Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA s...Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA sequences,ultimately affecting protein function.In this study,RNA editing was identified at the 499th base(c.499)of human vaccinia-related kinase 2(VRK2).This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine(with adenine base)to valine(with guanine base).Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2,which leads to an increase in tumor cell proliferation.Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein(dysbindin)and results in reducing its stability.Herein,we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valinecontaining VRK2.Dysbindin interacts with cyclin D and thereby regulates its expression and function.The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression,resulting in increased tumor growth and reduction in survival rates.It has also been observed that in patient samples,VRK2 level was elevated in breast cancer tissue compared to normal breast tissue.Additionally,the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue.Therefore,it is concluded that VRK2,especially dependent on the 167th variant amino acid,can be one of the indexes of tumor progression and proliferation.展开更多
Objective Mutations in 23 S rRNA gene are known to be associated with macrolide resistance in Mycoplasma pneumoniae(M. pneumoniae). However, these mutations alone do not fully explain the high resistance rates in As...Objective Mutations in 23 S rRNA gene are known to be associated with macrolide resistance in Mycoplasma pneumoniae(M. pneumoniae). However, these mutations alone do not fully explain the high resistance rates in Asia. The aim of this study was to investigate other possible mutations involved in macrolide resistance in M. pneumoniae. Methods The whole genomes of 10 clinical isolates of M. pneumoniae with macrolide resistance were sequenced by Illumina Hi Seq2000 platform. The role of the macrolide-specific efflux transporter was assessed by efflux-pump inhibition assays with reserpine and carbonyl cyanide m-chlorophenyl-hydrazone(CCCP). Results A total of 56 single nucleotide polymorphisms(SNPs) were identified in 10 clinical isolates in comparison to the reference strains M129 and FH. Strikingly, 4 of 30 SNPs causing non-synonymous mutations were clustered in macrolide-specific efflux system gene mac B encoding macrolide-specific efflux pump protein of the ATP-binding cassette transporter family. In assays of the minimal inhibitory concentrations(MIC) of macrolide antibiotics in the presence of the efflux pump inhibitors caused a significant decrease of MICs, even under detectable levels in some strains. Conclusion Our study suggests that macrolide efflux pump may contribute to macrolide resistance in M. pneumoniae in addition to the common point mutations in 23 S r RNA gene.展开更多
AIM:To determine whether alteration of the mitochondria DNA(mtDNA) copy number and its oxidative damage index(mtDNA CT) can be detected by analysis of peripheral blood cells in hepatitis C virus(HCV)infected patients....AIM:To determine whether alteration of the mitochondria DNA(mtDNA) copy number and its oxidative damage index(mtDNA CT) can be detected by analysis of peripheral blood cells in hepatitis C virus(HCV)infected patients.METHODS:This study enrolled two groups of patients aged 40-60 years:a control group and an HCVinfected group in Department of Gastroenterology and Hepatology in Changhua Christian Hospital.Patients with co-infection with hepatitis B virus or human immunodeficiency virus,autoimmune disease,malignant neoplasia,pregnancy,thyroid disease,or alcohol consumption > 40 g/d were excluded.HCV-infected patients who met the following criteria were included:(1) positive HCV antibodies for > 6 mo;(2) alanine aminotransferase(ALT) levels more than twice the upper limit of normal on at least two occasions during the past 6 mo;and(3) histological fibrosis stage higher than F1.The mtDNA copy number and oxidative damage index of HCV mtDNA(mtDNA CT) were measured in peripheral blood leukocytes.The association between mtDNA copy number and mtDNA CT was further analyzed using clinical data.RESULTS:Forty-seven normal controls(male/female:26/21,mean age 50.51 ± 6.15 years) and 132 HCVinfected patients(male/female:76/61,mean age 51.65 ± 5.50 years) were included in the study.The genotypes of HCV-infected patients include type 1a(n = 3),type 1b(n = 83),type 2a(n = 32),and type 2b(n = 14).Liver fibrosis stages were distributed as follows:F1/F2/F3/F4 = 1/61/45/25 and activity scores were A0/A1/A2/A3 = 7/45/55/25.There were no age or gender differences between the two groups.HCV-infected patients had higher hepatitis activity(aspartate transaminase levels 108.77 ± 60.73 vs 23.19 ± 5.47,P < 0.01;ALT levels 168.69 ± 93.12 vs 23.15 ± 9.45,P < 0.01) and lower platelet count(170.40 ± 58.00 vs 251.24 ± 63.42,P < 0.01) than controls.The mtDNA copy number was lower in HCV-infected patients than in controls(173.49 vs 247.93,P < 0.05).The mtDNA CT was higher in HCV-infected patients than in controls(2.92 vs 0.64,P < 0.05).To clarify the clinical significance of these results in HCV-infected patients,their association with different clinical parameters among HCV-infected patients was analyzed.A negative association was found between mtDNA copy number and elevated aspartate transaminase levels(r =-0.17,P < 0.05).Changes in mtDNA copy number were not associated with HCV RNA levels,HCV genotypes,liver fibrosis severity,or inflammatory activity in the liver biopsy specimen.However,a correlation was observed between mtDNA CT and platelet count(r =-0.22,P < 0.01),HCV RNA level(r = 0.36,P < 0.01),and hepatitis activity(r = 0.20,P = 0.02).However,no difference in the change in mtDNA CT was observed between different fibrosis stages or HCV genotypes.CONCLUSION:Oxidative stress and mtDNA damage are detectable in patient's peripheral leukocytes.Increased leukocyte mtDNA CT correlates with higher HCV viremia,increased hepatitis activity,and lower platelet count.展开更多
Hepatitis C virus(HCV)affects 130-210 million people worldwide and is one of the major risk factors for hepatocellular carcinoma.Globally,at least one third of hepatocellular carcinoma cases are attributed to HCV infe...Hepatitis C virus(HCV)affects 130-210 million people worldwide and is one of the major risk factors for hepatocellular carcinoma.Globally,at least one third of hepatocellular carcinoma cases are attributed to HCV infection,and 350000 people died from HCV related diseases per year.There is a great geographical variation of HCV infection globally,with risk factors for the HCV infection differing in various countries.The progression of chronic hepatitis C to end-stage liver disease also varies in different study populations.A long-term follow-up cohort enrolling participants with asymptomatic HCV infection is essential for elucidating the natural history of HCV-caused hepatocellular carcinoma,and for exploring potential seromarkers that have high predictability for risk of hepatocellular carcinoma.However,prospective cohorts comprising individuals with HCV infection are still uncommon.The risk evaluation of viral load elevation and associated liver disease/cancer in HCV(REVEAL-HCV)study has followed a cohort of 1095 residents seropositive for antibodies against hepatitis C virus living in seven townships in Taiwan for more than fifteen years.Most of them have acquired HCV infection through iatrogenic transmission routes.As the participants in the REVEALHCV study rarely receive antiviral therapies,it provides a unique opportunity to study the natural history of chronic HCV infection.In this review,the prevalence,risk factors and natural history of HCV infection are comprehensively reviewed.The study cohort,data collection,and findings on liver disease progression of the REVEAL-HCV study are described.展开更多
