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Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.
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Citidina Desaminase , Hipermutação Somática de Imunoglobulina , Animais , Camundongos , Anticorpos/genética , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , DNA/genética , DNA de Cadeia Simples , Mutação , Evolução Molecular , Regiões Determinantes de Complementaridade/genética , Motivos de NucleotídeosRESUMO
BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3ß signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.
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Proteínas Quinases Dependentes de AMP Cíclico , Complexo de Endopeptidases do Proteassoma , Camundongos , Ratos , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Camundongos Transgênicos , Peptídeos/metabolismo , MamíferosRESUMO
BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.
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Hipóxia , Miócitos Cardíacos , Camundongos , Masculino , Feminino , Animais , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Hipóxia/complicações , Hipóxia/metabolismo , Proliferação de Células , Oxigênio/metabolismo , Hipertrofia/complicações , Hipertrofia/metabolismoRESUMO
This study investigates genetic mutations and immune cell dynamics in stomach adenocarcinoma (STAD), focusing on identifying prognostic markers and therapeutic targets. Analysis of TCGA-STAD samples revealed C > A as the most common single nucleotide variant (SNV) in both high and low-risk groups. Key mutated driver genes included TTN, TP53 and MUC16, with frame-shift mutations more prevalent in the low-risk group and missense mutations in the high-risk group. Interaction analysis of hub genes such as C1QA and CD68 showed significant correlations, impacting immune cell infiltration patterns. Using ssGSEA, we found higher immune cell infiltration (B cells, CD4+ T cells, CD8+ T cells, DC cells, NK cells) in the high-risk group, correlated with increased risk scores. xCell algorithm results indicated distinct immune infiltration levels between the groups. The study's risk scoring model proved effective in prognosis prediction and immunotherapy efficacy assessment. Key molecules like CD28, CD27 and SLAMF7 correlated significantly with risk scores, suggesting potential targets for high-risk STAD patients. Drug sensitivity analysis showed a negative correlation between risk scores and sensitivity to certain treatments, indicating potential therapeutic options for high-risk STAD patients. We also validated the carcinogenic role of RPL14 in gastric cancer through phenotypic experiments, demonstrating its influence on cancer cell proliferation, invasion and migration. Overall, this research provides crucial insights into the genetic and immune aspects of STAD, highlighting the importance of a risk scoring model for personalized treatment strategies and clinical decision-making in gastric cancer management.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Linfócitos T CD8-Positivos , Imunoterapia , Mutação/genéticaRESUMO
Establishing reliable noninvasive tools to precisely diagnose clinically significant liver fibrosis (SF, ≥F2) remains an unmet need. We aimed to build a combined radiomics-clinic (CoRC) model for triaging SF and explore the additive value of the CoRC model to transient elastography-based liver stiffness measurement (FibroScan, TE-LSM). This retrospective study recruited 595 patients with biopsy-proven liver fibrosis at two centers between January 2015 and December 2021. At Center 1, the patients before December 2018 were randomly split into training (276) and internal test (118) sets, the remaining were time-independent as a temporal test set (96). Another data set (105) from Center 2 was collected for external testing. Radiomics scores were built with selected features from Deep learning-based (ResUNet) automated whole liver segmentations on MRI (T2FS and delayed enhanced-T1WI). The CoRC model incorporated radiomics scores and relevant clinical variables with logistic regression, comparing routine approaches. Diagnostic performance was evaluated by the area under the receiver operating characteristic curve (AUC). The additive value of the CoRC model to TE-LSM was investigated, considering necroinflammation. The CoRC model achieved AUCs of 0.79 (0.70, 0.86), 0.82 (0.73, 0.89), and 0.81 (0.72-0.91), outperformed FIB-4, APRI (all p < 0.05) in the internal, temporal, and external test sets and maintained the discriminatory power in G0-1 subgroups (AUCs range, 0.85-0.86; all p < 0.05). The AUCs of joint CoRC-LSM model were 0.86 (0.79-0.94), and 0.81 (0.72-0.90) in the internal and temporal sets (p = 0.01). The CoRC model was useful for triaging SF, and may add value to TE-LSM.
