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This study aimed to compare the blood metabolic status of neonates with idiopathic polyhydramnios (IPH) and those with normal amniotic fluid, and to explore the relationship between IPH and fetal health. Blood metabolites of 32 patients with IPH and 32 normal controls admitted to the Sixth Affiliated Hospital of Sun Yat-sen University between January 2017 and December 2022 were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Orthogonal partial least squares discriminant analysis (OPLS-DA) and metabolite enrichment analyses were performed to identify the differential metabolites and metabolic pathways. There was a significant difference in the blood metabolism between newborns with IPH and those with normal amniotic fluid. Six discriminant metabolites were identified: glutamate, serine, asparagine, aspartic acid, homocysteine, and phenylalanine. Differential metabolites were mainly enriched in two pathways: aminoacyl-tRNA biosynthesis, and alanine, aspartate, and glutamate metabolism. CONCLUSIONS: This study is the first to investigate metabolomic profiles in newborns with IPH and examine the correlation between IPH and fetal health. Differential metabolites and pathways may affect amino acid synthesis and the nervous system. Continuous attention to the development of the nervous system in children with IPH is necessary. WHAT IS KNOWN: ⢠There is an increased risk of adverse pregnancy outcomes with IPH, such as perinatal death, neonatal asphyxia, neonatal intensive care admission, cesarean section rates, and postpartum hemorrhage. ⢠Children with a history of IPH have a higher proportion of defects than the general population, particularly central nervous system problems, neuromuscular disorders, and other malformations. WHAT IS NEW: ⢠In neonates with IPH, six differential metabolites were identified with significant differences and good AUC values using LC-MS/MS analysis: glutamic acid, serine, asparagine, aspartic acid, homocysteine, and phenylalanine, which were mainly enriched in two metabolic pathways: aminoacyl-tRNA biosynthesis and alanine, aspartate, and glutamate metabolism. ⢠These differential metabolites and pathways may affect amino acid synthesis and development of the nervous system in neonates with IPH.
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Ácido Aspártico , Poli-Hidrâmnios , Criança , Humanos , Recém-Nascido , Gravidez , Feminino , Cromatografia Líquida , Poli-Hidrâmnios/diagnóstico , Asparagina , Cesárea , Espectrometria de Massas em Tandem , Alanina , Fenilalanina , Serina , Glutamatos , Homocisteína , RNA de TransferênciaRESUMO
OBJECTIVES: To study new biomarkers for the early diagnosis of retinopathy of prematurity (ROP) by analyzing the differences in blood metabolites based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and metabolomics. METHODS: Dried blood spots were collected from 21 infants with ROP (ROP group) and 21 infants without ROP (non-ROP group) who were hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2013 to December 2016. LC-MS/MS was used to measure the metabolites, and orthogonal partial least squares-discriminant analysis was used to search for differentially expressed metabolites and biomarkers. RESULTS: There was a significant difference in blood metabolic profiles between the ROP and non-ROP groups. The pattern recognition analysis, Score-plot, and weight analysis obtained 10 amino acids with a relatively large difference. Further statistical analysis showed that the ROP group had significant increases in blood levels of glutamic acid, leucine, aspartic acid, ornithine, and glycine compared with the non-ROP group (P<0.05). The receiver operating characteristic curve analysis showed that glutamic acid and ornithine had the highest value in diagnosing ROP. CONCLUSIONS: Blood metabolites in preterm infants with ROP are different from those without ROP. Glutamic acid and ornithine are the metabolic markers for diagnosing ROP. LC-MS/MS combined with metabolomics analysis has a potential application value in the early identification and diagnosis of ROP.
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Retinopatia da Prematuridade , Espectrometria de Massas em Tandem , Recém-Nascido , Lactente , Humanos , Recém-Nascido Prematuro , Cromatografia Líquida , Retinopatia da Prematuridade/diagnóstico , Ácido Glutâmico , OrnitinaRESUMO
OBJECTIVE: To carry out genetic testing for a child featuring global developmental delay, abnormal liver function, congenital heart disease, and brain malformation. METHODS: Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA and trio-whole exome sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: Genetic testing revealed that the child has harbored a heterozygous c.2002G>T (p.Glu668Ter) variant of the SMARCA2 gene, which was predicted to be likely pathogenic by bioinformatic analysis. His mother was found to be a low-percentage mosaic for the same variant, with a ratio of 0.054 (246/4549). CONCLUSION: The child was diagnosed with Nicolaides-Baraitser syndrome resulting from maternal mosaicism for the SMARCA2 gene variant.
