RESUMO
Background & Aims: Regenerating gene family member 4 (REG4) is a novel marker for enteroendocrine cells and is selectively expressed in specialised enteroendocrine cells of the small intestine. However, the exact roles of REG4 are largely unknown. In this study we investigate the effects of REG4 on the development of dietary fat-dependent liver steatosis and the mechanisms involved. Methods: Mice with intestinal-specific Reg4 deficiency (Reg4 ΔIEC ) and Reg4-floxed alleles (Reg4 fl/fl ) were generated to investigate the effects of Reg4 on diet-induced obesity and liver steatosis. Serum levels of REG4 were also measured in children with obesity using ELISA. Results: Reg4 ΔIEC mice fed a high-fat diet demonstrated significantly increased intestinal fat absorption and were prone to obesity and hepatic steatosis. Importantly, Reg4 ΔIEC mice exhibit enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of the intestinal fat transporters, as well as enzymes involved in triglyceride synthesis and packaging at the proximal small intestine. Moreover, REG4 administration reduced fat absorption, and decreased the expression of intestinal fat absorption-related proteins in cultured intestinal cells possibly via the CaMKK2-AMPK pathway. Serum REG4 levels were markedly lower in children with obesity with advanced liver steatosis (p <0.05). Serum REG4 levels were inversely correlated with levels of liver enzymes, homeostasis model assessment of insulin resistance, low-density lipoprotein cholesterol, and triglycerides. Conclusions: Our findings directly link Reg4 deficiency with increased fat absorption and obesity-related liver steatosis, and suggest that REG4 may provide a potential target for prevention and treatment of liver steatosis in children. Impact and Implications: Hepatic steatosis is a key histological feature of non-alcoholic fatty liver disease, which is the leading chronic liver disease in children leading to the development of metabolic diseases; however, little is known about mechanisms induced by dietary fat. Intestinal REG4 acts as a novel enteroendocrine hormone reducing high-fat-diet-induced liver steatosis with decreasing intestinal fat absorption. REG4 may be a novel target for treatment of paediatric liver steatosis from the perspective of crosstalk between intestine and liver.
RESUMO
Background: Hypertension is one of the main causes of cardiovascular death. Inflammation was considered influential factors of cardiovascular (CVD) death in patients with hypertension. Advanced lung cancer inflammation index (ALI) is an index to assess inflammation, few studies have investigated the relationship between advanced lung cancer inflammation index and cardiovascular death in hypertensive patients. Objective: The aim of this study was to investigate the association between advanced lung cancer inflammation index and long-term cardiovascular death in hypertensive patients. Method: Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 with mortality follow-up through 31 December 2019 were analyzed. Advanced lung cancer inflammation index was calculated as BMI (kg/ã¡) × serum albumin level (g/dL)/neutrophil to lymphocyte ratio (NLR). A total of 20,517 participants were evaluated. Patients were divided into three groups based on tertiles of advanced lung cancer inflammation index as follows: T1 (n = 6,839), T2 (n = 6,839), and T3 (n = 6,839) groups. The relationship between advanced lung cancer inflammation index and long-term cardiovascular death was assessed by survival curves and Cox regression analysis based on the NHANES recommended weights. Results: The median advanced lung cancer inflammation index value in this study was 61.9 [44.4, 84.6]. After full adjustment, the T2 group (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.50-0.69; p < 0.001) and T3 group (HR: 0.48, 95% CI: 0.39-0.58; p < 0.001) were found to have a significantly lower risk of cardiovascular death compared to the T1 group. Conclusion: High levels of advanced lung cancer inflammation index were associated with reduced risk of cardiovascular death in hypertensive patients.