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Técnicas de Imagem por Elasticidade , Cirrose Hepática , Fígado , Imageamento por Ressonância Magnética , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Adulto , Técnicas de Imagem por Elasticidade/métodos , Fígado/patologia , Fígado/diagnóstico por imagem , Curva ROC , Aprendizado Profundo , Idoso , Triagem/métodosRESUMO
BACKGROUND: Observational studies have reported that circulating cytokines are associated with sarcopenia. However, the causal relationship between circulating cytokines and sarcopenia has not been elucidated. OBJECTIVES: This study aimed to investigate the causal relationship between circulating cytokines and sarcopenia with genetic data using Mendelian randomization (MR). METHODS: Two-sample bidirectional MR analysis was performed to investigate the causal relationship in individuals of European ancestry. The publicly available genome-wide association study statistics were used to select the key eligible single nucleotide polymorphisms significantly associated with circulating cytokines. Multiple MR analysis approaches, including inverse variance weighted (IVW), MR-Egger, weighted median method (WMM), and MR-Pleiotropy residual Sum and Outlier (MR-PRESSO) methods, were used for the analysis. Sarcopenia-related traits were appendicular lean mass (ALM) and grip strength. RESULTS: This study demonstrated the causal effect of genetically predicted circulating interleukin interleukin-16 (IL16) levels on both ALM [odds ratio (OR) = 0.990, 95% confidence interval (CI): 0.980-1.000, P = 0.049] and grip strength (OR = 0.971, 95% CI: 0.948-0.995, P = 0.020]. Additionally, C-X-C motif chemokine ligand 10 (CXCL10), interleukin-1beta (IL1B), and hepatocyte growth factor (HGF) were correlated with ALM, while vascular endothelial growth factor (VEGF), interleukin-12 (IL12), and interleukin-15 (IL15) were correlated with grip strength. The results of MR-Egger, weighted median, weighted mode, and simple mode methods were consistent with the IVW estimates. Sensitivity analysis revealed that horizontal pleiotropy did not bias the causal estimates. CONCLUSION: These findings indicate that inflammatory cytokines exert a significant causal effect on sarcopenia and provide promising leads for the development of novel therapeutic targets for the disease. By evaluating the role of circulating cytokines in the pathologic condition via a genetic epidemiological approach, our study made contributions to a further investigation of underlying mechanisms of sarcopenia.
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Citocinas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Sarcopenia , Humanos , Sarcopenia/sangue , Sarcopenia/genética , Polimorfismo de Nucleotídeo Único/genética , Citocinas/sangue , Força da Mão , Fator de Crescimento de Hepatócito/sangue , Fator de Crescimento de Hepatócito/genética , Masculino , FemininoRESUMO
Breast cancer, the most common cancer, presents a significant challenge to the health and longevity of women. Aspongopus chinensis Dallas is an insect with known anti-breast cancer properties. However, the anti-breast cancer effects and underlying mechanisms have not been elucidated. Exogenous microRNAs (miRNAs), which are derived from plants and animals, have been revealed to have notable capacities for controlling the proliferation of cancerous cells. To elucidate the inhibitory effects of miRNAs derived from A. chinensis and the regulatory mechanism involved in the growth of breast cancer cells, miRNA sequencing was initially employed to screen for miRNAs both in A. chinensis hemolymph and decoction and in mouse serum and tumor tissue after decoction gavage. Subsequently, the experiments were performed to assess the suppressive effect of ach-miR-276a-3p, the miRNA screened out from a previous study, on the proliferation of MDA-MB-231 and MDA-MB-468 breast cancer cell lines in vitro and in vivo. Finally, the regulatory mechanism of ach-miR-276a-3p in MDA-MB-231 and MDA-MB-468 breast cancer cells was elucidated. The results demonstrated that ach-miR-276a-3p notably inhibited breast cancer cell proliferation, migration, colony formation, and invasion and induced cell cycle arrest at the G0/G1 phase. Moreover, the ach-miR-276a-3p mimics significantly reduced the tumor volume and weight in xenograft tumor mice. Furthermore, ach-miR-276a-3p could induce cell cycle arrest by targeting APPL2 and regulating the CDK2-Rb-E2F1 signaling pathway. In summary, ach-miR-276a-3p, derived from A. chinensis, has anti-breast cancer activity by targeting APPL2 and regulating the CDK2-Rb-E2F1 signaling pathway and can serve as a promising candidate anticancer agent.
