RESUMO
Rechargeable aprotic lithium (Li)-oxygen battery (LOB) is a potential next-generation energy storage technology because of its high theoretical specific energy. However, the role of redox mediator on the oxide electrochemistry remains unclear. This is partly due to the intrinsic complexity of the battery chemistry and the lack of in-depth studies of oxygen electrodes at the atomic level by reliable techniques. Herein, cryo-transmission electron microscopy (cryo-TEM) is used to study how the redox mediator LiI affects the oxygen electrochemistry in LOBs. It is revealed that with or without LiI in the electrolyte, the discharge products are plate-like LiOH or toroidal Li2O2, respectively. The I2 assists the decomposition of LiOH via the formation of LiIO3 in the charge process. In addition, a LiI protective layer is formed on the Li anode surface by the shuttle of I3 -, which inhibits the parasitic Li/electrolyte reaction and improves the cycle performance of the LOBs. The LOBs returned to 2e- oxygen reduction reaction (ORR) to produce Li2O2 after the LiI in the electrolyte is consumed. This work provides new insight on the role of redox mediator on the complex electrochemistry in LOBs which may aid the design LOBs for practical applications.
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Paternal stress exposure-induced high corticosterone (CORT) levels may contribute to depression in offspring. Clinical studies disclose the association of depressive symptoms in fathers with their adolescent offspring. However, there is limited information regarding the intervention for intergenerational inheritance of depression. In this study we evaluated the intervention of cinnamaldehyde, a major constituent of Chinese herb cinnamon bark, for intergenerational inheritance of depression in CORT- and CMS-induced mouse models of depression. Depressive-like behaviors were induced in male mice by injection of CORT (20 mg·kg-1·d-1, sc) for 6 weeks or by chronic mild stress (CMS) for 6 weeks. We showed that co-administration of cinnamaldehyde (10, 20, or 40 mg·kg-1·d-1, ig) for 6 weeks in F0 males prevented the depressive-like phenotypes of F1 male offspring. In addition, co-administration of cinnamaldehyde (20 mg·kg-1·d-1, ig) for 4 weeks significantly ameliorated depressive-like behaviors of chronic variable stress (CVS)-stimulated F1 offspring born to CMS mice. Notably, cinnamaldehyde had no reproductive toxicity, while positive drug fluoxetine showed remarkable reproductive toxicity. We revealed that CMS and CORT significantly reduced testis glucocorticoid receptor (GR) expression, and increased testis and sperm miR-190b expression in F0 depressive-like models. Moreover, pre-miR-190b expression was upregulated in testis of F0 males. The amount of GR on miR-190b promoter regions was decreased in testis of CORT-stimulated F0 males. Cinnamaldehyde administration reversed CORT-induced GR reduction in testis, miR-190b upregulation in testis and sperm, pre-miR-190b upregulation in testis, and the amount of GR on miR-190b promoter regions of F0 males. In miR-190b-transfected Neuro 2a (N2a) cells, we demonstrated that miR-190b might directly bind to the 3'-UTR of brain-derived neurotrophic factor (BDNF). In the hippocampus of F1 males of CORT- or CMS-induced depressive-like models, increased miR-190b expression was accompanied by reduced BDNF and GR, which were ameliorated by cinnamaldehyde. In conclusion, cinnamaldehyde is a potential intervening agent for intergenerational inheritance of depression, probably by regulating GR/miR-190b/BDNF pathway.
Assuntos
Acroleína , Fator Neurotrófico Derivado do Encéfalo , Depressão , MicroRNAs , Receptores de Glucocorticoides , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/metabolismo , Depressão/tratamento farmacológico , Depressão/genética , Pai/psicologia , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Herança Paterna , Receptores de Glucocorticoides/metabolismo , Sêmen/metabolismoRESUMO
OBJECTIVE: To investigate the genetic etiology of skeletal dysplasia in highly selected fetuses during the first and second trimesters using deep phenotyping and exome sequencing (ES). METHOD: Fetuses with short femurs were identified using the established prenatal diagnostic approach. A multidisciplinary team reviewed fetal phenotypic information (prenatal ultrasound findings, fetal postmortem, and radiographs) in a cohort of highly selected fetuses with skeletal dysplasia during the first and second trimesters. The affected families underwent multiplatform genetic tests. RESULTS: Of the 27 affected fetuses, 21 (77.8%) had pathogenic or potential pathogenic variations in the following genes: COL1A1, FGFR3, COL2A1, COL1A2, FLNB, DYNC2LI1, and TRIP11. Two fetuses had compound heterozygous mutations in DYNC2LI1 and TRIP11, respectively, and the other 19 carried de novo autosomal dominant variants. Novel variants were identified in COL1A1, COL2A1, COL1A2, DYNC2LI1, and TRIP11 in 11 fetuses. We also included the first description of the phenotype of odontochondrodysplasia in a prenatal setting. CONCLUSIONS: ES or panel sequencing offers a high diagnostic yield for fetal skeletal dysplasia during the first and second trimesters. Comprehensive and complete phenotypic information is indispensable for genetic analysis and the expansion of genotype-phenotype correlations in fetal skeletal abnormalities.
