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While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.
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Neoplasias , Linfocitos T Reguladores , Animales , Ratones , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Microambiente Tumoral , Neoplasias/metabolismoRESUMEN
Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.
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Melanoma , Neoplasias Cutáneas , Animales , Animales Modificados Genéticamente , Carcinogénesis/genética , Pie , Mano , Humanos , Melanoma/patología , Uñas , Oncogenes/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Transcripción Genética , Pez Cebra/genética , Melanoma Cutáneo MalignoRESUMEN
Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.
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Análisis de la Célula Individual , Masculino , Humanos , Análisis de la Célula Individual/métodos , Animales , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Antígenos de Superficie/metabolismo , Antígenos de Superficie/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/tratamiento farmacológico , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológicoRESUMEN
The burgeoning crisis of antibiotic resistance has directed attention to bacteriophages as natural antibacterial agents capable of circumventing bacterial defenses. Central to this are the bacterial defense mechanisms, such as the BREX system, which utilizes the methyltransferase BrxX to protect against phage infection. This study presents the first in vitro characterization of BrxX from Escherichia coli, revealing its substrate-specific recognition and catalytic activity. We demonstrate that BrxX exhibits nonspecific DNA binding but selectively methylates adenine within specific motifs. Kinetic analysis indicates a potential regulation of BrxX by the concentration of its co-substrate, S-adenosylmethionine, and suggests a role for other BREX components in modulating BrxX activity. Furthermore, we elucidate the molecular mechanism by which the T7 phage protein Ocr (Overcoming classical restriction) inhibits BrxX. Despite low sequence homology between BrxX from different bacterial species, Ocr effectively suppresses BrxX's enzymatic activity through high-affinity binding. Cryo-electron microscopy and biophysical analyses reveal that Ocr, a DNA mimic, forms a stable complex with BrxX, highlighting a conserved interaction interface across diverse BrxX variants. Our findings provide insights into the strategic counteraction by phages against bacterial defense systems and offer a foundational understanding of the complex interplay between phages and their bacterial hosts, with implications for the development of phage therapy to combat antibiotic resistance.
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Proteínas de Escherichia coli , Escherichia coli , Proteínas Virales , Escherichia coli/virología , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas Virales/metabolismo , S-Adenosilmetionina/metabolismo , Unión Proteica , Bacteriófago T7/genética , Metiltransferasas/metabolismo , CinéticaRESUMEN
CTL differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. In this study, we show that polycomb repressive complex 1 subunit chromobox (Cbx)4 favors effector CTL differentiation in a murine model. Cbx4 deficiency in CTLs induced a transcriptional signature of memory cells and increased the memory CTL population during acute viral infection. It has previously been shown that besides binding to H3K27me3 through its chromodomain, Cbx4 functions as a small ubiquitin-like modifier (SUMO) E3 ligase in a SUMO-interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in an SIM-dependent way and partially through its chromodomain. Our data suggest a novel role of a polycomb group protein Cbx4 controlling CTL differentiation and indicated SUMOylation as a key molecular mechanism connected to chromatin modification in this process.
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Complejo Represivo Polycomb 1 , Ubiquitina-Proteína Ligasas , Animales , Ratones , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
In this study, a 4-(hydroxymethyl)-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-oxide (PEPA)-functionalized acrylate monomer, PEPAA, is designed and utilized for the synthesis of macromolecular flame retardants poly(PEPAA-co-AM) with varying PEPAA/AM ratio through copolymerization with acrylamide (AM). The poly(PEPAA-co-AM) is then incorporated into polypropylene (PP) to prepare PP/poly(PEPAA-co-AM) composites. The flame retardant effect of poly(PEPAA-co-AM) on PP is investigated using cone calorimetric test (CCT), and compared with that of PEPAA homopolymer (P-PEPAA), AM homopolymer (PAM), and blends of P-PEPAA/PAM. The results demonstrate that, in comparison with P-PEPAA, PAM, and blends of P-PEPAA/PAM, the incorporation of poly(PEPAA-co-AM) significantly enhances the flame retardancy of PP. Notably, the best flame retardancy is achieved when the ratio of PEPAA/AM copolymerization in poly(PEPAA-co-AM) is 2/8. The morphology and composition of residual chars from combustion are analyzed using SEM-EDS while the residual graphitization degree is examined through Raman spectroscopy. Additionally, TG-FTIR-MS is utilized to investigate the pyrolysis products in gas phase during thermal decomposition of poly(PEPAA-co-AM). Based on these experimental results, a flame retardant mechanism for poly(PEPAA-co-AM) is proposed. The PP/poly(PEPAA-co-AM) composites not only retain the excellent processing properties of pure PP but also exhibit enhanced mechanical properties.