High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and ...High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and AXIN1,and identified several novel genes with moderate mutation frequencies,including ARID1A,ARID2,MLL,MLL2,MLL3,MLL4,IRF2,ATM,CDKN2A,FGF19,PIK3CA,RPS6KA3,JAK1,KEAP1,NFE2L2,C16orf62,LEPR,RAC2,and IL6ST.Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling,Wnt/β-catenin signaling,JAK/STAT signaling,and oxidative stress play critical roles in HCC tumorigenesis.Nevertheless,because there are few druggable genes used in HCC therapy,the identification of new therapeutic targets through integrated genomic approaches remains an important task.Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain,copy number alteration(CNA)analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons,homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression.Moreover,integration of CNAs with other high-throughput genomic data,such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models,provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.展开更多
The human microbiome functions as an intricate and coordinated microbial network,residing throughout the mucosal surfaces of the skin,oral cavity,gastrointestinal tract,respiratory tract,and reproductive system.The or...The human microbiome functions as an intricate and coordinated microbial network,residing throughout the mucosal surfaces of the skin,oral cavity,gastrointestinal tract,respiratory tract,and reproductive system.The oral microbiome encompasses a highly diverse microbiota,consisting of over 700 microorganisms,including bacteria,fungi,and viruses.As our understanding of the relationship between the oral microbiome and human health has evolved,we have identified a diverse array of oral and systemic diseases associated with this microbial community,including but not limited to caries,periodontal diseases,oral cancer,colorectal cancer,pancreatic cancer,and inflammatory bowel syndrome.The potential predictive relationship between the oral microbiota and these human diseases suggests that the oral cavity is an ideal site for disease diagnosis and development of rapid point-of-care tests.The oral cavity is easily accessible with a non-invasive collection of biological samples.We can envision a future where early life salivary diagnostic tools will be used to predict and prevent future disease via analyzing and shaping the infant’s oral microbiome.In this review,we present evidence for the establishment of the oral microbiome during early childhood,the capability of using childhood oral microbiome to predict future oral and systemic diseases,and the limitations of the current evidence.展开更多
Risk calculators are widely used in many clinical fields,and integrate several important risk factors through the conversion of a risk function into a single measure of risk.Several studies have been carried out to cr...Risk calculators are widely used in many clinical fields,and integrate several important risk factors through the conversion of a risk function into a single measure of risk.Several studies have been carried out to create risk calculators for the prediction of hepatocellular carcinoma(HCC)in patients with chronic hepatitis B(CHB).Most of them were hospital-based,with limited sample sizes and insufficient external validation.These study groups collaborated to establish the REACH-B risk score,which incorporated five clinical variables to predict HCC risk.This risk score was then validated ininternational clinical cohorts.Evidence suggests that quantitative serum HBsAg level provides additional predictability of HCC,especially in patients with low levels of hepatitis B virus DNA.This novel marker was incorporated into a risk calculator and was internally validated.This tool will hopefully be externally validated in the near future.Risk calculators can be used to support clinical practice,and to establish preventive measures;several"off-label"extension usages have also been implemented.Albeit beneficial,several precautions and discussions should be noted in using the risk calculators.The future development of risk calculators for CHB patients can be extended by applying them to additional CHB-related outcomes,and by incorporating emerging risk parameters.展开更多
AIM: To search the independent factors determining gastric juice acidity and to investigate the acidity of gastric juices in various benign and malignant upper gastrointestinal diseases. METHODS: Fasting gastric juice...AIM: To search the independent factors determining gastric juice acidity and to investigate the acidity of gastric juices in various benign and malignant upper gastrointestinal diseases. METHODS: Fasting gastric juice acidity of 165 healthysubjects and 346 patients with esophageal ulcer (n = 21), gastric ulcer (n = 136), duodenal ulcer (n = 100) or gastric cancer (n = 89) were measured and compared. Additionally, gastric specimens were taken from the antrum and body for rapid urease test and histological examination. RESULTS: Multivariate analysis revealed that bile stain of gastric juice, high acute inflammatory score of the corpus, and atrophy of the corpus were independent risk factors for the development of gastric hypoacidity with odds ratios of 3.1 (95% CI: 1.3-7.3), 3.1 (95% CI: 1.2-7.9) and 3.5 (95% CI: 1.3-9.2). Esophageal ulcer and duodenal ulcer patients had a lower pH level (1.9 and 2.1 vs 2.9, both P < 0.05) of gastric juices than healthy subjects. In contrast, gastric ulcer and gastric cancer patients had a higher pH level (3.4 and 6.6 vs 2.9, both P < 0.001) than healthy controls. Hypoacidity existed in 22%, 5%, 29%, 5% and 88% of healthy subjects, esophageal ulcer, gastric ulcer, duodenal ulcer and gastric cancer patients, respectively. CONCLUSION: Bile reflux, atrophy and dense neutrophil infiltrate of the corpus are three independent factors determining the acidity of gastric juice.展开更多
The multifactorial and multistage pathogenesis of hepatocellular carcinoma(HCC)has fascinated a wide spectrum of scientists for decades.While a number of major risk factors have been identified,their mechanistic roles...The multifactorial and multistage pathogenesis of hepatocellular carcinoma(HCC)has fascinated a wide spectrum of scientists for decades.While a number of major risk factors have been identified,their mechanistic roles in hepatocarcinogenesis still need to be elucidated.Many tumor suppressor genes(TSGs)have been identified as being involved in HCC.These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors:the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele.Hepatitis B virus(HBV)is one of the most important risk factors associated with HCC.Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor,one advantage of mouse models for HBV/HCC research is the numerous and powerfulgenetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs.Here,we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner.Discoveries obtained using mouse models will have a great impact on HCC translational medicine.展开更多
Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplif...Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplified; one way to achieve this is by dividing the disease into subgroups. Toward this effort, recent advances in high-throughput sequencing technology have revealed four molecular subtypes of gastric cancer, which are classified as Epstein-Barr viruspositive, microsatellite instability, genomically stable, and chromosomal instability subtypes. We anticipate that this molecular subtyping will help to extend our knowledge for basic research purposes and will be valuable for clinical use. Here, we review the genomic and epigenomic heterogeneity of the four molecular subtypes of gastric cancer. We also describe a mutational meta-analysis and a reanalysis of DNA methylation that were performed using previously reported gastric cancer datasets.展开更多
BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer(CRC), facilitating diagnosis, prognosis and selection of treatments,including targeted regimens. A report suggested that...BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer(CRC), facilitating diagnosis, prognosis and selection of treatments,including targeted regimens. A report suggested that a 19-gene-based risk classifier(TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.AIM To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.METHODS A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival(PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction(qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry(IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro.RESULTS In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen(P = 0.041).In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7(SLAMF7) and triggering receptor expressed on myeloid cells 1(TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR,and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD73 were significantly lower at day 5 of co-culture than at day 0.CONCLUSION The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.展开更多
Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation,which results in decreased bone mineral density.The MEF2C locus,which encodes the transcription factor MAD...Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation,which results in decreased bone mineral density.The MEF2C locus,which encodes the transcription factor MADS box transcription enhancer factor 2,polypeptide C(MEF2C),is strongly associated with adult osteoporosis and osteoporotic fractures.Although the role of MEF2C in bone and cartilage formation by osteoblasts,osteocytes,and chondrocytes has been studied,the role of MEF2C in osteoclasts,which mediate bone resorption,remains unclear.In this study,we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation.While decreased MEF2C expression resulted in diminished osteoclastogenesis,ectopic expression of MEF2C enhanced osteoclast generation.Using transcriptomic and bioinformatic approaches,we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1,which play a key role in osteoclastogenesis.Mechanistically,MEF2C binds to FOS regulatory regions to induce c-FOS expression,leading to the activation of NFATC1 and downstream osteoclastogenesis.Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis,a murine model of inflammatory arthritis.Our findings reveal direct regulation of osteoclasts by MEF2C,thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.展开更多
The axon guidance cue SLIT3 was identified as an osteoanabolic agent in two recent reports. However, these reports conflict in their nomination of osteoblasts versus osteoclasts as the key producers of skeletal SLIT3 ...The axon guidance cue SLIT3 was identified as an osteoanabolic agent in two recent reports. However, these reports conflict in their nomination of osteoblasts versus osteoclasts as the key producers of skeletal SLIT3 and additionally offer conflicting data on the effects of SLIT3 on osteoclastogenesis. Here, aiming to address this discrepancy, we found no observable SLIT3 expression during human or mouse osteoclastogenesis and the only modest SLIT3-mediated effects on osteoclast differentiation. Conditional deletion of SLIT3 in cathepsin K(CTSK)-positive cells, including osteoclasts, had no effect on the number of osteoclast progenitors, in vitro osteoclast differentiation, overall bone mass, or bone resorption/formation parameters. Similar results were observed with the deletion of SLIT3 in Lys M-positive cells, including osteoclast lineage cells. Consistent with this finding, bone marrow chimeras made from Slit3-/-donors that lacked SLIT3 expression at all stages of osteoclast development displayed normal bone mass relative to controls. Taken in context, multiple lines of evidence were unable to identify the physiologic function of osteoclast-derived SLIT3,indicating that osteoblasts are the major source of skeletal SLIT3.展开更多
AIM: To determine if gene-specific DNA methylation in prospectively collected blood samples is associated with later development of hepatocellular carcinoma(HCC).METHODS: Comparing genome-wide DNA methylation profiles...AIM: To determine if gene-specific DNA methylation in prospectively collected blood samples is associated with later development of hepatocellular carcinoma(HCC).METHODS: Comparing genome-wide DNA methylation profiles using Illumina Human methylation 450 K arrays, we previously identified a list of loci that were differentially methylated between tumor and adjacent nontumor tissues. To examine if dysregulation of DNAmethylation patterns observed in tumor tissues can be detected in white blood cell(WBC) DNA, we conducted a prospective case-control study nested within a community-based cancer screening cohort in Taiwan with 16 years of follow up. We measured methylation levels in ninety-six loci that were aberrant in DNA methylation in HCC tumor tissues compared to adjacent tissues. Baseline WBC DNA from 159 HCC cases and 312 matched controls were bisulfite treated and assayed by Illumina Bead Array. We used the χ2 test for categorical variables and student's t-test for continuous variables to assess the difference in selected characteristics between cases and controls. To estimate associations with HCC risk, we used conditional logistic regression models stratified on the matching factors to calculate odds ratios(OR) and 95%CI. RESULTS: We found that high methylation level in cg10272601 in WNK2 was associated with increased risk of HCC, with an OR of 1.91(95%CI: 1.27-2.86). High methylation levels in both cg12680131 in TPO and cg22511877 in MYT1 L, however, were associated with decreased risk. The ORs(95%CI) were 0.59(0.39-0.87) and 0.50(0.33-0.77), respectively, for those with methylation levels of cg12680131 and cg22511877 above the median compared with those with levels below the median. These associations were still statistically significant in multivariable conditional logistic regression models after adjusting for hepatitis B virus infection and alcohol consumption. CONCLUSION: These findings support the measurement of methylation markers in WBC DNA as biomarkers of HCC susceptibility but should be replicated in additional prospective studies.展开更多