RESUMO
Background: Previous studies have shown that aldolase B (ALDOB) might play controversial roles in multiple types of cancer, which could act as a cancer-promoting factor or a cancer-inhibiting factor depending on the subtype of the cancer. However, the role of ALDOB in clear cell renal cell carcinoma (ccRCC) patients has not been clearly elucidated. Therefore, this study aimed to comprehensively explore the expression level, prognostic value, functional enrichment, immune infiltration, and N6-methyladenosine (m6A) modification of ALDOB in ccRCC patients. Methods: A total of 1,070 ccRCC tissues and 409 normal tissues from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database, and the ArrayExpress database were enrolled to evaluate the expression level and prognostic value of ALDOB in ccRCC. The Kaplan-Meier survival curves and the Log-Rank test were performed to assess the prognostic value. The univariate and multivariate Cox regression analysis were used to identify the independent prognostic predictors in ccRCC patients. In addition, R version 4.2.0 with its suitable packages were used to perform the functional enrichment analysis, immune infiltration analysis, and m6A methylation analysis. Statistical significance was set at the P value <0.05. Results: The expression level of ALDOB was significantly down-regulated in ccRCC compared to normal tissue, and the ALDOB expression level was noticeably correlated with T stage, M stage, and histologic grade of patients with ccRCC. The survival analysis revealed that ALODB was the independent predictor of overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) of ccRCC patients. In addition, the functional enrichment analysis showed that ALDOB and its related genes were mainly involved in the metabolism and metabolic pathways of multiple substances, including glycolysis, gluconeogenesis, and fatty acid degradation. Finally, the immune infiltration analysis and the m6A methylation analysis suggested that ALDOB was closely correlated with the infiltration abundance of immune cells and stromal cells in the tumor microenvironment and several types of m6A regulators in ccRCC. Conclusions: As a potential prognostic biomarker for patients with ccRCC, downregulation of ALDOB was closely associated with the clinicopathological features, poor prognosis, immune infiltration, and m6A modification in ccRCC patients.
RESUMO
Background: Cuproptosis has been reported as a new form of cell death. However, its potential mechanism of action in clear cell renal cell carcinoma (ccRCC) remains unclear. Therefore, we systematically clarified the role of cuproptosis in ccRCC and aimed to develop a novel signature of cuproptosis-related long noncoding RNAs (lncRNA) (CRLs) to assess the clinical characteristics of ccRCC patients. Methods: Gene expression, copy number variation, gene mutation, and clinical data for ccRCC were obtained from The Cancer Genome Atlas (TCGA). CRL signature was constructed with least absolute shrinkage and selection operator (LASSO) regression analysis. The clinical diagnostic value of the signature was verified by clinical data. The prognostic value of the signature was detected by Kaplan-Meier analysis and receiver operating characteristic (ROC) curve. The prognostic value of the nomogram was evaluated by calibration curves, ROC curves, and decision curve analysis (DCA). Gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA) and cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm were used to analyze the differences of immune function and immune cell infiltration among different risk groups. Prediction of clinical treatment differences in populations with different risks and susceptibilities was completed with R package (The R Foundation of Statistical Computing). Verification of key lncRNA expression was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The cuproptosis-related genes were extensively dysregulated in ccRCC. A total of 153 differentially expressed prognostic CRLs were identified in ccRCC. Furthermore, a 5-lncRNA signature (AC015912.3, AC026401.3, AC103706.1, AC134312.5, and EMX2OS) were obtained that showed good performance in the diagnosis and prognosis of ccRCC. The nomogram could more accurately predict overall survival (OS). Immune functions such as T-cell and B-cell receptor signaling pathways showed differences between different risk groups. Clinical treatment value analysis showed that the signature may be able to effectively guide immunotherapy and target therapy. In addition, qRT-PCR results showed significant differences in the expression of key lncRNAs in ccRCC. Conclusions: Cuproptosis plays an important role in the progression of ccRCC. The 5-CRL signature can guide the prediction of clinical characteristics and tumor immune microenvironment of ccRCC patients.
RESUMO
Purpose: Pancreatic adenocarcinoma (PAAD) presents an extremely high morbidity and mortality rate. Broccoli has excellent anti-cancer properties. However, the dosage and serious side effects still limit the application of broccoli and its derivatives for cancer therapy. Recently, extracellular vesicles (EVs) derived from plants are emerging as novel therapeutic agents. Thus, we conducted this study to determine the effectiveness of EVs isolated from Se-riched broccoli (Se-BDEVs) and conventional broccoli (cBDEVs) for the treatment of PAAD. Methods: In this study, we first isolated Se-BDEVs and cBDEVs by a differential centrifugation method, and characterized them by using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Then, miRNA-seq was combined with target genes prediction, and functional enrichment analysis to reveal the potential function of Se-BDEVs and cBDEVs. Finally, the functional verification was conducted in PANC-1 cells. Results: Se-BDEVs and cBDEVs exhibited similar characteristics in size and morphology. Subsequent miRNA-seq revealed the expression of miRNAs in Se-BDEVs and cBDEVs. Using a combination of miRNA target prediction and KEGG functional analysis, we found miRNAs in Se-BDEVs and cBDEVs may play an important role in treating pancreatic cancer. Indeed, our in vitro study showed that Se-BDEVs had greater anti-PAAD potency than cBDEVs due to increased bna-miR167a_R-2 (miR167a) expression. Transfection with miR167a mimics significantly induced apoptosis of PANC-1 cells. Mechanistically, further bioinformatics analysis showed that IRS1, which is involved in the PI3K-AKT pathway, is the key target gene of miR167a. Conclusion: This study highlights the role of miR167a transported by Se-BDEVs which could be a new tool for counteracting tumorigenesis.
