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The synthesis of medicinally interesting aryldifluoromethylated compounds has drawn significant research attention in recent years. Herein, we report an unprecedented iron-mediated process for the selective defluorination of trifluoromethylarenes to achieve the 1,2-difluoroalkylthiolation of alkenes. Preliminary mechanistic studies revealed that thiolate anion, trifluoromethylarene, and iron cation could form an electron donor-acceptor (EDA) complex, which induced selective defluorination and then difunctionalization of alkenes to obtain aryldifluoromethylated products. The generated aryldifluoromethylated compounds make it difficult to form an EDA complex again, thus avoiding excessive defluorination. This conversion has concise and ambient reaction conditions and provides an alternative solution for obtaining difluorobenzylic intermediates.
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Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.
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Antineoplásicos , Diseño de Fármacos , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ratones , Relación Estructura-Actividad , Línea Celular Tumoral , Ratones Desnudos , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Células HeLa , Simulación del Acoplamiento Molecular , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Ftalazinas/farmacología , Ftalazinas/química , Ftalazinas/síntesis químicaRESUMEN
Herein, we investigate the product type and distribution during the synthesis of azido-functionalized larger polyhedral oligomeric silsesquioxanes (POSSs) using 3-chloropropyl- and chloromethyldimethylsilylethyl-functionalized T8, T10, and T12 POSSs as precursors. Our findings indicate that cage rearrangement occurs for the 3-chloropropyl-functionalized POSS cages with a stability order of T12 > T10 > T8, while the chloromethyldimethylsilylethyl-functionalized POSS cages remain structurally intact after the nucleophilic substitution.
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Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in ß-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet ß-cells under steady and ERS conditions and found that ERS reshaped the MIP of ß-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting ß-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.
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Linfocitos T CD8-positivos , Diabetes Mellitus Tipo 1 , Estrés del Retículo Endoplásmico , Células Secretoras de Insulina , Ratones Endogámicos NOD , Animales , Diabetes Mellitus Tipo 1/inmunología , Humanos , Linfocitos T CD8-positivos/inmunología , Estrés del Retículo Endoplásmico/inmunología , Ratones , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Femenino , Autoantígenos/inmunología , Péptidos/inmunología , Péptidos/farmacología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismoRESUMEN
The covalent attachment of polyoxometalates (POMs) to polymers has been developed as a strategic approach for the advancement of POM-based hybrid materials with versatile applications. In this study, we utilized thiol-maleimide Michael addition to investigate the kinetics and efficacy of the "one-to-one" conjugation between Keggin type POM and polystyrene. We explored the effects of solvent polarity, catalyst, molecular weight of PS and synthetic strategies on the reaction kinetics and efficiency, by means of reverse-phase high-performance liquid chromatography (RP-HPLC). A series of comparative analysis affirmed the superior efficiency of the one-pot method, particularly when facilitated by the addition of a high-polarity solvent and an excess of maleimide. These findings offer valuable insights into the intricate interplay between reaction conditions, kinetics, and selectivity in thiol-maleimide reactions of POMs and polymers. They hold profound implications for advancing the study of POM-based multifunctional materials and the synthesis of complex hybrid molecules.
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Aniones , Polielectrolitos , Polímeros , Compuestos de Sulfhidrilo , Polímeros/química , Maleimidas/química , SolventesRESUMEN
C-C σ-bond cleavage and reconstruction is a significant tool for structural modification in synthetic chemistry but it remains a formidable challenge to perform on unstrained skeletons. Herein, we describe a radical addition-enabled C-C σ-bond cleavage/reconstruction reaction of unstrained allyl ketones to access various functional indanones bearing a benzylic quaternary center. The synthetic utility of this method has been showcased by the first total synthesis of carexane L, an indanone-based natural product.
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Alopecia , Cicatriz , Dermoscopía , Folículo Piloso , Rayos Ultravioleta , Humanos , Folículo Piloso/diagnóstico por imagen , Folículo Piloso/patología , Alopecia/diagnóstico por imagen , Alopecia/patología , Cicatriz/diagnóstico por imagen , Cicatriz/patología , Rayos Ultravioleta/efectos adversos , Fluorescencia , Diagnóstico Diferencial , Femenino , Masculino , AdultoRESUMEN
BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation inâ vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3â K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.
