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1.
Proc Natl Acad Sci U S A ; 120(42): e2302482120, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37816050

RESUMEN

Myocardial infarction (MI) is a leading cause of heart failure (HF), associated with morbidity and mortality worldwide. As an essential part of gene expression regulation, the role of alternative polyadenylation (APA) in post-MI HF remains elusive. Here, we revealed a global, APA-mediated, 3' untranslated region (3' UTR)-lengthening pattern in both human and murine post-MI HF samples. Furthermore, the 3' UTR of apoptotic repressor gene, AVEN, is lengthened after MI, contributing to its downregulation. AVEN knockdown increased cardiomyocyte apoptosis, whereas restoration of AVEN expression substantially improved cardiac function. Mechanistically, AVEN 3' UTR lengthening provides additional binding sites for miR-30b-5p and miR-30c-5p, thus reducing AVEN expression. Additionally, PABPN1 (poly(A)-binding protein 1) was identified as a potential regulator of AVEN 3' UTR lengthening after MI. Altogether, our findings revealed APA as a unique mechanism regulating cardiac injury in response to MI and also indicated that the APA-regulated gene, AVEN, holds great potential as a critical therapeutic target for treating post-MI HF.


Asunto(s)
Lesiones Cardíacas , MicroARNs , Infarto del Miocardio , Animales , Humanos , Ratones , Regiones no Traducidas 3'/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Regulación hacia Abajo , Lesiones Cardíacas/genética , Proteínas de la Membrana/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Miocitos Cardíacos/metabolismo , Proteína I de Unión a Poli(A)
2.
Brief Bioinform ; 24(5)2023 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-37529921

RESUMEN

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for uncovering cellular heterogeneity. However, the high costs associated with this technique have rendered it impractical for studying large patient cohorts. We introduce ENIGMA (Deconvolution based on Regularized Matrix Completion), a method that addresses this limitation through accurately deconvoluting bulk tissue RNA-seq data into a readout with cell-type resolution by leveraging information from scRNA-seq data. By employing a matrix completion strategy, ENIGMA minimizes the distance between the mixture transcriptome obtained with bulk sequencing and a weighted combination of cell-type-specific expression. This allows the quantification of cell-type proportions and reconstruction of cell-type-specific transcriptomes. To validate its performance, ENIGMA was tested on both simulated and real datasets, including disease-related tissues, demonstrating its ability in uncovering novel biological insights.


Asunto(s)
Perfilación de la Expresión Génica , Transcriptoma , Humanos , Perfilación de la Expresión Génica/métodos , Programas Informáticos , RNA-Seq/métodos , Análisis de Secuencia de ARN/métodos
3.
Immunity ; 44(4): 821-32, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-26850657

RESUMEN

MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. They act by coordinate repression of multiple target genes, a property that we exploited to uncover regulatory networks that govern T helper-2 (Th2) cells. A functional screen of individual miRNAs in primary T cells uncovered multiple miRNAs that inhibited Th2 cell differentiation. Among these were miR-24 and miR-27, miRNAs coexpressed from two genomic clusters, which each functioned independently to limit interleukin-4 (IL-4) production. Mice lacking both clusters in T cells displayed increased Th2 cell responses and tissue pathology in a mouse model of asthma. Gene expression and pathway analyses placed miR-27 upstream of genes known to regulate Th2 cells. They also identified targets not previously associated with Th2 cell biology which regulated IL-4 production in unbiased functional testing. Thus, elucidating the biological function and target repertoire of miR-24 and miR-27 reveals regulators of Th2 cell biology.


Asunto(s)
Asma/inmunología , Interleucina-4/biosíntesis , MicroARNs/genética , Células Th2/inmunología , Animales , Secuencia de Bases , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Inflamación/inmunología , Interleucina-4/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Noqueados , Familia de Multigenes/genética , Análisis de Secuencia de ARN , Células Th2/citología
4.
Nucleic Acids Res ; 51(D1): D1046-D1052, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36043442

