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BACKGROUND: Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features include vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Thrombocytopenia is one of the common adverse effects of interferon therapy. However, a more serious but rare side effect is thrombotic microangiopathy. CASE PRESENTATION: We report the case of a 36-year-old Asian male patient with clinical manifestations of hypertension, blurred vision, acute renal failure, thrombocytopenia, and thrombotic microangiopathy. Renal biopsy showed interstitial edema with fibrosis, arteriolar thickening with vitreous changes, and epithelial podocytes segmental fusion. Immunofluorescence microscopy showed C3(+), Ig A(+) deposition in the mesangial region, which was pathologically consistent with thrombotic microangiopathy renal injury and Ig A deposition. The patient had a history of hepatitis B virus infection for more than 5 years. Lamivudine was used in the past, but the injection of long-acting interferon combined with tenofovir alafenamide fumarate was used since 2018. The comprehensive clinical investigation and laboratory examination diagnosed the condition as thrombotic microangiopathy kidney injury caused by interferon. After stopping interferon in his treatment, the patient's renal function partially recovered after three consecutive therapeutic plasma exchange treatments and follow-up treatment without immunosuppressant. The renal function of the patient remained stable. CONCLUSIONS: This report indicates that interferon can induce thrombotic microangiopathy with acute renal injury, which can progress to chronic renal insufficiency.
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Antivirales , Microangiopatías Trombóticas , Humanos , Masculino , Microangiopatías Trombóticas/inducido químicamente , Adulto , Antivirales/efectos adversos , Lesión Renal Aguda/inducido químicamente , Intercambio Plasmático , Hepatitis B/complicaciones , Interferones/efectos adversosRESUMEN
Currently, no antifibrotic drug in clinical use can effectively treat renal fibrosis. Fluorofenidone (AKFPD), a novel pyridone agent, significantly reduces renal fibrosis by inhibiting the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome; however, the underlying mechanism of this inhibition is not fully understood. The present study aimed to reveal the molecular mechanism underlying the suppression of NLRP3 inflammasome activation by AKFPD. It investigated the effect of AKFPD on NLRP3 activation and lysosomal cathepsins in a unilateral ureteral obstruction (UUO) rat model, and hypoxia/reoxygenation (H/R)-treated HK-2 cells and murine peritoneal-derived macrophages (PDMs) stimulated with lipopolysaccharide (LPS) and ATP. The results confirmed that AKFPD suppressed renal interstitial fibrosis and inflammation by inhibiting NLRP3 inflammasome activation in UUO rat kidney tissues. In addition, AKFPD reduced the production of activated caspase-1 and maturation of IL-1ß by suppressing NLRP3 inflammasome activation in H/R-treated HK-2 cells and murine PDMs stimulated with LPS and ATP. AKFPD also decreased the activities of cathepsins B, L and S both in vivo and in vitro. Notably, AKFPD downregulated cathepsin B expression and NLRP3 colocalization in the cytoplasm after lysosomal disruptions. Overall, the results suggested that AKFPD attenuates renal fibrosis by inhibiting lysosomal cathepsin-mediated activation of the NLRP3 inflammasome.
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BACKGROUND: The common cutworm, Spodoptera litura (Fabricius), is one of the most widespread and destructive polyphagous pests in tropical and subtropical Asia. S. litura has evolved resistance to different insecticides, including diamide insecticides. Here, we identified a ryanodine receptor (RyR) mutation (I4728M) associated with target site resistance to diamides in a field-collected population of S. litura. The contribution of this mutation to diamide resistance was investigated through establishing a near-isogenic resistant strain of S. litura. RESULTS: The ND21 population of S. litura, collected from Ningde, Fujian province of China in 2021, exhibited 130.6-fold resistance to chlorantraniliprole compared to the susceptible NJ-S strain. S. litura RyR mutation I4728M, corresponding to Plutella xylostella RyR I4790M, was identified in the ND21 population. SlRyR I4728M mutation of ND21 was introgressed into a susceptible background strain (NJ-S) with marker-assisted backcrossing. The introgressed strain named ND21-R, which was homozygous for the mutant 4728M allele, shared about 94% of the genetic background with the NJ-S strain. ND21-R strain showed moderate levels of resistance to two anthranilic diamides (19.1-fold to chlorantraniliprole, 19.7-fold to cyantraniliprole) and the phthalic diamide flubendiamide (23.4-fold). Genetic analysis showed that chlorantraniliprole resistance was autosomal, incompletely recessive and tightly linked with SlRyR I4728M mutation in the introgressed ND21-R strain of S. litura. CONCLUSION: Identification of the I4728M mutation and its contribution to diamide resistance in S. litura will help develop allelic discrimination assays for resistance monitoring and guide resistance management practices for diamides in S. litura. © 2023 Society of Chemical Industry.