Assuntos
Adenocarcinoma , Brassica , Vesículas Extracelulares , MicroRNAs , Neoplasias Pancreáticas , Selênio , Humanos , Brassica/genética , Brassica/metabolismo , Selênio/uso terapêutico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Biofortificação , Fosfatidilinositol 3-Quinases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Apoptose , Proteínas Substratos do Receptor de Insulina/metabolismoRESUMO
BACKGROUND: The congenital disorder of glycosylation associated with ALG1 (ALG1-CDG) is a rare autosomal recessive disease. Due to the deficiency of ß1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi-organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype-phenotype correlation. METHOD: Clinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants. RESULTS: The proband was a 13-month-old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less-conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations. CONCLUSIONS: The case reported herein adds to the mutations identified in ALG1-CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.
RESUMO
Importance: Although numerous prognostic factors have been found for patients after lung transplantation (LTx) over the years, an accurate prognostic tool for LTx recipients remains unavailable. Objective: To develop and validate a prognostic model for predicting overall survival in patients after LTx using random survival forests (RSF), a machine learning algorithm. Design, Setting, and Participants: This retrospective prognostic study included patients who underwent LTx between January 2017 and December 2020. The LTx recipients were randomly assigned to training and test sets in accordance with a ratio of 7:3. Feature selection was performed using variable importance with bootstrapping resampling. The prognostic model was fitted using the RSF algorithm, and a Cox regression model was set as a benchmark. The integrated area under the curve (iAUC) and integrated Brier score (iBS) were applied to assess model performance in the test set. Data were analyzed from January 2017 to December 2019. Main Outcomes And Measures: Overall survival in patients after LTx. Results: A total of 504 patients were eligible for this study, consisting of 353 patients in the training set (mean [SD] age, 55.03 [12.78] years; 235 [66.6%] male patients) and 151 patients in the test set (mean [SD] age, 56.79 [10.95] years; 99 [65.6%] male patients). According to the variable importance of each factor, 16 were selected for the final RSF model, and postoperative extracorporeal membrane oxygenation time was identified as the most valuable factor. The RSF model had excellent performance with an iAUC of 0.879 (95% CI, 0.832-0.921) and an iBS of 0.130 (95% CI, 0.106-0.154). The Cox regression model fitted by the same modeling factors to the RSF model was significantly inferior to the RSF model with an iAUC of 0.658 (95% CI, 0.572-0.747; P < .001) and an iBS of 0.205 (95% CI, 0.176-0.233; P < .001). According to the RSF model predictions, the patients after LTx were stratified into 2 prognostic groups displaying significant difference, with mean overall survival of 52.91 months (95% CI, 48.51-57.32) and 14.83 months (95% CI, 9.44-20.22; log-rank P < .001), respectively. Conclusions and relevance: In this prognostic study, the findings first demonstrated that RSF could provide more accurate overall survival prediction and remarkable prognostic stratification than the Cox regression model for patients after LTx.