Low-temperature stresses limit the sustainability and productivity of grapevines when early spring frosts damage young grapevine leaves.Spring conditions often expose grapevines to low,but not damaging,chilling temper...Low-temperature stresses limit the sustainability and productivity of grapevines when early spring frosts damage young grapevine leaves.Spring conditions often expose grapevines to low,but not damaging,chilling temperatures and these temperatures have been shown to increase freeze resistance in other model systems.In this study,we examined whole-transcriptome gene expression patterns of young leaf tissue from cuttings of five different grapevine cultivars,exposed to chill and freeze shock,in order to understand the underlying transcriptional landscape associated with cold stress response.No visible damage was observed when grapevine leaves were exposed to chilling temperatures while freeze temperatures resulted in variable damage in all cultivars.Significant differences in gene expression were observed between warm control conditions and all types of cold stress.Exposure to chill stress(4°C)versus freezing stress(−3°C)resulted in very different patterns of gene expression and enriched pathway responses.Genes from the ethylene signaling,ABA signaling,the AP2/ERF,WRKY,and NAC transcription factor families,and starch/sucrose/galactose pathways were among the most commonly observed to be differentially regulated.Preconditioning leaves to chill temperatures prior to freezing temperatures resulted in slight buffering of gene expression responses,suggesting that differences between chill and freeze shock perception complicates identification of candidate genes for cold resistance in grapevine.Overall,the transcriptional landscape contrasts observed between low temperature and freezing stresses demonstrate very different activation of candidate pathways impacting grapevine cold response.展开更多
To improve several agronomic traits in crisphead lettuce(Lactuca sativa L.)under high-temperature growth conditions,we investigated the correlation among those traits in multiple cultivars and performed genetic mappin...To improve several agronomic traits in crisphead lettuce(Lactuca sativa L.)under high-temperature growth conditions,we investigated the correlation among those traits in multiple cultivars and performed genetic mapping of their causal genes.In a field cultivation test of Empire type(serrated leaf)and Salinas type(wavy leaf)cultivars,Empire type cultivars showed increased tipburn susceptibility and late bolting compared with Salinas type cultivars.We attempted genetic mapping of leaf shape and bolting time by ddRAD-seq using the F2 population derived from a cross between‘VI185’(Empire type)and‘ShinanoGreen’(Salinas type).These analyses suggested that both traits are controlled by a single locus in LG5.Genotyping of 51 commercial lettuce cultivars with a tightly linked marker(LG5_v8_252.743Mbp)at this locus showed an association between its genotype and the serrated leaf phenotype.By further fine mapping and transcriptome analysis,a gene encoding putative CIN-like TCP transcription factor was determined to be a candidate gene at this locus and was designated as LsTCP4.An insertion of retrotransposable element was found in the allele of‘VI185’,and its transcript level in the leaves was lower than that in‘ShinanoGreen’.Because shapes of leaf epidermal cells in‘VI185’were similar to those in the TCP family mutant of Arabidopsis thaliana,the leaf shape phenotype was likely caused by reduced expression of LsTCP4.Furthermore,because it is known that the TCP family protein also controls flowering time via interaction with FT in A.thaliana,it was highly possible that LsTCP4 gave pleiotropic effects on both leaf shape and bolting time in lettuce.展开更多
Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,...Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,the role of M-CSF in arthritic bone erosion is not completely understood.Here,we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS,a receptor for M-CSF,leading to the generation of FMS intracellular domain(FICD)fragments.Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses.Moreover,myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model.The FICD formed a complex with DAP5,and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATcl protein expression.Moreover,targeting the MNK1/2 pathway diminished arthritic bone erosion.These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.展开更多
Even though mutations in LMNA have been reported in patients with typical dilated cardio-myopathy(DCM)and atrioventricular block(AVB)previously,the purpose of this study was to disclose this novel genetic abnormality ...Even though mutations in LMNA have been reported in patients with typical dilated cardio-myopathy(DCM)and atrioventricular block(AVB)previously,the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval.Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2,where the LMNA gene was located.Direct DNA sequence analysis revealed a heterozygous G t...展开更多
基金supported by the BK21 FOUR funded by the Ministry of Education,Republic of Korea,the National Research Foundation of Korea(NRF-2022R1F1A1066642,RS-2023-00272063)grant funded by the Korean government(MSIT),and POSTECH Basic Science Research Institute Grant(NRF-2021R1A6A1A10042944).Research was also supported by funds donated by Dr.Jae Kyu Lee and Mr.Jason Gim.Following are results of a study on the“Leaders in INdustry-University Cooperation 3.0”Project,supported by the Ministry of Education and National Research Foundation of Korea.
文摘Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA sequences,ultimately affecting protein function.In this study,RNA editing was identified at the 499th base(c.499)of human vaccinia-related kinase 2(VRK2).This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine(with adenine base)to valine(with guanine base).Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2,which leads to an increase in tumor cell proliferation.Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein(dysbindin)and results in reducing its stability.Herein,we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valinecontaining VRK2.Dysbindin interacts with cyclin D and thereby regulates its expression and function.The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression,resulting in increased tumor growth and reduction in survival rates.It has also been observed that in patient samples,VRK2 level was elevated in breast cancer tissue compared to normal breast tissue.Additionally,the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue.Therefore,it is concluded that VRK2,especially dependent on the 167th variant amino acid,can be one of the indexes of tumor progression and proliferation.