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Insecticidas , Mariposas Nocturnas , Animales , Spodoptera/genética , Insecticidas/farmacología , Canal Liberador de Calcio Receptor de Rianodina/genética , Diamida/farmacología , Resistencia a los Insecticidas/genética , ortoaminobenzoatos/farmacología , Mutación , Mariposas Nocturnas/genéticaRESUMEN
BACKGROUND: Previous research has demonstrated that the personal use of social media, i.e., social cyberloafing, is associated with employee mental health. However, the underlying mechanism through which social cyberloafing is related to mental health has received limited attention. OBJECTIVE: Drawing on conservation of resource theory and work/nonwork enhancement literatures, we developed and tested a model that examines health effect of social cyberloafing. As such, employees' social cyberloafing is posited as positively related to psychological detachment and personal life enhancement of work, which in turn would act as mediators that explain why social cyberloafing improves mental health. METHODS: Data from 375 Chinese employees were analyzed to test research hypotheses using the structural equation modeling and bias-corrected bootstrap method with Mplus 7.4. RESULTS: The results found that social cyberloafing is positively related to psychological detachment, but not with personal life enhancement of work. Social cyberloafing was positively related to employees' mental health through both psychological detachment and through psychological detachment and personal life enhancement of work serially. CONCLUSION: Psychological detachment alone and alongside personal life enhancement of work form part of the mechanisms explaining how and why engaging in social cyberloafing is positively associated with employees' mental health. These mechanisms offer insights to organizations into how the mental health of employees can be improved in the digital workplace.
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Salud Laboral , Medios de Comunicación Sociales , Humanos , Salud Mental , Lugar de Trabajo , Análisis de Clases LatentesRESUMEN
INTRODUCTION: IQGAP3 possesses oncogenic actions; its impact on prostate cancer (PC) remains unclear. OBJECTIVE: We will investigate IQGAP3's association with PC progression, key mechanisms, prognosis, and immune evasion. METHODS: IQGAP3 expression in PC was examined by immunohistochemistry and using multiple datasets. IQGAP3 network was analyzed for pathway alterations and used to construct a multigene signature (SigIQGAP3NW). SigIQGAP3NW was characterized using LNCaP cell-derived castration-resistant PCs (CRPCs), analyzed for prognostic value in 26 human cancer types, and studied for association with immune evasion. RESULTS: Increases in IQGAP3 expression associated with PC tumorigenesis, tumor grade, metastasis, and p53 mutation. IQGAP3 correlative genes were dominantly involved in mitosis. IQGAP3 correlated with PLK1 and TOP2A expression at Spearman correlation/R = 0.89 (p ≤ 3.069e-169). Both correlations were enriched in advanced PCs and Taxane-treated CRPCs and occurred at high levels (R > 0.8) in multiple cancer types. SigIQGAP3NW effectively predicted cancer recurrence and poor prognosis in independent PC cohorts and across 26 cancer types. SigIQGAP3NW stratified PC recurrence after adjustment for age at diagnosis, grade, stage, and surgical margin. SigIQGAP3NW component genes were upregulated in PC, metastasis, LNCaP cell-produced CRPC, and showed an association with p53 mutation. SigIQGAP3NW correlated with immune cell infiltration, including Treg in PC and other cancers. RELT, a SigIQGAP3NW component gene, was associated with elevations of multiple immune checkpoints and the infiltration of Treg and myeloid-derived suppressor cells in PC and across cancer types. RELT and SigIQGAP3NW predict response to immune checkpoint blockade (ICB) therapy. CONCLUSIONS: In multiple cancers, IQGAP3 robustly correlates with PLK1 and TOP2A expression, and SigIQGAP3NW and/or RELT effectively predict mortality risk and/or resistance to ICB therapy. PLK1 and TOP2A inhibitors should be investigated for treating cancers with elevated IQGAP3 expression. SigIQGAP3NW and/or RELT can be developed for clinical applications in risk stratification and management of ICB therapy.
