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Staphylococcus aureus sequence type (ST) 398 is a lineage affecting both humans and livestock worldwide. However, the mechanisms underlying its clonal evolution are still not clearly elucidated. We applied whole-genome sequencing (WGS) typing to 45 S. aureus strains from China and Canada between 2005 and 2014, in order to gain insight into their evolutionary pathway. Based on WGS phylogenetic analysis, 42 isolates were assigned to the human-associated clade (I/II-GOI) and 3 isolates to livestock-associated clade (IIa). Phylogeny of ÏSa3 sequences revealed five phage groups (Groups 1-5), with Group 1 carrying ÏSa3-Group 1 (ÏSa3-G1), Group 2 carrying ÏSa3-G2, Group 3 carrying ÏSa3-G3, Group 4 carrying ÏSa3-G4 and Group 5 lacking ÏSa3. ÏSa3-G1 was only found in strains that accounted for the most ancestral human clade I, while ÏSa3-G2, ÏSa3-G3 and ÏSa3-G4 were found restricted to sublineages within clade II-GOI. Some isolates of clade II-GOI were also found to be ÏSa3-negative or resistant to methicillin which are unusual characteristics for human-adapted isolates. This study demonstrated a strong association between phylogenetic grouping and phage type, suggesting an important role of ÏSa3 prophage in the evolution of human-adapted ST398 subclones. In addition, our results suggest that this subclone slowly began to adapt to animal hosts by losing ÏSa3 and acquiring methicillin resistance, which was observed in some strains of human-associated clade II-GOI, an intermediate human to livestock transmission clade.
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Huntington's disease (HD) is a progressive dominantly inherited neurodegenerative disease caused by the expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the huntingtin gene, which encodes the mutant huntingtin protein containing an expanded polyglutamine tract. One of neuropathologic hallmarks of HD is selective degeneration in the striatum. Mechanisms underlying selective neurodegeneration in the striatum of HD remain elusive. Neurodegeneration is suggested to be preceded by abnormal synaptic transmission at the early stage of HD. However, how mutant huntingtin protein affects synaptic vesicle exocytosis at single presynaptic terminals of HD striatal neurons is poorly understood. Here, we measured synaptic vesicle exocytosis at single presynaptic terminals of cultured striatal neurons (mainly inhibitory neurons) in a knock-in mouse model of HD (zQ175) during electrical field stimulation using real-time imaging of FM 1-43 (a lipophilic dye). We found a significant decrease in bouton density and exocytosis of synaptic vesicles at single presynaptic terminals in cultured striatal neurons. Real-time imaging of VGAT-CypHer5E (a pH sensitive dye conjugated to an antibody against vesicular GABA transporter (VGAT)) for inhibitory synaptic vesicles revealed a reduction in bouton density and exocytosis of inhibitory synaptic vesicles at single presynaptic terminals of HD striatal neurons. Thus, our results suggest that the mutant huntingtin protein decreases bouton density and exocytosis of inhibitory synaptic vesicles at single presynaptic terminals of striatal neurons, causing impaired inhibitory synaptic transmission, eventually leading to the neurodegeneration in the striatum of HD.
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Norovirus infection is the leading cause of foodborne gastroenteritis worldwide, causing more than 200,000 deaths each year. As a result of a lack of reproducible and robust in vitro culture systems and suitable animal models for human norovirus (HuNoV) infection, the pathogenesis of HuNoV is still poorly understood. In recent years, human intestinal enteroids (HIEs) have been successfully constructed and demonstrated to be able to support the replication of HuNoV. The NLRP3 inflammasome plays a key role in host innate immune responses by activating caspase1 to facilitate IL-1ß and IL-18 secretion and N-GSDMD-driven apoptosis, while NLRP3 inflammasome overactivation plays an important role in the development of various inflammatory diseases. Here, we found that HuNoV activated enteric stem cell-derived human intestinal enteroids (HIEs) NLRP3 inflammasome, which was confirmed by transfection of Caco2 cells with full-length cDNA clones of HuNoV. Further, we found that HuNoV non-structural protein P22 activated the NLRP3 inflammasome and then matured IL-1ß and IL-18 and processed the cleavage of gasdermin-D (GSDMD) to N-GSDMD, leading to pyroptosis. Besides, berberine (BBR) could ameliorate the pyroptosis caused by HuNoV and P22 by inhibiting NLRP3 inflammasome activation. Together, these results reveal new insights into the mechanisms of inflammation and cell death caused by HuNoV and provide potential treatments.