Assuntos
Síndrome do Intestino Irritável , Transplante de Pulmão , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Prognóstico , Estudos Retrospectivos , Aprendizado de MáquinaRESUMO
Acetic acid and furfural (AF) are two major inhibitors of microorganisms during lignocellulosic ethanol production. In our previous study, we successfully engineered Zymomonas mobilis 532 (ZM532) strain by genome shuffling, but the molecular mechanisms of tolerance to inhibitors were still unknown. Therefore, this study investigated the responses of ZM532 and its wild-type Z. mobilis (ZM4) to AF using multi-omics approaches (transcriptomics, genomics, and label free quantitative proteomics). Based on RNA-Seq data, two differentially expressed genes, ZMO_RS02740 (up-regulated) and ZMO_RS06525 (down-regulated) were knocked out and over-expressed through CRISPR-Cas technology to investigate their roles in AF tolerance. Overall, we identified 1865 and 14 novel DEGs in ZM532 and wild-type ZM4. In contrast, 1532 proteins were identified in ZM532 and wild-type ZM4. Among these, we found 96 important genes in ZM532 involving acid resistance mechanisms and survival rates against stressors. Furthermore, our knockout results demonstrated that growth activity and glucose consumption of mutant strains ZM532∆ZMO_RS02740 and ZM4∆ZMO_RS02740 decreased with increased fermentation time from 42 to 55 h and ethanol production up to 58% in ZM532 than that in ZM532∆ZMO_RS02740. Hence, these findings suggest ZMO_RS02740 as a protective strategy for ZM ethanol production under stressful conditions.
Assuntos
Ácido Acético , Zymomonas , Ácido Acético/metabolismo , Zymomonas/genética , Furaldeído/metabolismo , Embaralhamento de DNA , Fermentação , Etanol/metabolismoRESUMO
BACKGROUND: Understanding the ecological and environmental functions of phototrophic biofilms in the biological crust is crucial for improving metal(loid) (e.g. Cd, As) bioremediation in mining ecosystems. In this study, in combination with metal(loid) monitoring and metagenomic analysis, we systematically evaluated the effect of biofilm in a novel biological aqua crust (biogenic aqua crust-BAC) on in situ metal(loid) bioremediation of a representative Pb/Zn tailing pond. RESULTS: We observed strong accumulation of potentially bioavailable metal(loid)s and visible phototrophic biofilms in the BAC. Furthermore, dominating taxa Leptolyngbyaceae (10.2-10.4%, Cyanobacteria) and Cytophagales (12.3-22.1%, Bacteroidota) were enriched in biofilm. Along with predominant heterotrophs (e.g. Cytophagales sp.) as well as diazotrophs (e.g. Hyphomonadaceae sp.), autotrophs/diazotrophs (e.g. Leptolyngbyaceae sp.) in phototrophic biofilm enriched the genes encoding extracellular peptidase (e.g. family S9, S1), CAZymes (e.g. CBM50, GT2) and biofilm formation (e.g. OmpR, CRP and LuxS), thus enhancing the capacity of nutrient accumulation and metal(loid) bioremediation in BAC system. CONCLUSIONS: Our study demonstrated that a phototrophic/diazotrophic biofilm constitutes the structured communities containing specific autotrophs (e.g. Leptolyngbyaceae sp.) and heterotrophs (e.g. Cytophagales sp.), which effectively control metal(loid) and nutrient input using solar energy in aquatic environments. Elucidation of the mechanisms of biofilm formation coupled with metal(loid) immobilization in BAC expands the fundamental understanding of the geochemical fate of metal(loid)s, which may be harnessed to enhance in situ metal(loid) bioremediation in the aquatic ecosystem of the mining area. Video Abstract.
Assuntos
Ecossistema , Monitoramento Ambiental , Biodegradação Ambiental , BiofilmesRESUMO
The first total synthesis of aspidostomide G using a brominated tryptamine is described. The synthetic route features several notable aspects: (a) the starting material, compound 13, contains a built-in hydroxy group and was transformed to the Sonogashira reaction precursor; (b) the construction of the indole ring was achieved through a transition-metal catalyzed synthesis and a 5-endo-dig cyclization. The desired indole 9 was synthesized in only 7 steps with an overall yield of 54% and required only three columns; (c) a late C2-bromination was achieved by using the 4-acetoxyindole analogue 14c.