基金supported by the grants from National Nature Science Foundation of China(81601778 and 81672062)the Beijing Natural Science Foundation(7152025)Beijing Talents Fund(2015000021469G192)
文摘Objective Mutations in 23 S rRNA gene are known to be associated with macrolide resistance in Mycoplasma pneumoniae(M. pneumoniae). However, these mutations alone do not fully explain the high resistance rates in Asia. The aim of this study was to investigate other possible mutations involved in macrolide resistance in M. pneumoniae. Methods The whole genomes of 10 clinical isolates of M. pneumoniae with macrolide resistance were sequenced by Illumina Hi Seq2000 platform. The role of the macrolide-specific efflux transporter was assessed by efflux-pump inhibition assays with reserpine and carbonyl cyanide m-chlorophenyl-hydrazone(CCCP). Results A total of 56 single nucleotide polymorphisms(SNPs) were identified in 10 clinical isolates in comparison to the reference strains M129 and FH. Strikingly, 4 of 30 SNPs causing non-synonymous mutations were clustered in macrolide-specific efflux system gene mac B encoding macrolide-specific efflux pump protein of the ATP-binding cassette transporter family. In assays of the minimal inhibitory concentrations(MIC) of macrolide antibiotics in the presence of the efflux pump inhibitors caused a significant decrease of MICs, even under detectable levels in some strains. Conclusion Our study suggests that macrolide efflux pump may contribute to macrolide resistance in M. pneumoniae in addition to the common point mutations in 23 S r RNA gene.
基金Supported by The Basic Research Program of the Korea Science & Engineering Foundation,No.R01-2006-000-10021-0the Korea Health 21 R&D Project,Ministry of Health & Welfare No.A062254
基金Supported by Changhua Christian Hospital,99-CCH-IPR-12
文摘AIM:To determine whether alteration of the mitochondria DNA(mtDNA) copy number and its oxidative damage index(mtDNA CT) can be detected by analysis of peripheral blood cells in hepatitis C virus(HCV)infected patients.METHODS:This study enrolled two groups of patients aged 40-60 years:a control group and an HCVinfected group in Department of Gastroenterology and Hepatology in Changhua Christian Hospital.Patients with co-infection with hepatitis B virus or human immunodeficiency virus,autoimmune disease,malignant neoplasia,pregnancy,thyroid disease,or alcohol consumption > 40 g/d were excluded.HCV-infected patients who met the following criteria were included:(1) positive HCV antibodies for > 6 mo;(2) alanine aminotransferase(ALT) levels more than twice the upper limit of normal on at least two occasions during the past 6 mo;and(3) histological fibrosis stage higher than F1.The mtDNA copy number and oxidative damage index of HCV mtDNA(mtDNA CT) were measured in peripheral blood leukocytes.The association between mtDNA copy number and mtDNA CT was further analyzed using clinical data.RESULTS:Forty-seven normal controls(male/female:26/21,mean age 50.51 ± 6.15 years) and 132 HCVinfected patients(male/female:76/61,mean age 51.65 ± 5.50 years) were included in the study.The genotypes of HCV-infected patients include type 1a(n = 3),type 1b(n = 83),type 2a(n = 32),and type 2b(n = 14).Liver fibrosis stages were distributed as follows:F1/F2/F3/F4 = 1/61/45/25 and activity scores were A0/A1/A2/A3 = 7/45/55/25.There were no age or gender differences between the two groups.HCV-infected patients had higher hepatitis activity(aspartate transaminase levels 108.77 ± 60.73 vs 23.19 ± 5.47,P < 0.01;ALT levels 168.69 ± 93.12 vs 23.15 ± 9.45,P < 0.01) and lower platelet count(170.40 ± 58.00 vs 251.24 ± 63.42,P < 0.01) than controls.The mtDNA copy number was lower in HCV-infected patients than in controls(173.49 vs 247.93,P < 0.05).The mtDNA CT was higher in HCV-infected patients than in controls(2.92 vs 0.64,P < 0.05).To clarify the clinical significance of these results in HCV-infected patients,their association with different clinical parameters among HCV-infected patients was analyzed.A negative association was found between mtDNA copy number and elevated aspartate transaminase levels(r =-0.17,P < 0.05).Changes in mtDNA copy number were not associated with HCV RNA levels,HCV genotypes,liver fibrosis severity,or inflammatory activity in the liver biopsy specimen.However,a correlation was observed between mtDNA CT and platelet count(r =-0.22,P < 0.01),HCV RNA level(r = 0.36,P < 0.01),and hepatitis activity(r = 0.20,P = 0.02).However,no difference in the change in mtDNA CT was observed between different fibrosis stages or HCV genotypes.CONCLUSION:Oxidative stress and mtDNA damage are detectable in patient's peripheral leukocytes.Increased leukocyte mtDNA CT correlates with higher HCV viremia,increased hepatitis activity,and lower platelet count.
文摘Hepatitis C virus(HCV)affects 130-210 million people worldwide and is one of the major risk factors for hepatocellular carcinoma.Globally,at least one third of hepatocellular carcinoma cases are attributed to HCV infection,and 350000 people died from HCV related diseases per year.There is a great geographical variation of HCV infection globally,with risk factors for the HCV infection differing in various countries.The progression of chronic hepatitis C to end-stage liver disease also varies in different study populations.A long-term follow-up cohort enrolling participants with asymptomatic HCV infection is essential for elucidating the natural history of HCV-caused hepatocellular carcinoma,and for exploring potential seromarkers that have high predictability for risk of hepatocellular carcinoma.However,prospective cohorts comprising individuals with HCV infection are still uncommon.The risk evaluation of viral load elevation and associated liver disease/cancer in HCV(REVEAL-HCV)study has followed a cohort of 1095 residents seropositive for antibodies against hepatitis C virus living in seven townships in Taiwan for more than fifteen years.Most of them have acquired HCV infection through iatrogenic transmission routes.As the participants in the REVEALHCV study rarely receive antiviral therapies,it provides a unique opportunity to study the natural history of chronic HCV infection.In this review,the prevalence,risk factors and natural history of HCV infection are comprehensively reviewed.The study cohort,data collection,and findings on liver disease progression of the REVEAL-HCV study are described.