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Human norovirus (HNV) is one of the emerging and rapidly spreading groups of pathogens and the main cause of epidemic viral gastroenteritis globally. Due to a lack of in vitro culture systems and suitable animal models for HNV infection, murine norovirus (MNV) has become a common model. A recent study showed that MNV activates NLRP3 inflammasome leading to pyroptosis. Jatrorrhizine (JAT) is a natural isoquinoline alkaloid isolated from Coptis Chinensis, which has been proven to have antibacterial, anti-inflammatory, and antitumor effects. However, whether JAT has an effect on norovirus gastroenteritis and the underlying molecular mechanism remain unclear. Here, we found that JAT could ameliorate NLRP3-N-GSDMD-dependent pyroptosis induced by MNV infection through inhibiting the MAPKs/NF-κB signaling pathways and decrease MNV replication in RAW264.7 macrophages, suggesting that JAT has the potential to be a therapeutic agent for treating norovirus gastroenteritis.
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The biosynthesis of unsaturated fatty acids is involved in the initiation and progression of colon adenocarcinoma (COAD). In this study, we aimed to investigate the multi-omics characteristics of unsaturated fatty acid biosynthesis-related genes and explore their prognostic value in colon cancer by analyzing the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. An unsaturated fatty acid biosynthesis pathway related-genes enrichment score (BUFAS) was constructed utilizing the single sample gene set enrichment analysis (ssGSEA). We discovered that a high BUFAS was associated with longer overall survival (OS) in both the training and the validation sets. Multivariable analysis including the clinical characteristics further verified the independent prognostic value of the BUFAS in both the TCGA-COAD and the GSE39582 datasets. In addition, GSEA analysis revealed that BUFAS was positively associated with several signaling pathways, including MTORC1, peroxisome, and pathways related to fatty acid metabolism, while was negatively associated with other signaling pathways, such as hedgehog, NOTCH, and Wnt/beta-catenin pathway. Furthermore, in the COAD cell lines of the Genomics of Drug Sensitivity in Cancer (GDSC) database, we found that BUFAS was positively correlated with the drug sensitivities of cisplatin, gemcitabine, camptothecin, lapatinib, and afatinib, while was negatively correlated with that of ponatinib. Moreover, in the COAD single-cell transcriptomic dataset (GSE146771), the BUFAS varied among different cell types and was enriched in mast cells and fibroblasts. Taken together, the BUFAS we constructed could be used as an independent prognostic signature in predicting the OS and drug resistance of colon cancer. Unsaturated fatty acid biosynthesis pathway might serve as potential therapeutic targets for cancer treatment.
