ABSTRACT
N6-methyladenosine (m6A) modification plays an important role in RNA molecular functions, therefore affecting the initiation and development of hepatocellular carcinoma (HCC). Herein, multiple datasets were applied to conduct a comprehensive analysis of DEGs within HCC and the analysis revealed significant dysregulation of numerous genes. Functional and signaling pathway enrichment analyses were performed. Further, TP53RK binding protein (TPRKB) emerged as a significant factor, exhibiting high expression level within HCC tissue samples and cells which could predict HCC patients' poor OS. Knockdown investigations of TPRKB in vitro demonstrated the effect of TPRKB knockdown on attenuating the aggressiveness of HCC cells by suppressing the viability, colony formation, invasive ability, and migratory ability, inducing cell cycle arrest, and facilitating the apoptosis of HCC cells. Investigations in vivo revealed that TPRKB knockdown significantly suppressed tumor growth in mice model. Additionally, the study identified methyltransferase 5, N6-adenosine (METTL5) as a potential regulator of TPRKB expression via m6A modification, positively regulating TPRKB expression by enhancing TPRKB mRNA stability. The dynamic effects of METTL5 and TPRKB upon the phenotypes of HCC cells further confirmed that TPRKB overexpression partially abolished the anti-cancer effects of METTL5 knockdown upon the aggressiveness of HCC cells. Conclusively, our findings uncover that TPRKB, significantly overexpressed in HCC, exerts a critical effect on promoting tumor aggressiveness, and its expression shows to be positively regulated by METTL5 via m6A methylation. These insights deepen the understanding of HCC pathogenesis and open new avenues for targeted therapies, highlighting that METTL5-TPRKB axis is an underlying new therapeutic target in HCC management.
ABSTRACT
A novel Gram-stain-negative, curved rod-shaped, motile and chitin-degrading strain, designated CD1T, was isolated from crawfish pond sediment in Caidian District (30° 58' N 114° 03' E), Wuhan City, Hubei Province, PR China. Growth of this strain was observed at 15-40°C (optimum between 28 and 30â°C), at pH 7.0-9.0 (optimum between pH 7.0 and 8.0) and with 0-1â% (w/v) NaCl (optimum at 0â%). With respect to the 16S rRNA gene sequences, strain CD1T had the highest similarity (96.91-97.25â%) to four type strains of the genera 'Chitinolyticbacter' and Chitiniphilus within the family Chitinibacteraceae. The phylogenetic trees based on genome sequences and 16S rRNA gene sequences indicated that strain CD1T was close to members of these two genera, in particular to the genus Chitiniphilus. The genomic DNA G+C content of strain CD1T was 64.8 mol%. The average nucleotide identity and the Genome-to-Genome Distance Calculator results showed low relatedness (below 95 and 70â%, respectively) between strain CD1T and the closely related type strains. Ubiquinone-8 was the predominant quinone. The major cellular fatty acids were C10â:â0, C16â:â0, summed feature 3 (C16â:â1 ω7c and/or C16â:â1 ω6c) and summed feature 8 (C18â:â1 ω7c and/or C18â:â1 ω6c). The polar lipid profile was composed of a mixture of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, four unidentified lipids, two unidentified phospholipids, two unidentified aminolipids and an unidentified aminoglycolipid. On the basis of the evidences presented in this study, strain CD1T represents a novel species of the genus Chitiniphilus, for which the name Chitiniphilus purpureus sp. nov. is proposed, with strain CD1T (=CCTCC AB 2022395T=KCTC 92850T) as the type strain.
Subject(s)
Betaproteobacteria , Chitin , Phylogeny , Ponds , RNA, Ribosomal, 16S/genetics , Base Composition , Fatty Acids/chemistry , Sequence Analysis, DNA , DNA, Bacterial/genetics , Bacterial Typing Techniques , BacteriaABSTRACT
Arsenic (As) is widely present in the environment, and virtually all bacteria possess a conserved ars operon to resist As toxicity. High selenium (Se) concentrations tend to be cytotoxic. Se has an uneven regional distribution and is added to mitigate As contamination in Se-deficient areas. However, the bacterial response to exogenous Se remains poorly understood. Herein, we found that As(III) presence was crucial for Enterobacter sp. Z1 to develop resistance against Se(IV). Se(IV) reduction served as a detoxification mechanism in bacteria, and our results demonstrated an increase in the production of Se nanoparticles (SeNPs) in the presence of As(III). Tandem mass tag proteomics analysis revealed that the induction of As(III) activated the inositol phosphate, butanoyl-CoA/dodecanoyl-CoA, TCA cycle, and tyrosine metabolism pathways, thereby enhancing bacterial metabolism to resist Se(IV). Additionally, arsHRBC, sdr-mdr, purHD, and grxA were activated to participate in the reduction of Se(IV) into SeNPs. Our findings provide innovative perspectives for exploring As-induced Se biotransformation in prokaryotes.