基金Supported by The National Research Program for Biopharmaceuticalsby the National Science Council,Taiwan with grant numbers No.101-2320-B-010-066-MY3,No.101-2325-B-001-011 and No.101-2320-B-001-029-MY3
文摘High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and AXIN1,and identified several novel genes with moderate mutation frequencies,including ARID1A,ARID2,MLL,MLL2,MLL3,MLL4,IRF2,ATM,CDKN2A,FGF19,PIK3CA,RPS6KA3,JAK1,KEAP1,NFE2L2,C16orf62,LEPR,RAC2,and IL6ST.Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling,Wnt/β-catenin signaling,JAK/STAT signaling,and oxidative stress play critical roles in HCC tumorigenesis.Nevertheless,because there are few druggable genes used in HCC therapy,the identification of new therapeutic targets through integrated genomic approaches remains an important task.Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain,copy number alteration(CNA)analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons,homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression.Moreover,integration of CNAs with other high-throughput genomic data,such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models,provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.
基金supported by the National Institute for Dental and Craniofacial Research K23 DE027412。
文摘The human microbiome functions as an intricate and coordinated microbial network,residing throughout the mucosal surfaces of the skin,oral cavity,gastrointestinal tract,respiratory tract,and reproductive system.The oral microbiome encompasses a highly diverse microbiota,consisting of over 700 microorganisms,including bacteria,fungi,and viruses.As our understanding of the relationship between the oral microbiome and human health has evolved,we have identified a diverse array of oral and systemic diseases associated with this microbial community,including but not limited to caries,periodontal diseases,oral cancer,colorectal cancer,pancreatic cancer,and inflammatory bowel syndrome.The potential predictive relationship between the oral microbiota and these human diseases suggests that the oral cavity is an ideal site for disease diagnosis and development of rapid point-of-care tests.The oral cavity is easily accessible with a non-invasive collection of biological samples.We can envision a future where early life salivary diagnostic tools will be used to predict and prevent future disease via analyzing and shaping the infant’s oral microbiome.In this review,we present evidence for the establishment of the oral microbiome during early childhood,the capability of using childhood oral microbiome to predict future oral and systemic diseases,and the limitations of the current evidence.
基金Supported by The Department of Health,Executive Yuan,Taipei,Taiwan,Bristol-Myers Squibb Co.,United StatesAcademia Sinica,Taipei,Taiwan+1 种基金the National Science Council No.NSC101-2314-B-039-029-MY3,Taipei,Taiwanthe National Health Research Institutes(NHRI-EX98-9806PI),Chunan,Taiwan
文摘Risk calculators are widely used in many clinical fields,and integrate several important risk factors through the conversion of a risk function into a single measure of risk.Several studies have been carried out to create risk calculators for the prediction of hepatocellular carcinoma(HCC)in patients with chronic hepatitis B(CHB).Most of them were hospital-based,with limited sample sizes and insufficient external validation.These study groups collaborated to establish the REACH-B risk score,which incorporated five clinical variables to predict HCC risk.This risk score was then validated ininternational clinical cohorts.Evidence suggests that quantitative serum HBsAg level provides additional predictability of HCC,especially in patients with low levels of hepatitis B virus DNA.This novel marker was incorporated into a risk calculator and was internally validated.This tool will hopefully be externally validated in the near future.Risk calculators can be used to support clinical practice,and to establish preventive measures;several"off-label"extension usages have also been implemented.Albeit beneficial,several precautions and discussions should be noted in using the risk calculators.The future development of risk calculators for CHB patients can be extended by applying them to additional CHB-related outcomes,and by incorporating emerging risk parameters.
基金Supported by Research grant NSC-96-2314-B-075B-009 from the National Science Council, Taiwan
文摘AIM: To search the independent factors determining gastric juice acidity and to investigate the acidity of gastric juices in various benign and malignant upper gastrointestinal diseases. METHODS: Fasting gastric juice acidity of 165 healthysubjects and 346 patients with esophageal ulcer (n = 21), gastric ulcer (n = 136), duodenal ulcer (n = 100) or gastric cancer (n = 89) were measured and compared. Additionally, gastric specimens were taken from the antrum and body for rapid urease test and histological examination. RESULTS: Multivariate analysis revealed that bile stain of gastric juice, high acute inflammatory score of the corpus, and atrophy of the corpus were independent risk factors for the development of gastric hypoacidity with odds ratios of 3.1 (95% CI: 1.3-7.3), 3.1 (95% CI: 1.2-7.9) and 3.5 (95% CI: 1.3-9.2). Esophageal ulcer and duodenal ulcer patients had a lower pH level (1.9 and 2.1 vs 2.9, both P < 0.05) of gastric juices than healthy subjects. In contrast, gastric ulcer and gastric cancer patients had a higher pH level (3.4 and 6.6 vs 2.9, both P < 0.001) than healthy controls. Hypoacidity existed in 22%, 5%, 29%, 5% and 88% of healthy subjects, esophageal ulcer, gastric ulcer, duodenal ulcer and gastric cancer patients, respectively. CONCLUSION: Bile reflux, atrophy and dense neutrophil infiltrate of the corpus are three independent factors determining the acidity of gastric juice.