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Neoplasias de la Próstata , Proteína p53 Supresora de Tumor , Masculino , Humanos , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Pronóstico , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismoRESUMEN
Resulting from the short production cycle and rapid design technology development, traditional prognostic and health management (PHM) approaches become impractical and fail to match the requirement of systems with structural and functional complexity. Among all PHM designs, testability design and maintainability design face critical difficulties. First, testability design requires much labor and knowledge preparation, and wastes the sensor recording information. Second, maintainability design suffers bad influences by improper testability design. We proposed a test strategy optimization based on soft-sensing and ensemble belief measurements to overcome these problems. Instead of serial PHM design, the proposed method constructs a closed loop between testability and maintenance to generate an adaptive fault diagnostic tree with soft-sensor nodes. The diagnostic tree generated ensures high efficiency and flexibility, taking advantage of extreme learning machine (ELM) and affinity propagation (AP). The experiment results show that our method receives the highest performance with state-of-art methods. Additionally, the proposed method enlarges the diagnostic flexibility and saves much human labor on testability design.
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Aprendizaje , Aprendizaje Automático , Humanos , PronósticoRESUMEN
Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC. The current understanding and management of pRCC remain poor. We report here OIP5 being a novel oncogenic factor and possessing robust prognostic values and therapeutic potential. OIP5 upregulation is observed in pRCC. The upregulation is associated with pRCC adverse features (T1P < T2P < CIMP, Stage1 + 2 < Stage 3 < Stage 4, and N0 < N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation; the latter is correlated with network alterations related to immune regulation, metabolism, and hypoxia. A set of differentially expressed genes (DEFs) was derived from ACHN OIP5 xenografts and primary pRCCs (n = 282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p < 2 × 10-16) and relapse (p < 2 × 10-16) possibilities. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5. PLK1 inhibitor BI2356 inhibits the growth of xenografts formed by ACHN OIP5 cells. Collectively, the OIP5 network can be explored for personalized therapies in management of pRCC patients.
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Contactin 1 (CNTN1) is a new oncogenic protein of prostate cancer (PC); its impact on PC remains incompletely understood. We observed CNTN1 upregulation in LNCaP cell-derived castration-resistant PCs (CRPC) and CNTN1-mediated enhancement of LNCaP cell proliferation. CNTN1 overexpression in LNCaP cells resulted in enrichment of the CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_3 gene set that facilitates endocrine resistance in breast cancer. The leading-edge (LE) genes (n = 10) of this enrichment consist of four genes with limited knowledge on PC and six genes novel to PC. These LE genes display differential expression during PC initiation, metastatic progression, and CRPC development, and they predict PC relapse following curative therapies at hazard ratio (HR) 2.72, 95% confidence interval (CI) 1.96-3.77, and p = 1.77 × 10-9 in The Cancer Genome Atlas (TCGA) PanCancer cohort (n = 492) and HR 2.72, 95% CI 1.84-4.01, and p = 4.99 × 10-7 in Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 140). The LE gene panel classifies high-, moderate-, and low-risk of PC relapse in both cohorts. Additionally, the gene panel robustly predicts poor overall survival in clear cell renal cell carcinoma (ccRCC, p = 1.13 × 10-11), consistent with ccRCC and PC both being urogenital cancers. Collectively, we report multiple CNTN1-related genes relevant to PC and their biomarker values in predicting PC relapse.