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Mosaicismo , Pais , Criança , Feminino , Humanos , Deficiências do Desenvolvimento , MãesRESUMO
This article reports the clinical and genetic features of a case of Tatton-Brown-Rahman syndrome (TBRS) caused by DNMT3A gene mutation. A girl, aged 8 months and 14 days, had the clinical manifestations of psychomotor retardation, hypotonia, ventricular enlargement, and tonsillar hernia malformation. Gene analysis identified a novel heterozygous mutation, c.134C>T(p.A45V), in the DNMT3A gene, and the wild type was observed at this locus in her parents. This mutation was determined as a possible pathogenic mutation according to the guidelines of American College of Medical Genetics and Genomics, which had not been reported in previous studies and conformed to autosomal dominant inheritance. This child was diagnosed with TBRS. TBRS often has a good prognosis, with overgrowth and mental retardation as the most common clinical manifestations, and behavioral and psychiatric problems, scoliosis, and afebrile seizures are possible complications of TBRS. The possibility of TBRS should be considered for children with overgrowth and mental retardation, and genetic diagnosis should be conducted when necessary.
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Anormalidades Múltiplas , DNA (Citosina-5-)-Metiltransferases/genética , Deficiência Intelectual , DNA Metiltransferase 3A , Feminino , Heterozigoto , Humanos , Lactente , MutaçãoRESUMO
BACKGROUND: The prognostic value of programmed death-ligand 1 (PD-L1) and BRAF expression in nasopharyngeal carcinoma (NPC) is not well-defined. In this study we investigated alterations in PD-L1, BRAF and EGFR by using immunohistochemistry analysis in a cohort of consecutively enrolled NPC patients. METHODS: A retrospective review of 154 NPC patients form our previous study (BMC Cancer. 2013; 13:226) were conducted. Survival and prognostic impacts were analyzed based on PD-L1, BRAF and EGFR expression levels. RESULTS: One hundred fifty four patients were included in this study. PD-L1 expression was detected in 87.7% of patients; 14.3% had 1-5% PD-L1 expression, 47.4% had 5-49% expression while 26% had ≥50% expression Higher PD-L1 expression was significantly associated with shorter PFS and OS. The median PFS was 25 months (95% CI 15.7-34.3 months) and OS was 35 months (95% CI 22.60-47.4 months) for patients with PD-L1 expression ≥50%; both median PFS and OS were not yet reached for patients with PD-L1 expression < 50%. PFS was significantly higher in BRAF mutation positive patients (5-year PFS: 55.1% vs. 30.8%, P = 0.044). CONCLUSION: Tumor PD-L1 expression and BRAF mutation are associated with poor outcomes in patients with NPC. This study was retrospectively registered in ClinicalTrials.gov (NCT03989297) on 2019-6-18.
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Antígeno B7-H1/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Quimiorradioterapia , Receptores ErbB/metabolismo , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/terapia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
MicroRNA (miR) is important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to colorectal cancer (CRC). Here, we determined that miR-23a is overexpressed in human colorectal cancer cell lines and tissues compared with that of normal cells. The stable over-expression of miR-23a in CRC cells was sufficient to promote cell proliferation in vitro and in vivo. Further studies showed that miR-23a can directly bind to the 3'untranslated region (3'UTR) of PDK4 mRNA and subsequently repress both the mRNA and protein expressions of PDK4. PDK4 negatively regulate CRC proliferation via suppressing PDH activity. Ectopic expression of PDK4 by transiently transfected with PDK4 vector encoding the entire coding sequence could reverse the effects of miR-23a on CRC proliferation. By this way, miR-23a promotes PDH activation and oxidative phosphorylation to generate sufficient ATP for cell proliferation. Our results illustrated that the up-regulation of miR-23a played an important role in CRC cell proliferation through direct repressing PDK4, suggesting a potential application of miR-23a in prognosis prediction and therapeutic application in CRC.
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Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase (Lipoamida)/metabolismo , Piruvato Desidrogenase Quinase de Transferência de AcetilRESUMO
OBJECTIVE: To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA). METHODS: For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed. RESULTS: The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c.1159A>C, 753+1delGinsTGGTTATTA and c.504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c.566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation. CONCLUSION: The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.
