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G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.
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Encefalopatías , Receptores de Formil Péptido , Humanos , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Receptores de Formil Péptido/metabolismo , Encéfalo/metabolismoRESUMEN
The intestines of mice are colonized by diverse, as-yet-uncultivated bacteria. In this report, we describe the isolation, culture, genotypic and phenotypic characterization, as well as taxonomic classification of three novel anaerobic bacterial strains derived from the caecal contents of C57BL/6J male mice. According to the phenotypic and genotype-based polyphasic taxonomy, we propose three novel species within the family Oscillospiraceae. They are Acutalibacter caecimuris sp. nov. (type strain M00118T=CGMCC 1.18042T=KCTC 25739T), Acutalibacter intestini sp. nov. (type strain M00204T=CGMCC 1.18044T=KCTC 25741T) and Neglectibacter caecimuris sp. nov. (type strain M00184T=CGMCC 1.18043T=KCTC 25740T).
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Técnicas de Tipificación Bacteriana , Ciego , ADN Bacteriano , Ratones Endogámicos C57BL , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Animales , Masculino , Ciego/microbiología , Ratones , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , Ácidos Grasos/química , Composición de BaseRESUMEN
Because of global warming, people have paid more attention to greenhouse gas emitted by vehicles. To quantify the impact of temperature on vehicle CO2 emissions, this study was conducted using the world light vehicle test cycle on two light-duty E10 gasoline vehicles at ambient temperatures of -10, 0, 23, and 40â, and found that CO2 emission factors of Vehicle 1 in the low-speed phase were 22.07% and 20.22% higher than those of Vehicle 2 at cold start and hot start under -10â. The reason was vehicle 1 had a larger displacement and more friction pairs than vehicle 2. There was the highest CO2 emission at the low-speed phase due to low average speed, frequent acceleration, and deceleration. The CO2 temperature factor and the ambient temperature had a strong linear correlation (R2 = 0.99). According to CO2 temperature factors and their relationships, CO2 emission factors of other ambient temperatures could be calculated when the CO2 emission factor of 23â was obtained, and the method also could be used to obtain the CO2 temperature factors of different vehicles. To separate the effect of load setting and temperature variation on CO2 emission quantitatively, a method was proposed. And results showed that the load setting was dominant for the CO2 emission variation. Compared with 23â, the CO2 emission for vehicle 1 caused by load setting variation were 62.83 and 47.42 g/km, respectively at -10 and 0â, while those for vehicle 2 were 45.01 and 35.63 g/km, respectively.
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Contaminantes Atmosféricos , Humanos , Contaminantes Atmosféricos/análisis , Temperatura , Dióxido de Carbono/análisis , Emisiones de Vehículos/análisis , Gasolina/análisis , Vehículos a MotorRESUMEN
Hypoxia is characteristic of the ovarian tumor (OC) microenvironment and profoundly affects tumorigenesis and therapeutic response. Long noncoding RNAs (lncRNAs) play various roles in tumor progression; however, the characteristics of lncRNAs in pathological responses of the OC microenvironment are not entirely understood. Through high-throughput sequencing, lncRNA expression in hypoxia (1% O2 ) and normoxia (21% O2 ) SKOV3 cells was explored and analyzed. The 5'- and 3'-rapid amplification of complementary DNA ends was used to detect the full length of the novel HIF1A-AS3 transcript. Real-time quantitative polymerase chain reaction was used to assess HIF1A-AS3 expression in OC cells and tissues. In vitro and in vivo evaluations of the biological functions of hypoxic HIF1A-AS3 were conducted. To clarify the underlying mechanisms of HIF1A-AS3 in hypoxic OC, a dual-luciferase assay, chromatin immunoprecipitation, RNA pull-down, RNA immunoprecipitation, and RNA-sequencing were used. We used high-throughput sequencing to investigate a novel lncRNA, HIF1A-AS3, as a hypoxic candidate significantly elevated in OC cells/tissues. HIF1A-AS3 was predominantly localized in the nucleus and promoted in vitro and in vivo OC growth and tumorigenesis. Hypoxia-inducible factor 1α bound to hypoxia response elements in the HIF1A-AS3 promoter region and stimulated its expression in hypoxia. Under hypoxia, HIF1A-AS3 directly integrated with Y-Box binding protein 1 and inhibited its ability to bind to the promoters of p21 and AJAP1 to repress their transcriptional activity, thereby promoting hypoxic OC progression. Our results revealed the crucial role and mechanism of the novel hypoxic HIF1A-AS3 in the oncogenesis of OC. The novel HIF1A-AS3 could be a crucial biomarker and therapeutic target for future OC treatments.