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Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Animais , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , MicroRNAs/genética , MicroRNAs/metabolismo , Pontos de Checagem do Ciclo Celular , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Quinase 2 Dependente de Ciclina/genética , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
OBJECTIVES: The performance of the new Respiratory Pathogen panel (fluorescent probe melting curve, FPMC) for the qualitative detection of 12 organisms (chlamydia pneumoniae, mycoplasma pneumoniae, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, rhinovirus, etc.) was assessed. METHODS: Prospectively collected nasopharyngeal swab (NPS) and sputum specimens (n = 635) were detected by using the FPMC panel, with the Sanger sequencing method as the comparative method. RESULTS: The overall percent concordance between the FPMC analysis method and the Sanger sequencing method was 100% and 99.66% for NPS and sputum specimens, respectively. The FPMC testified an overall positive percent concordance of 100% for both NPS and sputum specimens. The FPMC analysis method also testified an overall negative percent concordance of 100% and 99.38% for NPS and sputum specimens, respectively. CONCLUSIONS: The FPMC analysis method is a stable and accurate assay for rapid, comprehensive detecting for respiratory pathogens.
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Técnicas de Diagnóstico Molecular , Nasofaringe , Infecções Respiratórias , Escarro , Humanos , Escarro/microbiologia , Escarro/virologia , Nasofaringe/virologia , Nasofaringe/microbiologia , Infecções Respiratórias/virologia , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Técnicas de Diagnóstico Molecular/métodos , Vírus/isolamento & purificação , Vírus/genética , Vírus/classificação , Adulto , Estudos Prospectivos , Pessoa de Meia-Idade , Adolescente , Feminino , Adulto Jovem , Criança , Masculino , Idoso , Pré-Escolar , Lactente , Manejo de Espécimes/métodos , Sensibilidade e Especificidade , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood. Little is known about how infancy growth trajectories affect adiposity in early childhood in LGA. METHODS: In the Shanghai Birth Cohort, we followed up 259 LGA (birth weight >90th percentile) and 1673 appropriate-for-gestational age (AGA, 10th-90th percentiles) children on body composition (by InBody 770) at age 4 years. Adiposity outcomes include body fat mass (BFM), percent body fat (PBF), body mass index (BMI), overweight/obesity, and high adiposity (PBF >85th percentile). RESULTS: Three weight growth trajectories (low, mid, and high) during infancy (0-2 years) were identified in AGA and LGA subjects separately. BFM, PBF and BMI were progressively higher from low- to mid-to high-growth trajectories in both AGA and LGA children. Compared to the mid-growth trajectory, the high-growth trajectory was associated with greater increases in BFM and the odds of overweight/obesity or high adiposity in LGA than in AGA children (tests for interactions, all P < 0.05). CONCLUSIONS: Weight trajectories during infancy affect adiposity in early childhood regardless of LGA or not. The study is the first to demonstrate that high-growth weight trajectory during infancy has a greater impact on adiposity in early childhood in LGA than in AGA subjects. IMPACT: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood, but little is known about how weight trajectories during infancy affect adiposity during early childhood in LGA subjects. The study is the first to demonstrate a greater impact of high-growth weight trajectory during infancy (0-2 years) on adiposity in early childhood (at age 4 years) in subjects with fetal overgrowth (LGA) than in those with normal birth size (appropriate-for-gestational age). Weight trajectory monitoring may be a valuable tool in identifying high-risk LGA children for close follow-ups and interventions to decrease the risk of obesity.
