in the deep sea. The DSHPS also exhibited consistent and reproducible positioning performance for subtle hydrodynamic stimulus sources across this wide range of water depths. We envision that the development of the DSHPS not only enhances our understanding of the evolutionary aspects of deep-sea canal lateral lines but also paves the way for the advancement of artificial hydrodynamic pressure sensors.

7.
Int J Gen Med ; 17: 401-418, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38333021

RESUMO

Background: Psoriasis, a chronic inflammatory disorder with an unknown cause, significantly impacts the physical and psychological well-being of patients. However, current biomarkers related to psoriasis lack clinical specificity, sensitivity, and predictive ability. Methods: In this study, we collected skin lesion tissues from 20 psoriasis patients and 20 normal skin samples. Additionally, we obtained four datasets from the GEO database, which included human psoriasis and healthy specimens. We utilized SVM-RFE analysis and the LASSO regression model to identify potential biomarkers. Furthermore, we examined the composition of immune cell types in psoriasis and their correlation with specific genes. Results: Our investigation revealed 57 differentially expressed genes (DEGs), and we identified significantly enriched pathways through KEGG pathway analysis. The results of machine learning and WGCNA suggested that LCE3D and SPRR1B could potentially be used as marker genes for diagnosing psoriasis. RT-PCR and immunohistochemical detection confirmed the abnormally high expression of the SPRR1B gene in psoriasis. Analysis of immune cell infiltration revealed a strong positive correlation between SPRR1B and Macrophages M0 and T cells follicular helper, while showing the strongest negative correlation with resting Mast cells. In addition, we found that silencing SPRR1B in IFN-γ-treated HaCat cells could significantly reduce the increase in IL-17, IL-22, KRT6, and KRT16 caused by IFN-γ. Conclusion: These findings suggest that SPRR1B may have a significant role in the pathogenesis of psoriasis and could be employed as a novel immunomarker for its development.

8.
Artigo em Inglês | MEDLINE | ID: mdl-38270690

RESUMO

PURPOSE: Although a number of studies involving small-vessel de novo coronary disease showed clinical benefits of drug-coated balloons (DCB), the role of DCB in large vessel lesions is still unclear. METHODS: We searched main electronic databases for randomized controlled trials (RCTs) comparing DCB with stents for large vessel de novo coronary artery disease. The primary endpoint was major cardiovascular adverse events (MACE), composite cardiovascular death (CD), myocardial infarction (MI), or target lesion revascularization (TLR). RESULTS: This study included 7 RCTs with 770 participants. DCB were associated with a marked risk reduction in MACE [Risk Ratio (RR): 0.48; 95% confidence interval [CI]: 0.24 to 0.97; P = 0.04], TLR (RR: 0.53; 95% CI: 0.25 to 1.14; P = 0.10), and late lumen loss [standard mean difference (SMD): -0.57; 95% CI: -1.09 to -0.05; P = 0.03] as compared with stents. There is no significant difference in MI (RR: 0.58; 95% CI: 0.21 to 1.54; P = 0.27), CD (RR: 0.33; 95% CI: 0.06 to 1.78; P = 0.19), and minimal lumen diameter (SMD: -0.34; 95% CI: -0.72 to 0.05; P = 0.08) between groups. In subgroup analyses, the risk reduction of MACE persisted in patients with chronic coronary syndrome (RR: 0.25; 95% CI: 0.07 to 0.89; P = 0.03), and patients receiving DCB vs. bare metal stent (RR: 0.19; 95% CI: 0.05 to 0.73; P = 0.01). In addition, there was no significant difference between the DCB group and the drug eluting stent group for MACE (RR: 0.69; 95% CI: 0.30 to 1.60; P = 0.38). CONCLUSION: DCB may be an effective therapeutic option in patients with large vessel de novo coronary artery disease.