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Background: Glycerolipid metabolism is involved in the genesis and progression of colon cancer. The current study aims at exploring the prognostic value and potential molecular mechanism of glycerolipid metabolism-related genes in colon cancer from the perspective of multi-omics. Methods: Clinical information and mRNA expression data of patients with colon cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Single-sample gene set enrichment analysis (ssGSEA) was applied to calculate the glycerolipid metabolism-related gene enrichment score (GLMS). Univariable and multivariable Cox regression analyses were used to study the prognostic value of GLMS in TCGA-COAD and GSE39582 cohorts. The molecular mechanism of the prognostic factor was investigated via immune cell infiltration estimation and correlation analysis of cancer hallmark pathways. Single-cell transcriptomic dataset GSE146771 was used to identify the cell populations which glycerolipid metabolism targeted on. Results: The GLMS was found to be associated with tumor location and consensus molecular types (CMSs) of colon cancer in TCGA-COAD cohort (P < 0.05). Patients in the low-GLMS group exhibited poorer overall survival (OS) in TCGA cohort (P = 0.03; HR, 0.63; 95% CI, 0.42-0.94), which was further validated in the GSE39582 dataset (P < 0.001; HR, 0.57; 95% CI, 0.43-0.76). The association between the GLMS and OS remained significant in the multivariable analysis (TCGA cohort: P = 0.04; HR, 0.64; 95% CI, 0.42-0.98; GSE39582 cohort: P < 0.001; HR, 0.60; 95% CI, 0.45-0.80). The GLMS was positively correlated with cancer hallmark pathways including bile acid metabolism, xenobiotic metabolism, and peroxisome and negatively correlated with pathways such as interferon gamma response, allograft rejection, apoptosis, and inflammatory response (P < 0.05). Increased immune infiltration and upregulated expression of immune checkpoints were observed in patients with lower GLMS (P < 0.05). Single-cell datasets verified the different distribution of GLMS in cell subsets, with significant enrichment of GLMS in malignant cells and Tprolif cells. Conclusion: We demonstrated that GLMS was a potential independent prognostic factor for colon cancer. The GLMS was also correlated with several cancer hallmark pathways, as well as immune microenvironment.
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OBJECTIVE: At present, there are some no-notice drill mode evaluation systems for public health emergencies in Chinese hospitals, which are the subjects of assessment in this study. However, there is a lack of CDC. This study builds a set of no-notice drill mode evaluation systems for public health emergencies that involve the CDC. METHODS: The indexes for these systems were based on the performance of two no-notice drills for public health emergencies in Guangdong Province. Twenty experts were invited to screen the indicators during two rounds of the Delphi method to determine the weight of first- and second-level indexes through the analytic hierarchy process, and the weight of the third-level index was calculated using the percentage method. RESULTS: After two rounds of expert consultation, we obtained four first-level indicators, twenty-six second-level indicators and eighty-six third-level indicators. According to the weight calculated by analytic hierarchy process, the weights of the first-level indicators are emergency preparation (0.2775), verification and consultation regarding an epidemic situation (0.165), field investigation and control (0.3925) and summary report (0.165). Sensitivity analysis shows that the stability of the index is good. CONCLUSION: The no-notice drill mode evaluation system for public health emergencies constructed in this study can be applied to public health departments such as the CDC. Through promotion, it can provide a scientific basis for epidemiological investigation assessment.
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Urgencias Médicas , Salud Pública , Técnica Delphi , Hospitales , Humanos , Encuestas y CuestionariosRESUMEN
Although defective synaptic transmission was suggested to play a role in neurodegenerative diseases, the dynamics and vesicle pools of synaptic vesicles during neurodegeneration remain elusive. Here, we performed real-time three-dimensional tracking of single synaptic vesicles in cortical neurons from a mouse model of Huntington's disease (HD). Vesicles in HD neurons had a larger net displacement and radius of gyration compared with wild-type neurons. Vesicles with high release probability (Pr) were interspersed with low-Pr vesicles in HD neurons, whereas high-Pr vesicles were closer to fusion sites than low-Pr in wild-type neurons. Non-releasing vesicles in HD neurons had an abnormally high prevalence of irregular oscillatory motion. These abnormal dynamics and vesicle pools were rescued by overexpressing Rab11, and the abnormal irregular oscillatory motion was rescued by jasplakinolide. Our studies reveal the abnormal dynamics and pools of synaptic vesicles in the early stages of HD, suggesting a possible pathogenic mechanism of neurodegenerative diseases.