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Erros Inatos do Metabolismo dos Aminoácidos/genética , Alquil e Aril Transferases/genética , China , Humanos , Metilmalonil-CoA Mutase/genética , Oxirredutases/genética , Linhagem , Estudos RetrospectivosRESUMO
OBJECTIVE: To construct a W203X-mutant mouse model of cblC type methylmalonic acidemia based on the CRISPR/Cas9 technology. METHODS: At first, BLAST was used to compare the conservative nature of the cblC gene and protein sequences in humans and mice, and then, the CRISPR/Cas9 technology was used for microinjection of mouse fertilized eggs to obtain heterozygous F1 mice. Hybridization was performed for these mice to obtain homozygous W203X-mutant mice. The blood level of the metabolite propionyl carnitine (C3) was measured for homozygous mutant mice, heterozygous littermates, and wild-type mice. RESULTS: The gene and protein sequences of MMACHC, the pathogenic gene for cblC type methylmalonic acidemia, were highly conserved in humans and mice. The homozygous W203X-mutant mice were successfully obtained by the CRISPR/Cas9 technology, and there was a significant increase in C3 in these mice at 24 hours after birth (P<0.001). CONCLUSIONS: A W203X-mutant mouse model of cblC type methylmalonic acidemia is successfully constructed by the CRISPR/Cas9 technology.
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Sistemas CRISPR-Cas , Erros Inatos do Metabolismo dos Aminoácidos , Animais , Proteínas de Transporte , Heterozigoto , Camundongos , Mutação , OxirredutasesRESUMO
Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) protects the intestines from injury in experimental necrotizing enterocolitis (NEC). We hypothesized that polymorphisms in the HB-EGF gene lead to low HB-EGF production in peripheral blood and increased risk of NEC in the Chinese Han population. To test this hypothesis, 30 NEC patients and 80 control subjects were selected. Five HB-EGF single-nucleotide polymorphisms (SNPs) and its plasma levels were measured by genotyping and enzyme-linked immunosorbent assay, respectively. Only 1 out of the 5 SNPs showed a notable result. The notable SNP (rs4912711) was associated with NEC in its minor allele frequency and its "G/T" genotype distribution. In addition, plasma HB-EGF levels were reduced especially the "G/T" genotype in NEC patients. Our data suggest that if validated in larger studies screening for HB-EGF SNPs/genotypes and plasma levels may be useful as a risk factor for NEC in the future.
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Enterocolite Necrosante/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Povo Asiático/genética , Enterocolite Necrosante/sangue , Ensaio de Imunoadsorção Enzimática , Predisposição Genética para Doença , Genótipo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/sangue , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Polimorfismo GenéticoRESUMO
BACKGROUND The aim of this study was to perform gene detection in 2 clinical cases of highly suspected ornithine transcarbamylase deficiency (OTCD) pediatric patients by first-generation sequencing technology in order to confirm the pathogenic genetic factors of their families and allow the families to undergo genetic counselling and prenatal diagnosis. MATERIAL AND METHODS The peripheral DNA samples of 2 children with highly suspected OTCD (the probands) and their parents were collected. DNA fragments corresponding to exons 1-10 of the OTC gene from the samples were amplified using polymerase chain reaction (PCR), and then subjected to Sanger sequencing to confirm the pathogenic mutation sites. RESULTS The probands were both confirmed to have OTCD. The proband in Family 1 was a male carrying a c.867+1G>C mutation at a splice site within the OTC gene. The gene detection results of amniotic fluid cells at 16 weeks of pregnancy showed that the fetus was a male who also carried the c.867+1G>C mutation. The proband in Family 2 was a male carrying a c.782T>C(p. I261T) mutation in the OTC gene. The gene detection results of amniotic fluid cells at 18 weeks showed that the fetus was a male without pathogenic mutations in the OTC gene. The gene detection results of peripheral blood from the fetus after birth were consistent with those obtained from amniotic fluid cells. CONCLUSIONS Pediatric children who are clinically suspected of OTCD can receive a definitive diagnosis through OTC gene detection.