RESUMO
Human cytomegalovirus (HCMV) infection is globally distributed, and the liver is one of the major targeting organs. So far, the mechanisms for cell and organ damage have not fully been elucidated and the treatments for the infection are mainly at symptoms. IL-37 has shown a protective role in certain inflammatory diseases. In the present study, potential protective effect of exogenous IL-37 on murine cytomegalovirus- (MCMV-) infected hepatitis was evaluated through analyses of serum transaminases, the liver histopathology and cytokine expression, and functional state of dendritic cells (DCs) and regulatory T cells (Tregs). These analyses showed a significant decrease in serum transaminase levels and a lower Ishak histopathologic score at the early stage of MCMV-infected mice with exogenous IL-37 pretreatment. The frequencies of MHC-â ¡, CD40, CD80, and CD86 positive DCs in the liver and spleen were decreased significantly at 7 days postinfection (dpi) in MCMV-infected mice with IL-37 pretreatment when compared with those without the pretreatment, while the total number of DCs in the liver was reduced in IL-37-pretreated mice. The induction of Tregs in the spleen was enhanced at dpi 3 with IL-37 pretreatment in MCMV-infected mice. The mRNA expression levels of cytokines in the liver were decreased significantly (IL-1ß, IL-6, IL-10, IL-4) or to some extent (TGF-ß and TNF-α). The present study suggested that exogenous IL-37 can alleviate MCMV-infected hepatitis, likely through reduced DCs and induced Tregs with a weaker cytokine storm, demonstrating its potential value in clinical management for HCMV-infected hepatitis.
Assuntos
Infecções por Citomegalovirus , Hepatite A , Hepatite , Infecções por Herpesviridae , Muromegalovirus , Humanos , Animais , Camundongos , Muromegalovirus/metabolismo , Linfócitos T Reguladores/metabolismo , Citocinas/metabolismo , Infecções por Herpesviridae/tratamento farmacológico , Células Dendríticas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos BALB CRESUMO
RATIONALE: This study explored the safety and feasibility of 3D laparoscopy and intraoperative ultrasound techniques, which made minimally invasive pancreatic surgery more precise and detailed. PATIENT CONCERN: Case 1 was a 51-year-old man with a primary complaint of pancreatic tumor. Case 2 was a 60-year-old woman with complaints of tinnitus for 1 week. Case 3 was a 21-year-old woman with complaints of epigastric pain and abdominal distension for 1 day. DIAGNOSIS: Case 1 and Case 2 were diagnosed with pancreatic neuroendocrine tumors, and Case 3 was diagnosed with an infected solid pseudopapillary tumor of the pancreas. INTERVENTIONS: All 3 patients underwent laparoscopic pancreatic surgery in our hospital. OUTCOMES: All cases received the same perioperative management and no localized stenosis or dilatation of the pancreatic duct was found during follow-up. LESSONS: With the development of minimally invasive surgery and the application of 3D laparoscopy and intraoperative ultrasound technology, pancreatic tumors that are tightly adhered to the main pancreatic duct can successfully be removed using 3D laparoscopic operation.
Assuntos
Laparoscopia , Neoplasias Pancreáticas , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Adulto , Pancreatectomia/métodos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Laparoscopia/métodos , Ductos Pancreáticos/diagnóstico por imagem , Ductos Pancreáticos/cirurgia , Ductos Pancreáticos/patologiaRESUMO
Coxsackievirus belongs to the Picornaviridae family and is one of the major pathogens that cause hand, foot and mouth disease (HFMD) in infants and children with potential serious complications and even deaths. The pathogenesis of this virus is not fully elucidated and no vaccine or antiviral drug has been approved. In this study, a full-length infectious cDNA clone of coxsackievirus B5 virus was assembled and the recombinant virus displayed similar growth kinetics and ability to cause cytopathic effects as the parental virus. Luciferase reporter was then incorporated to generate both full-length and subgenomic replicon (SGR) reporter viruses. The full-length reporter virus is suitable for high-throughput antiviral screening, while the SGR is a useful tool to study viral-host interactions. More importantly, the full-length reporter virus has also been shown to infect the suckling mouse model and the reporter gene could be detected using an in vivo imaging system, thus providing a powerful tool to track viruses in vivo. In summary, we have generated coxsackievirus B5 reporter viruses and provided unique tools for studying virus-host interactions in vitro and in vivo as well as for high-throughput screenings (HTS) to identify novel antivirals.
RESUMO
Out-of-plane (OP) exciton-based emitters in two-dimensional semiconductor materials are attractive candidates for novel photonic applications, such as radially polarized sources, integrated photonic chips, and quantum communications. However, their low quantum efficiency resulting from forbidden transitions limits their practicality. In this work, we achieve a giant enhancement of up to 34000 for OP exciton emission in indium selenide (InSe) via a designed Ag nanocube-over-Au film plasmonic nanocavity. The large photoluminescence enhancement factor (PLEF) is attributed to the induced OP local electric field (Ez) within the nanocavity, which facilitates effective OP exciton-plasmon interaction and subsequent tremendous enhancement. Moreover, the nanoantenna effect resulting from the effective interaction improves the directivity of spontaneous radiation. Our results not only reveal an effective photoluminescence enhancement approach for OP excitons but also present an avenue for designing on-chip photonic devices with an OP dipole orientation.