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Genome-wide association study recently identified a novel antiviral gene INTS10 (index rs7000921) in suppression of hepatitis B virus (HBV) replication. However, data were lacking on single nucleotide polymorphisms (SNPs) of INTS10 in the context of hepatocellular carcinoma (HCC) induced by HBV infection. Herein, we conducted a case-control study, including 737 HBV-related HCC cases and 750 persistently HBV-infected controls, to investigate the effect of INTS10 SNPs and their gene-environment interactions on HBV-related HCC. In multivariate analysis, the CT genotype of rs7000921 conferred a decreased risk of HBV-related HCC compared to the TT genotype (adjusted odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p for permutation test = .038). Among the 12 tagSNPs, the rs4268139 yielded a borderline significant association with disease risk under the additive model (adjusted OR = 0.80, 95% CI = 0.63-1.00, p for permutation test = .061). Random forest model further suggested the rs7000921 and rs7822495 as the two-top ranked important SNPs, and thus a weighted genetic risk score (wGRS) was generated from these two SNPs plus rs4268139. The highest tertile of wGRS was associated with an increased risk, with an adjusted OR of 1.36 (95% CI = 1.05-1.75, p for permutation test = .016) compared to the lowest wGRS. Furthermore, an additive interaction was seen between wGRS and drinking (attributable proportion due to interaction [AP] = 0.21, 95% CI = 0.02-0.43, p = .016). The additive interaction between wGRS and smoking approached near significance (AP = 0.15, 95% CI = 0.00-0.32, p = .045). INTS10 polymorphisms may contribute to the progression from HBV infection to HCC. More importantly, INTS10 polymorphisms interact with drinking and smoking to affect the progression.
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Carcinoma Hepatocelular/etiología , Proteínas Portadoras/genética , Interacción Gen-Ambiente , Hepatitis B/complicaciones , Neoplasias Hepáticas/etiología , Alelos , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Genotipo , Hepatitis B/virología , Virus de la Hepatitis B , Humanos , Mutación , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: A recent genome-wide association study (GWAS) has posed STAT4 as a promising susceptibility gene for hepatocellular carcinoma (HCC). However, the most significant variant in this GWAS, rs7574865, yielded inconsistent results. OBJECTIVE: This study, in a Southern Chinese population, was aimed to clarify the roles in HCC incidence of the rs7574865 and other two potentially functional variants, rs897200 and rs1031507 in STAT4. METHODS: This study enrolled 631 new HCC cases and 631 cancer-free controls. The genetic association was estimated using the multivariate logistic regression model. The pairwise gene-environment interactions were assessed using the multiplicative term in regression model and the "Delta" method for the additive scale. RESULTS: In the multivariate analysis, the rs7574865 TT genotype conferred a decreased risk of HCC compared to the GG genotype (adjusted OR = 0.62, 95%CI = 0.38â¼0.99). The significant association of rs7574865 was also observed under the additive genetic model, with an adjusted OR of 0.81 (95%CI = 0.65â¼0.99). Nevertheless, other two variants alone showed no significant association, as well as the haplotypes and genetic risk scores. Further analysis indicated a potential interaction between the rs897200 and alcohol drinking (P= 0.048 and 0.072 for additive and multiplicative interactions, respectively). Drinkers with the rs897200 CT+CC genotypes presented an increased disease-risk, as compared with non-drinkers carrying the TT genotype (adjusted OR = 1.68, 95%CI = 1.11â¼2.54). CONCLUSIONS: The variant in STAT4, rs7574865, serves as a potential marker for predicting incidence of HCC. The rs897200 variant possibly interplays with alcohol drinking to alter HCC risk in the Southern Chinese, but warrants further investigation.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Factor de Transcripción STAT4/genética , Carcinoma Hepatocelular/epidemiología , China/epidemiología , Exposición a Riesgos Ambientales , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Neoplasias Hepáticas/epidemiología , Persona de Mediana Edad , Variantes Farmacogenómicas , Factor de Transcripción STAT4/metabolismoRESUMEN