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Antineoplásicos , Neoplasias Pulmonares , Animales , Humanos , Ratones , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Cinética , Neoplasias Pulmonares/tratamiento farmacológico , Ratones Desnudos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Fenoles/síntesis química , Fenoles/química , Fenoles/farmacologíaRESUMEN
The dire problem of climate change has garnered more attention in recent years and, with it, the necessity of reducing its damaging effects on the environment. Nevertheless, despite the green finance index's (GFI) potential advantages in combating climate change, empirical studies on the subject's consequences have been few, mostly because of the index's restricted data availability. This study's primary goal is to close this gap by employing panel data analysis to investigate the environmental effects of GFI in China between 2004 and 2021. Econometric methods like the Driscoll-Kraay standard error and other robustness test models are used to look into the links between political risk, green finance, the ecological footprint, and the economic complexity index. According to the research findings, there is a 0.31% and 0.81% decrease in ecological footprint resulting from the implementation of GFI and rises in GDP (gross domestic product). These results suggest that these strategies could play a major role in establishing a sustainable environment. However, in the chosen countries, the ecological footprint increases by 0.81% and 0.80%, respectively, due to the presence of political risk and economic complexity. This study suggests that government involvement is necessary to reduce carbon footprints and protect the ecosystem, based on these empirical findings. Implementing green financing initiatives, fostering technological development, economic diversification, and fostering a stable political environment are all ways to achieve sustainable investments.
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Cambio Climático , Ecosistema , Inversiones en Salud , Huella de Carbono , China , Desarrollo Económico , Dióxido de CarbonoRESUMEN
The ability to selectively introduce diverse functionality onto hydrocarbons is of substantial value in the synthesis of both small molecules and pharmaceuticals. In this endeavour, as a photocatalyst- and metal-free process, the electron donor-acceptor (EDA) strategy has not been well explored. Here we report an approach to aliphatic carbon-hydrogen bond diversification through an EDA complex constituted by HCl and SIV=O groups. As an efficient hydrogen atom transfer (HAT) reagent, chlorine radical can be produced via a proton-coupled electron transfer process in this system. Based on this unusual path, a photo-promoted versatile aliphatic C-H functionalization is developed without photo- and metal-catalysts, including thiolation, arylation, alkynylation, and allylation. This conversion has concise and ambient reaction conditions, good functional group tolerance, and substrate diversity, and provides an alternative solution for the high value-added utilization of bulk light alkanes.
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Prior research has found that the go/no-go (GNG) task primarily reflects participants' motor-restraint process, while the stop-signal task (SST) primarily represents participants' motor-cancellation process. However, traditional binary keyboards used in these experiments are unable to capture the subtleties of sub-threshold response-force dynamics. This has led to the neglect of potential sub-threshold motor-inhibition processes. In two experiments, we explored sub-threshold inhibition by using a custom force-sensitive keyboard to record response force in both GNG and SST. In experiment 1, participants displayed increased response force when correctly rejecting no-go targets in the GNG task compared to the baseline. In addition, they exhibited higher response force in hit trials than in false alarms, revealing engagement of both motor-restraint and motor-cancellation processes in GNG. Initially, participants utilised motor restraint, but if it failed to prevent inappropriate responses, they employed motor cancellation to stop responses before reaching the keypress threshold. In experiment 2, we used participants' average response-force amplitude and response-force latency in SST stop trials to characterise the motor-cancellation process. Average amplitude significantly predicted false-alarm rates in the GNG task, but the relationship between response latency and false-alarm rates was insignificant. We hypothesised that response latency reflects reactive inhibition control in motor cancellation, whereas average amplitude indicates proactive inhibition control. Our findings underscore the complexity of motor inhibition.