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Carcinogénesis/genética , Carcinoma de Células Renales/genética , Contactina 1/genética , Neoplasias Renales/genética , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Atlas como Asunto , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular , Estudios de Cohortes , Contactina 1/metabolismo , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Familia de Multigenes , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Pronóstico , Modelos de Riesgos Proporcionales , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
BACKGROUND: The leaf surface microstructure can greatly influence predator feeding behavior. However, its effects on predator oviposition preference, which is crucial for arthropod fitness at the population level, are largely unknown. This study aimed to test leaf discs and plants of five common host plant species of Bemisia tabaci, including Chinese kale, cotton, cucumber, eggplant, and sweetpotato, to determine the oviposition preference and offspring and adult performance of the whitefly predator Serangium japonicum. Cannibalism risk, attachment force, microstructure of the abaxial leaf surface (ALS), and ladybeetle tarsal morphology were examined. RESULTS: Ladybeetle's oviposition preference had no correlation with offspring performance but positively correlated with fecundity. Further, oviposition preference to leaf discs and fecundity positively correlated with attachment force. The cannibalism risk was not significantly different between plant species. The ALS of Chinese kale and eggplant supported the smallest and the largest attachment forces, respectively. The first one had epicuticular wax crystals, whereas the latter had stellate trichomes. The ALS of cotton and sweetpotato did not bear wax crystals or long trichomes. Cucumber leaves were covered with tapered trichomes. Tenant setae on the distal second tarsomere and a pair of curved, tapered claws on the distal fourth tarsomere were the attachment structures of S. japonicum, which interacted with the plant surface structures and generated the attachment force. CONCLUSION: Plant morphological traits, associated with ladybeetle attachment force and adult performance might be key factors in ladybeetle oviposition preference, and are expected to occur in other host plant herbivore-predator systems.
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Escarabajos , Hemípteros , Adulto , Animales , Femenino , Herbivoria , Humanos , Oviposición , Hojas de la PlantaRESUMEN
BACKGROUND: The aim of this study was to investigate the contributions of FAM84B in prostate tumorigenesis and progression. METHODS: A FAM84B mutant with deletion of its HRASLS domain (ΔHRASLS) was constructed. DU145 prostate cancer (PC) cells stably expressing an empty vector (EV), FAM84B, or FAM84B (ΔHRASLS) were produced. These lines were examined for proliferation, invasion, and growth in soft agar in vitro. DU145 EV and FAM84B cells were investigated for tumor growth and lung metastasis in NOD/SCID mice. The transcriptome of DU145 EV xenografts (n = 2) and DU145 FAM84B tumors (n = 2) was determined using RNA sequencing, and analyzed for pathway alterations. The FAM84B-affected network was evaluated for an association with PC recurrence. RESULTS: FAM84B but not FAM84B (ΔHRASLS) increased DU145 cell invasion and growth in soft agar. Co-immunoprecipitation and co-localization analyses revealed an interaction between FAM84B and FAM84B (ΔHRASLS), suggesting an intramolecular association among FAM84B molecules. FAM84B significantly enhanced DU145 cell-derived xenografts and lung metastasis. In comparison with DU145 EV cell-produced tumors, those generated by DU145 FAM84B cells showed a large number of differentially expressed genes (DEGs; n = 4976). A total of 51 pathways were enriched in these DEGs, which function in the Golgi-to-endoplasmic reticulum processes, cell cycle checkpoints, mitochondrial events, and protein translation. A novel 27-gene signature (SigFAM) was derived from these DEGs; SigFAM robustly stratifies PC recurrence in two large PC populations (n = 490, p = 0; n = 140, p = 4e-11), and remains an independent risk factor of PC recurrence after adjusting for age at diagnosis, Gleason scores, surgical margin, and tumor stages. CONCLUSIONS: FAM84B promotes prostate tumorigenesis through a complex network that predicts PC recurrence.
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Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelialâ»mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types.