RESUMEN

Functional interpretation of disease-associated non-coding variants remains a significant challenge in the post-GWAS era. Our recent study has identified 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) and connects APA events with QTLs as a major driver of human traits and diseases. Besides 3'UTR, APA events can also occur in intron regions, and increasing evidence has connected intronic polyadenylation with disease risk. However, systematic investigation of the roles of intronic polyadenylation in human diseases remained challenging due to the lack of a comprehensive database across a variety of human tissues. Here, we developed ipaQTL-atlas (http://bioinfo.szbl.ac.cn/ipaQTL) as the first comprehensive portal for intronic polyadenylation. The ipaQTL-atlas is based on the analysis of 15 170 RNA-seq data from 838 individuals across 49 Genotype-Tissue Expression (GTEx v8) tissues and contains ∼0.98 million SNPs associated with intronic APA events. It provides an interface for ipaQTLs search, genome browser, boxplots, and data download, as well as the visualization of GWAS and ipaQTL colocalization results. ipaQTL-atlas provides a one-stop portal to access intronic polyadenylation information and could significantly advance the discovery of APA-associated disease susceptibility genes.


Asunto(s)
Intrones , Poliadenilación , Sitios de Carácter Cuantitativo , Humanos , Regiones no Traducidas 3'/genética , Intrones/genética , Perfilación de la Expresión Génica , Atlas como Asunto
5.
Proc Natl Acad Sci U S A ; 119(49): e2113504119, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36454750

RESUMEN

Alternative polyadenylation (APA) plays an important role in posttranscriptional gene regulation such as transcript stability and translation efficiency. However, our knowledge about APA dynamics at the single-cell level is largely unexplored. Here, we developed single-cell polyadenylation sequencing, a strand-specific approach for sequencing the 3' end of transcripts, to investigate the landscape of APA at the single-cell level. By analyzing several cell lines, we found many genes using multiple polyA sites in bulk data are prone to use only one polyA site in each single cell. Interestingly, cell cycle genes were significantly enriched in genes with high variation in polyA site usages. Furthermore, the 414 genes showing a polyA site usage switch after cell synchronization enriched cell cycle genes, while the differentially expressed genes after cell synchronization did not enrich cell cycle genes. We further identified 812 genes showing polyA site usage changes between neighboring cell cycles, which were grouped into six clusters, with cell phase-specific functional categories enriched in each cluster. Deletion of one polyA site in MSL1 and SCCPDH results in slower and faster cell cycle progression, respectively, supporting polyA site usage switch played an important role in cell cycle. These results indicate that APA is an important layer for cell cycle regulation.


Asunto(s)
Poli A , Poliadenilación , Poliadenilación/genética , Genes cdc , Ciclo Celular/genética , División Celular
6.
Curr Issues Mol Biol ; 46(7): 7730-7744, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39057099

RESUMEN

Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and post-transcriptional regulation. Moreover, PTBP1 has been implicated as a causal factor in tumorigenesis. However, the involvement of PTBP1 in cellular senescence, a key biological process in aging and cancer suppression, remains to be clarified. Here, it is shown that PTBP1 is associated with the facilitation of tumor growth and the prognosis in lung adenocarcinoma (LUAD). PTBP1 exhibited significantly increased expression in various cancer types including LUAD and showed consistently decreased expression in multiple cellular senescence models. Suppression of PTBP1 induced cellular senescence in LUAD cells. In terms of molecular mechanisms, the silencing of PTBP1 enhanced the skipping of exon 3 in F-box protein 5 (FBXO5), resulting in the generation of a less stable RNA splice variant, FBXO5-S, which subsequently reduces the overall FBXO5 expression. Additionally, downregulation of FBXO5 was found to induce senescence in LUAD. Collectively, these findings illustrate that PTBP1 possesses an oncogenic function in LUAD through inhibiting senescence, and that targeting aberrant splicing mediated by PTBP1 has therapeutic potential in cancer treatment.

7.
Genome Res ; 31(5): 890-899, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33875481

RESUMEN

Single nucleotide variants (SNVs) within polyadenylation signals (PASs), a specific six-nucleotide sequence required for mRNA maturation, can impair RNA-level gene expression and cause human diseases. However, there is a lack of genome-wide investigation and systematic confirmation tools for identifying PAS variants. Here, we present a computational strategy to integrate the most reliable resources for discovering distinct genomic features of PAS variants and also develop a credible and convenient experimental tool to validate the effect of PAS variants on expression of disease-associated genes. This approach will greatly accelerate the deciphering of PAS variation-related human diseases.