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Hops are a common ingredient in beer production, and a considerable quantity of hops is usually discarded as a waste material once the brewing process is completed. Transforming this waste material into valuable nanomaterials offers a sustainable approach that has the potential to significantly mitigate environmental impact. Herein, a facile and green protocol for the production of zinc oxide nanozymes (ZnO NZs) using wasted hop extract (WHE) as a natural precursor was demonstrated. The process involved a hydrothermal synthesis method followed by a calcination step to form the final ZnO NZs. The results revealed that lupulon, the main ß-acid in hops, particularly the phenolic hydroxy group, is primarily responsible for the biosynthesis of ZnO NZs. The WHE-ZnO NZs exhibited exceptional peroxidase-like (POD-like) activity and served as effective catalysts for the oxidation of 3,3,5,5-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). Analysis of the catalytic mechanism revealed that the POD-like activity of these WHE-ZnO NZs originated from their ability to expedite the transfer of electrons between TMB and H2O2, resulting in the enzymatic kinetics following the standard Michaelis-Menten mechanism. Furthermore, we developed a straightforward and user-friendly colorimetric technique for detecting both H2O2 and glucose. By utilizing the WHE-ZnO NZs as POD-like catalysts, we achieved a linear detection range of 1-1000 µM and a limit of detection of 0.24 µM (S/N = 3) for H2O2 detection and a linear range of 0-100 mM and a detection limit of 16.73 µM (S/N = 3) for glucose detection. These results highlighted the potential applications of our waste-to-resource approach for nanozyme synthesis in the field of analytical chemistry.
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Peroxidasa , Óxido de Zinc , Peróxido de Hidrógeno/análisis , Colorimetría/métodos , Peroxidasas , Glucosa/análisis , ColorantesRESUMEN
PURPOSE: The purpose of this paper is to study the impact of enterprises' digital transformation on the risk of stock price crashes, but also to study the mediating role of enterprises' financialization and accounting conservatism in the enterprises' digital transformation on stock price crash risk. DESIGN/METHODOLOGY/APPROACH: Based on the data of 2,599 listed companies in China from 2010 to 2019, this paper constructs indicators of enterprise digital transformation through word frequency analysis method, and uses fixed-effects model and mediated-effects model to explore the impact and mechanism of enterprise digital transformation on the stock price crash risk. FINDINGS: This study shows that firms' digital transformation reduces the risk of stock price crashes and that financialization of firms and accounting conservatism play a significant mediating effect between enterprises' digital transformation and the risk of stock price crashes. ORIGINALITY/VALUE: This study enriches the study of stock price crash risk by including digital transformation in the field of stock price crash research, and it examines the mediating roles of financialization of enterprises and accounting conservatism, which provides a new explanatory mechanism to the study of the correlation between digital transformation of enterprises and the risk of stock price crash.
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Accidentes de Tránsito , Organizaciones , ChinaRESUMEN
Cancer is a major threat to the lives and health of people around the world, and the development of effective antitumor drugs that exhibit fewer toxic effects is an important aspect of cancer treatment. PARP inhibitors are antitumor drugs that target pathways involved in DNA-damage repair. The currently approved PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, fuzuloparib, and pamiparib. Hematological toxicities associated with the simultaneous inhibition of PARP-1 and PARP-2 have limited the clinical applications of these drugs. The present review introduces the necessity for research on the development of selective PARP-1 inhibitors from the perspective of structural and functional mechanisms of PARP-1 inhibition. A review of recently reported selective PARP-1 inhibitors provides the foundation for exploring novel strategies for designing selective PARP-1 inhibitors from the perspective of structure-activity relationships combined with computer simulations.
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Antineoplásicos , Neoplasias , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Reparación del ADN , Neoplasias/tratamiento farmacológicoRESUMEN
Promoting health behavior among the public is always a pressing issue. The present research systematically investigated the association between future time perspective and adherence to health behavior including dietary habits, physical activities, and substance use in a Chinese college student sample (N = 519). Results showed that individuals with stronger future time perspective were more likely to adhere to health behavior. Moreover, building upon the health belief model and the protection motivation theory, the present research further explored the underlying mechanisms. Results revealed that it is perceived threats of not carrying out health behavior, but not perceived benefits of carrying out health behavior, that asymmetrically explained the association between stronger future time perspective and greater adherence to health behavior. These findings contribute to both the future time perspective literature and the health behavior literature.