Assuntos
Dentinogênese Imperfeita/diagnóstico , Sequenciamento do Exoma/normas , Osteocondrodisplasias/diagnóstico , Fenótipo , Adulto , Dentinogênese Imperfeita/genética , Feminino , Feto , Idade Gestacional , Humanos , Osteocondrodisplasias/genética , Gravidez , Primeiro Trimestre da Gravidez/genética , Segundo Trimestre da Gravidez/genética , Ultrassonografia Pré-Natal/métodos , Ultrassonografia Pré-Natal/normas , Ultrassonografia Pré-Natal/estatística & dados numéricos , Sequenciamento do Exoma/métodos , Sequenciamento do Exoma/estatística & dados numéricosRESUMO
As a kind of malignant tumor, nasopharyngeal carcinoma (NPC) has attracted increasing attention from researchers. As a member of the circular RNA (circRNA) family, circ_0008450 has been investigated in hepatocellular carcinoma but not in NPC. This study aims to reveal the special biologic role and mechanism of circ_0008450 in NPC. qRT-PCR analysis was conducted to test the level of circ_0008450 in different tissues and cells. Loss/Gain of function assay was utilized to detect the influence of silenced/overexpressed circ_0008450 on the proliferation, apoptosis, migration, and invasion of NPC cells. The mechanism of circ_0008450 was assessed by performing qRT-PCR and luciferase reporter experiments. The results showed that circ_0008450 was elevated in NPC tissues and cells. Silenced circ_0008450 could inhibit cell proliferation, and metastatic properties and increased the number of apoptotic cells. Ectopically expressed circ_0008450 strengthened the abovementioned malignant biological behaviors. Mechanistically, circ_0008450 reduced miR-577-mediated repression of CXCL9, resulting in facilitating the oncogenic functions of NPC. In conclusion, circ_0008450 acts as an oncogene in NPC cells through regulating miR-577/CXCL9 signaling. Our findings might provide a new therapeutic target for treating NPC.
Assuntos
Movimento Celular , Proliferação de Células , Quimiocina CXCL9/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Carcinoma Nasofaríngeo/patologia , RNA Circular/genética , Apoptose , Quimiocina CXCL9/genética , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Invasividade Neoplásica , Transdução de Sinais , Células Tumorais CultivadasRESUMO
To prevent marine macrofouling, the anti-fouling effect of liquid discharge on mussels Mytilus galloprovincialis Lamarck was investigated in a simulated water-cooling system. The effects of input energy, mussel distance from discharge center, continuous discharge time, and discharge energy distribution mode on mussel response (death or detachment) were systematically studied. The results showed that excellent anti-fouling effects could be achieved by increasing input energy, but the detachment rate and mortality of mussels decreased sharply when the mussels were farther away from the discharge center. Low frequency discharge for a long, continuous time and multiple stimuli at long intervals improved the anti-fouling effect. Shock waves are the most likely cause of mussel eradication, and the threshold values of peak pressure to prevent mussel settlement and to cause death were 0.02 MPa and 0.05 MPa, respectively.
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Mytilus , Poluentes Químicos da Água , Animais , Plasma , ÁguaRESUMO
PurposeThe aim of this study was to assess the performance of a noninvasive prenatal screening (NIPS) assay for accurate fetal genotyping of pregnancies at genetic risk for autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsA total of 80 pregnant couples carrying known mutations in either the GJB2 or SLC26A4 genes associated with a risk for ARNSHL were recruited to the study. Fetal amniocyte samples were genotyped by invasive prenatal screening (IPS), whereas the cell-free fetal DNA present in maternal plasma samples was genotyped using a novel NIPS method based on circulating single-molecule amplification and resequencing technology (cSMART).ResultsIPS of the 80 at-risk pregnancies identified 20 normal homozygote, 42 heterozygote, 5 affected homozygote, and 13 affected compound heterozygote fetuses. Benchmarking against IPS, 73 of 80 fetuses (91.3%) were correctly genotyped by the cSMART NIPS assay. A low fetal DNA fraction (<6%) was identified as the main contributing factor in five of seven discordant NIPS results. At fetal DNA fractions >6%, the sensitivity and specificity of the cSMART assay for correctly diagnosing ARNSHL were 100 and 96.5%, respectively.ConclusionBased on key performance indicators, the cSMART NIPS assay has clinical potential as an alternative to traditional IPS of ARNSHL.