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Neoplasias Ováricas , ARN Largo no Codificante , Humanos , Femenino , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transformación Celular Neoplásica/genética , Carcinogénesis/genética , Hipoxia/genética , Neoplasias Ováricas/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Proteína 1 de Unión a la Caja Y/metabolismo , Moléculas de Adhesión Celular/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
Replacing the bulky traditional optical elements in the optical system with a holographic optical element (HOE) is conducive to the functional integration and volume miniaturization. However, when the HOE is used in the infrared system, the mismatch between the recording wavelength and the working wavelength will lead to the reduction of diffraction efficiency and the introduction of aberration, which will seriously affect the performance of the optical system. This paper proposes a design and fabrication method of multifunctional infrared HOEs that can be used in laser Doppler velocimeter (LDV), which can reduce the effect of wavelength mismatch on HOE performance while integrating the functions of the optical system. The restriction relationship and selection method of parameters in typical LDV are summarized; the decrease of diffraction efficiency due to the mismatch between recording and working wavelengths is compensated by designing the angle of signal and reference wave of the HOE; and the aberration caused by wavelength mismatch is compensated by cylindrical lens. The optical experiment shows that the HOE can produce two groups of fringes with opposite gradient, which proves the feasibility of the proposed method. Moreover, this method has a certain degree of universality, and it is expected to design and fabricate HOEs for any working wavelength in the near-infrared band.
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ChatGPT is receiving increasing attention and has a variety of application scenarios in clinical practice. In clinical decision support, ChatGPT has been used to generate accurate differential diagnosis lists, support clinical decision-making, optimize clinical decision support, and provide insights for cancer screening decisions. In addition, ChatGPT has been used for intelligent question-answering to provide reliable information about diseases and medical queries. In terms of medical documentation, ChatGPT has proven effective in generating patient clinical letters, radiology reports, medical notes, and discharge summaries, improving efficiency and accuracy for health care providers. Future research directions include real-time monitoring and predictive analytics, precision medicine and personalized treatment, the role of ChatGPT in telemedicine and remote health care, and integration with existing health care systems. Overall, ChatGPT is a valuable tool that complements the expertise of health care providers and improves clinical decision-making and patient care. However, ChatGPT is a double-edged sword. We need to carefully consider and study the benefits and potential dangers of ChatGPT. In this viewpoint, we discuss recent advances in ChatGPT research in clinical practice and suggest possible risks and challenges of using ChatGPT in clinical practice. It will help guide and support future artificial intelligence research similar to ChatGPT in health.