Asunto(s)
Poliadenilación , ARN Mensajero , ARN , Secuencia de Bases , Enfermedad/genética , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Polimorfismo de Nucleótido Simple , ARN/genética , ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
8.
Genome Res ; 31(11): 2095-2106, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34475268

RESUMEN

Intronic polyadenylation (IpA) usually leads to changes in the coding region of an mRNA, and its implication in diseases has been recognized, although at its very beginning status. Conveniently and accurately identifying IpA is of great importance for further evaluating its biological significance. Here, we developed IPAFinder, a bioinformatic method for the de novo identification of intronic poly(A) sites and their dynamic changes from standard RNA-seq data. Applying IPAFinder to 256 pan-cancer tumor/normal pairs across six tumor types, we discovered 490 recurrent dynamically changed IpA events, some of which are novel and derived from cancer-associated genes such as TSC1, SPERD2, and CCND2 Furthermore, IPAFinder revealed that IpA could be regulated by factors related to splicing and m6A modification. In summary, IPAFinder enables the global discovery and characterization of biologically regulated IpA with standard RNA-seq data and should reveal the biological significance of IpA in various processes.


Asunto(s)
Neoplasias , Poliadenilación , Humanos , Intrones/genética , Neoplasias/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , RNA-Seq
9.
Pharmacol Res ; 209: 107420, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39293586

RESUMEN

Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory ß subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 µM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial cancer therapy.

10.
Microb Cell Fact ; 23(1): 7, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-38172836

RESUMEN

BACKGROUND: The 5´ untranslated region (5´ UTR) plays a key role in regulating translation efficiency and mRNA stability, making it a favored target in genetic engineering and synthetic biology. A common feature found in the 5´ UTR is the poly-adenine (poly(A)) tract. However, the effect of 5´ UTR poly(A) on protein production remains controversial. Machine-learning models are powerful tools for explaining the complex contributions of features, but models incorporating features of 5´ UTR poly(A) are currently lacking. Thus, our goal is to construct such a model, using natural 5´ UTRs from Kluyveromyces marxianus, a promising cell factory for producing heterologous proteins. RESULTS: We constructed a mini-library consisting of 207 5´ UTRs harboring poly(A) and 34 5´ UTRs without poly(A) from K. marxianus. The effects of each 5´ UTR on the production of a GFP reporter were evaluated individually in vivo, and the resulting protein abundance spanned an approximately 450-fold range throughout. The data were used to train a multi-layer perceptron neural network (MLP-NN) model that incorporated the length and position of poly(A) as features. The model exhibited good performance in predicting protein abundance (average R2 = 0.7290). The model suggests that the length of poly(A) is negatively correlated with protein production, whereas poly(A) located between 10 and 30 nt upstream of the start codon (AUG) exhibits a weak positive effect on protein abundance. Using the model as guidance, the deletion or reduction of poly(A) upstream of 30 nt preceding AUG tended to improve the production of GFP and a feruloyl esterase. Deletions of poly(A) showed inconsistent effects on mRNA levels, suggesting that poly(A) represses protein production either with or without reducing mRNA levels. CONCLUSION: The effects of poly(A) on protein production depend on its length and position. Integrating poly(A) features into machine-learning models improves simulation accuracy. Deleting or reducing poly(A) upstream of 30 nt preceding AUG tends to enhance protein production. This optimization strategy can be applied to enhance the yield of K. marxianus and other microbial cell factories.


Asunto(s)
Kluyveromyces , Regiones no Traducidas 5' , Secuencia de Bases , Kluyveromyces/genética , Kluyveromyces/metabolismo , ARN Mensajero/genética
11.
BMC Med Imaging ; 24(1): 140, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38858631

RESUMEN

OBJECTIVE: To construct the deep learning convolution neural network (CNN) model and machine learning support vector machine (SVM) model of bone remodeling of chronic maxillary sinusitis (CMS) based on CT image data to improve the accuracy of image diagnosis. METHODS: Maxillary sinus CT data of 1000 samples in 500 patients from January 2018 to December 2021 in our hospital was collected. The first part is the establishment and testing of chronic maxillary sinusitis detection model by 461 images. The second part is the establishment and testing of the detection model of chronic maxillary sinusitis with bone remodeling by 802 images. The sensitivity, specificity and accuracy and area under the curve (AUC) value of the test set were recorded, respectively. RESULTS: Preliminary application results of CT based AI in the diagnosis of chronic maxillary sinusitis and bone remodeling. The sensitivity, specificity and accuracy of the test set of 93 samples of CMS, were 0.9796, 0.8636 and 0.9247, respectively. Simultaneously, the value of AUC was 0.94. And the sensitivity, specificity and accuracy of the test set of 161 samples of CMS with bone remodeling were 0.7353, 0.9685 and 0.9193, respectively. Simultaneously, the value of AUC was 0.89. CONCLUSION: It is feasible to use artificial intelligence research methods such as deep learning and machine learning to automatically identify CMS and bone remodeling in MSCT images of paranasal sinuses, which is helpful to standardize imaging diagnosis and meet the needs of clinical application.