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OBJECTIVE: To investigate the clinical efficacy of percutaneous screw fixation combined with minimally invasive transpedicular bone grafting and non-bone grafting in the treatment of thoracolumbar fractures. METHODS: From Janury 2021 to June 2022, 40 patients with thoracolumbar fracture were divided into the experimental group and the control group. There were 26 patients in the experimental group, including 21 males and 5 females with an aberage age of (47.3±12.3) years old, who underwent percutaneous pedicle screw fixation combined with transpedicular autogenous bone grafting. In the control group, 14 patients received percutaneous pedicle screw fixation only. including 7 makes and 7 females with an average age of (50.2±11.2) years old. The operative time, intraoperative blood loss, anterior height ratio of injured vertebrae, Cobb angle, visual analogue score (VAS), MacNab scores, loosening or broken of the implants. were compared and analyzed. RESULTS: There was no significant difference in operation time, intraoperative blood loss, VAS and anterior height ratio of injured vertebrae between the two groups. Compared with the preoperative results, VAS and anterior height ratio of injured vertebrae were improved statistically(P<0.05). For Cobb angle of injured vertebra, there was no significant difference between the two groups before surgery (P=0.766). While at 1 week, 3 months and 12 months after surgery, there were statistically differences between the two groups (P values were 0.042, 0.007 and 0.039, respectively). The Cobb angle of injured vertebrae one year after operation was statistically decreased in both groups compared with that before surgery (P<0.001). One year after surgery, the excellent and good rate of Macnab scores was 96.15% in the experimental group and 92.86% in the control group, and there was no statistical differences between the two groups (P=0.648). There was one patient in the control group suffering superficial wound infection on the third day, which was cured by dressing change and anti-infection treatment. There were no postoperative screw loosening and broken in both groups. CONCLUSION: The two surgical methods have the advantages of less trauma, less pain and quicker recovery, which can restore the height of the injured vertebra, reconstruct the spinal sequence and reduce the fracture of the vertebral body. Transpedicular autogenous bone grafting can increase the stability of the fractured vertebra and maintain the height of the vertebra better after surgery, thus reducing the possibility of complications such as kyphosis, screw loosening and broken.
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Tornillos Pediculares , Fracturas de la Columna Vertebral , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Trasplante Óseo , Pérdida de Sangre Quirúrgica , Vértebras Lumbares/cirugía , Vértebras Lumbares/lesiones , Vértebras Torácicas/cirugía , Vértebras Torácicas/lesiones , Fijación Interna de Fracturas/métodos , Fracturas de la Columna Vertebral/cirugía , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
The escalating levels of carbon dioxide (CO2) emissions represent the primary driver of global warming, and addressing them is of paramount importance. Timely and accurate prediction, as well as effective control of CO2 emissions, are pivotal for guiding mitigation measures. This paper aims to select the best prediction model for near-real-time daily CO2 emissions in China. The prediction models are based on univariate daily time-series data spanning January 1st, 2020, to September 30st, 2022. Six models are proposed, including three statistical models: grey prediction (GM(1,1)), autoregressive integrated moving average (ARIMA), and seasonal autoregressive integrated moving average with exogenous factors (SARIMAX), and three machine learning models: artificial neural network (ANN), random forest (RF), and long short-term memory (LSTM). The performance of these six models is evaluated using five criteria: mean squared error (MSE), root-mean squared error (RMSE), mean absolute error (MAE), mean absolute percentage error (MAPE), and coefficient of determination (R2). Our findings reveal that the three machine learning models consistently outperform the three statistical models across all five criteria. Among them, the LSTM model demonstrates exceptional performance for daily CO2 emission prediction, boasting an impressively low MSE value of 3.5179e-04, an RMSE value of 0.0187, an MAE value of 0.0140, an MAPE value of 14.8291%, and a high R2 value of 0.9844. This underscores the robustness of the LSTM model in capturing and predicting complex emission patterns, positioning it as the most suitable option for near-real-time daily CO2 emission prediction based on the provided daily time series data. Moreover, our study's results provide valuable insights into emissions forecasting, enabling data-driven decision-making for policymakers and stakeholders. The accurate and timely predictions offered by the LSTM model can aid in the formulation of effective strategies to mitigate carbon emissions, contributing to a more sustainable future. Furthermore, the findings of this study can enhance our understanding of the dynamics of CO2 emissions, leading to more informed environmental policies and actions aimed at reducing carbon emissions.