9.
ACS Appl Mater Interfaces ; 16(6): 7721-7731, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38289237

RESUMO

Metal-organic frameworks (MOFs) have great potential in quartz crystal microbalance (QCM) platforms for volatile organic compound (VOCs) detection and recognition due to their unique properties. However, the MOFs' hydrophilicity degrades performance in high-humidity environments, limiting reliable VOC sensing in complex environments. Herein, we propose a novel VOC virtual sensor array (VSA) using a single QCM sensor with an adsorption layer composed of MIL-101(Cr) MOF and polydimethylsiloxane (PDMS), realizing stable sensing and accurate identification for different VOCs under various relative humidity (RH) conditions. The hydrophobic PDMS layer improves the moisture resistance of the sensor to 4 and 14 times in terms of shifts in resonant frequency and scattering parameters, respectively. In addition, performance is maintained over 2 days of water treatment, demonstrating superior water resistance. The highest sensitivity of 2.68 mdB ppm-1 is achieved for isopropanol detection, with the lowest limit of detection of 20.06 ppm for acetone. Combining resonant signals and lumped parameters, the proposed VSA technique effectively discriminates four VOCs (ethanol, 2-propanol, acetone, and acetonitrile) with a high accuracy of 95.3% under both 60% and 90% RH backgrounds. The studies provide a promising solution for reliable low-concentration VOC detection using QCM sensors in high-humidity environments such as underground spaces.

10.
Angew Chem Int Ed Engl ; 63(3): e202316016, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38038685

RESUMO

The first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α-amination of a ketone forged the piperidine ring, while a Horner-Wadsworth-Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.

11.
ISA Trans ; 144: 308-318, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38052707

RESUMO

In this paper, a nearly optimal tracking control is proposed for n-links robotic manipulators subject to parameter uncertainties, time-profile failures, and input saturation constraints. Firstly, the practical terminal sliding-mode (PTSM) manifold with a linear additional term is proposed to combine the system states related to joint rotation, such that the controlled states quickly fall into a tiny neighborhood of the equilibrium once they reach the PTSM manifold. Secondly, a nearly optimal sliding-mode reaching law is designed by using the adaptive dynamic programming (ADP) technique. Benefiting from a non-quadratic positive defined mapping of the proposed performance index, which relates to the derivative of the sliding-mode function, reduced-order system dynamics can be constrained to a desired region. For the bounded actuator fault caused by various inducements such as the power supply fluctuation and the wear of parts, a radial basis function neural network (RBFNN) is introduced to compensate for this, and the input saturation constraints of the controlled plant are also compensated at the same time. Innovatively, the node weights of RBFNN are updated by the critic network of the ADP framework, such that the integrity of the proposed control strategy is improved. Simulations verify the main conclusions.

12.
Sci Total Environ ; 913: 169309, 2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38103604

RESUMO

The unknown daytime source of HONO has been extensively investigated due to unexplained atmospheric oxidation capacity and current modelling bias, especially during cold seasons. In this study, abrupt morning increases in atmospheric HONO at a rural site in the North China Plain (NCP) were observed almost on daily basis, which were closely linked to simultaneous rises in atmospheric water vapor content and NH3 concentrations. Dew and guttation water formation was frequently observed on wheat leaves, from which water samples were taken and chemically analyzed for the first time. Results confirmed that such natural processes likely governed the daily nighttime deposition and daytime release of HONO and NH3, which have not been considered in the numerous HONO budget studies investigating its large missing daytime source in the NCP. The dissolved HONO and NH3 in leaf surface water droplets reached 1.4 and 23 mg L-1 during the morning on average, resulting in averaged atmospheric HONO and NH3 increases of 0.89 ± 0.61 and 43.7 ± 29.3 ppb during morning hours, with relative increases of 186 ± 212 % and 233 ± 252 %, respectively. The high atmospheric oxidation capacity contained within HONO was stored in near surface liquid water (such as dew, guttation and soil surface water) during nighttime, which prevented its atmospheric dispersion after sunset and protected it from photodissociation during early morning hours. HONO was released in a blast during later hours with stronger solar radiation, which triggered and then accelerated daytime photochemistry through the rapid photolysis of HONO and subsequent OH production, especially under high RH conditions, forming severe secondary gaseous and particulate pollution. Results of this study demonstrate that global ecosystems might play significant roles in atmospheric photochemistry through nighttime dew formation and guttation processes.

13.
PLoS One ; 18(12): e0295621, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38064474

RESUMO

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition whose current psychiatric diagnostic process is subjective and behavior-based. In contrast, functional magnetic resonance imaging (fMRI) can objectively measure brain activity and is useful for identifying brain disorders. However, the ASD diagnostic models employed to date have not reached satisfactory levels of accuracy. This study proposes the use of MAACNN, a method that utilizes multi-view convolutional neural networks (CNNs) in conjunction with attention mechanisms for identifying ASD in multi-scale fMRI. The proposed algorithm effectively combines unsupervised and supervised learning. In the initial stage, we employ stacked denoising autoencoders, an unsupervised learning method for feature extraction, which provides different nodes to adapt to multi-scale data. In the subsequent stage, we perform supervised learning by employing multi-view CNNs for classification and obtain the final results. Finally, multi-scale data fusion is achieved by using the attention fusion mechanism. The ABIDE dataset is used to evaluate the model we proposed., and the experimental results show that MAACNN achieves superior performance with 75.12% accuracy and 0.79 AUC on ABIDE-I, and 72.88% accuracy and 0.76 AUC on ABIDE-II. The proposed method significantly contributes to the clinical diagnosis of ASD.