Asunto(s)
Remodelación Ósea , Aprendizaje Profundo , Sinusitis Maxilar , Sensibilidad y Especificidad , Máquina de Vectores de Soporte , Tomografía Computarizada por Rayos X , Humanos , Sinusitis Maxilar/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Enfermedad Crónica , Femenino , Masculino , Persona de Mediana Edad , Adulto , Redes Neurales de la Computación , Anciano , Inteligencia Artificial
12.
Brief Bioinform ; 22(3)2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-32480415

RESUMEN

Alcohol consumption is a critical risk factor for multiple types of cancer. A genome can be attacked and acquire numerous somatic mutations in the environment of alcohol exposure. Mutational signature has the capacity illustrating the complex somatic mutation patterns in cancer genome. Recent studies have discovered distinct mutational signatures associating with alcohol consumption in liver and esophageal cancers. However, their prevalence among diverse cancers, impact of genetic background and origin of alcohol-induced mutational signatures remain unclear. By a comprehensive bioinformatics analysis on somatic mutations from patients of four cancer types with drinking information, we identified nine mutational signatures (signatures B-J), among which signature J (similar to COSMIC signature 16) was distinctive to alcohol drinking. Signature J was associated with HNSC, ESCA and LIHC but not PAAD. Interestingly, patients with mutated allele rs1229984 in ADH1B had lower level of signature J while mutated allele rs671 in ALDH2 exhibited higher signature J abundance, suggesting acetaldehyde is one cause of signature J. Intriguingly, somatic mutations of three potential cancer driver genes (TP53, CUL3 and NSD1) were found the critical contributors for increased mutational load of signature J in alcohol consumption patients. Furthermore, signature J was enriched with early accumulated clonal mutations compared to mutations derived from late tumor growth. This study systematically characterized alcohol-related mutational signature and indicated mechanistic insights into the prevalence, origin and gene-environment interaction regarding the risk oncogenic mutations associated with alcohol intake.


Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Mutación , Neoplasias/genética , Alcohol Deshidrogenasa , Consumo de Bebidas Alcohólicas/fisiopatología , Aldehído Deshidrogenasa Mitocondrial/genética , Humanos , Neoplasias/fisiopatología , Factores de Riesgo
13.
Arch Microbiol ; 205(12): 362, 2023 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-37904066

RESUMEN

Salmonella, a Gram-negative bacterium that infects humans and animals, causes diseases ranging from gastroenteritis to severe systemic infections. Here, we discuss various strategies used by Salmonella against host cell defenses. Epithelial cell invasion largely depends on a Salmonella pathogenicity island (SPI)-1-encoded type 3 secretion system, a molecular syringe for injecting effector proteins directly into host cells. The internalization of Salmonella into macrophages is primarily driven by phagocytosis. After entering the host cell cytoplasm, Salmonella releases many effectors to achieve intracellular survival and replication using several secretion systems, primarily an SPI-2-encoded type 3 secretion system. Salmonella-containing vacuoles protect Salmonella from contacting bactericidal substances in epithelial cells and macrophages. Salmonella modulates the immunity, metabolism, cell cycle, and viability of host cells to expand its survival in the host, and the intracellular environment of Salmonella-infected cells promotes its virulence. This review provides insights into how Salmonella subverts host cell defenses for survival.


