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Coxsackievirus B3 (CVB3) triggers viral myocarditis, with no effective vaccine yet. This fecal-oral transmitted pathogen has prompted interest in mucosal immunization strategies to impede CVB3 spread. We developed a new attenuated vaccine strain, named CVB3(mu). The potential of CVB3(mu) to stimulate mucosal immune protection remains to be elucidated. This study evaluates the attenuation characteristics of CVB3(mu) via a rapid evolution cellular model and RNA sequencing. Its temperature sensitivity and safety were evaluated through in vitro and in vivo experiments. The mucosal immunity protection of CVB3(mu) was assessed via intranasal immunization in Balb/c mice. The results indicate that CVB3(mu) exhibits temperature sensitivity and forms smaller plaques. It sustains fewer genetic mutations and still possesses certain attenuated traits up to the 25th passage, in comparison to CVB3(WT). Intranasal immunization elicited a significant serum neutralizing antibodies, and a substantial sIgA response in nasal washes. In vivo trials revealed CVB3(mu) protection in adult mice and passive protection in suckling mice against lethal CVB3(WT) challenges. In conclusion, CVB3(mu), a live attenuated intranasal vaccine, provides protection involving humoral and mucosal immunity, making it a promising candidate to control CVB3 spread and infection.
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Administração Intranasal , Anticorpos Neutralizantes , Anticorpos Antivirais , Infecções por Coxsackievirus , Enterovirus Humano B , Imunidade nas Mucosas , Camundongos Endogâmicos BALB C , Vacinas Atenuadas , Vacinas Virais , Animais , Enterovirus Humano B/imunologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/prevenção & controle , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Camundongos , Imunoglobulina A Secretora/imunologia , Humanos , Feminino , Modelos Animais de DoençasRESUMO
BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups. CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. TRIAL REGISTRATION: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.
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Estado Terminal , Apoio Nutricional , China , Estado Terminal/terapia , Humanos , Unidades de Terapia Intensiva , Fatores de TempoRESUMO
During the influenza pandemic or seasonal influenza outbreak, influenza infection can cause acute influenza-associated encephalopathy/encephalitis (IAE), even death. Patients with severe IAE will also have severe neurological sequelae. Neurologic disorders have been demonstrated in the mice treated with peripheral influenza viruses infection, whether neurotropic or non-neurotropic viruses. However, previous studies focused on the acute phase of infection, and rarely paid attention to a longer range of observations. Therefore, the long-term effect of non-neurotropic virus infection on the host is not very clear. In this study, adult mice were infected with influenza virus H1N1/PR8. Then, spontaneous behavior, body weight, expression of cytokines in brain, spatial learning ability and spatial memory ability were observed, until the complete recovery period. The results showed that cytokines in the brain were highly expressed in the convalescent phase (14 day post inoculation, dpi), especially BDNF, IBA1, CX3CL1 and CD200 were still highly expressed in the recovery phase (28 dpi). Otherwise the emotional and spatial memory ability of mice were impacted in the convalescent phase (14 dpi) and the recovery phase (28 dpi). In brief, BALB/c mice infected with non-neurotropic influenza virus H1N1, the weight and motor ability decreased in acute stage. During the recovery period, the body weight and activity ability were completely restored, whereas the emotion disordered, and the ability of spatial learning and memory were impacted in the infected mice. This long-term behavior impact may be the lag injury caused by non-neurotropic influenza infection.