Subject(s)
Arsenic , Arsenites , Selenium , Selenium/pharmacology , Selenium/metabolism , Selenious Acid/pharmacology , Selenious Acid/metabolism , Enterobacter/metabolism , Oxidation-ReductionABSTRACT
Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines Coptis chinensis and Phellodendron chinense. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine's physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure-activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives.
ABSTRACT
Genome-wide association studies have identified 10q24.32 as a robust schizophrenia risk locus. Here we identify a regulatory variant (rs10786700) that disrupts binding of transcription factors at 10q24.32. We independently confirmed the association between rs10786700 and schizophrenia in a large Chinese cohort (n = 11 547) and uncovered the biological mechanism underlying this association. We found that rs10786700 resides in a super-enhancer element that exhibits dynamic activity change during the development process and that the risk allele (C) of rs10786700 conferred significant lower enhancer activity through enhancing binding affinity to repressor element-1 silencing transcription factor (REST). CRISPR-Cas9-mediated genome editing identified SUFU as a potential target gene by which rs10786700 might exert its risk effect on schizophrenia, as deletion of rs10786700 downregulated SUFU expression. We further investigated the role of Sufu in neurodevelopment and found that Sufu knockdown inhibited proliferation of neural stem cells and neurogenesis, affected molecular pathways (including neurodevelopment-related pathways, PI3K-Akt and ECM-receptor interaction signalling pathways) associated with schizophrenia and altered the density of dendritic spines. These results reveal that the functional risk single nucleotide polymorphism rs10786700 at 10q24.32 interacts with REST synergistically to regulate expression of SUFU, a novel schizophrenia risk gene which is involved in schizophrenia pathogenesis by affecting neurodevelopment and spine morphogenesis.
Subject(s)
Schizophrenia , Humans , Schizophrenia/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Phosphatidylinositol 3-Kinases/genetics , Polymorphism, Single Nucleotide/genetics , Transcription Factors/geneticsABSTRACT
Selenium (Se) is a trace element that is essential for human health. Daily dietary Se intake is governed by the food chain through soil-plant systems. However, the cadmium (Cd) content tends to be excessive in seleniferous soil, in which Se and Cd have complex interactions. Therefore, it is a great challenge to grow crops containing appreciable amounts of Se but low amounts of Cd. We compared the effects of five Se-transforming bacteria on Se and Cd uptake by Brassica rapa L. in a native seleniferous Cd-polluted soil. The results showed that three Se-oxidizing bacteria (LX-1, LX-100, and T3F4) increased the Se content of the aboveground part of the plant by 330.8%, 309.5%, and 724.3%, respectively, compared to the control (p < 0.05). The three bacteria also reduced the aboveground Cd content by 15.1%, 40.4%, and 16.4%, respectively (p < 0.05). In contrast, the Se(IV)-reducing bacterium ES2-45 and weakly Se-transforming bacterium LX-4 had no effect on plant Se uptake, although they did decrease the aboveground Cd content. In addition, the three Se-oxidizing bacteria increased the Se available in the soil by 38.4%, 20.4%, and 24.0%, respectively, compared to the control (p < 0.05). The study results confirm the feasibility of using Se-oxidizing bacteria to simultaneously enhance plant Se content and reduce plant Cd content in seleniferous Cd-polluted soil.
Subject(s)
Selenium , Soil Pollutants , Humans , Cadmium/analysis , Sand , Biodegradation, Environmental , Biofortification , Soil , Crops, Agricultural , Oxidation-Reduction , Soil Pollutants/analysisABSTRACT
Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5Ethynyl2'deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.