RESUMO
Background: We aimed to develop and validate a prognostic model for predicting malignant brain oedema in patients with acute ischaemic stroke in a real-world setting of practice. Methods: A prospective multicentre study enrolled adult patients with acute ischaemic stroke with brain CT < 24 h of onset of symptoms admitted to nine tertiary-level hospitals in China between September 2017 and December 2019. Malignant brain oedema was defined as any patient who had decompressive craniectomy, discharge in coma, or in-hospital death attributed to symptomatic brain swelling. The derivation cohort was a consecutive cohort of patients from one centre and the validation cohort was non-consecutive patients from the other centres. Multivariable logistic regression was used to define independent predictors from baseline clinical characteristics, imaging features, complications, and management. A web-based nomogram and a risk score were developed based on the final model. Model performance was assessed for discrimination and calibration in both derivation and validation cohorts. The study is registered, NCT03222024. Findings: Based on the derivation cohort (n = 1627), the model was developed with seven variables including large infarct (adjusted odds ratio [OR] 40.90, 95% CI 20.20-82.80), National Institutes of Health Stroke Scale (NIHSS) score (OR 1.09, 1.06-1.12), thrombolysis (OR 2.11, 1.18-3.78), endovascular treatment (OR 2.87, 1.47-5.59), pneumonia (OR 2.47, 1.53-3.97), brain atrophy (OR 0.57, 0.37-0.86), and recanalisation (OR 0.36, 0.17-0.75). The classification threshold of a predicted probability ≥0.14 showed good discrimination and calibration in both derivation cohort (area under the receiver-operating curve [AUC] 0.90, 0.87-0.92; sensitivity 0.95, 0.92-0.98) and validation cohort (n = 556, AUC 0.88, 0.82-0.95; sensitivity 0.84, 0.73-0.95). The risk score based on this model had a total point that ranged from -1 to 20, with an optimal score of ≥10 showing good discrimination and calibration in both derivation (AUC 0.89, 0.87-0.92; sensitivity 0.95, 0.92-0.98) and validation (AUC 0.88, 0.82-0.95; sensitivity 0.84, 0.73-0.95) cohorts. Interpretation: The INTEP-AR model (i.e. large Infarct, NIHSS score, Thrombolysis, Endovascular treatment, Pneumonia, brain Atrophy, and Recanalisation) incorporating multiple clinical and radiological characteristics has shown good prognostic value for predicting malignant brain oedema after acute ischaemic stroke. Funding: National Natural Science Foundation of China; Science and Technology Department of Sichuan Province; West China Hospital.
RESUMO
Biodiversity is vital for ecosystem functions and services, and many studies have reported positive, negative, or neutral biodiversity-ecosystem functioning (BEF) relationships in plant and animal systems. However, if the BEF relationship exists and how it evolves remains elusive in microbial systems. Here, we selected 12 Shewanella denitrifiers to construct synthetic denitrifying communities (SDCs) with a richness gradient spanning 1 to 12 species, which were subjected to approximately 180 days (with 60 transfers) of experimental evolution with generational changes in community functions continuously tracked. A significant positive correlation was observed between community richness and functions, represented by productivity (biomass) and denitrification rate, however, such a positive correlation was transient, only significant in earlier days (0 to 60) during the evolution experiment (180 days). Also, we found that community functions generally increased throughout the evolution experiment. Furthermore, microbial community functions with lower richness exhibited greater increases than those with higher richness. Biodiversity effect analysis revealed positive BEF relationships largely attributable to complementary effects, which were more pronounced in communities with lower richness than those with higher richness. This study is one of the first studies that advances our understanding of BEF relationships and their evolutionary mechanisms in microbial systems, highlighting the crucial role of evolution in predicting the BEF relationship in microbial systems. IMPORTANCE Despite the consensus that biodiversity supports ecosystem functioning, not all experimental models of macro-organisms support this notion with positive, negative, or neutral biodiversity-ecosystem functioning (BEF) relationships reported. The fast-growing, metabolically versatile, and easy manipulation nature of microbial communities allows us to explore well the BEF relationship and further interrogate if the BEF relationship remains constant during long-term community evolution. Here, we constructed multiple synthetic denitrifying communities (SDCs) by randomly selecting species from a candidate pool of 12 Shewanella denitrifiers. These SDCs differ in species richness, spanning 1 to 12 species, and were monitored continuously for community functional shifts during approximately 180-day parallel cultivation. We demonstrated that the BEF relationship was dynamic with initially (day 0 to 60) greater productivity and denitrification among SDCs of higher richness. However, such pattern was reversed thereafter with greater productivity and denitrification increments in lower-richness SDCs, likely due to a greater accumulation of beneficial mutations during the experimental evolution.