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Vírus da Influenza A Subtipo H1N1/patogenicidade , Memória , Aprendizagem Espacial , Tropismo Viral , Animais , Antígenos CD/metabolismo , Peso Corporal , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocina CX3CL1/metabolismo , Emoções , Masculino , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos/metabolismoRESUMO
ZW10 interactor (Zwint-1) is an important component of the centromere and can recruit the dynamic protein kinase and dynein to promote chromosome movement and regulate the spindle assembly checkpoint (SAC). Zwint-1 activity is tightly regulated during the cell cycle. However, how the stability of Zwint-1 is regulated has not been clarified. Here, we show that the relative levels of Zwint-1 expression gradually decreased with the progression of cell cycling and decline sharply during mitotic exit. Treatment with cycloheximide reduced the levels of Zwint-1 while treatment with MG132 to inhibit endogenous ubiquitin-proteasome elevated the levels of Zwint-1 in HEK293T cells or Hela cells. Such data suggest that Zwint-1 may be degraded by endogenous ubiquitin-proteasome. Furthermore, induction of cell-division cycle protein 20 (Cdc20) overexpression decreased the levels of Zwint-1, which was abrogated by MG132 treatment. In contrast, Cdc20 silencing promoted the accumulation of Zwint-1. in vivo ubiquitination assay revealed that Cdc20 promoted the formation of Zwint-1 and ubiquitin-proteasome conjugates. Cotransfection with Cdc20 and wild-type Zwint-1, but not Zwint-1ΔD-box , reduced the levels of Zwint-1. Immunoprecipitation and western blot analyses showed that Cdc20 interacted with wild-type Zwint-1, but not Zwint-1ΔD-box although both Zwint-1 and Zwint-1ΔD-box overexpression did not induce mitotic arrest. Collectively, our data indicated that Zwint-1 was ubiquitinated by anaphase-promoting complex/cyclosome (APC/C)-Cdc20 in a D-box-dependent manner. Therefore, the APC/C-Cdc20 controls the stability of Zwint-1, ensuring accurate regulation of the spindle assembly during the cell cycling in HEK293T cells.
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Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Proteínas Cdc20/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Proteólise , Ciclossomo-Complexo Promotor de Anáfase/genética , Proteínas Cdc20/genética , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismoRESUMO
Oxymatrine (OMT) is a strong immunosuppressive agent that has been used in the clinic for many years. In the present study, by using plaque inhibition, luciferase reporter plasmids, qRT-PCR, western blotting, and ELISA assays, we have investigated the effect and mechanism of OMT on influenza A virus (IAV) replication and IAV-induced inflammation in vitro and in vivo. The results showed that OMT had excellent anti-IAV activity on eight IAV strains in vitro. OMT could significantly decrease the promoter activity of TLR3, TLR4, TLR7, MyD88, and TRAF6 genes, inhibit IAV-induced activations of Akt, ERK1/2, p38 MAPK, and NF-κB pathways, and suppress the expressions of inflammatory cytokines and MMP-2/-9. Activators of TLR4, p38 MAPK and NF-κB pathways could significantly antagonize the anti-IAV activity of OMT in vitro, including IAV replication and IAV-induced cytopathogenic effect (CPE). Furthermore, OMT could reduce the loss of body weight, significantly increase the survival rate of IAV-infected mice, decrease the lung index, pulmonary inflammation and lung viral titter, and improve pulmonary histopathological changes. In conclusion, OMT possesses anti-IAV and anti-inflammatory activities, the mechanism of action may be linked to its ability to inhibit IAV-induced activations of TLR4, p38 MAPK, and NF-κB pathways.
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Alcaloides/farmacologia , Vírus da Influenza A/efeitos dos fármacos , NF-kappa B/metabolismo , Quinolizinas/farmacologia , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células A549 , Animais , Antivirais/farmacologia , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , Cães , HumanosRESUMO
Lasting activations of toll-like receptors (TLRs), MAPK and NF-κB pathways can support influenza A virus (IAV) infection and promote pneumonia. In this study, we have investigated the effect and mechanism of action of emodin on IAV infection using qRT-PCR, western blotting, ELISA, Nrf2 luciferase reporter, siRNA and plaque inhibition assays. The results showed that emodin could significantly inhibit IAV (ST169, H1N1) replication, reduce IAV-induced expressions of TLR2/3/4/7, MyD88 and TRAF6, decrease IAV-induced phosphorylations of p38/JNK MAPK and nuclear translocation of NF-κB p65. Emodin also activated the Nrf2 pathway, decreased ROS levels, increased GSH levelss and GSH/GSSG ratio, and upregulated the activities of SOD, GR, CAT and GSH-Px after IAV infection. Suppression of Nrf2 via siRNA markedly blocked the inhibitory effects of emodin on IAV-induced activations of TLR4, p38/JNK, and NF-κB pathways and on IAV-induced production of IL-1ß, IL-6 and expression of IAV M2 protein. Emodin also dramatically increased the survival rate of mice, reduced lung edema, pulmonary viral titer and inflammatory cytokines, and improved lung histopathological changes. In conclusion, emodin can inhibit IAV replication and influenza viral pneumonia, at least in part, by activating Nrf2 signaling and inhibiting IAV-induced activations of the TLR4, p38/JNK MAPK and NF-κB pathways.