Asunto(s)
Salmonella enterica , Sistemas de Secreción Tipo III , Animales , Humanos , Sistemas de Secreción Tipo III/genética , Sistemas de Secreción Tipo III/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Salmonella typhimurium/metabolismo , Salmonella enterica/metabolismo , Virulencia
14.
Nucleic Acids Res ; 49(18): 10369-10381, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34508351

RESUMEN

Somatic single nucleotide variants (SNVs) in cancer genome affect gene expression through various mechanisms depending on their genomic location. While somatic SNVs near canonical splice sites have been reported to cause abnormal splicing of cancer-related genes, whether these SNVs can affect gene expression through other mechanisms remains an open question. Here, we analyzed RNA sequencing and exome data from 4,998 cancer patients covering ten cancer types and identified 152 somatic SNVs near splice sites that were associated with abnormal intronic polyadenylation (IPA). IPA-associated somatic variants favored the localization near the donor splice sites compared to the acceptor splice sites. A proportion of SNV-associated IPA events overlapped with premature cleavage and polyadenylation events triggered by U1 small nuclear ribonucleoproteins (snRNP) inhibition. GC content, intron length and polyadenylation signal were three genomic features that differentiated between SNV-associated IPA and intron retention. Notably, IPA-associated SNVs were enriched in tumor suppressor genes (TSGs), including the well-known TSGs such as PTEN and CDH1 with recurrent SNV-associated IPA events. Minigene assay confirmed that SNVs from PTEN, CDH1, VEGFA, GRHL2, CUL3 and WWC2 could lead to IPA. This work reveals that IPA acts as a novel mechanism explaining the functional consequence of somatic SNVs in human cancer.


Asunto(s)
Neoplasias/genética , Polimorfismo de Nucleótido Simple , ARN , Bases de Datos Genéticas , Humanos , Intrones , Poliadenilación
15.
Nucleic Acids Res ; 49(9): e54, 2021 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-33619563

RESUMEN

With the tremendous increase of publicly available single-cell RNA-sequencing (scRNA-seq) datasets, bioinformatics methods based on gene co-expression network are becoming efficient tools for analyzing scRNA-seq data, improving cell type prediction accuracy and in turn facilitating biological discovery. However, the current methods are mainly based on overall co-expression correlation and overlook co-expression that exists in only a subset of cells, thus fail to discover certain rare cell types and sensitive to batch effect. Here, we developed independent component analysis-based gene co-expression network inference (ICAnet) that decomposed scRNA-seq data into a series of independent gene expression components and inferred co-expression modules, which improved cell clustering and rare cell-type discovery. ICAnet showed efficient performance for cell clustering and batch integration using scRNA-seq datasets spanning multiple cells/tissues/donors/library types. It works stably on datasets produced by different library construction strategies and with different sequencing depths and cell numbers. We demonstrated the capability of ICAnet to discover rare cell types in multiple independent scRNA-seq datasets from different sources. Importantly, the identified modules activated in acute myeloid leukemia scRNA-seq datasets have the potential to serve as new diagnostic markers. Thus, ICAnet is a competitive tool for cell clustering and biological interpretations of single-cell RNA-seq data analysis.


Asunto(s)
RNA-Seq/métodos , Análisis de la Célula Individual/métodos , Animales , Encéfalo/metabolismo , Línea Celular , Análisis por Conglomerados , Biología Computacional/métodos , Redes Reguladoras de Genes , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Ratones , Oligodendroglía/clasificación , Oligodendroglía/metabolismo , Pronóstico , Programas Informáticos
16.
Int J Mol Sci ; 24(24)2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38139250

RESUMEN

The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.


Asunto(s)
Reprogramación Metabólica , Neoplasias , Humanos , Transducción de Señal , Vigilancia Inmunológica , Inmunoterapia , Microambiente Tumoral
17.
Zhongguo Zhong Yao Za Zhi ; 48(6): 1491-1497, 2023 Mar.
Artículo en Zh | MEDLINE | ID: mdl-37005836

RESUMEN

By investigating the contamination status and predicting the exposure risk of mycotoxin in Coicis Semen, we aim to provide guidance for the safety supervision of Chinese medicinal materials and the formulation(revision) of mycotoxin limit standards. The content of 14 mycotoxins in the 100 Coicis Semen samples collected from five major markets of Chinese medicinal materials in China was determined by UPLC-MS/MS. The probability evaluation model based on Monte Carlo simulation method was established after Chi-square test and One-way ANOVA of the sample contamination data. Health risk assessment was performed on the basis of margin of exposure(MOE) and margin of safety(MOS). The results showed that zearalenone(ZEN), aflatoxin B_1(AFB_1), deoxynivalenol(DON), sterigmatocystin(ST), and aflatoxin B_2(AFB_2) in the Coicis Semen samples had the detection rates of 84%, 75%, 36%, 19%, and 18%, and the mean contamination levels of 117.42, 4.78, 61.16, 6.61, and 2.13 µg·kg~(-1), respectively. According to the limit standards in the Chinese Pharmacopoeia(2020 edition), AFB_1, AFs and ZEN exceeded the standards to certain extents, with the over-standard rates of 12.0%, 9.0%, and 6.0%, respectively. The exposure risks of Coicis Semen to AFB_1, AFB2, ST, DON, and ZEN were low, while 86% of the samples were contaminated with two or more toxins, which needs more attention. It is suggested that the research on the combined toxicity of different mycotoxins should be strengthened to accelerate the cumulative exposure assessment of mixed contaminations and the formulation(revision) of toxin limit standards.