Assuntos
Transtorno do Espectro Autista , Encefalopatias , Transtornos do Neurodesenvolvimento , Humanos , Transtorno do Espectro Autista/diagnóstico por imagem , Redes Neurais de Computação , Algoritmos , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem
14.
J Bras Pneumol ; 49(5): e20230154, 2023.
Artigo em Inglês, Português | MEDLINE | ID: mdl-37909551

RESUMO

OBJECTIVE: To determine the absolute number of serum T lymphocytes and cytokine levels and the characteristics of patients with active pulmonary tuberculosis and to assess their effect on the immune status of these patients and their diagnostic and predictive value for tuberculosis. METHODS: We included 1,069 patients with active tuberculosis, 51 patients with latent tuberculosis infection, and 600 health individuals. Absolute serum T-lymphocyte counts and cytokine levels were quantified. RESULTS: T lymphocytes were significantly reduced in patients with active tuberculosis when compared with healthy individuals. The immune function of patients gradually decreased with age and was stronger in female patients than in males. Th1 cells expressed higher levels of cytokines than did Th2 cells. Logistic regression analysis showed that reduced CD3+ T, CD8+ T, and NK cell counts, as well as reduced IL-4 and IFN-g expression, were independent influencing factors for active tuberculosis. ROC analysis showed that the sensitivity and specificity of absolute CD3+ T and CD8+ T lymphocyte counts and combined factors were significantly higher than were those of IL-4 and IFN-g for diagnosing active tuberculosis. CONCLUSIONS: Serum T-lymphocyte counts and cytokine levels can assess the immune status of tuberculosis patients; they are also useful biomarkers for predicting and diagnosing tuberculosis.


Assuntos
Tuberculose Pulmonar , Tuberculose , Masculino , Humanos , Feminino , Citocinas , Interleucina-4/metabolismo , Células Th1/metabolismo , Tuberculose Pulmonar/diagnóstico
15.
Microsyst Nanoeng ; 9: 120, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37780810

RESUMO

Cellular deformability is a promising biomarker for evaluating the physiological state of cells in medical applications. Microfluidics has emerged as a powerful technique for measuring cellular deformability. However, existing microfluidic-based assays for measuring cellular deformability rely heavily on image analysis, which can limit their scalability for high-throughput applications. Here, we develop a parallel constriction-based microfluidic flow cytometry device and an integrated computational framework (ATMQcD). The ATMQcD framework includes automatic training set generation, multiple object tracking, segmentation, and cellular deformability quantification. The system was validated using cancer cell lines of varying metastatic potential, achieving a classification accuracy of 92.4% for invasiveness assessment and stratifying cancer cells before and after hypoxia treatment. The ATMQcD system also demonstrated excellent performance in distinguishing cancer cells from leukocytes (accuracy = 89.5%). We developed a mechanical model based on power-law rheology to quantify stiffness, which was fitted with measured data directly. The model evaluated metastatic potentials for multiple cancer types and mixed cell populations, even under real-world clinical conditions. Our study presents a highly robust and transferable computational framework for multiobject tracking and deformation measurement tasks in microfluidics. We believe that this platform has the potential to pave the way for high-throughput analysis in clinical applications, providing a powerful tool for evaluating cellular deformability and assessing the physiological state of cells.

16.
Bioinformatics ; 39(11)2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37874953

RESUMO

MOTIVATION: Quantitative determination of protein thermodynamic stability is a critical step in protein and drug design. Reliable prediction of protein stability changes caused by point variations contributes to developing-related fields. Over the past decades, dozens of structure-based and sequence-based methods have been proposed, showing good prediction performance. Despite the impressive progress, it is necessary to explore wild-type and variant protein representations to address the problem of how to represent the protein stability change in view of global sequence. With the development of structure prediction using learning-based methods, protein language models (PLMs) have shown accurate and high-quality predictions of protein structure. Because PLM captures the atomic-level structural information, it can help to understand how single-point variations cause functional changes. RESULTS: Here, we proposed THPLM, a sequence-based deep learning model for stability change prediction using Meta's ESM-2. With ESM-2 and a simple convolutional neural network, THPLM achieved comparable or even better performance than most methods, including sequence-based and structure-based methods. Furthermore, the experimental results indicate that the PLM's ability to generate representations of sequence can effectively improve the ability of protein function prediction. AVAILABILITY AND IMPLEMENTATION: The source code of THPLM and the testing data can be accessible through the following links: https://github.com/FPPGroup/THPLM.