RESUMO
Enterovirus consists of a variety of viruses that could cause a wide range of illness in human. The pathogenesis of these viruses remains incompletely understood and no specific treatment is available. Better methods to study enterovirus infection in live cells will help us better understand the pathogenesis of these viruses and might contribute to antiviral development. Here in this study, we developed fluorescent cell-based reporter systems that allow sensitive distinction of individual cells infected with enterovirus 71 (EV71). More importantly, these systems could be easily used for live-cell imaging by monitoring viral-induced fluorescence translocation after EV71 infection. We further demonstrated that these reporter systems could be used to study other enterovirus-mediated MAVS cleavage and they are sensitive for antiviral activity testing. Therefore, integration of these reporters with modern image-based analysis has the potential to generate new insights into enterovirus infection and facilitate antiviral development.
Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Humanos , Antivirais/farmacologia , Replicação ViralRESUMO
BACKGROUND: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. METHODS: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. FINDINGS: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). INTERPRETATION: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. FUNDING: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.
RESUMO
OBJECTIVES: This prospective study aimed to explore the clinical efficacy and inflammatory reaction of submental endoscopic thyroidectomy versus conventional thyroidectomy. METHODS: We prospectively recruited 45 patients (total 90 patients) who met the eligibility criteria to undergo conventional open thyroidectomy or submental endoscopic thyroidectomy from January 2021 to July 2022 in the Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. These patients were evaluated using the following indices: number of lymph nodes dissected, complications, pain severity, inflammatory indicators, cosmetic satisfaction, and economic cost. All data were analyzed by the t-test or chi-squared test. RESULTS: Ninety patients were enrolled. The two groups did not significantly differ regarding baseline characteristics. All patients who underwent thyroidectomy had a similar trauma index and increased level of inflammation. There were no significant differences between the open thyroidectomy and submental endoscopic thyroidectomy groups in the total number of lymph nodes dissected, number of positive lymph nodes, drainage volume, and complications. The Vancouver scar score and cosmetic satisfaction score were significantly better in the submental endoscopic thyroidectomy group than the open thyroidectomy group. The submental endoscopic thyroidectomy group had a significantly lower pain scores on postoperative days 1 and 2, less downtime, and cheaper medical and esthetic costs than the open thyroidectomy group. CONCLUSION: Compared with conventional open thyroidectomy, submental endoscopic thyroidectomy did not increase the degree of trauma, had superior clinical efficacy, caused less pain, required a shorter downtime, achieved a better cosmetic effect, and was associated with lower healthcare costs.
RESUMO
Denitrification is an important process of the global nitrogen cycle as some of its intermediates are environmentally important or related to global warming. However, how the phylogenetic diversity of denitrifying communities affects their denitrification rates and temporal stability remains unclear. Here we selected denitrifiers based on their phylogenetic distance to construct two groups of synthetic denitrifying communities: one closely related (CR) group with all strains from the genus Shewanella and the other distantly related (DR) group with all constituents from different genera. All synthetic denitrifying communities (SDCs) were experimentally evolved for 200 generations. The results showed that high phylogenetic diversity followed by experimental evolution promoted the function and stability of synthetic denitrifying communities. Specifically, the productivity and denitrification rates were significantly (P < 0.05) higher with Paracocus denitrificans as the dominant species (since the 50th generation) in the DR community than those in the CR community. The DR community also showed significantly (t = 7.119, df = 10, P < 0.001) higher stability through overyielding and asynchrony of species fluctuations, and showed more complementarity than the CR group during the experimental evolution. This study has important implications for applying synthetic communities to remediate environmental problems and mitigate greenhouse gas emissions.