Asunto(s)
Coix , Micotoxinas , Humanos , Micotoxinas/análisis , Aflatoxina B1/análisis , Cromatografía Liquida/métodos , Contaminación de Alimentos/análisis , Espectrometría de Masas en Tándem/métodos
19.
Nature ; 537(7620): 412-428, 2016 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-27501245

RESUMEN

During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Centro Germinal/citología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Receptores CXCR5/metabolismo , Traslado Adoptivo , Animales , Linfocitos B/inmunología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/trasplante , Diferenciación Celular , Enfermedad Crónica , Femenino , Centro Germinal/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Virus de la Coriomeningitis Linfocítica/crecimiento & desarrollo , Masculino , Ratones , Receptores CXCR5/deficiencia , Transducción de Señal , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/trasplante , Carga Viral/inmunología , Replicación Viral/inmunología
20.
BMC Anesthesiol ; 22(1): 248, 2022 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-35931948

RESUMEN

BACKGROUND: The radial artery cannulation helps to maintain the stability of maternal hemodynamics and reduce complications, however, it is difficult for women with gestational hypertension. Ultrasound-guided median nerve block can cause arterial vasodilation, which may improve the success rate of radial artery cannulation. METHODS: Ninety-two women with gestational hypertension and risks of intra-operative bleeding undergoing cesarean section following failed ultrasound-guided cannulation were identified and randomized into the median nerve block group and control group. Median nerve block was performed under the guidance of ultrasound in the middle forearm and 5 ml of 0.5% lidocaine was injected. Subcutaneous local block was administered in the control group. The ultrasound-guided radial artery cannulation was performed ten minutes after blocking. Baseline measurements (T1) were performed after 10 minutes of rest. All variables were measured again at 10 (T2) and 30 (T3) minutes after median nerve block or local block. The primary outcome was the success rate of radial artery cannulation within 10 minutes after blocking. The puncture time, number of attempts, the overall complications, and ultrasonographic measurements including radial artery diameter and cross-sectional area were recorded before (T1), 10 minutes (T2) after, and 30 minutes (T3) after block. RESULTS: A total of 92 pregnant women were identified and completed the follow-up. As compared to control group, the first-attempt success rate of radial artery cannulation was significantly higher (95.7% vs78.3%, p = 0.027) and procedure time to success was significantly shorter (118 ± 19 s vs 172 ± 66 s, p < 0.001) in median nerve group. Median nerve group also had a significantly less overall number of attempts (p = 0.024). Compared with control group, the diameter and cross-sectional area of radial artery increased significantly at the T2 and T3 points in median nerve group (p < 0.001), as well as percentage change of radial artery diameter and CSA. No difference was observed in the overall complication at chosen radial artery, which including vasospasm (21.7% vs 28.3%; p = 0.470) and hematoma (4.3% vs 8.7%; p = 0.677). CONCLUSIONS: Ultrasound-guided median nerve block can increase the first-attempt success rate of chosen radial artery cannulation in women with gestational hypertension and risks of intra-operative bleeding undergoing cesarean section following failed radial artery cannulation, and especially for those anesthesiologists with less experienced in radial artery cannulation. TRIAL REGISTRATION: ChiCTR2100052862; http://www.chictr.org.cn , Principal investigator: MEN, Date of registration: 06/11/2021.


Asunto(s)
Cateterismo Periférico , Hipertensión Inducida en el Embarazo , Cateterismo Periférico/métodos , Cesárea , Femenino , Humanos , Nervio Mediano , Embarazo , Arteria Radial/diagnóstico por imagen , Ultrasonografía Intervencional/métodos
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