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Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Ornitina Carbamoiltransferase/genética , Adulto , Líquido Amniótico/citologia , DNA/genética , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Ornitina Carbamoiltransferase/metabolismo , Linhagem , Reação em Cadeia da Polimerase , Gravidez , Diagnóstico Pré-Natal/métodos , Análise de Sequência de DNARESUMO
Two fluorescent probes, 1 and 2, derived from borondipyrromethene (BODIPY) modified with macrocyclic polyamine [12]aneN3, were synthesized and applied in the discrimination of cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) with absorption and fluorescent spectroscopy in comparison. It was found that Boc-protected 1 showed highly sensitive and selective recognition of GSH over Cys and Hcy; while probe 2 was able to distinguish the three different thiols due to their different reactivities. With its water-solubility, rapid responsiveness, high sensitivity and low cytotoxicity, probe 2 was successfully applied in the fast detection of three biothiols in living cells.
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Compostos de Boro/química , Corantes Fluorescentes/análise , Corantes Fluorescentes/química , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/química , Sobrevivência Celular , Relação Dose-Resposta a Droga , Células HeLa , Células Hep G2 , Humanos , Estrutura Molecular , Solubilidade , Soluções , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Água/químicaRESUMO
In recent years, foundation pit construction has been rapidly developing in the direction of deep and large-scale, leading to the frequent occurrence of construction accidents. The pit construction process is characterised by a complex environment, high construction risk, and numerous coupling effects between the construction risk factors. In this paper, 23 main accident-causing factors in foundation pit construction are determined based on the six major risk accident types. In addition, the Grey-DEMATEL-Fuzzy comprehensive evaluation method of the risk evaluation model is introduced for better prediction and judgment of risk level, which combines the grey system theory with the method of decision-making experimental analysis, and in the case of inaccurate or incomplete information, the use of less data can achieve the evaluation results with a high degree of reliability, and it will effectively avoid the impact of the lack of information as well as the subjectivity in the process of risk evaluation. Through the Grey-DEMATEL method, the central degree value for each risk indicator factor is calculated, the coupling role and importance of each risk indicator are analysed, and the indicator weights are calculated. Based on the calculated weights, the fuzzy comprehensive evaluation method is used to evaluate the overall risk level. The empirical research on the deep foundation pit construction project of Haitangxi subway station in Chongqing reveals that the excessive lateral earth pressure on the pile wall is the most prominent risk factor. The overall risk level of the construction process is medium, and the risk is within the controllable range. On this basis, corresponding preventive measures can be formulated, providing a basis for risk prevention in the construction of deep foundation pit projects.
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Indústria da Construção , Lógica Fuzzy , Medição de Risco/métodos , Humanos , Modelos Teóricos , Fatores de Risco , ChinaRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0277324.].
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BACKGROUND: The notable decline in the number of Tregs within Necrotizing enterocolitis (NEC) intestinal tissuesï¼contribute to excessive inflammation and necrosis, yet the precise underlying factors remain enigmatic. Ferroptosis, a novel cell death stemming from a disrupted lipid redox metabolism, is the focus of this investigation. Specifically, this study delves into the ferroptosis of Treg cells in the context of NEC and observes the protective effects exerted by vitamin E intervention, which aims to mitigate ferroptosis of Treg cells. METHODS: To investigate the reduction of Treg cells in NEC intestine, we analyzed its association with ferroptosis from multiple angles. We constructed a mouse with a specific knockout of Gpx4 in Treg cells, aiming to examine the impact of Treg cell ferroptosis on NEC intestinal injury and localized inflammation. Ultimately, we employed vitamin E treatment to mitigate ferroptosis in NEC intestine's Treg cells, monitoring the subsequent amelioration in intestinal inflammatory damage. RESULTS: The diminution of Treg cells in NEC is attributed to ferroptosis stemming from diminished GPX4 expression. Gpx4-deficient Treg cells exhibit impaired immunosuppressive function and are susceptible to ferroptosis. This ferroptosis of Treg cells exacerbates intestinal damage and inflammatory response in NEC. Notably, Vitamin E can inhibit the ferroptosis of Treg cells, subsequently alleviating intestinal damage and inflammation in NEC. Additionally, Vitamin E bolsters the anti-lipid peroxidation capability of Treg cells by upregulating the expression of GPX4. CONCLUSION: In the context of NEC, the ferroptosis of Treg cells represents a significant factor contributing to intestinal tissue damage and an exaggerated inflammatory response. GPX4 is pivotal for the viability and functionality of Treg cells. Vitamin E exhibits the capability to mitigate the ferroptosis of Treg cells, thereby enhancing their number and function, which plays a crucial role in mitigating intestinal tissue damage and inflammatory response in NEC.