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Inteligencia Artificial , Organizaciones , Humanos , Toma de Decisiones Clínicas , Diagnóstico Diferencial , DocumentaciónRESUMEN
BACKGROUND: Artificial intelligence models tailored to diagnose cognitive impairment have shown excellent results. However, it is unclear whether large linguistic models can rival specialized models by text alone. OBJECTIVE: In this study, we explored the performance of ChatGPT for primary screening of mild cognitive impairment (MCI) and standardized the design steps and components of the prompts. METHODS: We gathered a total of 174 participants from the DementiaBank screening and classified 70% of them into the training set and 30% of them into the test set. Only text dialogues were kept. Sentences were cleaned using a macro code, followed by a manual check. The prompt consisted of 5 main parts, including character setting, scoring system setting, indicator setting, output setting, and explanatory information setting. Three dimensions of variables from published studies were included: vocabulary (ie, word frequency and word ratio, phrase frequency and phrase ratio, and lexical complexity), syntax and grammar (ie, syntactic complexity and grammatical components), and semantics (ie, semantic density and semantic coherence). We used R 4.3.0. for the analysis of variables and diagnostic indicators. RESULTS: Three additional indicators related to the severity of MCI were incorporated into the final prompt for the model. These indicators were effective in discriminating between MCI and cognitively normal participants: tip-of-the-tongue phenomenon (P<.001), difficulty with complex ideas (P<.001), and memory issues (P<.001). The final GPT-4 model achieved a sensitivity of 0.8636, a specificity of 0.9487, and an area under the curve of 0.9062 on the training set; on the test set, the sensitivity, specificity, and area under the curve reached 0.7727, 0.8333, and 0.8030, respectively. CONCLUSIONS: ChatGPT was effective in the primary screening of participants with possible MCI. Improved standardization of prompts by clinicians would also improve the performance of the model. It is important to note that ChatGPT is not a substitute for a clinician making a diagnosis.
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Inteligencia Artificial , Disfunción Cognitiva , Humanos , Disfunción Cognitiva/diagnóstico , Semántica , Lingüística , LenguajeRESUMEN
ChatGPT has promising applications in health care, but potential ethical issues need to be addressed proactively to prevent harm. ChatGPT presents potential ethical challenges from legal, humanistic, algorithmic, and informational perspectives. Legal ethics concerns arise from the unclear allocation of responsibility when patient harm occurs and from potential breaches of patient privacy due to data collection. Clear rules and legal boundaries are needed to properly allocate liability and protect users. Humanistic ethics concerns arise from the potential disruption of the physician-patient relationship, humanistic care, and issues of integrity. Overreliance on artificial intelligence (AI) can undermine compassion and erode trust. Transparency and disclosure of AI-generated content are critical to maintaining integrity. Algorithmic ethics raise concerns about algorithmic bias, responsibility, transparency and explainability, as well as validation and evaluation. Information ethics include data bias, validity, and effectiveness. Biased training data can lead to biased output, and overreliance on ChatGPT can reduce patient adherence and encourage self-diagnosis. Ensuring the accuracy, reliability, and validity of ChatGPT-generated content requires rigorous validation and ongoing updates based on clinical practice. To navigate the evolving ethical landscape of AI, AI in health care must adhere to the strictest ethical standards. Through comprehensive ethical guidelines, health care professionals can ensure the responsible use of ChatGPT, promote accurate and reliable information exchange, protect patient privacy, and empower patients to make informed decisions about their health care.
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Inteligencia Artificial , Revelación , Humanos , Reproducibilidad de los Resultados , Recolección de Datos , Cooperación del PacienteRESUMEN
BACKGROUND: Deep learning (DL) prediction models hold great promise in the triage of COVID-19. OBJECTIVE: We aimed to evaluate the diagnostic test accuracy of DL prediction models for assessing and predicting the severity of COVID-19. METHODS: We searched PubMed, Scopus, LitCovid, Embase, Ovid, and the Cochrane Library for studies published from December 1, 2019, to April 30, 2022. Studies that used DL prediction models to assess or predict COVID-19 severity were included, while those without diagnostic test accuracy analysis or severity dichotomies were excluded. QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2), PROBAST (Prediction Model Risk of Bias Assessment Tool), and funnel plots were used to estimate the bias and applicability. RESULTS: A total of 12 retrospective studies involving 2006 patients reported the cross-sectionally assessed value of DL on COVID-19 severity. The pooled sensitivity and area under the curve were 0.92 (95% CI 0.89-0.94; I2=0.00%) and 0.95 (95% CI 0.92-0.96), respectively. A total of 13 retrospective studies involving 3951 patients reported the longitudinal predictive value of DL for disease severity. The pooled sensitivity and area under the curve were 0.76 (95% CI 0.74-0.79; I2=0.00%) and 0.80 (95% CI 0.76-0.83), respectively. CONCLUSIONS: DL prediction models can help clinicians identify potentially severe cases for early triage. However, high-quality research is lacking. TRIAL REGISTRATION: PROSPERO CRD42022329252; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD 42022329252.