基金Supported by Research grants from the Ministry of Science and Technology(MOST)in Taiwan,No.NSC99-2628-B-010-001-MY3,MOST 103-2321-B-010-003,MOST 103-2633-H-010-001,MOST 103-2633-B-400-002 and MOST104-3011-B-010-001a grant from the Ministry of Education,Aim for the Top University Plan
文摘The multifactorial and multistage pathogenesis of hepatocellular carcinoma(HCC)has fascinated a wide spectrum of scientists for decades.While a number of major risk factors have been identified,their mechanistic roles in hepatocarcinogenesis still need to be elucidated.Many tumor suppressor genes(TSGs)have been identified as being involved in HCC.These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors:the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele.Hepatitis B virus(HBV)is one of the most important risk factors associated with HCC.Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor,one advantage of mouse models for HBV/HCC research is the numerous and powerfulgenetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs.Here,we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner.Discoveries obtained using mouse models will have a great impact on HCC translational medicine.
基金Supported by Grants from the genomics program of the National Research Foundation of Korea funded by the Ministry of ScienceICT+4 种基金and Future PlanningNRF-2012M3A9D1054670 and NRF-2014M3C9A3068554(to Kim SY)Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of EducationNRF-2013R1A1A2006621(to Kim M)the Korea Research Institute of Bioscience and Biotechnology research initiative grant
文摘Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplified; one way to achieve this is by dividing the disease into subgroups. Toward this effort, recent advances in high-throughput sequencing technology have revealed four molecular subtypes of gastric cancer, which are classified as Epstein-Barr viruspositive, microsatellite instability, genomically stable, and chromosomal instability subtypes. We anticipate that this molecular subtyping will help to extend our knowledge for basic research purposes and will be valuable for clinical use. Here, we review the genomic and epigenomic heterogeneity of the four molecular subtypes of gastric cancer. We also describe a mutational meta-analysis and a reanalysis of DNA methylation that were performed using previously reported gastric cancer datasets.
基金Korea Research Foundation,No.2016R1E1A1A02919844 to Kim JC and No.2017R1A2B1009062 to Roh SAMinistry of Science,ICT,and Future Planning,Republic of Koreathe Asan Institute for Life Sciences,No.2016-710 to Lee JL
文摘BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer(CRC), facilitating diagnosis, prognosis and selection of treatments,including targeted regimens. A report suggested that a 19-gene-based risk classifier(TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.AIM To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.METHODS A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival(PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction(qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry(IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro.RESULTS In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen(P = 0.041).In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7(SLAMF7) and triggering receptor expressed on myeloid cells 1(TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR,and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD73 were significantly lower at day 5 of co-culture than at day 0.CONCLUSION The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.
文摘Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation,which results in decreased bone mineral density.The MEF2C locus,which encodes the transcription factor MADS box transcription enhancer factor 2,polypeptide C(MEF2C),is strongly associated with adult osteoporosis and osteoporotic fractures.Although the role of MEF2C in bone and cartilage formation by osteoblasts,osteocytes,and chondrocytes has been studied,the role of MEF2C in osteoclasts,which mediate bone resorption,remains unclear.In this study,we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation.While decreased MEF2C expression resulted in diminished osteoclastogenesis,ectopic expression of MEF2C enhanced osteoclast generation.Using transcriptomic and bioinformatic approaches,we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1,which play a key role in osteoclastogenesis.Mechanistically,MEF2C binds to FOS regulatory regions to induce c-FOS expression,leading to the activation of NFATC1 and downstream osteoclastogenesis.Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis,a murine model of inflammatory arthritis.Our findings reveal direct regulation of osteoclasts by MEF2C,thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.
基金an Award Program for the Minjiang Scholar Professorship in Fujian Province, a start-up grant from Xiamen University and support from the National Natural Science Foundation of China (81972034 to RX)supported by the NIH grant DP5OD021351supported by NIH grants (R01AR068970, AR071463)。
文摘The axon guidance cue SLIT3 was identified as an osteoanabolic agent in two recent reports. However, these reports conflict in their nomination of osteoblasts versus osteoclasts as the key producers of skeletal SLIT3 and additionally offer conflicting data on the effects of SLIT3 on osteoclastogenesis. Here, aiming to address this discrepancy, we found no observable SLIT3 expression during human or mouse osteoclastogenesis and the only modest SLIT3-mediated effects on osteoclast differentiation. Conditional deletion of SLIT3 in cathepsin K(CTSK)-positive cells, including osteoclasts, had no effect on the number of osteoclast progenitors, in vitro osteoclast differentiation, overall bone mass, or bone resorption/formation parameters. Similar results were observed with the deletion of SLIT3 in Lys M-positive cells, including osteoclast lineage cells. Consistent with this finding, bone marrow chimeras made from Slit3-/-donors that lacked SLIT3 expression at all stages of osteoclast development displayed normal bone mass relative to controls. Taken in context, multiple lines of evidence were unable to identify the physiologic function of osteoclast-derived SLIT3,indicating that osteoblasts are the major source of skeletal SLIT3.