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BACKGROUND: The causal relationship between type 2 diabetes (T2D) and frozen shoulder is unclear. This study aims to explore the genetic causal association between T2D and glycemic traits (fasting glucose [FG], fasting insulin [FI], glycated hemoglobin [HbA1c], and 2-hour postprandial glucose [2hGlu]) on frozen shoulder. METHODS: Using 2-sample Mendelian randomization (MR), we analyzed nonconfounded estimates of the effects of T2D and glycemic traits on frozen shoulder. Single-nucleotide polymorphisms (SNPs) strongly associated (P < 5 × 10-8) with exposures from genome-wide association studies (GWAS) were identified. We employed fixed effect mode inverse variance weighting (IVW-FE), random effect mode IVW (IVW-MRE), MR-Egger, and weighted median to assess the association of exposures and outcome. Sensitivity analysis was conducted to test for heterogeneity and multidirectionality bias in MR. RESULTS: We found a significant genetic causal correlation between T2D (IVW-MRE P = .007, odds ratio [OR] 1.093, 95% confidence interval [CI] 1.03-1.16), FG (IVW-FE P < .001, OR 1.455, 95% CI 1.173-1.806), and frozen shoulder, but no evidence for causal correlation between FI, HbA1c, and 2hGlu and frozen shoulder. Although there was certain heterogeneity, sensitivity analysis reveals no deviation from the MR assumptions. CONCLUSION: This study supports a genetic causal relationship between T2D and FG and frozen shoulder.
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Bursitis , Diabetes Mellitus Tipo 2 , Humanos , Análisis de la Aleatorización Mendeliana , Diabetes Mellitus Tipo 2/genética , Estudio de Asociación del Genoma Completo , Ayuno , Insulina , Glucosa , Polimorfismo de Nucleótido SimpleRESUMEN
Naive CD8+ T cells, upon encountering their cognate Ag in vivo, clonally expand and differentiate into distinct cell fates, regulated by transcription factors and epigenetic modulators. Several models have been proposed to explain the differentiation of CTLs, although none fully recapitulate the experimental evidence. In this review article, we will summarize the latest research on the epigenetic regulation of CTL differentiation as well as provide a combined model that contemplates them.
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Diferenciación Celular/genética , Epigénesis Genética/inmunología , Memoria Inmunológica , Modelos Genéticos , Linfocitos T Citotóxicos/inmunología , Animales , Diferenciación Celular/inmunología , Heterogeneidad Genética , Humanos , Activación de Linfocitos , Factores de Transcripción/metabolismoRESUMEN
The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs, respectively. In this study, we demonstrate that the lysine demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific knockout mice or knockdown using short hairpin RNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.
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Linfocitos T CD8-positivos/inmunología , Cromatina/inmunología , Histona Demetilasas con Dominio de Jumonji/inmunología , Animales , Células Cultivadas , Cromatina/genética , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
The performance of bearings plays a pivotal role in determining the dependability and security of rotating machinery. In intricate systems demanding exceptional reliability and safety, the ability to accurately forecast fault occurrences during operation holds profound significance. Such predictions serve as invaluable guides for crafting well-considered reliability strategies and executing maintenance practices aimed at enhancing reliability. In the real operational life of bearings, fault information often gets submerged within the noise. Furthermore, employing Long Short-Term Memory (LSTM) neural networks for time series prediction necessitates the configuration of appropriate parameters. Manual parameter selection is often a time-consuming process and demands substantial prior knowledge. In order to ensure the reliability of bearing operation, this article investigates the application of three advanced techniques-Maximum Correlation Kurtosis Deconvolution (MCKD), Multi-Scale Permutation Entropy (MPE), and Long Short-Term Memory (LSTM) recurrent neural networks-for the prediction of the remaining useful life (RUL) of rolling bearings. The improved sparrow search algorithm (ISSA) is employed for configuring parameters in the Long Short-Term Memory (LSTM) network. Each technique's principles, methodologies, and applications are comprehensively reviewed, offering insights into their respective strengths and limitations. Case studies and experimental evaluations are presented to assess their performance in RUL prediction. Findings reveal that MCKD enhances fault signatures, MPE captures complexity, and LSTM excels in modeling temporal patterns. The root mean square error of the prediction results is 0.007. The fusion of these techniques offers a comprehensive approach to RUL prediction, leveraging their unique attributes for more accurate and reliable predictions.