Subject(s)
Apoptosis , Cell Proliferation , Diterpenes, Kaurane , Pituitary Neoplasms , Diterpenes, Kaurane/pharmacology , Apoptosis/drug effects , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/pathology , Cell Proliferation/drug effects , Cell Line, Tumor , Humans , Cell Movement/drug effects , Cell Survival/drug effects , Adenoma/drug therapy , Adenoma/pathologyABSTRACT
Immune dysregulation has been consistently reported in psychiatric disorders, however, the causes and mechanisms underlying immune dysregulation in psychiatric disorders remain largely unclear. Here we conduct a Mendelian randomization study by integrating plasma proteome and GWASs of schizophrenia, bipolar disorder and depression. The primate-specific immune-related protein BTN3A3 showed the most significant associations with all three psychiatric disorders. In addition, other immune-related proteins, including AIF1, FOXO3, IRF3, CFHR4, IGLON5, FKBP2, and PI3, also showed significant associations with psychiatric disorders. Our study showed that a proportion of psychiatric risk variants may contribute to disease risk by regulating immune-related plasma proteins, providing direct evidence that connect the genetic risk of psychiatric disorders to immune system.
Subject(s)
Bipolar Disorder , Mental Disorders , Animals , Proteome/genetics , Proteome/metabolism , Mendelian Randomization Analysis , Mental Disorders/genetics , Bipolar Disorder/genetics , Blood Proteins , Genome-Wide Association Study , Polymorphism, Single NucleotideABSTRACT
Bacterial strain H33T was isolated from tobacco plant soil and was characterized using a polyphasic taxonomy approach. Strain H33T was a Gram-stain-negative, rod-shaped, non-motile and strictly aerobic bacterium. Phylogenetic analyses based on 16S rRNA gene sequences and coding sequences of the up-to-date bacterial core gene set (92 protein clusters) indicated that H33T belongs to the genus Sphingobium. Strain H33T showed the highest 16S rRNA gene sequence similarity to Sphingobium xanthum NL9T (97.2%) and showed 72.3-80.6â% average nucleotide identity and 19.7-29.2â% digital DNA-DNA hybridization identity with the strains of other species of the genus Sphingobium. Strain H33T grew optimally at 30°C, pH 7 and could tolerate 0.5â% (w/v) NaCl. The isoprenoid quinones were ubiquinone-9 (64.1%) and ubiquinone-10 (35.9%). Spermidine was the major polyamine. The major fatty acids of H33T were summed feature 8 (C18â:â1 ω7c and/or C18â:â1 ω6c). The polar lipid profile consisted of a mixture of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, sphingoglycolipid, two unidentified lipids, two unidentified glycolipids, two unidentified aminoglycolipids and an unidentified phospholipid. The genomic DNA G+C content of H33T was 64.9 mol%. Based on the phylogenetic and phenotypic data, H33T was considered a representative of a novel species in the genus Sphingobium. We propose the name Sphingobium nicotianae sp. nov., with H33T (=CCTCC AB 2022073T=LMG 32569T) as the type strain.
Subject(s)
Fatty Acids , Nicotiana , Fatty Acids/chemistry , Phylogeny , RNA, Ribosomal, 16S/genetics , DNA, Bacterial/genetics , Base Composition , Bacterial Typing Techniques , Sequence Analysis, DNA , Phospholipids/chemistryABSTRACT
A Gram-negative, aerobic bacterial strain, designated LX-88T, was isolated from seleniferous soil in Enshi, Hubei Province, PR China. Strain LX-88Toxidized elemental selenium to selenite, and produced carotenoids but not bacteriochlorophyll. The isolate grew optimally at 28 °C, pH 8.0 and with 0.5â% (w/v) NaCl. Phylogenetic analysies of the organism's 16S rRNA and bacterial core gene set sequences indicated that LX-88T belongs to the genus Croceibacterium, and has the highest degree of 16S rRNA gene sequence similarity to Croceibacterium soli MN-1T (97.4â%). The LX-88T genome was 3.4 Mbp and had a G+C content of 63.6âmol%. The average nucleotide identity and digital DNA-DNA hybridization values showed low relatedness (below 95 and 70â%, respectively) between strain LX-88T and other strains in the genus Croceibacterium. Ubiquinone-10 was the predominant quinone. The polar lipid profile was dominated by diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, an unidentified aminolipid, an unidentified phospholipid and an unidentified lipid. The major fatty acid was summed feature 8 (C18â:â1 ω7c and/or C18â:â1 ω6c). These physiological and biochemical tests facilitated the differentiation of strain LX-88T from other members of the genus Croceibacterium. The results of this multifaceted taxonomic study indicate that strain LX-88T represents a novel species in the genus Croceibacterium, for which the name Croceibacterium selenioxidans sp. nov. is proposed. The type strain is LX-88T (=MCCC 1K08007T=LMG 32570T).