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COVID-19 , Aprendizaje Profundo , Humanos , COVID-19/diagnóstico , Estudios Retrospectivos , PubMed , Pruebas Diagnósticas de Rutina , Prueba de COVID-19RESUMEN
BACKGROUND: Cervical squamous cell carcinoma (SCC) is known to arise through increasingly higher-grade squamous intraepithelial lesions (SILs) or cervical intraepithelial neoplasias (CINs). This study aimed to describe sequential molecular changes and identify biomarkers in cervical malignant transformation. METHODS: Multidimensional data from five publicly available microarray and TCGA-CESC datasets were analyzed. Immunohistochemistry was carried out on 354 cervical tissues (42 normal, 62 CIN1, 26 CIN2, 47 CIN3, and 177 SCC) to determine the potential diagnostic and prognostic value of identified biomarkers. RESULTS: We demonstrated that normal epithelium and SILs presented higher molecular homogeneity than SCC. Genes in the region (e.g., 3q, 12q13) with copy number alteration or HPV integration were more likely to lose or gain expression. The IL-17 signaling pathway was enriched throughout disease progression with downregulation of IL17C and decreased Th17 cells at late stage. Furthermore, we identified AURKA, TOP2A, RFC4, and CEP55 as potential causative genes gradually upregulated during the normal-SILs-SCC transition. For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89). They had equivalent diagnostic performance alone to the combination of p16INK4a and Ki-67. Meanwhile, increased expression of RFC4 significantly and independently predicted favorable outcomes in multi-institutional cohorts of SCC patients. CONCLUSIONS: Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes during cervical carcinogenesis. RFC4 is proposed as a novel surrogate biomarker for determining HSIL and HSIL+, and an independent prognostic biomarker for SCC.
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Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Pronóstico , Biomarcadores de Tumor/metabolismo , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Expresión Génica , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/genética , Proteína de Replicación C/genética , Proteína de Replicación C/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/patologíaRESUMEN
Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.
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Quinasa 5 Dependiente de la Ciclina , Proteínas tau , Quinasa 5 Dependiente de la Ciclina/metabolismo , Quinasa 5 Dependiente de la Ciclina/farmacología , Humanos , Isquemia , Lisofosfolípidos , Neuronas , Reperfusión , Proteínas tau/metabolismoRESUMEN
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.
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Proteína HMGB1/metabolismo , Insuficiencia Multiorgánica/patología , Sepsis/patología , Autofagia/fisiología , Trastornos de la Coagulación Sanguínea/patología , Síndrome de Liberación de Citoquinas/patología , Estrés del Retículo Endoplásmico/fisiología , Humanos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Mitocondrias/patología , Insuficiencia Multiorgánica/tratamiento farmacológico , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Sepsis/tratamiento farmacológico , Transducción de Señal/fisiología , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: Septic heart failure accounts for high mortality rates globally. With a strong reducing capacity, zero-valent iron nanoparticles (nanoFe) have been applied in many fields. However, the precise roles and mechanisms of nanoFe in septic cardiomyopathy remain unknown. RESULTS: NanoFe was prepared via the liquid-phase reduction method and functionalized with the biocompatible polymer sodium carboxymethylcellulose (CMC). We then successfully constructed a mouse model of septic myocardial injury by challenging with cecal ligation and puncture (CLP). Our findings demonstrated that nanoFe has a significant protective effect on CLP-induced septic myocardial injury. This may be achieved by attenuating inflammation and oxidative stress, improving mitochondrial function, regulating endoplasmic reticulum stress, and activating the AMPK pathway. The RNA-seq results supported the role of nanoFe treatment in regulating a transcriptional profile consistent with its role in response to sepsis. CONCLUSIONS: The results provide a theoretical basis for the application strategy and combination of nanoFe in sepsis and septic myocardial injury.