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The direct decarbonylative cyanation of benzoic acids with TMSCN was achieved through palladium catalysis. By this strategy, a wide range of nitriles including those with functional groups was synthesized in good to high yields. Moreover, this reaction applied to modifying bioactive molecules such as adapalene, probenecid, telmisartan, and 3-methylflavone-8-carboxylic acid. These results demonstrate that this new reaction has potential synthetic value in organic synthesis.
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Ácidos Carboxílicos , Paladio , Catálisis , Cianuros , Compuestos de TrimetilsililoRESUMEN
A nickel-catalyzed decarbonylative thioetherification of carboxylic acids with thiols was developed. Under the reaction conditions, benzoic acids, cinnamic acids, and benzyl carboxylic acids coupled with various thiols including both aromatic and aliphatic ones produce the corresponding thioethers in up to 99% yields. Moreover, this reaction was applicable to the modification of bioactive molecules such as 3-methylflavone-8-carboxylic acid, probenecid, and flufenamic acid, and the synthesis of acaricide chlorbenside. These results well demonstrated the potential synthetic value of this new reaction in organic synthesis.
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Ácidos Carboxílicos , Níquel , Catálisis , Compuestos de Sulfhidrilo , SulfurosRESUMEN
BACKGROUND: With rapid economic development, the world's average life expectancy is increasing, leading to the increasing prevalence of osteoporosis worldwide. However, due to the complexity and high cost of dual-energy x-ray absorptiometry (DXA) examination, DXA has not been widely used to diagnose osteoporosis. In addition, studies have shown that the psoas index measured at the third lumbar spine (L3) level is closely related to bone mineral density (BMD) and has an excellent predictive effect on osteoporosis. Therefore, this study developed a variety of machine learning (ML) models based on psoas muscle tissue at the L3 level of unenhanced abdominal computed tomography (CT) to predict osteoporosis. METHODS: Medical professionals collected the CT images and the clinical characteristics data of patients over 40 years old who underwent DXA and abdominal CT examination in the Second Affiliated Hospital of Wenzhou Medical University database from January 2017 to January 2021. Using 3D Slicer software based on horizontal CT images of the L3, the specialist delineated three layers of the region of interest (ROI) along the bilateral psoas muscle edges. The PyRadiomics package in Python was used to extract the features of ROI. Then Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) algorithm were used to reduce the dimension of the extracted features. Finally, six machine learning models, Gaussian naïve Bayes (GNB), random forest (RF), logistic regression (LR), support vector machines (SVM), Gradient boosting machine (GBM), and Extreme gradient boosting (XGBoost), were applied to train and validate these features to predict osteoporosis. RESULTS: A total of 172 participants met the inclusion and exclusion criteria for the study. 82 participants were enrolled in the osteoporosis group, and 90 were in the non-osteoporosis group. Moreover, the two groups had no significant differences in age, BMI, sex, smoking, drinking, hypertension, and diabetes. Besides, 826 radiomic features were obtained from unenhanced abdominal CT images of osteoporotic and non-osteoporotic patients. Five hundred fifty radiomic features were screened out of 826 by the Mann-Whitney U test. Finally, 16 significant radiomic features were obtained by the LASSO algorithm. These 16 radiomic features were incorporated into six traditional machine learning models (GBM, GNB, LR, RF, SVM, and XGB). All six machine learning models could predict osteoporosis well in the validation set, with the area under the receiver operating characteristic (AUROC) values greater than or equal to 0.8. GBM is more effective in predicting osteoporosis, whose AUROC was 0.86, sensitivity 0.70, specificity 0.92, and accuracy 0.81 in validation sets. CONCLUSION: We developed six machine learning models to predict osteoporosis based on psoas muscle images of abdominal CT, and the GBM model had the best predictive performance. GBM model can better help clinicians to diagnose osteoporosis and provide timely anti-osteoporosis treatment for patients. In the future, the research team will strive to include participants from multiple institutions to conduct external validation of the ML model of this study.