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We report here numerous novel genes and multiple new signatures which robustly predict prostate cancer (PC) recurrence. We extracted 696 differentially expressed genes relative to a reported PC signature from the TCGA dataset (n = 492) and built a 15-gene signature (SigMuc1NW) using Elastic-net with 10-fold cross-validation through analyzing their expressions at 1.5 standard deviation/SD below and 2 SD above a population mean. SigMuc1NW predicts biochemical recurrence (BCR) following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free (MMDF) (P = 1.12e-12). The prediction accuracy is improved with the use of SigMuc1NW's cutpoint (P = 3e-15) and is further enhanced (sensitivity 67%, specificity 75.7%, MMDF 45.2, P = 0) when all 15 genes were analyzed through their cutpoints instead of their SDs. These genes individually associate with BCR using either SD or cutpoint as the cutoff points. Eight of 15 genes are individual risk factors after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Eleven of 15 genes are novel to PC. SigMuc1NW discriminates BCR with time-dependent AUC (tAUC) values of 76.6% at 11.5 months (76.6%-11.5 m), 73.8%-22.3 m, 78.5%-32.1 m, and 76.4%-48.4 m. SigMuc1NW is correlated with adverse features of PC, high Gleason scores (odds ratio/OR 1.48, P < 2e-16), and advanced tumor stages (OR 1.33, P = 4.37e-13). SigMuc1NW remains an independent risk factor of BCR (HR 2.44, 95% CI 1.53-3.87, P = 1.62e-4) after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. In an independent PC (MSKCC) cohort (n = 140), these 15 genes were altered in PC vs normal tissue, metastatic PCs vs primary PCs, and recurrent PCs vs nonrecurrent PCs. Importantly, a 10-gene subsignature SigMuc1NW1 predicts BCR in MSKCC (P = 3.11e-15) and TCGA (P = 3.13e-12); SigMuc1NW1 discriminates BCR at 18.4 m with tAUC as 82.5%. Collectively, our analyses support SigMuc1NW as a novel and robust signature in predicting BCR of PC.
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Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Transcriptoma , Estudios de Cohortes , Minería de Datos , Bases de Datos Genéticas , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Modelos Logísticos , Masculino , Análisis Multivariante , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Prostatectomía/efectos adversos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Factores de RiesgoRESUMEN
Butyrylcholinesterase (BChE) is a plasma enzyme that hydrolyzes ghrelin and bioactive esters, suggesting a role in modulating metabolism. Serum BChE is reduced in cancer patients. In prostate cancer (PC), the down-regulation is associated with disease recurrence. Nonetheless, how BChE is expressed in PC and its impact on PC remain unclear. We report here the biphasic changes of BChE expression in PC. In vitro, BChE expression was decreased in more tumorigenic PC stem-like cells (PCSLCs), DU145, and PC3 cells compared to less tumorigenic non-stem PCs and LNCaP cells. On the other hand, BChE was expressed at a higher level in LNCaP cells than immortalized but non-tumorigenic prostate epithelial BPH-1 cells. In vivo, BChE expression was up-regulated in DU145 xenografts compared to LNCaP xenografts; DU145 cell-derived lung metastases displayed comparable levels of BChE as subcutaneous tumors. Furthermore, LNCaP xenografts produced in castrated mice exhibited a significant increase of BChE expression compared to xenografts generated in intact mice. In patients, BChE expression was down-regulated in PCs (n = 340) compared to prostate tissues (n = 86). In two independent PC populations MSKCC (n = 130) and TCGA Provisional (n = 490), BChE mRNA levels were reduced from World Health Organization grade group 1 (WHOGG 1) PCs to WHOGG 3 PCs, followed by a significant increase in WHOGG 5 PCs. The up-regulation was associated with a reduction in disease-free survival (P = .008). Collectively, we demonstrated for the first time a biphasic alteration of BChE, its down-regulation at early stage of PC and its up-regulation at advanced PC.