Despite initially being described in North America, Staphylococcus aureus (SA) sequence type ST59 is the most commonly isolated sequence type in Eastern Asia. The origins and evolution of this strain type remains unclear and therefore we gathered a collection of ST59 isolates from Canada and mainland China for a detailed genetic analysis of the lineage. Bayesian inference phylogenomic analysis of our isolates, along with previously published ST59 sequences indicated that the lineage could be divided into 6 distinct subgroups (WGS-1 thorough 6), each having distinct molecular characteristics. Analysis also demonstrated the concurrent but separate evolution of North American and East Asian lineages, as well as the extensive diversification of the East Asian lineage. The presence of a mobile element structure (MES) was found to be the major difference between these two continental lineages, absent in all North American isolates, and present in all East Asian ones. Other mobile genetic elements, such as the Immune Evasion Complex (IEC), Panton Valentine Leukocidin (PVL), and Staphylococcal Cassette Chromosome mec (SCCmec), showed significant variability within each sub-group and likely represents local selective pressures rather than major characteristics defining the groups. Our analysis also demonstrated the existence of a more ancient ST59 sub-lineage from North America, which was MES negative and contained some of the earliest reported ST59 isolates. Combined with the existence of a MES negative isolate from Taiwan, predicted to have appeared prior to diversification of the East Asian lineages, these results hint at the possibility of a North American origin for the lineage, which gained hold in Eastern Asia following acquisition of MES, and subsequently diversified.
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The dysregulation of glycolysis leads to serials of disease. Rabeprazole is a representative of proton pump inhibitors and widely used in anti-ulcer treatment. However, the function of Rabeprazole on glycolysis in gastric epithelial cells remained to be identified. In this study, 30ï¼Helicobacter pyloriï¼H. pylori-negative cases and 26H. pylori-positive cases treated with Rabeprazole were recruited. The qPCR and Western blotting results showed that Rabeprazole suppressed cell proliferation by inhibition of HK2-mediated glycolysis in BGC823 cells, leading to decrease glucose uptake and lactate production in a dose-dependent way. Furthermore, the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was drastically reduced in response to Rabeprazole stimulation, leading to attenuate STAT3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis showed that Rabeprazole treatment led to a significant inhibition of the binding of STAT3 to the promoter of the HK2 gene, repressing transcriptional activation of HK2. Moreover, the ectopic expression of STAT3 in BGC823 cells resulted in recovery of HK2 transactivation and cell proliferation in Rabeprazole-treated cells. Most importantly, HK2 expression was significantly increased in H. pylori-infected gastric mucosa. These findings suggested that Rabeprazole inhibited cell proliferation by targeting STAT3/HK2 signaling-mediated glucose metabolism in gastric epithelial cells. Therefore, targeting HK2 is an alternative strategy in improving the treatment of patients with H. pylori infection.
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Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Glucólisis/efectos de los fármacos , Rabeprazol/administración & dosificación , Factor de Transcripción STAT3/antagonistas & inhibidores , Antiulcerosos/administración & dosificación , Línea Celular , Proliferación Celular/fisiología , Niño , Sistemas de Liberación de Medicamentos/métodos , Células Epiteliales/metabolismo , Femenino , Mucosa Gástrica/metabolismo , Glucólisis/fisiología , Humanos , Masculino , Factor de Transcripción STAT3/metabolismoRESUMEN
How cancer cells respond to different mechanical environments remains elusive. Here, we investigated the tension in single focal adhesions of MDA-MB-231 (metastatic breast cancer cells) and MCF-10A (normal human breast cells) cells on substrates of varying stiffness using single-cell measurements. Tension measurements in single focal adhesions using an improved FRET-based tension sensor showed that the tension in focal adhesions of MDA-MB-231 cells increased on stiffer substrates while the tension in MCF-10A cells exhibited no apparent change against the substrate stiffness. Viscoelasticity measurements using magnetic tweezers showed that the power-law exponent of MDA-MB-231 cells decreased on stiffer substrates whereas MCF-10A cells had similar exponents throughout the whole stiffness, indicating that MDA-MB-231 cells change their viscoelasticity on stiffer substrates. Such changes in tension in focal adhesions and viscoelasticity against the substrate stiffness represent an adaptability of cancer cells in mechanical environments, which can facilitate the metastasis of cancer cells to different tissues.