Subject(s)
Fatty Acids , Phospholipids , Fatty Acids/chemistry , Phylogeny , RNA, Ribosomal, 16S/genetics , Base Composition , Bacterial Typing Techniques , DNA, Bacterial/genetics , Sequence Analysis, DNA , Phospholipids/chemistry , Ubiquinone/chemistryABSTRACT
Genome-wide association studies have shown that genetic variants at 2q33.1 are strongly associated with schizophrenia. However, potential causal variants in this locus and their roles in schizophrenia remain unknown. Here, we identified two functional variants (rs796364 and rs281759) that disrupt CTCF, RAD21 and FOXP2 binding at 2q33.1. We systematically investigated the regulatory mechanisms of these two variants with serial experiments, including reporter gene assays and electrophoretic mobility shift assay. Intriguingly, these two single nucleotide polymorphisms physically interacted with TYW5 and showed the most significant associations with TYW5 expression in human brain. Consistently, CRISPR-Cas9-mediated genome editing confirmed the regulatory effect of the two single nucleotide polymorphisms on TYW5 expression. Additionally, expression analysis indicated that TYW5 was significantly upregulated in brains of schizophrenia cases compared with controls, suggesting that rs796364 and rs281759 might confer schizophrenia risk by modulating TYW5 expression. We over-expressed TYW5 in mouse neural stem cells and rat primary neurons to mimic its upregulation in schizophrenia and found significant alterations in the proliferation and differentiation of neural stem cells, as well as dendritic spine density following TYW5 overexpression, indicating its important roles in neurodevelopment and spine morphogenesis. Furthermore, we independently confirmed the association between rs796364 and schizophrenia in a Chinese cohort of 8202 subjects. Finally, transcriptome analysis revealed that TYW5 affected schizophrenia-associated pathways. These lines of evidence consistently revealed that rs796364 and rs281759 might contribute to schizophrenia risk by regulating the expression of TYW5, a gene whose expression dysregulation affects two important schizophrenia pathophysiological processes (i.e. neurodevelopment and dendritic spine formation).
Subject(s)
Genome-Wide Association Study , Mixed Function Oxygenases/genetics , Schizophrenia , Animals , Asian People/genetics , Genetic Predisposition to Disease/genetics , Humans , Mice , Polymorphism, Single Nucleotide/genetics , Rats , Schizophrenia/geneticsABSTRACT
Recent genome-wide association studies have reported multiple schizophrenia risk loci, yet the functional variants and their roles in schizophrenia remain to be characterized. Here we identify a functional single nucleotide polymorphism (rs2270363: G>A) at the schizophrenia risk locus 16p13.3. rs2270363 lies in the E-box element of the promoter of NMRAL1 and disrupts binding of the basic helix-loop-helix leucine zipper family proteins, including USF1, MAX and MXI1. We validated the regulatory effects of rs2270363 using reporter gene assays and electrophoretic mobility shift assay. Besides, expression quantitative trait loci analysis showed that the risk allele (A) of rs2270363 was significantly associated with elevated NMRAL1 expression in the human brain. Transcription factors knockdown and CRISPR-Cas9-mediated editing further confirmed the regulatory effects of the genomic region containing rs2270363 on NMRAL1. Intriguingly, NMRAL1 was significantly downregulated in the brain of schizophrenia patients compared with healthy subjects, and knockdown of Nmral1 expression affected proliferation and differentiation of mouse neural stem cells, as well as genes and pathways associated with brain development and synaptic transmission. Of note, Nmral1 knockdown resulted in significant decrease of dendritic spine density, revealing the potential pathophysiological mechanisms of NMRAL1 in schizophrenia. Finally, we independently confirmed the association between rs2270363 and schizophrenia in the Chinese population and found that the risk allele of rs2270363 was the same in European and Chinese populations. These lines of evidence suggest that rs2270363 may confer schizophrenia risk by regulating NMRAL1, a gene whose expression dysregulation might be involved in the pathogenesis of schizophrenia by affecting neurodevelopment and synaptic plasticity.