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PURPOSE: The aim of this study was to clarify DNA methylation profiles determining the clinicopathological diversity of urothelial carcinomas. METHODS: Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip in 46 paired samples of non-cancerous urothelium (N) and corresponding cancerous tissue (T), and 26 samples of normal control urothelium obtained from patients without urothelial carcinomas (C). For genes of interest, correlation between DNA methylation and mRNA expression was examined using the Cancer Genome Atlas database. In addition, the role of a selected target for cancer-relevant endpoints was further examined in urothelial carcinoma cell lines. RESULTS: The genes showing significant differences in DNA methylation levels between papillary carcinomas and more aggressive non-papillary (nodular) carcinomas were accumulated in signaling pathways participating in cell adhesion and cytoskeletal remodeling. Five hundred ninety-six methylation sites showed differences in DNA methylation levels between papillary and nodular carcinomas. Of those sites, that were located in CpG-islands around transcription start site, 5'-untranslated region or 1st exon, 16 genes exhibited inverse correlations between DNA methylation and mRNA expression levels. Among the latter, only the KLF11 gene showed papillary T sample-specific DNA hypermethylation in comparison to C and N samples. The DNA methylation levels of KLF11 were not significantly different between T samples and N samples or T samples and C samples for patients with papillo-nodular or nodular carcinomas. Knockdown experiments using the urothelial carcinoma cell lines HT1376 and 5637, which are considered models for papillary carcinoma, revealed that KLF11 participates in altering the adhesiveness of cells to laminin-coated dishes, although cell growth was not affected. CONCLUSION: These data indicate that DNA hypermethylation of KLF11 may participate in the generation of papillary urothelial carcinomas through induction of aberrant cancer cell adhesion to the basement membrane.
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Carcinoma Papilar , Adesão Celular , Metilação de DNA , Neoplasias da Bexiga Urinária , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Repressoras/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Urotélio/metabolismoRESUMO
BACKGROUND: The aim of this study was to summarize the optimal strategy for early feeding in patients with acute pancreatitis. METHODS: The search was undertaken in electronic databases, which compared early with delayed feeding in acute pancreatitis. The primary outcome was the length of hospital stay (LOHS). The second outcomes were intolerance of refeeding, mortality, and total cost of each patient. This meta-analysis followed the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guideline. Research is registered by PROSPERO, CRD42020192133. RESULTS: A total of 20 trials involving 2168 patients were included, randomly assigned to the early feeding group (N = 1033) and delayed feeding group (N = 1135). The LOHS was significantly lower in the early feeding group than the delayed feeding group (mean difference: -2.35, 95% CI: -2.89 to -1.80; P < 0.0001), no matter the mild or severe subgroup ( Pint = 0.69). The secondary outcome of feeding intolerance and mortality were no significant difference (risk ratio: 0.96, 0.40 to 2.16, P = 0.87 and 0.91, 0.57 to 1.46, P = 0.69; respectively). Moreover, the hospitalization cost was significantly less in the early feeding group, resulting in an average savings of 50%. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial ( Pint = 0.001). CONCLUSION: Early oral feeding can significantly reduce the LOHS and hospitalization costs in patients with acute pancreatitis without increasing feeding intolerance or mortality. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial.
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Nutrição Enteral , Pancreatite , Humanos , Recém-Nascido , Nutrição Enteral/métodos , Doença Aguda , Pancreatite/terapia , Hospitalização , Tempo de Internação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Carbon equity is the balance between carbon reduction responsibilities and development rights. The review of carbon equity in China can help it achieve carbon neutrality targets and provide valuable insights to other emerging countries. This study aimed to systematically sort, classify, compare, and prospect the research dimensions and measure methods for carbon equity. The research dimensions were first classified into intergenerational, regional, trade, and income carbon equity by literature analysis. Intergenerational carbon equity explores the balance of carbon emission rights among generations using integrated assessment models (IAM). Regional carbon equity analyzes the socioeconomic effect of regional carbon emission rights allocation by IAM or regional differences under a specific allocation assumption by the Theil index. Trade carbon equity studies the relationship between carbon emissions and economic benefit transfer embodied in inter-regional trade, which is more suitable for calculating by methods with comparable results, such as the optimized regional environmental inequality index. Income carbon equity investigates the carbon footprint heterogeneity among income groups by the carbon Gini coefficient. This paper further discusses potential research directions for each dimension. Notably, all research dimensions did not consider promoted strategies for carbon equity, which should be a priority for future studies.