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Fenómenos Biomecánicos , Neoplasias de la Mama/patología , Microambiente Celular , Análisis de la Célula Individual , Viscosidad , Adhesión Celular , Línea Celular , Femenino , Transferencia Resonante de Energía de Fluorescencia , HumanosRESUMEN
An increasing number of severe infections caused by Staphylococcus aureus ST398 strains has been observed. However, it has not been elucidated whether all ST398 strains are equally virulent. We collected 13 strains from China and Canada to test in a Caenorhabditis elegans infection model and compared their whole genome sequences (WGS) to explore potential insights into their virulence. All isolates belonged to ST398-methicillin-susceptible S. aureus (MSSA) with variant spa types (t034, t571, t1451, t1250). Pulsed field gel electrophoresis (PFGE) and WGS analyses showed that the 13 isolates clustered into 3 genomic types (Types A-C). WGS and prophage phylogenetic analyses also revealed that the strains could be divided into 3 phage groups (Groups 1-3), which correlated with high-, moderate-, and low-nematocidal activities, with mean killing rates of 94, 67, and 40%, respectively. Group 1 carried ÏSa3-Group 1 (ÏSa3-G1), Group 2 carried ÏSa3-G2, and Group 3 lacked ÏSa3. Interestingly, strain GD1706 (that genetically clustered within Type C) and strain GD487 (within Type B) both carried ÏSa3-G1 like phages and killed 92% of the nematodes, similar to the Type A strains carrying ÏSa3-G1. This study demonstrated that different ST398 sub-lineages possess variable virulence capacities, depending on the presence or absence, as well as the structure of the prophage ÏSa3 that carries virulence factors. IMPORTANCE: Since first being reported in the early 2000s, Staphylococcus aureus ST398 has not only become recognized as a frequent colonizing strain in economically important livestock animals, but has also proven to be a concern for infection in humans and, in particular, has been linked to higher rates of severe invasive human infections. We collected ST398 strains from China and Canada to test in a worm (Caenorhabditis elegans) infection model and compared their whole genome sequences to gain insight into pathogenesis. We have shown that different ST398 sub-strains differ in their virulence potential based on the presence or absence and structure of prophage ÏSa3, which carries important virulence factors. Our observations suggest that ST398 strains are relatively heterogeneous from a clinical perspective, and more studies are needed to differentiate between virulent and non-virulent ST398 strains to determine the true global spread of relevant sub-strains.
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As a long non-coding RNA (lncRNA) and a transcriptional regulator, Metastasis associated lung adenocarcioma transcript-1 (MALAT-1) has been reported to be associated with proliferation and metastasis of hepatocellular carcinoma (HCC). However, the effects of MALAT-1 single nucleotide polymorphisms (SNPs) on HCC remains poorly understood. This study, including 624 HCC cases and 618 controls, aimed to explore the potential associations between three common tagSNPs at MALAT-1 and HCC risk in a Southern Chinese population. No significant associations were observed between the three tagSNPs and HCC risk under any genetic models after adjusting for potential confounders. Additionally, there were no any significant associations in the stratified analysis, combined effect analysis, and multifactor dimensionality reduction (MDR) analysis. Unification analysis of mediation and interaction on HCC risk further showed that four decomposition of total effects ((controlled direct effect (CDE), the reference interaction effect (INTref), the mediated interaction effect (INTmed), or the pure indirect effect (PIE)) were also not significant. Neither was the association between the MALAT-1 SNPs and progression factors of HCC, including TNM staging, metastasis, and cancer embolus; Overall, this study suggested that tagSNPs rs11227209, rs619586, and rs3200401 at MALAT-1 were not significantly associated with HCC susceptibility. Nevertheless, large population-based studies are warranted to further explore the role of MALAT-1 SNPs in HCC incidence and development.