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DNA damage response (DDR) coordinates lesion repair and checkpoint activation. DDR is intimately connected with transcription. However, the relationship between DDR and transcription has not been clearly established. We report here RNA-sequencing analyses of MCF7 cells containing double-strand breaks induced by etoposide. While etoposide does not apparently cause global changes in mRNA abundance, it altered some gene expression. At the setting of fold alteration ≥ 2 and false discovery rate (FDR) ≤ 0.001, FDR < 0.05, or p < 0.05, etoposide upregulated 96, 268, or 860 genes and downregulated 41, 133, or 503 genes in MCF7 cells. Among these differentially expressed genes (DEGs), the processes of biogenesis, metabolism, cell motility, signal transduction, and others were affected; the pathways of Ras GTPase activity, RNA binding, cytokine-mediated signaling, kinase regulatory activity, protein binding, and translation were upregulated, and those pathways related to coated vesicle, calmodulin binding, and microtubule-based movement were downregulated. We further identified RABL6, RFTN2, FAS-AS1, and TCEB3CL as new DDR-affected genes in MCF7 and T47D cells. By metabolic labelling using 4-thiouridine, we observed dynamic alterations in the transcription of these genes in etoposide-treated MCF7 and T47D cells. During 0-2 hour etoposide treatment, RABL6 transcription was robustly increased at 0.5 and 1 hour in MCF7 cells and at 2 hours in T47D cells, while FAS-AS1 transcription was dramatically and steadily elevated in both cell lines. Taken together, we demonstrate dynamic alterations in transcription and that these changes affect multiple cellular processes in etoposide-induced DDR.
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This study investigates the in-class and out-of-class cyberloafing activities of students in China, and tests the relationship between those activities and academic performance. A sample of 1,050 undergraduate students at a large University in China reported their in-class (N = 548) and out-of-class (N = 502) cyberloafing activities, which were tested against the students' academic performance. The test results show a negative relationship between in-class cyberloafing and academic performance, but an inverted U-shaped relationship between out-of-class cyberloafing and academic performance. The results support our propositions that cyberloafing is a harmful distraction in the classroom, but can have positive effects when performed in moderation outside the classroom as a means of effort recovery.
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Rendimiento Académico/estadística & datos numéricos , Internet , Medios de Comunicación Sociales , Estudiantes/estadística & datos numéricos , Adulto , China , Estudios Transversales , Humanos , Internet/estadística & datos numéricos , Medios de Comunicación Sociales/estadística & datos numéricos , Factores de Tiempo , Universidades , Adulto JovenRESUMEN
AIM: We explored whether Fluorofenidone reduced interleukin-1ß (IL-1ß) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO). METHODS: Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1ß were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1ß and cleavage IL-1ß were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence. RESULTS: Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1ß. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1ß into IL-1ß in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells. CONCLUSION: Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1ß production in UUO model by interacting with NLRP3 inflammasome.
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Antiinflamatorios/farmacología , Inflamasomas/efectos de los fármacos , Interleucina-1beta/metabolismo , Riñón/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nefritis/prevención & control , Piridonas/farmacología , Obstrucción Ureteral/tratamiento farmacológico , Animales , Proteínas Adaptadoras de Señalización CARD/metabolismo , Caspasa 1/metabolismo , Quimiotaxis de Leucocito/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación hacia Abajo , Fibrosis , Células HEK293 , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-1beta/genética , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Nefritis/inmunología , Nefritis/metabolismo , Nefritis/patología , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Obstrucción Ureteral/inmunología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
The insulated gate bipolar transistor (IGBT) is a kind of excellent performance switching device used widely in power electronic systems. How to estimate the remaining useful life (RUL) of an IGBT to ensure the safety and reliability of the power electronics system is currently a challenging issue in the field of IGBT reliability. The aim of this paper is to develop a prognostic technique for estimating IGBTs' RUL. There is a need for an efficient prognostic algorithm that is able to support in-situ decision-making. In this paper, a novel prediction model with a complete structure based on optimally pruned extreme learning machine (OPELM) and Volterra series is proposed to track the IGBT's degradation trace and estimate its RUL; we refer to this model as Volterra k-nearest neighbor OPELM prediction (VKOPP) model. This model uses the minimum entropy rate method and Volterra series to reconstruct phase space for IGBTs' ageing samples, and a new weight update algorithm, which can effectively reduce the influence of the outliers and noises, is utilized to establish the VKOPP network; then a combination of the k-nearest neighbor method (KNN) and least squares estimation (LSE) method is used to calculate the output weights of OPELM and predict the RUL of the IGBT. The prognostic results show that the proposed approach can predict the RUL of IGBT modules with small error and achieve higher prediction precision and lower time cost than some classic prediction approaches.