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Enterocolite Necrosante , Ferroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Linfócitos T Reguladores , Vitamina E , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Vitamina E/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Camundongos , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/patologia , Enterocolite Necrosante/tratamento farmacológico , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/patologia , Humanos , Camundongos Knockout , Intestinos/patologiaRESUMO
Bile acids (BAs) have increasingly been implicated in the onset and progression of necrotizing enterocolitis (NEC); multiple findings have demonstrated their ability to induce damage to the intestinal epithelium, thereby exacerbating disease severity. Although we previously showed that melatonin was able to treat NEC by correcting the Treg/Th17 imbalance, the modulatory effect of melatonin on BAs remains unclear. In this study, we conducted transcriptome analysis on intestinal tissues from patients with NEC and validated these findings. Subsequently, we treated mice with melatonin alone or in combination with an agonist/inhibitor of Sirtuin 1 (SIRT1) to assess faecal and serum BA levels, the expression levels of BA transporters and regulators, and the extent of intestinal injury. Our transcriptome results indicated dysregulation of BA metabolism and abnormal expression of BA transporters in patients with NEC, which were also observed in our NEC mouse model. Furthermore, exogenous BAs were found to aggravate NEC severity in mice. Notably, melatonin effectively restored the aberrant expression of BA transporters, such as apical membrane sodium-dependent bile acid transporters (ASBT), ileal bile acid-binding protein (IBABP), and organic solute transporter-alpha (OST-α), by upregulating SIRT1 expression while reducing farnesoid X receptor (FXR) acetylation, consequently leading to decreased serum and faecal BA levels and mitigated NEC severity. Thus, we propose a potential mechanism through which melatonin reduces BA levels via the SIRT1/FXR signalling axis in an NEC mouse model. Collectively, these results highlight that melatonin holds promise for reducing BA levels and represents a promising therapeutic strategy for treating NEC.
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Enterocolite Necrosante , Melatonina , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/metabolismo , Intestinos , Fígado , Melatonina/farmacologia , Melatonina/uso terapêutico , Sirtuína 1/metabolismoRESUMO
The gryllacridid genus Woznessenskia Gorochov, 2002 comprises 13 extant species from Asia, with 8 species reported from China and 5 species reported from Vietnam. A new species from Xizang, China, Woznessenskia lianhua sp. nov., is reported in this paper.
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Ortópteros , Animais , Distribuição Animal , Estruturas Animais , Tamanho Corporal , Tamanho do Órgão , ChinaRESUMO
Objective: To accurately verify the pathogenicity of variants of uncertain significance (VUS) in MUT and MMACHC genes through mass spectrometry and silico analysis. Methods: This multicenter retrospective study included 35 participating units (ClinicalTrials.gov ID: NCT06183138). A total of 3,071 newborns (within 7 days of birth) were sorted into carrying pathogenic/likely pathogenic (P/LP) variants and carrying VUS, non-variant groups. Differences in metabolites among the groups were calculated using statistical analyses. Changes in conservatism, free energy, and interaction force of MMUT and MMACHC variants were analyzed using silico analysis. Results: The percentage of those carrying VUS cases was 68.15% (659/967). In the MMUT gene variant, we found that C3, C3/C2, and C3/C0 levels in those carrying the P/LP variant group were higher than those in the non-variant group (p < 0.000). The conservative scores of those carrying the P/LP variant group were >7. C3, C3/C0, and C3/C2 values of newborns carrying VUS (c.1159A>C and c.1286A>G) were significantly higher than those of the non-variant group and the remaining VUS newborns (p < 0.005). The conservative scores of c.1159A>C and c.1286A>G calculated by ConSurf analysis were 9 and 7, respectively. Unfortunately, three MMA patients with c.1159A>C died during the neonatal period; their C3, C3/C0, C3/C2, and MMA levels were significantly higher than those of the controls. Conclusion: Common variants of methylmalonic acidemia in the study population were categorized as VUS. In the neonatal period, the metabolic biomarkers of those carrying the P/LP variant group of the MUT gene were significantly higher than those in the non-variant group. If the metabolic biomarkers of those carrying VUS are also significantly increased, combined with silico analysis the VUS may be elevated to a likely pathogenic variant. The results also suggest that mass spectrometry and silico analysis may be feasible screening methods for verifying the pathogenicity of VUS in other inherited metabolic diseases.