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Carcinoma Hepatocelular/genética , Genotipo , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Anciano , Carcinogénesis , Carcinoma Hepatocelular/patología , Proliferación Celular , China , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
HOX transcript antisense intergenic RNA (HOTAIR) has been widely regarded as a functional lncRNA contributing to multiple cancers. However, few studies have examined the effect of single nucleotide polymorphisms (SNPs) in HOTAIR on the occurrence and development of hepatocellular carcinoma (HCC). In this study, three potentially functional HOTAIR SNPs (rs17105613, rs12427129, and rs3816153) were selected using bioinformatic tools. A case-control study including 1262 cases and 1559 controls was conducted to explore the association of HOTAIR SNPs with the risk of HCC in a Southern Chinese population. We found that SNPs rs12427129 and rs3816153 were associated with the risk of HCC in dominant genetic models (CC: CT + TT, adjusted odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.57-0.90 and GG: GT + TT, adjusted OR = 1.30, 95%CI = 1.08-1.57). Additionally, SNP-environment interactions for rs12427129, rs3816153, and HBsAg status were found to enhance the risk of HCC, with FDR-P as an additive interaction equal to 0.0006 and 0.0144, respectively. In multifactor dimensionality reduction (MDR) analysis, the three-factor model (HBsAg status, rs12427129 and rs3816153) yielded the highest test accuracy of 77.74% (permutation P < 0.001). Interestingly, the effect of rs12427129 and rs3816153 on the risk of HCC could be modified by HBsAg status, while the rs12427129 CT/TT genotype could antagonize the detrimental effect of rs3816153 GT/TT genotype on HCC. Our findings suggest that rs12427129 and rs3816153, including their SNP-SNP and SNP-environment interaction with HBsAg status, potentially play important roles on the susceptibility to HCC.
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Pueblo Asiatico/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/etiología , Interacción Gen-Ambiente , Neoplasias Hepáticas/etiología , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Antígenos de Superficie de la Hepatitis B/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an increase in CAG repeats in the Huntingtin gene (HTT). The striatum is one of the most vulnerable brain regions in HD, and altered delivery of BDNF to the striatum is believed to underlie this high vulnerability. However, the delivery of BDNF to the striatum in HD remains poorly understood. Here, we used real-time imaging to visualize release of BDNF from cortical neurons cultured alone or co-cultured with striatal neurons. BDNF release was significantly decreased in the cortical neurons of zQ175 mice (a knock-in model of HD), and total internal reflection fluorescence microscopy revealed several release patterns of single BDNF-containing vesicles, with distinct kinetics and prevalence, in co-cultured cortical HD neurons. Notably, a smaller proportion of single BDNF-containing vesicles underwent full release in HD neurons than in wild-type neurons. This decreased release of BDNF in cortical neurons might lead to decreased BDNF levels in the striatum because the striatum receives BDNF mainly from the cortex. In addition, we observed a decrease in the total travel length and speed of BDNF-containing vesicles in HD neurons, indicating altered transport of these vesicles in HD. Our findings suggest a potential mechanism for the vulnerability of striatal neurons in HD and offer new insights into the pathogenic mechanisms underlying the degeneration of neurons in HD.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Enfermedad de Huntington/metabolismo , Neuronas/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/citología , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Exocitosis , Proteínas Fluorescentes Verdes/genética , Enfermedad de Huntington/genética , Ratones , Ratones Transgénicos , Transporte de ProteínasRESUMEN
Common burden tests have different statistical performance in genetic association studies of rare variants. Here, we compare the statistical performance of burden tests, such as CMC, WST, SUM and extension methods, using the computer-simulated datasets of rare variants with different parameters of sample sizes, linkage disequilibrium (LD), and different numbers of mixed non-associated variants. The simulation results showed that the type I error for all methods is near 0.05. When the rare variants had the same direction of effect, the higher LD and the less non-associated variants, the higher the power of these method, except the data adaptive SUM test. When the direction was different, the power was significantly reduced for all methods. The methods that consider the direction yielded larger statistical power than those methods without considering the effect direction, except the strong LD condition. And the larger the sample size, the larger the power. The statistical performance of burden tests is affected by a variety of factors, including the sample size, effect direction of variants, non-associated variants, and LD. Therefore, when choosing the method and setting the collection unit and weight, the prior biological information of genetic variation should be integrated to improve study efficiency.