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Carbono , China , Pegada de Carbono , Fatores SocioeconômicosRESUMO
AIM: The aim of this study was to clarify the significance of DNA methylation alterations of cryptogenic hepatocellular carcinomas (HCCs). METHODS: Using the Infinium assay, we performed genome-wide DNA methylation analysis of 250 liver tissue samples, including noncancerous liver tissue (U-N) and corresponding cancerous tissue (U-T) from patients with cryptogenic HCC without a history of excessive alcohol use and hepatitis virus infection, and whose U-N samples showed no remarkable histological features (no microscopic evidence of simple steatosis, any form of hepatitis including nonalcoholic steatohepatitis, or liver cirrhosis). RESULTS: We identified 3272 probes that showed significant differences of DNA methylation levels between U-N and normal liver tissue samples from patients without HCC, indicating that a distinct DNA methylation profile had already been established at the precancerous U-N stage. U-Ns have a DNA methylation profile differing from that of noncancerous liver tissue of patients with nonalcoholic steatohepatitis-related, viral hepatitis-related, and alcoholic liver disease-related HCCs. Such DNA methylation alterations in U-Ns were inherited by U-Ts. The U-Ns showed DNA methylation alteration of ADCY5, resulting in alteration of its mRNA expression, whereas noncancerous liver tissue of patients with nonalcoholic steatohepatitis-, viral hepatitis-, or alcoholic liver disease-related HCCs did not. DNA methylation levels of MICAL2 and PLEKHG2 in U-Ts were correlated with larger tumor diameter and portal vein involvement, respectively. CONCLUSIONS: U-N-specific DNA hypermethylation of ADCY5 may have significance, even from the precancerous stage in liver showing no remarkable histological features. DNA hypomethylation of MICAL2 and PLEKHG2 may determine the clinicopathological features of cryptogenic HCC.
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Aim: To identify the optimal first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Materials & methods: We conducted a network meta-analysis (CRD42023486863) to systematically evaluate the efficacy and safety of eight first-line treatment regimens for ES-SCLC, including 15 clinical trials. Results: Our analysis showed that the PD-1/PD-L1 + etoposide combined with platinum (EP) and PD-L1 + vascular endothelial growth factor (VEGF) + EP regimens significantly enhanced overall survival and progression-free survival, with subgroup analysis revealing that serplulimab ranked as the most promising option for improving overall survival. Integrating anti-angiogenesis drugs into immunochemotherapy presents potential benefits, with an increased incidence of adverse events necessitating further investigation. Conclusion: Our findings offer valuable insights for future research and for developing more effective treatment strategies for ES-SCLC, underscoring the critical need for continued innovation in this therapeutic area.
[Box: see text].
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BACKGROUND: Rhodococcus equi (R. equi) is a Gram-positive zoonotic pathogen that frequently leads to illness and death in young horses (foals). This study presents the complete genome sequence of R. equi strain BJ13, which was isolated from a thoroughbred racehorse breeding farm in Beijing, China. RESULTS: The BJ13 genome has a length of 5.30 Mb and consists of a complete chromosome and a plasmid measuring 5.22 Mb and 0.08 Mb, respectively. We predicted 4,929 coding gene open reading frames, along with 52 tRNAs and 12 rRNAs. Through analysis of mobile genetic elements, we identified 6 gene islands and 1 prophage gene. Pathogenic system analysis predicted the presence of 418 virulence factors and 225 drug resistance genes. Secretion system analysis revealed the prediction of 297 secreted proteins and 1,106 transmembrane proteins. BJ13 exhibits genomic features, virulence-associated genes, potential drug resistance, and a virulence plasmid structure that may contribute to the evolution of its pathogenicity. Lastly, the pathogenicity of the isolated strain was assessed through animal experiments, which resulted in inflammatory reactions or damage in the lungs, liver, and spleen of mice. Moreover, by the 7th day post-infection, the mortality rate of the mice reached 50.0%, indicating complex immune regulatory mechanisms, including overexpression of IL-10 and increased production of pro-inflammatory cytokines like TNF-α. These findings validate the strong pathogenicity of the isolated strain and provide insights for studying the pathogenic mechanisms of Rhodococcus equi infection. CONCLUSIONS: The complete genome sequence of R. equi strain BJ13 provides valuable insights into its genomic characteristics, virulence potential, drug resistance, and secretion systems. The strong pathogenicity observed in animal experiments underscores the need for further investigation into the pathogenic mechanisms of R. equi infection.