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Osteoporosis , Músculos Psoas , Teorema de Bayes , Humanos , Aprendizaje Automático , Osteoporosis/diagnóstico por imagen , Músculos Psoas/diagnóstico por imagen , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodosRESUMEN
PURPOSE: To identify the individualized method of quantifying lateralization of the tibial tubercle with the best diagnostic effectiveness, as evaluated by measurement repeatability using the intraclass correlation coefficient (ICC), the size of the difference between the case group and the control group, and receiver operating characteristic (ROC) curve analysis. METHODS: Patients who had undergone surgery for recurrent patellar dislocation (the case group) and patients who had no history of patellar dislocation (the control group) from January 2014 to December 2019 were included in the study. Six indices that describe lateralization of the tibial tubercle were calculated using either computed tomography (CT) or magnetic resonance imaging (MRI): tibial tubercle lateralization (TTL), tibial tubercle-trochlear groove (TT-TG) ratio, tibial tubercle-posterior cruciate ligament (TT-PCL) ratio, TT-TG index, (TT-TG)/patellar width (PW), and (TT-TG)/trochlear width (TW). Diagnostic effectiveness was evaluated by 1) intra-rater reliability (measurements on two occasions) and inter-rater reliability (measurements by two assessors) using the ICC, 2) the size of the difference between the case group and the control group, and 3) ROC curve analysis, measuring the area under the ROC curve (AUC) and the post hoc power. RESULTS: 100 knees in 88 patients who had undergone surgery for recurrent patellar dislocation and 55 knees in 53 patients who had no history of patellar dislocation were analyzed. The ICC for all the methods were higher than .75. The mean differences between the case group and the control group for TTL, TT-TG ratio, TT-PCL ratio, TT-TG index, (TT-TG)/PW, and (TT-TG)/TW were 2%, 8%, 2%, 12%, 24% and 56%, respectively. The mean differences between the case group and the control group for (TT-TG)/TW was significantly greater than those for the other methods (P < .0001, unpaired t-test). AUC of TTL, TT-TG ratio, TT-PCL ratio, TT-TG index, (TT-TG)/PW, and (TT-TG)/TW were .708, .880, .630, .814, .882, and .905. AUC of (TT-TG)/TW was significantly greater than those of TTL and TT-PCL ratio (P < .0001). The post hoc power for TT-PCL ratio, TT-TG index, (TT-TG)/PW, TT-TG ratio, (TT-TG)/TW, and TTL were 78%, 81%, 88%, 88%, 91%, and 71%, respectively. CONCLUSION: Of the six indices evaluated in this study, (TT-TG)/TW showed the greatest mean difference between the two groups, had the greatest diagnostic utility (as measured by AUC values) and had excellent inter-rater and intra-rater reliability (as measured by ICCs). Thus, it may be the best individualized index for diagnosing a lateralized tibial tubercle in patients with recurrent patellar dislocation requiring surgical stabilization compared to patients with no history of patellar dislocation. LEVEL OF EVIDENCE: Level III, diagnostic study, retrospective cohort study.
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Inestabilidad de la Articulación , Luxación de la Rótula , Articulación Patelofemoral , Humanos , Inestabilidad de la Articulación/cirugía , Imagen por Resonancia Magnética/métodos , Luxación de la Rótula/diagnóstico por imagen , Luxación de la Rótula/cirugía , Articulación Patelofemoral/patología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Tibia/diagnóstico por imagen , Tibia/patología , Tibia/cirugíaRESUMEN
The sodium-dependent NADH dehydrogenase (Na(+)-NQR) is the main ion transporter in Vibrio cholerae. Its activity is linked to the operation of the respiratory chain and is essential for the development of the pathogenic phenotype. Previous studies have described different aspects of the enzyme, including the electron transfer pathways, sodium pumping structures, cofactor and subunit composition, among others. However, the mechanism of the enzyme remains to be completely elucidated. In this work, we have studied the kinetic mechanism of Na(+)-NQR with the use of steady state kinetics and stopped flow analysis. Na(+)-NQR follows a hexa-uni ping-pong mechanism, in which NADH acts as the first substrate, reacts with the enzyme, and the oxidized NAD leaves the catalytic site. In this conformation, the enzyme is able to capture two sodium ions and transport them to the external side of the membrane. In the last step, ubiquinone is bound and reduced, and ubiquinol is released. Our data also demonstrate that the catalytic cycle involves two redox states, the three- and five-electron reduced forms. A model that gathers all available information is proposed to explain the kinetic mechanism of Na(+)-NQR. This model provides a background to understand the current structural and functional information.
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NADH Deshidrogenasa/metabolismo , Sodio/metabolismo , Vibrio cholerae/enzimología , Biocatálisis , Cinética , Especificidad por SustratoRESUMEN
Currently, monitoring system of awareness of the depth of anesthesia has been more and more widely used in clinical practices. The intelligent evaluation algorithm is the key technology of this type of equipment. On the basis of studies about changes of electroencephalography (EEG) features during anesthesia, a discussion about how to select reasonable EEG parameters and classification algorithm to monitor the depth of anesthesia has taken place. A scheme which combines time domain analysis, frequency domain analysis and the variability of EEG and decision tree as classifier and least squares to compute Depth of anesthesia Index (DOAI) is proposed in this paper. Using the EEG of 40 patients who underwent general anesthesia with propofol, and the classification and the score of the EEG annotated by anesthesiologist, we verified this scheme with experiments. Classification and scoring was based on a combination of modified observer assessment of alertness/sedation (MOAA/S), and the changes of EEG parameters of patients during anesthesia. Then we used the BIS index to testify the validation of the DOAI. Results showed that Pearson's correlation coefficient between the DOAI and the BIS over the test set was 0.89. It is demonstrated that the method is feasible and has good accuracy.