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Algoritmos , Bioestadística/métodos , Estudios de Asociación Genética/métodos , Variación Genética , Simulación por Computador , Predisposición Genética a la Enfermedad/genética , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Modelos GenéticosRESUMEN
BACKGROUND: Group B Streptococcus (GBS) remains a leading cause of neonatal mortality and morbidity. This study aimed to determine the prevalence, antimicrobial susceptibility, serotypes, and molecular characterization of GBS colonized in neonates. METHODS: A cross-sectional study was conducted using a multistage sampling method. Swabs for GBS identification were taken from infants' ear, oral cavity, and umbilicus immediately after birth. All GBS isolates were tested for antimicrobial susceptibility, resistance genes, serotyping, multilocus sequence typing, and virulence genes. RESULTS: Of the 1,814 neonates, 1.3% tested positive for GBS, with 66.7% tested as multidrug resistant. All GBS isolates were susceptible to penicillin, but rates of resistance to tetracycline and erythromycin were high (70.8%), with the predominant resistance genes being tetM and ermB. The predominant serotype was III, followed by Ia and Ib, and the most common genotypes were sequence type (ST) 19, ST10, and ST485. Notably, we found that ST19 and ST17 isolates were associated with serotype III, resistant to tetracycline, erythromycin, and clindamycin, and carrying ermB, tetM, and rib; ST10 and ST12 isolates were associated with serotype Ib, resistant to erythromycin and clindamycin, and carrying ermB and alphaC; and ST485 isolates were associated with serotype Ia and carrying mefA/E, tetM, and epsilon. CONCLUSIONS: These findings indicate a high prevalence of multidrug-resistant GBS and specific phenotype-genotype combinations for GBS clones.
Asunto(s)
Antibacterianos/farmacología , Portador Sano/microbiología , Farmacorresistencia Bacteriana , Serogrupo , Streptococcus agalactiae/genética , Streptococcus agalactiae/fisiología , China , Estudios Transversales , Femenino , Humanos , Recién Nacido , Masculino , Prevalencia , Streptococcus agalactiae/clasificaciónRESUMEN
BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is an important pathogen in causing global morbidity and mortality among children. This study aimed to determine phenotypic and molecular characteristics of S. pneumoniae causing infections in children under five years in China. METHODS: A hospital-based retrospective study was conducted. All 537 S. pneumoniae isolates were tested for antimicrobial susceptibility by E-test method, molecular characteristics including resistance genes, virulence genes and serotypes by multiplex polymerase chain reaction (PCR) method, and sequence types (STs) by sequencing seven housekeeping genes. Minimum spanning tree and correspondence analysis were used to reveal the potential relationship between serotypes and STs. RESULTS: Most of S. pneumoniae isolates were resistant to erythromycin (93.9%) and tetracycline (86.4%), with the predominant resistance genes being erm(B) (92.6%) and tet(M) (95.5%). The prevalent serotypes were 19F, 6B, 19A, 23F and 14, the coverage rate of PCV13 was high in 85.8%, and the predominant STs were ST271, ST320, ST3173, ST81 and ST876. A significant correlation existed between STs and serotypes, with ST271/19F and ST320/19A as the most prevalent clones. Notably, ST271/19F and ST320/19A isolates were associated with resistance to specific antibiotics and carrying of mef(A/E), rlrA and sipA genes. CONCLUSIONS: Our findings suggest the introduction of PCV13 vaccine to Chinese children, and underscore the value of monitoring multiple characteristics to detect new epidemiologic trends and provide implications for the formulation of multivalent pneumococcal vaccines.