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Infecções por Actinomycetales , Genoma Bacteriano , Doenças dos Cavalos , Rhodococcus equi , Sequenciamento Completo do Genoma , Rhodococcus equi/patogenicidade , Rhodococcus equi/genética , Animais , Cavalos , Doenças dos Cavalos/microbiologia , Infecções por Actinomycetales/veterinária , Infecções por Actinomycetales/microbiologia , Virulência/genética , Camundongos , Fatores de Virulência/genética , FemininoRESUMO
The G Protein-Coupled Receptor (GPCR) superfamily is the largest and most diverse transmembrane receptor family, playing crucial roles in regulating various physiological processes. As one of the most destructive pests, aphids have been subject to previous studies, which revealed fewer GPCR superfamily members in Acyrthosiphon pisum and Aphis gossypii and the loss of multiple neuropeptide GPCRs. To elucidate the contraction patterns and evolutionary features of the aphid GPCR superfamily, we identified 97, 105, and 95 GPCR genes in Rhopalosiphum maidis, A. pisum, and A. gossypii, respectively. Comparative analysis and phylogenetic investigations with other hemipteran insects revealed a contracted GPCR superfamily in aphids. This contraction mainly occurred in biogenic amine receptors, GABA-B-R, and fz families, and several neuropeptide receptors such as ACPR, CrzR, and PTHR were completely lost. This phenomenon may be related to the parasitic nature of aphids. Additionally, several GPCRs associated with aphid feeding and water balance underwent duplication, including Lkr, NPFR, CCHa1-R, and DH-R, Type A LGRs, but the SK/CCKLR that inhibits feeding was completely lost, indicating changes in feeding genes that underpin the aphid's prolonged phloem feeding behavior. Furthermore, we observed fine-tuning in opsins, with reduced long-wavelength opsins and additional duplications of short-wavelength opsin, likely associated with daytime activity. Lastly, we found variations in the number of mthl genes in aphids. In conclusion, our investigation sheds light on the GPCR superfamily in aphids, revealing its association with diet lifestyle and laying the foundation for understanding and developing control strategies for the aphid GPCR superfamily.
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Afídeos , Animais , Afídeos/genética , Filogenia , Floema , Comportamento Alimentar/fisiologia , Receptores Acoplados a Proteínas G/genética , Opsinas/genéticaRESUMO
BACKGROUND: The multimorbidity of Atherosclerotic cardiovascular disease (ASCVD) and many other chronic conditions is becoming common. This study aimed to assess multimorbidity distribution in ASCVD among adults in the United States from 1999 to 2018. METHODS: This cross-sectional survey from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 using stratified multistage probability design. Among the 53,083 survey respondents during the study period, 5,729 US adults aged ≥ 20 years with ASCVD. Joinpoint regression was used to assess the statistical significance of prevalence trends in the prevalence of ASCVD stratified by multimorbidity. The Apriori association rule mining algorithm was used to identify common multimorbidity association patterns in ASCVD patients. RESULTS: Overall, 5,729 of 53,083 individuals had ASCVD, and the prevalence showed a slow declining trend (biannual percentage change = -0.81%, p = 0.035, average 7.71%). The prevalence of ASCVD significantly decreased in populations without dyslipidemia, diabetes mellitus (DM), hypertension, asthma, chronic obstructive pulmonary disease (COPD), and arthritis (all groups, p < 0.05). Additionally, 65.6% of ASCVD patients had at least four of the 12 selected chronic conditions, with four and five being the most common numbers of conditions (17.9% and 17.7%, respectively). The five most common chronic conditions were (in order) dyslipidemia, hypertension, arthritis, chronic kidney disease, and DM. The coexistence of hypertension and dyslipidemia had the highest support in association rules (support = 0.63), while the coexistence of dyslipidemia, hypertension, metabolic syndrome, and DM had the highest lift (lift = 1.82). CONCLUSIONS: During the 20-year survey period, there was a significant decrease in the overall prevalence of ASCVD. However, this reduction was primarily observed in individuals without dyslipidemia, DM, hypertension, asthma, COPD, and arthritis. Among populations with any of the evaluated chronic conditions, the prevalence of ASCVD remained unchanged. Most of ASCVD patients had four or more concurrent chronic conditions.