Subject(s)
Schizophrenia , Transcription Factors , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Mice , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Transcription Factors/geneticsABSTRACT
This article presents a systematic review on autism care, diagnosis, and intervention based on mobile apps running on smartphones and tablets. Here, the term "intervention" means a carefully planned set of activities with the objective of improving autism symptoms. We guide our review on related studies using five research questions. First, who benefits the most from these mobile apps? Second, what are the primary purposes of these mobile apps? Third, what mechanisms have been incorporated in these mobiles apps to improve usability? Fourth, what guidelines have been used in the design and implementation of these mobile apps? Fifth, what theories and frameworks have been used as the foundation for these mobile apps to ensure the intervention effectiveness? As can be seen from these research questions, we focus on the usability and software development of the mobile apps. Informed by the findings of these research questions, we propose a taxonomy for the mobile apps and their users. The mobile apps can be categorized into autism support apps, educational apps, teacher training apps, parental support apps, and data collection apps. The individuals with autism spectrum disorder (ASD) are the primary users of the first two categories of apps. Teachers of children with ASD are the primary users of the teacher training apps. Parents are the primary users of the parental support apps, while individuals with ASD are usually the primary users of the data collection apps and clinicians and autism researchers are the beneficiaries. Gamification, virtual reality, and autism-specific mechanisms have been used to improve the usability of the apps. User-centered design is the most popular approach for mobile app development. Augmentative and alternative communication, video modeling, and various behavior change practices have been used as the theoretical foundation for intervention efficacy.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Mobile Applications , Child , Humans , Autistic Disorder/diagnosis , Autistic Disorder/therapy , Software Design , SmartphoneABSTRACT
BACKGROUND: Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson's disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD. METHODS: We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. RESULTS: We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls. CONCLUSION: Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development.
Subject(s)
Genome-Wide Association Study , Parkinson Disease , Genetic Predisposition to Disease/genetics , Genomics , Humans , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/geneticsABSTRACT
BACKGROUND: Large-scale genome-wide association studies (GWASs) have reported multiple risk variants for Parkinson's disease (PD). However, little is known about how these reported risk variants confer risk of PD. OBJECTIVE: To nominate genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. METHODS: We conducted a two-sample Mendelian randomization (MR) study by integrating large-scale genome-wide associations and expression quantitative trait loci (eQTL) data from dopaminergic neurons. RESULTS: MR analysis nominated 10 risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. These MR significant genes include FAM200B, NDUFAF2, NUP42, SH3GL2, STX1B, CCDC189, KAT8, PRSS36, VAMP4, and ZSWIM7. CONCLUSIONS: We report the first MR study of PD by using dopaminergic neuron-specific eQTL and nominate novel risk genes for PD. Further functional characterization of the nominated risk genes will provide mechanistic insights into PD pathogenesis and potential therapeutic targets. © 2022 International Parkinson and Movement Disorder Society.
Subject(s)
Genome-Wide Association Study , Parkinson Disease , Humans , Quantitative Trait Loci/genetics , Mendelian Randomization Analysis , Parkinson Disease/genetics , Parkinson Disease/metabolism , Dopaminergic Neurons/metabolism , Genetic Predisposition to Disease/genetics , Polymorphism, Single NucleotideABSTRACT
Genome-wide association studies (GWASs) have revealed that genetic variants at the 22q13.2 risk locus were robustly associated with schizophrenia. However, the causal variants at this risk locus and their roles in schizophrenia remain elusive. Here we identify the risk missense variant rs1801311 (located in the 1st exon of NDUFA6 gene) as likely causal for schizophrenia at 22q13.2 by disrupting binding of YY1, TAF1, and POLR2A. We systematically elucidated the regulatory mechanisms of rs1801311 and validated the regulatory effect of this missense variant. Intriguingly, rs1801311 physically interacted with NAGA (encodes the alpha-N-acetylgalactosaminidase, which is mainly involved in regulating metabolisms of glycoproteins and glycolipids in lysosome) and showed the most significant association with NAGA expression in the human brain, with the risk allele (G) associated with higher NAGA expression. Consistent with eQTL analysis, expression analysis showed that NAGA was significantly upregulated in brains of schizophrenia cases compared with controls, further supporting that rs1801311 may confer schizophrenia risk by regulating NAGA expression. Of note, we found that NAGA regulates important neurodevelopmental processes, including proliferation and differentiation of neural stem cells. Transcriptome analysis corroborated that NAGA regulates pathways associated with neuronal differentiation. Finally, we independently confirmed the association between rs1801311 and schizophrenia in a large Chinese cohort. Our study elucidates the regulatory mechanisms of the missense schizophrenia risk variant rs1801311 and provides mechanistic links between risk variant and schizophrenia etiology. In addition, this study also revealed the novel role of coding variants in gene regulation and schizophrenia risk, i.e., genetic variant in coding region of a specific gene may confer disease risk through regulating distal genes (act as regulatory variant for distal genes).