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Anestesia General , Árboles de Decisión , Despertar Intraoperatorio , Monitoreo Fisiológico , Algoritmos , Electroencefalografía , Entropía , Humanos , PropofolRESUMEN
C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved, found in both vertebrates and many invertebrates. It is a member of the pentraxin superfamily, characterized by its pentameric structure and calcium-dependent binding to ligands like phosphocholine (PC). In humans and various other species, the plasma concentration of this protein is markedly elevated during inflammatory conditions, establishing it as a prototypical acute phase protein that plays a role in innate immune responses. This feature can also be used clinically to evaluate the severity of inflammation in the organism. Human CRP (huCRP) can exhibit contrasting biological functions due to conformational transitions, while CRP in various species retains conserved protective functions in vivo. The focus of this review will be on the structural traits of CRP, the regulation of its expression, activate complement, and its function in related diseases in vivo.
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Proteína C-Reactiva , Humanos , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/inmunología , Animales , Inflamación/inmunología , Inflamación/metabolismo , Inmunidad Innata , Conformación Proteica , Relación Estructura-Actividad , Activación de ComplementoRESUMEN
Medicine intervention is the major clinical treatment used to relieve the symptoms and delay the progression of rheumatoid arthritis (RA), but is limited by its poor targeted delivery and short therapeutic duration. Herein, we developed an injectable and bioadhesive gelatin-based (Gel) hydrogel as a local depot of leonurine (Leon)-loaded and folate-functionalized polydopamine (FA-PDA@Leon) nanoparticles for anti-inflammation and chondroprotection in RA. The nanoparticles could protect Leon and facilitate its entry into the M1 phenotype macrophage for intracellular delivery of Leon, while the hydrogel tightly adhered to the tissues in the joint cavity and prolonged the retention of FA-PDA@Leon nanoparticles, thus achieving higher availability and therapeutic efficiency of Leon. In vitro and in vivo experiments demonstrated that the Gel/FA-PDA@Leon hydrogel could strongly suppress the inflammatory response by down-regulating the JAK2/STAT3 signaling pathway in macrophages and protect the chondrocytes from ferritinophagy/ferroptosis. This contributed to maintaining the structural integrity of articular cartilage and accelerating the joint functional recovery. This work provides an effective and convenient strategy to achieve higher bioavailability and long-lasting therapeutic duration of medicine intervention in arthritis diseases.
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Artritis Reumatoide , Ferroptosis , Hidrogeles , Inflamación , Nanopartículas , Polímeros , Animales , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Hidrogeles/química , Ratones , Nanopartículas/química , Inflamación/tratamiento farmacológico , Inflamación/patología , Ferroptosis/efectos de los fármacos , Polímeros/química , Células RAW 264.7 , Nanomedicina/métodos , Indoles/química , Indoles/farmacología , Indoles/administración & dosificación , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ácido Fólico/química , Gelatina/química , Humanos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismoRESUMEN
Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.
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Many cyberattacks begin with a malicious email message, known as spear phishing, targeted at unsuspecting victims. Although security technologies have improved significantly in recent years, spear phishing continues to be successful due to the bespoke nature of such attacks. Crafting such emails requires attackers to conduct careful research about their victims and collect personal information about them and their acquaintances. Despite the widespread nature of spear-phishing attacks, little is understood about the human factors behind them. This is particularly the case when considering the role of attack personalization on end-user vulnerability. To study spear-phishing attacks in the laboratory, we developed a simulation environment called SpearSim that simulates the tasks involved in the generation and reception of spear-phishing messages. Using SpearSim, we conducted a laboratory experiment with human subjects to study the effect of information availability and information exploitation end-user vulnerability. The results of the experiment show that end-users in the high information-availability condition were 2.97 times more vulnerable to spear-phishing attacks than those in the low information-availability condition. We found that access to more personal information about targets can result in attacks involving contextually meaningful impersonation and narratives. We discuss the implications of this research for the design of anti-phishing training solutions.