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Dióxido de Carbono , Modelos Estadísticos , Aprendizaje Automático , Redes Neurales de la Computación , China , PredicciónRESUMEN
China is the world's second-largest maize producer, contributing 23% to global production and playing a crucial role in stabilizing the global maize supply. Therefore, accurately mapping the maize distribution in China is of great significance for regional and global food security and international cereals trade. However, it still lacks a long-term maize distribution dataset with fine spatial resolution, because the existing high spatial resolution satellite datasets suffer from data gaps caused by cloud cover, especially in humid and cloudy regions. This study aimed to produce a long-term, high-resolution maize distribution map for China (China Crop Dataset-Maize, CCD-Maize) identifying maize in 22 provinces and municipalities from 2001 to 2020. The map was produced using a high spatiotemporal resolution fused dataset and a phenology-based method called Time-Weighted Dynamic Time Warping. A validation based on 54,281 field survey samples with a 30-m resolution showed that the average user's accuracy and producer's accuracy of CCD-Maize were 77.32% and 80.98%, respectively, and the overall accuracy was 80.06% over all 22 provinces.
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Agricultura , Zea mays , Agricultura/métodos , ChinaRESUMEN
Overexpression of eIF4E is common in patients with various solid tumors and hematologic cancers. As a potential anti-cancer target, eIF4E has attracted extensive attention from researchers. At the same time, mTOR kinases inhibitors and MNK kinases inhibitors, which are directly related to regulation of eIF4E, have been rapidly developed. To explore the optimal anti-cancer targets among MNK, mTOR, and eIF4E, this review provides a detailed classification and description of the anti-cancer activities of promising compounds. In addition, the structures and activities of some dual-target inhibitors are briefly described. By analyzing the different characteristics of the inhibitors, it can be concluded that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors. Simultaneous inhibition of MNK and eIF4E/eIF4G interaction may be the most promising anti-cancer method for targeting translation initiation.
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Neoplasias Hematológicas , Neoplasias , Humanos , Factor 4G Eucariótico de Iniciación , Serina-Treonina Quinasas TOR , Neoplasias/tratamiento farmacológico , Factor 4E Eucariótico de IniciaciónRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease characterized by severe pruritus and eczematous lesions. Heterogeneity of AD has been reported among different racial groups according to clinical, molecular and genetic differences. OBJECTIVE: This study aimed to conduct an in-depth transcriptome analysis of AD in Chinese population. METHODS: We performed single-cell RNA sequencing (scRNA-seq) analysis of skin biopsies from five Chinese adult patients with chronic AD and from four healthy controls, combined with multiplexed immunohistochemical analysis in whole-tissue skin biopsies. We explored the functions of IL19 in vitro. RESULTS: ScRNA-seq analysis was able to profile a total of 87,853 cells, with keratinocytes (KCs) in AD manifesting highly expressed keratinocyte activation and pro-inflammatory genes. KCs demonstrated a novel IL19+ IGFL1+ subpopulation that increased in AD lesions. Inflammatory cytokines IFNG, IL13, IL26 and IL22 were highly expressed in AD lesions. In vitro, IL19 directly downregulated KRT10 and LOR in HaCaT cells and activated HaCaT cells to produce TSLP. CONCLUSION: Abnormal proliferation and differentiation of keratinocytes contribute immensely to the pathogenesis of AD, whereas AD chronic lesions have witnessed significant presence of IL19+ IGFL1+ KCs, which may be involved in the disruption of the skin barrier, the connection and magnification of Th2 and Th17 inflammatory responses, and mediation of skin pruritus. Furthermore, progressive activation of multiple immune axes dominated by Type 2 inflammatory reaction occur in AD chronic lesions.