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BACKGROUND/AIMS: We evaluated the therapeutic effects of fluorofenidone (AKF-PD), a novel pyridone agent, targeting oxidative stress and fibrosis in obstructive nephropathy. METHODS: AKF-PD was used to treat renal interstitial fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of NOX2 (gp91phox), fibronectin and extracellular signal regulated kinase (ERK) were detected by western blot. A level of Malondialdehyde (MDA), an oxidative stress marker, was measured by ELISA. In addition, ROS and the expressions of NOX2, collagen I (a1), fibronectin and p-ERK were measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial cells (NRK-52E) in culture. RESULTS: In NRK-52E cells, AKF-PD reduced AngII induced expressions of ROS, NOX2, fibronectin, collagen I (a1) and p-ERK. In UUO kidney cortex, AKF-PD attenuated the degree of renal interstitial fibrosis, which was associated with reduced the expressions of collagen I (a1) and fibronectin. Furthermore, AKF-PD downregulated the expressions of NOX2, MDA and p-ERK. CONCLUSION: AKF-PD treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK/MAPK signaling pathway.
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Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/enzimología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Glicoproteínas de Membrana/antagonistas & inhibidores , NADPH Oxidasas/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Piridonas/uso terapéutico , Animales , Fibrosis , Regulación Enzimológica de la Expresión Génica , Enfermedades Renales/patología , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Glicoproteínas de Membrana/biosíntesis , NADPH Oxidasa 2 , NADPH Oxidasas/biosíntesis , Estrés Oxidativo/fisiología , Piridonas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Inflammation has a crucial role in renal interstitial fibrosis, which is the common pathway of chronic kidney diseases. Mefunidone (MFD) is a new compound which could effectively inhibit the proliferation of renal fibroblasts in vitro. However, the overall effect of Mefunidone in renal fibrosis remains unknown. METHODS: Sprague-Dawley rats were randomly divided intro 6 groups: sham operation, unilateral ureteral obstruction (UUO), UUO/Mefunidone (25, 50, 100mg/kg/day) and UUO/PFD (500mg/kg/day). The rats were sacrificed respectively on days 3, 7, and 14 after the operation. Tubulointerstitial injury index, interstitial collagen deposition, expression of fibronectin (FN), α-smooth muscle actin (α-SMA), type I and III collagen and the number of CD3+ and CD68+ cells were determined. The expressions of proinflammatory cytokines, p-ERK, p-IκB, and p-STAT3 were measured in human renal proximal tubular epithelial cells of HK-2 or macrophages. RESULTS: Mefunidone treatment significantly attenuated tubulointerstitial injury, interstitial collagen deposition, expression of FN, α-SMA, type I and III collagen in the obstructive kidneys, which correlated with significantly reduced the number of T cells and macrophages in the obstructive kidneys. Mechanistically, Mefunidone significantly inhibited tumor necrosis factor-α (TNF-α-) or lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. This effect is possibly due to the inhibition of phosphorylation of ERK, IκB, and STAT3. CONCLUSION: Mefunidone treatment attenuated tubulointerstitial fibrosis in a rat model of UUO, at least in part, through inhibition of inflammation.
Asunto(s)
Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/etiología , Piperazinas/uso terapéutico , Piridonas/uso terapéutico , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Animales , Proliferación Celular/efectos de los fármacos , Colágeno/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibronectinas/metabolismo , Fibrosis , Humanos , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Pruebas de Función Renal , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Piridonas/farmacología , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Obstrucción Ureteral/fisiopatologíaRESUMEN
Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.