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Insuficiencia Cardíaca , Lesiones Cardíacas , Nanopartículas , Sepsis , Animales , Insuficiencia Cardíaca/metabolismo , Hierro , Ratones , Miocardio/metabolismo , Sepsis/metabolismoRESUMEN
Heat stress (HS) seriously restricts the growth and development of plants. When plants are exposed to extreme high temperature, the heat stress response (HSR) is activated to enable plants to survive. Sessile plants have evolved multiple strategies to sense and cope with HS. Previous studies have established that PHYTOCHROME INTERACTING FACTOR 4 (PIF4) acts as a key component in thermomorphogenesis; however, whether PIF4 regulates plant thermotolerance and the molecular mechanism linking this light transcriptional factor and HSR remain unclear. Here, we show that the overexpression of PIF4 indeed provides plants with a stronger basal thermotolerance and greatly improves the survival ability of Arabidopsis under severe HS. Via phylogenetic analysis, we identified two sets (six) of PIF4 homologs in wheat, and the expression patterns of the PIF4 homologs were conservatively induced by heat treatment in both wheat and Arabidopsis. Furthermore, the PIF4 protein was accumulated under heat stress and had an identical expression level. Additionally, we found that the core regulator of HSR, HEAT SHOCK TRANSCRIPTION FACTOR A2 (HSFA2), was highly responsive to light and heat. Followed by promoter analysis and ChIP-qPCR, we further found that PIF4 can bind directly to the G-box motifs of the HSFA2 promoter. Via effector-reporter assays, we found that PIF4 binding could activate HSFA2 gene expression, thereby resulting in the activation of other HS-inducible genes, such as heat shock proteins. Finally, the overexpression of PIF4 led to a stronger basal thermotolerance under non-heat-treatment conditions, thereby resulting in an enhanced tolerance to severe heat stress. Taken together, our findings propose that PIF4 is linked to heat stress signaling by directly binding to the HSFA2 promoter and triggering the HSR at normal temperature conditions to promote the basal thermotolerance. These functions of PIF4 provide a candidate direction for breeding heat-resistant crop cultivars.
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Proteínas de Arabidopsis , Arabidopsis , Fitocromo , Termotolerancia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica de las Plantas , Factores de Transcripción del Choque Térmico/genética , Calor , Filogenia , Fitocromo/metabolismo , Fitomejoramiento , Proteínas de Plantas/genética , Termotolerancia/genéticaRESUMEN
Heat shock factors (Hsfs) play pivotal roles in plant stress responses and confer stress tolerance. However, the functions of several Hsfs in rice (Oryza sativa L.) are not yet known. In this study, genome-wide analysis of the Hsf gene family in rice was performed. A total of 25 OsHsf genes were identified, which could be clearly clustered into three major groups, A, B, and C, based on the characteristics of the sequences. Bioinformatics analysis showed that tandem duplication and fragment replication were two important driving forces in the process of evolution and expansion of the OsHsf family genes. Both OsHsfB4b and OsHsfB4d showed strong responses to the stress treatment. The results of subcellular localization showed that the OsHsfB4b protein was in the nucleus whereas the OsHsfB4d protein was located in both the nucleus and cytoplasm. Over-expression of the OsHsfB4b gene in Arabidopsis and rice can increase the resistance to drought stress. This study provides a basis for understanding the function and evolutionary history of the OsHsf gene family, enriching our knowledge of understanding the biological functions of OsHsfB4b and OsHsfB4d genes involved in the stress response in rice, and also reveals the potential value of OsHsfB4b in rice environmental adaptation improvement.