基金Supported by National Institutes of Health grants,RO1ES005116(Santella RM)and P30ES009089(Santella RM)
文摘AIM: To determine if gene-specific DNA methylation in prospectively collected blood samples is associated with later development of hepatocellular carcinoma(HCC).METHODS: Comparing genome-wide DNA methylation profiles using Illumina Human methylation 450 K arrays, we previously identified a list of loci that were differentially methylated between tumor and adjacent nontumor tissues. To examine if dysregulation of DNAmethylation patterns observed in tumor tissues can be detected in white blood cell(WBC) DNA, we conducted a prospective case-control study nested within a community-based cancer screening cohort in Taiwan with 16 years of follow up. We measured methylation levels in ninety-six loci that were aberrant in DNA methylation in HCC tumor tissues compared to adjacent tissues. Baseline WBC DNA from 159 HCC cases and 312 matched controls were bisulfite treated and assayed by Illumina Bead Array. We used the χ2 test for categorical variables and student's t-test for continuous variables to assess the difference in selected characteristics between cases and controls. To estimate associations with HCC risk, we used conditional logistic regression models stratified on the matching factors to calculate odds ratios(OR) and 95%CI. RESULTS: We found that high methylation level in cg10272601 in WNK2 was associated with increased risk of HCC, with an OR of 1.91(95%CI: 1.27-2.86). High methylation levels in both cg12680131 in TPO and cg22511877 in MYT1 L, however, were associated with decreased risk. The ORs(95%CI) were 0.59(0.39-0.87) and 0.50(0.33-0.77), respectively, for those with methylation levels of cg12680131 and cg22511877 above the median compared with those with levels below the median. These associations were still statistically significant in multivariable conditional logistic regression models after adjusting for hepatitis B virus infection and alcohol consumption. CONCLUSION: These findings support the measurement of methylation markers in WBC DNA as biomarkers of HCC susceptibility but should be replicated in additional prospective studies.
基金All research was supported by USDA appropriated funds for project number 1910-21220-006-00D.
文摘Low-temperature stresses limit the sustainability and productivity of grapevines when early spring frosts damage young grapevine leaves.Spring conditions often expose grapevines to low,but not damaging,chilling temperatures and these temperatures have been shown to increase freeze resistance in other model systems.In this study,we examined whole-transcriptome gene expression patterns of young leaf tissue from cuttings of five different grapevine cultivars,exposed to chill and freeze shock,in order to understand the underlying transcriptional landscape associated with cold stress response.No visible damage was observed when grapevine leaves were exposed to chilling temperatures while freeze temperatures resulted in variable damage in all cultivars.Significant differences in gene expression were observed between warm control conditions and all types of cold stress.Exposure to chill stress(4°C)versus freezing stress(−3°C)resulted in very different patterns of gene expression and enriched pathway responses.Genes from the ethylene signaling,ABA signaling,the AP2/ERF,WRKY,and NAC transcription factor families,and starch/sucrose/galactose pathways were among the most commonly observed to be differentially regulated.Preconditioning leaves to chill temperatures prior to freezing temperatures resulted in slight buffering of gene expression responses,suggesting that differences between chill and freeze shock perception complicates identification of candidate genes for cold resistance in grapevine.Overall,the transcriptional landscape contrasts observed between low temperature and freezing stresses demonstrate very different activation of candidate pathways impacting grapevine cold response.
基金supported by grants from the Ministry of Agriculture,Forestry and Fisheries of Japan(Project for Climate Change,Vegetable-4103)for K.S.,Cooperative Research Grant of the Genome Research for BioResource,NODAI Genome Research Center,Tokyo University of Agriculture for K.S.and K.K.,Grant-in-Aid for Scientific Research for K.K.,MEXT-Supported Program for the Strategic Research Foundation at Private Universities,2013-2017(S1311017)for K.K.We thank Rumi Ohtake of NODAI Genome Research Center,Tokyo University of Agriculture,and Masaki Kawakami of the Nagano Vegetable Ornamental Crops Experiment Station for helpful discussion and advice.We also thank Chizuru Kagami,Yoko Takahashi,Yoshie Nakayama,and especially Atsushi Tsukada and Hideaki Okazawa for technical assistance in the field experiment.We also thank Akane Igarashi,Reina Ohwaki,and Hiroto Kayama for technical assistance in the RNA-seq analysis and genome sequencing,Naho Takahashi for technical assistance in the extraction of genomic DNA.Moreover,we also thank‘Bas Breau’at hakuba for helpful assistance.
文摘To improve several agronomic traits in crisphead lettuce(Lactuca sativa L.)under high-temperature growth conditions,we investigated the correlation among those traits in multiple cultivars and performed genetic mapping of their causal genes.In a field cultivation test of Empire type(serrated leaf)and Salinas type(wavy leaf)cultivars,Empire type cultivars showed increased tipburn susceptibility and late bolting compared with Salinas type cultivars.We attempted genetic mapping of leaf shape and bolting time by ddRAD-seq using the F2 population derived from a cross between‘VI185’(Empire type)and‘ShinanoGreen’(Salinas type).These analyses suggested that both traits are controlled by a single locus in LG5.Genotyping of 51 commercial lettuce cultivars with a tightly linked marker(LG5_v8_252.743Mbp)at this locus showed an association between its genotype and the serrated leaf phenotype.By further fine mapping and transcriptome analysis,a gene encoding putative CIN-like TCP transcription factor was determined to be a candidate gene at this locus and was designated as LsTCP4.An insertion of retrotransposable element was found in the allele of‘VI185’,and its transcript level in the leaves was lower than that in‘ShinanoGreen’.Because shapes of leaf epidermal cells in‘VI185’were similar to those in the TCP family mutant of Arabidopsis thaliana,the leaf shape phenotype was likely caused by reduced expression of LsTCP4.Furthermore,because it is known that the TCP family protein also controls flowering time via interaction with FT in A.thaliana,it was highly possible that LsTCP4 gave pleiotropic effects on both leaf shape and bolting time in lettuce.
基金This work was supported by the National institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)of the NIH under Award Numbers R01 AR069562 and AR073156(to K.H.P.-M.).
文摘Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,the role of M-CSF in arthritic bone erosion is not completely understood.Here,we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS,a receptor for M-CSF,leading to the generation of FMS intracellular domain(FICD)fragments.Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses.Moreover,myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model.The FICD formed a complex with DAP5,and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATcl protein expression.Moreover,targeting the MNK1/2 pathway diminished arthritic bone erosion.These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.
文摘Even though mutations in LMNA have been reported in patients with typical dilated cardio-myopathy(DCM)and atrioventricular block(AVB)previously,the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval.Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2,where the LMNA gene was located.Direct DNA sequence analysis revealed a heterozygous G t...