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Emodina/administração & dosagem , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Pneumonia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/patogenicidade , Influenza Humana/complicações , Influenza Humana/genética , Influenza Humana/virologia , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 2 Relacionado a NF-E2/genética , Pneumonia/etiologia , Pneumonia/patologia , Pneumonia/virologia , RNA Interferente Pequeno/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/genética , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/genética , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
BACKGROUND: Sarcoma is a rare malignant tumor originating of the interstitial or connective tissue with a poor prognosis. Next-generation sequencing technology offers new opportunities for accurate diagnosis and treatment of sarcomas. There is an urgent need for new gene signature to predict prognosis and evaluate treatment outcomes. METHODS: We used transcriptome data from the Cancer Genome Atlas (TCGA) database and single sample gene set enrichment analysis (ssGSEA) to explore the cancer hallmarks most associated with prognosis in sarcoma patients. Then, weighted gene coexpression network analysis, univariate COX regression analysis and random forest algorithm were used to construct prognostic gene characteristics. Finally, the prognostic value of gene markers was validated in the TCGA and Integrated Gene Expression (GEO) (GSE17118) datasets, respectively. RESULTS: MYC targets V1 and V2 are the main cancer hallmarks affecting the overall survival (OS) of sarcoma patients. A six-gene signature including VEGFA, HMGB3, FASN, RCC1, NETO2 and BIRC5 were constructed. Kaplan-Meier analysis suggested that higher risk scores based on the six-gene signature associated with poorer OS (P < 0.001). The receiver Operating characteristic curve showed that the risk score based on the six-gene signature was a good predictor of sarcoma, with an area under the curve (AUC) greater than 0.73. In addition, the prognostic value of the six-gene signature was validated in GSE17118 with an AUC greater than 0.72. CONCLUSION: This six-gene signature is an independent prognostic factor in patients with sarcoma and is expected to be a potential therapeutic target for sarcoma.
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Sarcoma , Humanos , Prognóstico , Sarcoma/genética , Área Sob a Curva , Bases de Dados Factuais , Redes Reguladoras de GenesRESUMO
PURPOSE: Radiation-induced pneumonitis (RIP) seriously limits the application of radiation therapy in the treatment of thoracic tumors, and its etiology and pathogenesis remain elusive. This study aimed to elucidate the role of ubiquitin-specific peptidase 11 (USP11) in the progression of RIP and the associated underlying mechanisms. METHODS AND MATERIALS: Changes in cytokines and infiltrated immune cells were detected by enzyme-linked immunosorbent assays and immunohistochemistry after exposure to 20 Gy x-ray with whole-thorax irradiation. The effects of USP11 expression on endothelial cell proliferation and apoptosis were analyzed by costaining of CD31/Ki67 and CD31/caspase-3 in vivo, and the production of cytokines and reactive oxygen species was confirmed by reverse-transcription polymerase chain reaction and flow cytometry in vitro. Comprehensive proteome and ubiquitinome analyses were used for USP11 substrate screening after radiation. Results were verified by Western blotting and coimmunoprecipitation experiments. Recombinant adeno-associated virus lung vectors expressing OTUD5 were used for localized overexpression of OTUD5 in mouse pulmonary tissue, and immunohistochemistry was conducted to analyze cytokine expression. RESULTS: The progression of RIP was significantly alleviated by reduced expression of proinflammatory cytokines in both Usp11-knockout (Usp11-/-) mice and in mice treated with the USP11 inhibitor mitoxantrone. Likewise, the absence of USP11 resulted in decreased permeability of pulmonary vessels and neutrophils and macrophage infiltration. The proliferation rates of endothelial cells were prominently increased in the Usp11-/- lung, whereas apoptosis in Usp11-/- lungs decreased after irradiation compared with that observed in Usp11+/+ lungs. Conversely, USP11 overexpression increased proinflammatory cytokine expression and reactive oxygen species production in endothelial cells after radiation. Comprehensive proteome and ubiquitinome analyses indicated that USP11 overexpression upregulates the expression of several deubiquitinating enzymes, including USP22, USP33, and OTUD5. We demonstrate that USP11 deubiquitinates OTUD5 and implicates the OTUD5-STING signaling pathway in the progression of the inflammatory response in endothelial cells. CONCLUSIONS: USP11 exacerbates RIP by triggering an inflammatory response in endothelial cells both in vitro and in vivo, and the OTUD5-STING pathway is involved in the USP11-dependent promotion of RIP. This study provides experimental support for the development of precision intervention strategies targeting USP11 to mitigate RIP.