Assuntos
Aprendizado Profundo , Proteínas/química , Redes Neurais de Computação , Software , Processamento de Proteína Pós-Traducional
17.
Risk Manag Healthc Policy ; 16: 2171-2185, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37881168

RESUMO

Purpose: The willingness to utilize primary care services is crucial in explaining residents' healthcare-seeking behavior and decision-making in the context of the free choice of healthcare providers. This study examines China's family doctor contracting services system to elucidate the conceptual structure of the willingness to utilize primary care services and develop a reliable measurement tool. Methods: The study was conducted in two phases. Firstly, in-depth interviews were conducted with community residents, resulting in 42 qualitative data sets. Subsequently, a measurement scale for the willingness to utilize family doctor contracting services was developed, and the scale was validated through two surveys using exploratory factor analysis (N = 250) and confirmatory factor analysis (N = 278), respectively. Results: By employing a grounded theory approach, this study analyzes the connotation of willingness to utilize family doctor contracting services. It constructs a conceptual framework for the willingness to utilize primary care services. This conceptual framework consists of three dimensions: perceived feasibility, perceived desirability, and perceived initiative. Based on this framework, a measurement scale comprising 14 items was developed and subjected to rigorous validation procedures to ensure its reliability and validity. Conclusion: This study extends prior research on healthcare service utilization willingness by elucidating the internal willingness structure for primary healthcare services. It enhances our understanding of the connotation of healthcare service utilization willingness and develops a scientifically rigorous measurement tool. The findings of this study provide valuable insights into improving both the willingness and behavior of utilizing primary care services in healthcare systems where the hierarchical referral system still needs to be fully developed.

18.
Cell Chem Biol ; 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37751743

RESUMO

The tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N6-methyladenosine (m6A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m6A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

19.
Environ Sci Technol ; 57(35): 13124-13135, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37616592

RESUMO

Ammonia (NH3) is critical to the nitrogen cycle and PM2.5 formation, yet a great deal of uncertainty exists in its urban emission quantifications. Model-underestimated NH3 concentrations have been reported for cities, yet few studies have provided an explanation. Here, we explore reasons for severe WRF-Chem model underestimations of NH3 concentrations in Beijing in August 2018, including simulated gas-particle partitioning, meteorology, regional transport, and emissions, using spatially refined (3 km resolution) NH3 emission estimates in the agricultural sector for Beijing-Tianjin-Hebei and in the traffic sector for Beijing. We find that simulated NH3 concentrations are significantly lower than ground-based and satellite observations during August in Beijing, while wintertime underestimations are much more moderate. Further analyses and sensitivity experiments show that such discrepancies cannot be attributed to factors other than biases in NH3 emissions. Using site measurements as constraints, we estimate that both agricultural and non-agricultural NH3 emission totals in Beijing shall increase by ∼5 times to match the observations. Future research should be performed to allocate underestimations to urban fertilizer, power, traffic, or residential sources. Dense and regular urban NH3 observations are necessary to constrain and validate bottom-up inventories and NHx simulation.


Assuntos
Agricultura , Amônia , Pequim , China , Cidades
20.
IEEE Trans Cybern ; PP2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37527309

RESUMO

In this article, the event-triggered fixed-time tracking control is investigated for uncertain strict-feedback nonlinear systems involving state constraints. By employing the universal transformed function (UTF) and coordinate transformation techniques into backstepping design procedure, the proposed control scheme ensures that all states are constrained within the time-varying asymmetric boundaries, and meanwhile, the undesired feasibility condition existing in other constrained controllers can be removed elegantly. Different from the existing static event-triggered mechanism, a dynamic event-triggered mechanism (DETM) is devised via constructing a novel dynamic function, so that the communication burden from the controller to actuator is further alleviated. Furthermore, with the aid of adaptive neural network (NN) technique and generalized first-order filter, together with Lyapunov theory, it is proved that the states of closed-loop system converge to small regions around zero with fixed-time convergence rate. The simulation results confirm the benefits of developed scheme.

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