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BACKGROUND: Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we mainly learn the influence of hsa_circ_0026344 (circ_0026344) in GC progression. METHODS: Circ_0026344, miR-1290 and Fructose-1,6-bisphosphatase 2 (FBP2) expression was determined by quantitative real-time polymerase chain reaction (qRT-PCR). GC cell proliferation, migration, and invasion were detected by colony formation, 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays, respectively. The interaction between circ_0026344 and miR-1290 complex was evaluated by RNA pull-down assay. The interaction of miR-1290 with circ_0026344 or FBP2 was detected using dual-luciferase reporter assay. A xenograft model was established to determine the effect of circ_0026344 on GC tumor growth in vivo. RESULTS: Circ_0026344 expression was dramatically decreased in GC cells and tissues. Circ_0026344 overexpression inhibited GC cell proliferation, migration and invasion. MiR-1290 was predicted as a target of circ_0026344 and miR-1290 overexpression attenuated the anti-tumor effect of circ_0026344 on GC cells. Furthermore, we predicted FBP2 as the target of miR-1290. FBP2 knockdown reversed the effects of circ_0026344 knockdown on GC cell malignant behaviors. Functional analysis showed that circ_0026344 upregulated FBP2 expression via miR-1290. Additionally, in vivo studies demonstrated that circ_0026344 suppressed GC tumor progression. CONCLUSION: In conclusion, circ_0026344 inhibited GC cell proliferation via the miR-1290/FBP2 axis, which might provide a new therapeutic target for GC patients.
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MicroRNAs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , RNA Circular/genética , MicroRNAs/genética , Transformação Celular Neoplásica , Proliferação de Células/genética , Linhagem Celular TumoralRESUMO
As an important part of urban renewal, brownfield restoration and renovation are of great significance to the sustainable development of cities. The structure-process-outcome theory was introduced into this study to improve the rationality and scientific vigor of the redevelopment assessment process and to evaluate whether brownfield sites meet the conditions for redevelopment. Based on this theory, the relationship among structures, processes and outcomes can be well elucidated. Specifically, a good structure should contribute to an effective process, which will increase the possibility of a favorable outcome. The basic conditions, practice principles, and result orientation in the whole procedure of brownfield redevelopment were comprehensively analyzed. In addition, a more complete and reasonable three-level evaluation index system for brownfield redevelopment was established. In order to reduce the subjectivity in the evaluation process, an unbiased scientific brownfield redevelopment evaluation model was constructed using the continuous ordered weighted averaging operator-topology method. The evaluation decision system was applied to the renovation of a tract project in Chengdu, China. The results proved that the model could effectively and accurately evaluate the quality level of the brownfield redevelopment project, and the proposed recommendations can provide a basis for decision-making.
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Background: Insulin resistance has been implicated in the pathogenesis of children born small for gestational age (SGA) with catch-up growth (CUG). Adipose tissue macrophages (ATMs) regulate insulin resistance by secreting exosomes containing microRNA (miRNA) cargo; however, their pathogenic roles and molecular mechanism are not fully understood. This study aimed to investigate the role of miR-210-5p in rats born SGA with CUG and insulin resistance. Methods: The dietary needs of pregnant rats were restricted to ensure the birth of SGA rats. Transmission electron microscopy (TEM) and Western blot analysis were used to identify the exosomes from ATMs of CUG-SGA and adequate-for-gestational-age (AGA) rats. PKH-67 staining was performed to confirm the uptake of exosomes. miR-210-5p expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Glucose uptake and output were detected with glucose uptake and output assays, respectively. Insulin resistance was detected with glucose and insulin tolerance tests in vivo. The interaction between miR-210-5p and SID1 transmembrane family member 2 (SIDT2) was validated with dual-luciferase reporter assay. Results: miR-210-5p was observed to be highly expressed in the exosomes derived from the ATMs of CUG-SGA rats. ATM-derived exosomes can serve as vehicles to deliver miR-210-5p into adipocytes, myocytes, and hepatocytes, where it can enhance cellular insulin resistance. SIDT2 was identified as a direct target gene of miR-210-5p. The miR-210-5p-induced insulin resistance was reversed by the restored SIDT2 expression. However, overexpression of SIDT2 abolished the inhibitory effect of CUG-SGA-ATM-exosomal miR-210-5p on insulin sensitivity in vivo. Conclusions: ATM-derived exosomal miR-210-5p promoted insulin resistance in CUG-SGA rats by targeting SIDT2, which may act as a new potential therapeutic target for children born SGA with CUG.