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Células Endoteliais , Pneumonite por Radiação , Transdução de Sinais , Animais , Humanos , Camundongos , Apoptose , Proliferação de Células , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonite por Radiação/metabolismo , Pneumonite por Radiação/patologia , Espécies Reativas de Oxigênio/metabolismo , Tioléster Hidrolases/metabolismo , Tioléster Hidrolases/genéticaRESUMO
Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1fl/fl; Sftpa1-Cre+/- mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1lsl/lsl; Sftpa1-Cre+/- mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.
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Biopterinas , GTP Cicloidrolase , Lesão Pulmonar , Espécies Reativas de Oxigênio , Animais , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/etiologia , GTP Cicloidrolase/metabolismo , GTP Cicloidrolase/genética , Humanos , Tolerância a Radiação/genética , Lactato Desidrogenase 5/metabolismo , Camundongos Knockout , Óxido Nítrico/metabolismo , L-Lactato Desidrogenase/metabolismo , L-Lactato Desidrogenase/genética , Processamento de Proteína Pós-Traducional , Radiação IonizanteRESUMO
The lung has raised significant concerns because of its radiosensitivity. Radiation-induced lung injury (RILI) has a serious impact on the quality of patients' lives and limits the effect of radiotherapy on chest tumors. In clinical practice, effective drug intervention for RILI remains to be fully elucidated. Therefore, an in-depth understanding of the biological characteristics is essential to reveal the mechanisms underlying the complex biological processes and discover novel therapeutic targets in RILI. In this study, Wistar rats received 0, 10, 20 or 35 Gy whole-thorax irradiation (WTI). Lung and plasma samples were collected within 5 days post-irradiation. Then, these samples were processed using liquid chromatography-mass spectrometry (LC-MS). A panel of potential plasma metabolic markers was selected by correlation analysis between the lung tissue and plasma metabolic features, followed by the evaluation of radiation injury levels within 5 days following whole-thorax irradiation (WTI). In addition, the multiple metabolic dysregulations primarily involved amino acids, bile acids and lipid and fatty acid ß-oxidation-related metabolites, implying disturbances in the urea cycle, intestinal flora metabolism and mitochondrial dysfunction. In particular, the accumulation of long-chain acylcarnitines (ACs) was observed as early as 2 d post-WTI by dynamic plasma metabolic data analysis. Our findings indicate that plasma metabolic markers have the potential for RILI assessment. These results reveal metabolic characteristics following WTI and provide new insights into therapeutic interventions for RILI.
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AIMS: Scientists have recently discovered a link between the circulating microbiome and homeostasis, as well as the pathogenesis of a number of metabolic diseases. It has been demonstrated that low-grade chronic inflammation is one of the primary mechanisms that has long been implicated in the risk of cardio-metabolic disease (CMDs) and its progression. Currently, the dysbiosis of circulating bacteria is considered as a key regulator for chronic inflammation in CMDs, which is why we have conducted this systemic review focused on circulating bacterial dysbiosis. METHODS: A systemic review of clinical and research-based studies was conducted via PubMed, Scopus, Medline, and Web of Science. Literature was considered for risk of bias and patterns of intervention effects. A randomized effect model was used to evaluate the dysbiosis of circulating microbiota and clinical outcomes. We conducted a meta-analysis considering the circulating bacteria in both healthy people and people with cardio-metabolic disorders, in reports published mainly from 2008 to 2022, according to the PRISMA guidelines. RESULTS: We searched 627 studies and, after completing the risk of bias and selection, 31 studies comprising of 11,132 human samples were considered. This meta-analysis found that dysbiosis of phyla Proteobacteria, Firmicutes, and Bacteroidetes was associated with metabolic diseases. CONCLUSIONS: In most instances, metabolic diseases are linked to higher diversity and elevated bacterial DNA levels. Bacteroides abundance was higher in healthy people than with metabolic disorders. However, more rigorous studies are required to determine the role of bacterial dysbiosis in cardio-metabolic diseases. Understanding the relationship between dysbiosis and cardio-metabolic diseases, we can use the bacteria as therapeutics for the reversal of dysbiosis and targets for therapeutics use in cardio-metabolic diseases. In the future, circulating bacterial signatures can be used as biomarkers for the early detection of metabolic diseases.