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Artrite , Asma , Aterosclerose , Doenças Cardiovasculares , Dislipidemias , Hipertensão , Doença Pulmonar Obstrutiva Crônica , Adulto , Estados Unidos , Humanos , Estudos Transversais , Multimorbidade , Inquéritos NutricionaisRESUMO
PURPOSE: Oocyte maturation defect (OOMD) is a rare cause of in vitro fertilization failure characterized by the production of immature oocytes. Compound heterozygous or homozygous PATL2 mutations have been associated with oocyte arrest at the germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) stages, as well as morphological changes. METHODS: In this study, we recruited three OOMD cases and conducted a comprehensive multiplatform laboratory investigation. RESULTS: Whole exome sequence (WES) revealed four diagnostic variants in PATL2, nonsense mutation c.709C > T (p.R237*) and frameshift mutation c.1486_1487delinsT (p.A496Sfs*4) were novel mutations that have not been reported previously. Furthermore, the pathogenicity of these variants was predicted using in silico analysis, which indicated detrimental effects. Molecular dynamic analysis suggested that the A496S variant disrupted the hydrophobic segment, leading to structural changes that affected the overall protein folding and stability. Additionally, biochemical and molecular experiments were conducted on cells transfected with wild-type (WT) or mutant PATL2 (p.R237* and p.A496Sfs*4) plasmid vectors. CONCLUSIONS: The results demonstrated that PATL2A496Sfs*4 and PATL2R237* had impacts on protein size and expression level. Interestingly, expression levels of specific genes involved in oocyte maturation and early embryonic development were found to be simultaneously deregulated. The findings in our study expand the variation spectrum of the PATL2 gene, provide solid evidence for counseling on future pregnancies in affected families, strongly support the application of in the diagnosis of OOMD, and contribute to the understanding of PATL2 function.
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Sequenciamento do Exoma , Infertilidade Feminina , Proteínas Nucleares , Oócitos , Oogênese , Proteínas de Ligação a RNA , Adulto , Feminino , Humanos , Códon sem Sentido/genética , Fertilização in vitro , Mutação da Fase de Leitura/genética , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Mutação/genética , Oócitos/crescimento & desenvolvimento , Oócitos/patologia , Oócitos/metabolismo , Oogênese/genética , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genéticaRESUMO
To address the difficulty of accurately characterizing the fluctuations in equipment energy consumption and the dynamic evolution of whole energy consumption in low-carbon workshops, a low-carbon-operation-oriented construction method of the energy footprint model (EFM) for a digital twin workshop (DTW) is proposed. With a focus on considering the fluctuations in equipment energy consumption and the correlation between multiple pieces of equipment at the workshop production process level (CBMEatWPPL), the EFM of a DTW is obtained to characterize the dynamic evolution of whole energy consumption in the workshop. Taking a production unit as a case, on the one hand, an EFM of the production unit is constructed, which achieved the characterization and visualization of the fluctuations in equipment energy consumption and the dynamic evolution of whole energy consumption in the production unit; on the other hand, based on the EFM, an objective function of workshop energy consumption is established, which is combined with the tool life, robot motion stability, and production time to formulate a multi-objective optimization function. The bee colony algorithm is adopted to solve the multi-objective optimization function, achieving collaborative optimization of cross-equipment process parameters and effectively reducing energy consumption in the production unit. The effectiveness of the proposed method and constructed EFM is demonstrated from the above two aspects.
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INTRODUCTION: Aducanumab selectively targets aggregated forms of amyloid beta (Aß), a neuropathological hallmark of Alzheimer's disease (AD). METHODS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. RESULTS: Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab decreased brain amyloid levels in a dose- and time-dependent manner. Exploratory endpoints suggested a continued benefit in the reduction of clinical decline over 48 months. DISCUSSION: The safety profile of aducanumab remained unchanged in the LTE of PRIME. Amyloid plaque levels continued to decrease in participants treated with aducanumab. HIGHLIGHTS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. We report cumulative safety and 48-month efficacy results from PRIME. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event (AE); 61% of participants with ARIA-E were asymptomatic. Dose titration was associated with a decrease in the incidence of ARIA-E. Aducanumab decreased levels of amyloid beta (Aß) in a dose- and time-dependent manner.