Subject(s)
Schizophrenia , Alleles , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Mutation, Missense/genetics , Polymorphism, Single Nucleotide/genetics , Schizophrenia/genetics , YY1 Transcription Factor/genetics , alpha-N-Acetylgalactosaminidase/genetics , alpha-N-Acetylgalactosaminidase/metabolismABSTRACT
Cadmium (Cd) accumulation in rice grains poses a health risk for humans. In this study, a bacterium, Alishewanella sp. WH16-1-MT, was engineered to express metallothionein on the cell surface. Compared with the parental WH16-1 strain, Cd2+ adsorption efficiency of WH16-1-MT in medium was increased from 1.2 to 2.6 mg/kg dry weight. The WH16-1-MT strain was then incubated with rice in moderately Cd-contaminated paddy soil. Compared with WH16-1, inoculation with WH16-1-MT increased plant height, panicle length and thousand-kernel weight, and decreased the levels of ascorbic acid and glutathione and the activity of peroxidase. Compared with WH16-1, WH16-1-MT inoculation significantly reduced the concentrations of Cd in brown rice, husks, roots and shoots by 44.0 %, 45.5 %, 36.1 % and 47.2 %, respectively. Moreover, inoculation with WH16-1-MT reduced the bioavailability of Cd in soil, with the total Cd proportion in oxidizable and residual states increased from 29 % to 32 %. Microbiome analysis demonstrated that the addition of WH16-1-MT did not significantly alter the original bacterial abundance and community structure in soil. These results indicate that WH16-1-MT can be used as a novel microbial treatment approach to reduce Cd in rice grown in moderately Cd-contaminated paddy soil.
Subject(s)
Bacteria , Cadmium , Oryza , Soil Pollutants , Cadmium/analysis , Metallothionein/genetics , Microorganisms, Genetically-Modified , Soil , Soil Pollutants/analysisABSTRACT
BACKGROUND: Over 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations. METHODS: To identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis. RESULTS: We identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10-11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia. CONCLUSIONS: Our study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.
Subject(s)
Genome-Wide Association Study , Schizophrenia , Case-Control Studies , Genetic Predisposition to Disease , Humans , Polymorphism, Single Nucleotide , Quantitative Trait Loci , RNA-Binding Proteins , Schizophrenia/genetics , TranscriptomeABSTRACT
Both effective detection demand against diversified development of flight targets and remote sensing providing identifiable and fine target information all call for microwave radar system with flexible and ultra-wideband frequency-domain ability to provide more high-resolution and multi-source information. A microwave photonic radar system with theoretically full-band and ultra-wideband working ability is presented and experimentally demonstrated. An optical frequency operation module is employed in the transmitter to break the frequency-domain limitation on the emitted radar signal, while two types of optical mixing structures are switched to provide the ability to receive target echoes at any frequency band. In the experiments, high-SNR optical frequency operation and subsequent waveform generation at each normal radar band, that is from HF to Ka, are carried out. Good linearity and coherence of the generated waveforms are also demonstrated. Then, multi-band system-level detection experiments are completed to show the full-band working ability. Centimeter-scale or even sub-centimeter-scale resolution are realized at different bands, which identifies the proposed system can handle target detection with flexible performance and support acquiring rich target information at different frequency bands in future.
ABSTRACT
BACKGROUND: DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients. METHOD: The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves. RESULT: We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47-3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19-3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively. CONCLUSIONS: The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.