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The biological roles of epithelial-mesenchymal transition (EMT) in the pathogenesis of radiation-induced lung injury (RILI) have been widely demonstrated, but the mechanisms involved have been incompletely elucidated. N6 -methyladenosine (m6 A) modification, the most abundant reversible methylation modification in eukaryotic mRNAs, plays vital roles in multiple biological processes. Whether and how m6 A modification participates in ionizing radiation (IR)-induced EMT and RILI remain unclear. Here, significantly increased m6 A levels upon IR-induced EMT are detected both in vivo and in vitro. Furthermore, upregulated methyltransferase-like 3 (METTL3) expression and downregulated α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5) expression are detected. In addition, blocking METTL3-mediated m6 A modification suppresses IR-induced EMT both in vivo and in vitro. Mechanistically, forkhead box O1 (FOXO1) is identified as a key target of METTL3 by a methylated RNA immunoprecipitation (MeRIP) assay. FOXO1 expression is downregulated by METTL3-mediated mRNA m6 A modification in a YTH-domain family 2 (YTHDF2)-dependent manner, which subsequently activates the AKT and ERK signaling pathways. Overall, the present study shows that IR-responsive METTL3 is involved in IR-induced EMT, probably by activating the AKT and ERK signaling pathways via YTHDF2-dependent FOXO1 m6 A modification, which may be a novel mechanism involved in the occurrence and development of RILI.
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Lesão Pulmonar , Lesões por Radiação , Humanos , Transição Epitelial-Mesenquimal/genética , Proteína Forkhead Box O1 , Metiltransferases/genética , Proteínas Proto-Oncogênicas c-akt , RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Animais , Camundongos , RatosRESUMO
Despite some advances in the study of radiation injuries, effective methods of prevention and treatment of severe acute radiation syndrome or illness (ARS) are still lacking. Therefore, an in-depth understanding of the biological characteristics associated with high dose radiation is essential to reveal the mechanisms underlying the varied biological processes following high dose radiation and the development of novel potent radioprotective agents. In the present study, plasma metabolic characteristics were investigated using hematopoietic stem cell transplantation patients (n = 36) undergoing total body ionizing irradiation (TBI) utilizing gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Plasma was collected pre-irradiation, 3 days after completion of fractionated radiation therapy with a total dose of 12 Gy delivered at a dose rate of 8 cGy min-1. These metabolic disorders involve the dysregulation of the gut microflora, a shift in energy supply from aerobic respiration toward ketogenesis, protein synthesis and metabolism in response to TBI. Furthermore, the panel of four metabolic markers with most potential consisting of PC (O-38:5), urate, ornithine, and GCDCS for radiation injury was chosen by combining multiple methods of data processing that included univariate analysis, partial least squares discriminant analysis (PLS-DA), and multivariable stepwise linear regression analysis. While similar patterns of metabolic alterations were observed in patients of different genders, disease types and ages, specific changes were also found in specific patients following high doses of exposure. These findings provide valuable information for selecting metabolic biomarker panels for radiation injury, clues for radiation pathology and therapeutic interventions involved in high-dose radiation exposure.