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Arabidopsis , Oryza , Arabidopsis/genética , Arabidopsis/metabolismo , Sequías , Regulación de la Expresión Génica de las Plantas , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estrés Fisiológico/genéticaRESUMEN
Signal transducer and activator of transcription 3 (STAT3) is a cellular signal transcription factor that has recently attracted a great deal of attention. It can trigger a variety of genes transcription in response to cytokines and growth factors stimulation, which plays an important role in many cellular biological processes involved in anti/proinflammatory responses. Sepsis is a life-threatening organ dysfunction resulting from dysregulated host responses to infection. As a converging point of multiple inflammatory responses pathways, accumulating studies have presented the elaborate network of STAT3 in sepsis pathophysiology; these results generally indicate a promising therapeutic application for targeting STAT3 in the treatment of sepsis. In the present review, we evaluated the published literature describing the use of STAT3 in the treatment of experimental and clinical sepsis. The information presented here may be useful for the design of future studies and may highlight the potential of STAT3 as a future biomarker and therapeutic target for sepsis.
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Antiinflamatorios/uso terapéutico , Mediadores de Inflamación/antagonistas & inhibidores , Factor de Transcripción STAT3/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Terapia Molecular Dirigida , Insuficiencia Multiorgánica/inmunología , Insuficiencia Multiorgánica/metabolismo , Insuficiencia Multiorgánica/prevención & control , Fosforilación , Factor de Transcripción STAT3/metabolismo , Sepsis/inmunología , Sepsis/metabolismoRESUMEN
WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti-tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3-related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i-induced cell death. The tumor-selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double-strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti-tumor immunity. Furthermore, our study found that immune checkpoint programmed death-ligand 1 is upregulated by the combination therapy, and blocking PD-L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment.
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Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Antígeno B7-H1/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Muerte Celular , Línea Celular Tumoral , ADN/metabolismo , Daño del ADN , ADN de Neoplasias/biosíntesis , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Inestabilidad Genómica , Humanos , Inmunidad , Inmunoterapia/métodos , Indoles/uso terapéutico , Interferón Tipo I/biosíntesis , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Morfolinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinonas/uso terapéutico , Sulfonamidas/uso terapéutico , Microambiente Tumoral/inmunología , Ensayo de Tumor de Célula Madre , Regulación hacia ArribaRESUMEN
Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Piruvatos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Humanos , Piruvatos/farmacologíaRESUMEN
A novel galactosidase gene (gal3149) was identified from Bacillus velezensis SW5 and heterologously expressed in Escherichia coli BL21 (DE3). The novel galactosidase, Gal3149, encoded by gal3149 in an open reading frame of 1,299 bp, was 433 amino acids in length. Protein sequence analysis showed that Gal3149 belonged to family 4 of glycoside hydrolases (GH4). Gal3149 displayed higher enzyme activity for the substrate 2-nitrophenyl-ß-d-galactopyranoside (oNPG) than for 4-nitrophenyl-α-d-galactopyranoside (pNPαG). This is the first time that an enzyme belonging to GH4 has been shown to exhibit ß-galactosidase activity. Gal3149 showed optimal activity at pH 8.0 and 50°C, and exhibited excellent thermal stability, with retention of 50% relative activity after incubation at a temperature range of 0 to 50°C for 48 h. Gal3149 activity was significantly improved by K+ and Na+, and was strongly or completely inhibited by Ag+, Zn2+, Tween-80, Cu2+, carboxymethyl cellulose, and oleic acid. The rate of hydrolyzed lactose in 1 mL of milk by 1 U of Gal3149 reached about 50% after incubation for 4 h. These properties lay a solid foundation for Gal3149 in application of the lactose-reduced dairy industry.
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Bacillus , Galactosidasas , Animales , Bacillus/genética , Bacillus/metabolismo , Clonación Molecular , Concentración de Iones de Hidrógeno , Cinética , Lactosa , Temperatura , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
Following publication of the original article [1], the authors reported an error in Fig. 1f.