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Síndrome Aguda da Radiação , Irradiação Corporal Total , Humanos , Masculino , Feminino , Irradiação Corporal Total/efeitos adversos , Irradiação Corporal Total/métodos , Metabolômica , Síndrome Aguda da Radiação/etiologia , Síndrome Aguda da Radiação/patologia , Espectrometria de Massas , Cromatografia Gasosa-Espectrometria de MassasRESUMO
The innovative mechanism of college students' employment security is a series of security measures implemented by the state and society to solve the mismatch between the scale growth of college graduates and the jobs provided by the society. In order to promote the development of emerging Internet of things technologies, users can find interesting and valuable information from a large number of data sets and use this information to meet the needs of users. This article mainly studies the historical development trend and discrete dynamic modeling and analysis technology of college students' innovative employment security mechanism under the environment of Internet of things. Using two different modeling methods of Bayesian network and BP neural network, this article makes discrete dynamic modeling on the influencing factors and employment security mechanism of college students' employment, so as to improve the college biological network innovation employment security mechanism and better help college students' employment.
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Internet das Coisas , Teorema de Bayes , Emprego , Humanos , Internet , Estudantes , UniversidadesRESUMO
Currently, the aetiology and pathogenesis of idiopathic pulmonary fibrosis (IPF) are still largely unclear. Moreover, patients with IPF exhibit a considerable difference in clinical presentation, treatment, and prognosis. Optimal biomarkers or models for IPF prognosis are lacking. Therefore, this study quantified the levels of various hallmarks using a single-sample gene set enrichment analysis algorithm. The hazard ration was calculated using Univariate Cox regression analysis based on the transcriptomic profile of bronchoalveolar lavage cells and clinical survival information. Afterwards, weighted Gene Co-expression Network Analysis was performed to construct a network between gene expression, inflammation response, and hypoxia. Subsequently, univariate Cox, random forest, and multivariate Cox regressions were applied to develop a robust inflammation and hypoxia-related gene signature for predicting clinical outcomes in patients with IPF. Furthermore, a nomogram was constructed to calculate risk assessment. The inflammation response and hypoxia were identified as latent risk factors for patients with IPF. Five genes, including HS3ST1, WFDC2, SPP1, TFPI, and CDC42EP2, were identified that formed the inflammation-hypoxia-related gene signature. Kaplan-Meier plotter showed that the patients with high-risk scores had a worse prognosis than those with low-risk scores in training and validation cohorts. The time-dependent concordance index and the receiver operating characteristic analysis revealed that the risk model could accurately predict the clinical outcome of patients with IPF. Therefore, this study contributes to elucidating the role of inflammation and hypoxia in IPF, which can aid in assessing individual prognosis and personalised treatment decisions.
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Fibrose Pulmonar Idiopática , Humanos , Hipóxia/genética , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Inflamação/genética , Prognóstico , TranscriptomaRESUMO
Background: The spliceosome plays an important role in mRNA alternative splicing and is aberrantly expressed in several tumors. However, the potential roles of spliceosome-related genes in the progression of hepatocellular carcinoma (HCC) remain poorly understood. Materials and Methods: Patient data were acquired from public databases. Expression differences and survival analyses were used to assess the importance of spliceosome-related genes in HCC prognosis. To explore the potential regulatory mechanisms of these genes, a protein-protein interaction network was constructed and screened using univariate and multivariate Cox regression and random forest analyses. This was used to create a five-gene prognostic model. The prognostic value and predictive power of the five-gene signature were assessed using the Kaplan-Meier and time-dependent receiver operating characteristic analyses in the training set. These results were further validated in an independent external set. To facilitate clinical application, a nomogram was prepared to predict the overall survival of HCC patients. The relative expression of five genes was detected using real-time quantitative polymerase chain reaction. Results: The analysis revealed that LSM1-7, SNRPB, SNRPD1-3, SNRPE, SNRPF, SNRPG, and SNRPN could be used as prognostic biomarkers in HCC patients. Moreover, the five-gene risk model could clearly distinguish between the high-and low-risk groups. Furthermore, the risk model was associated with the tumor mutation burden, immune cell infiltration of CD8+ T cells, natural killer T cells, M2 macrophages, and immune checkpoint inhibitors, which also demonstrated the predictive efficacy of this risk model in HCC immunotherapy. Conclusion: Spliceosome-related genes and the five-gene signature could serve as novel prognostic biomarkers for HCC patients, aiding clinical patient monitoring and follow-up.
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Ferroptosis exerts a pivotal role in the formation and dissemination processes of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and the link between ferroptosis and immune responses have remained elusive. Based on ferroptosis-related genes (FRGs) and HCC patients from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) cohorts, we comprehensively explored the heterogeneous ferroptosis subtypes. The genetic alterations, consensus clustering and survival analysis, immune infiltration, pathway enrichment analysis, integrated signature development, and nomogram building were further investigated. Kaplan-Meier plotter confirmed statistically differential probabilities of survival among the three subclusters. Immune infiltration analysis showed there were clear differences among the types of immune cell infiltration, the expression of PD-L1, and the distribution of TP53 mutations among the three clusters. Univariate Cox regression analysis, random survival forest, and multivariate Cox analysis were used to identify the prognostic integrated signature, including MED8, PIGU, PPM1G, RAN, and SNRPB. Kaplan-Meier analysis and time-dependent receiver operating characteristic (ROC) curves revealed the satisfactory predictive potential of the five-gene model. Subsequently, a nomogram was established, which combined the signature with clinical factors. The nomogram including the ferroptosis-based signature was conducted and showed some clinical net benefits. These results facilitated an understanding of ferroptosis and immune responses for HCC.
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Blood microorganisms were once thought to indicate infection. Blood in healthy people appears to be devoid of growing bacteria; nonetheless, intracellular dormant forms of bacteria have been reported previously. With breakthroughs in sequencing and bioinformatics, the presence of bacterial DNA in healthy human blood initiated the controversy of human blood microbiota (HBM). Recently, bacteria-specific DNA and culturable bacteria were found in healthy human blood. Researchers wanted to study the phenomena of a "healthy blood microbiota" by providing a thorough description of bacterially produced nucleic acids using many complementing molecular and traditional microbiological approaches. Because blood is a relatively limited and particular environment, culturability and plate count issues can be overcome using enhanced cultured procedures. However, more evidence is required to confirm that healthy human blood contains normal microbiota. Cavities, mouth and intestinal microbiota, trauma, surgery, and animal/insect bites can introduce bacteria into human blood. All these factors strengthen the concept of transient blood bacteria too. The presence of blood bacteria may be caused by temporary immunological clearance and absorption by dendritic or M cells. This review provides an extensive and comprehensive analysis that suggests that healthy blood bacteria may not be typical microbiota but transient circulatory microorganisms. In this study, we look at how contaminants (Escherichia, Shigella, Pseudomonads, etc.) from the skin, laboratory environments, and reagents can affect the interpretation of blood-derived microbial information and the relationship between the circulating bacteria and non-communicable diseases. Circulating transient bacteria may play a role in the pathogenesis of non-infectious diseases such as diabetes and CVD. Contamination-free hematological studies can aid in understanding the disease mechanisms, therapy, and biomarkers.
Assuntos
Microbioma Gastrointestinal , Doenças não Transmissíveis , Animais , Bactérias/genética , DNA Bacteriano/genética , Disbiose/microbiologia , Humanos , Boca/patologiaRESUMO
Partition coefficients are important parameters for measuring the concentration of chemicals by passive sampling devices. Considering the wide application of the polyurethane foam (PUF) in passive air sampling, an attempt for developing several quantitative structure-property relationship (QSPR) models was made in this work, to predict PUF-air partition coefficients (KPUF-air) using linear (multiple linear regression, MLR) and non-linear (artificial neural network, ANN and support vector machine, SVM) methods by machine learning. All of the developed models were performed on a dataset of 170 compounds comprising 9 distinct classes. A series of statistical parameters and validation results showed that models had good prediction ability, robustness and goodness-of-fit. Furthermore, the underlying mechanisms of molecular descriptors emphasized that ionization potential, molecular bond, hydrophilicity, size of molecule and valence electron number had dominating influence on the adsorption process of chemicals. Overall, the obtained models were all established on the extensive applicability domains, and thus can be used as effective tools to predict the KPUF-air of new organic compounds or those have not been synthesized yet which, in turn, could help researchers better understand the mechanistic basis of adsorption behavior of PUF.