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Conexinas/genética , Surdez/diagnóstico , Surdez/genética , Genes Recessivos , Testes Genéticos , Proteínas de Membrana Transportadoras/genética , Mutação , Diagnóstico Pré-Natal , Conexina 26 , Testes Genéticos/métodos , Genótipo , Humanos , Diagnóstico Pré-Natal/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Transportadores de SulfatoRESUMO
Schisandrin B is a hepatoprotective component isolated from a traditional Chinese herb, Schisandra chinensis (Turcz.) Baill. This study determined the effect of Schisandrin B on d-galactosamine -induced liver injury and the role of heat shock proteins 27 and 70 against liver injury in mice. Acute liver injury was induced by intraperitoneal injection of d-galactosamine to mice, and Schisandrin B was given orally. The protein and gene expression of heat shock proteins 27 and 70 were detected by western blot and real-time quantitative polymerase chain reaction, respectively. Liver tissues were subjected to histological evaluation, and the activities of alanine aminotransferase and aspartate aminotransferase in the serum were measured. Pretreatment of Schisandrin B significantly attenuated d-galactosamine-induced liver injury in mice. This result was evidenced by improved alteration of histopathological hepatic necrosis and reduced alanine aminotransferase and aspartate aminotransferase activities in the serum. The hepatoprotective effect was accompanied with overexpression of heat shock proteins 27 and 70 both at the protein and mRNA levels. However, the aforementioned actions of Schisandrin B were all markedly suppressed by the heat shock protein inhibitor quercetin. Heat shock proteins 27 and 70 were involved in the protective effect of Schisandrin B against d-galactosamine-induced liver injury in mice.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Galactosamina/farmacologia , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Substâncias Protetoras/farmacologia , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ciclo-Octanos/farmacologia , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Quercetina/farmacologia , Schisandra/químicaRESUMO
AIM: Chronic kidney disease (CKD) is associated with an inflammation-mediated process, and the vitamin D (3) catabolizing enzyme, CYP24, is frequently overexpressed in CKD, where it may play a crucial role in kidney disease. METHODS: Herein, in this study, we investigated CYP24, reactive oxygen species (ROS), and inflammatory responses in an indoxyl sulfate (IS)-induced CKD model to elucidate the role of CYP24 in CKD. RESULTS: Our results showed that IS upregulates proinflammatory cytokine, CYP24 and nuclear factor-κB (NF-κB) expression in human renal proximal tubule epithelial cells. In addition, IS treatment increased ROS production and simultaneously upregulated CYP24 expression and NF-κB translocation. Moreover, the IS-induced upregulation of CYP24 expression was alleviated by an inhibitor of NF-κB, as well as a siRNA specific to NF-κB p65. Furthermore, the renal cortex of DN (Dahl salt-resistant normotensive) + IS, DH (Dahl salt-sensitive hypertensive), and DH + IS rats showed increased expression of NF-κB p65, CYP24, 8-hydroxydeoxyguanosine (8-OHdG), a marker of ROS and macrophage infiltration compared with DN rats. CONCLUSIONS: These results provide evidence that administration of IS in human renal tubular epithelial cells upregulates NF-κB, which leads to increase CYP24 expression and ROS production. They also suggest that suppressing NF-κB signalling is promising for the development into a strategy for CKD treatment.
Assuntos
Família 24 do Citocromo P450/metabolismo , Indicã/toxicidade , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Fator de Transcrição RelA/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Animais , Linhagem Celular Tumoral , Família 24 do Citocromo P450/genética , Citocinas/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hipertensão/complicações , Mediadores da Inflamação/metabolismo , Rim/enzimologia , Interferência de RNA , Ratos Endogâmicos Dahl , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética , Fator de Transcrição RelA/genética , Transfecção , Regulação para CimaRESUMO
AIM: Abnormal upregulation of CYP24 contributes to vitamin D insufficiency and resistance to vitamin D therapy in chronic kidney disease (CKD), because human CYP24 is a key enzyme involved in the inactivation of 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3; calcitriol) and 1,25(OH)2D3. There are multiple mechanisms regulating CYP24 in a variety of types of tissues and diseases. An increasing body of evidence suggests that microRNA-125b (miR-125b) plays an important role in post-transcriptional regulation of CYP24 mRNA. METHODS: We sought to test hypothesis that abnormal elevation of CYP24 in CKD is a consequence of loss of miR-125b in CKD in a uraemia rat model. RESULTS: We found that expression of miR-125b was significantly inhibited in uraemic rats coupled with increased CYP24 at both protein and mRNA levels compared with normal controls. In NRK-52 kidney cells, we further found that miR-125b antagomirs increased CYP24 but miR-125b mimics decreased CYP24, and luciferase assay confirmed that CYP24 is a direct target of miR-125b. Vitamin D status exerted no significant effects on expression of both miR-125b and CYP24 in uraemic rats. CONCLUSION: These results suggest that modulation of miR-125b may be used for treatment of Vitamin D insufficiency in CKD.
Assuntos
Rim/enzimologia , MicroRNAs/metabolismo , Insuficiência Renal Crônica/enzimologia , Uremia/enzimologia , Vitamina D3 24-Hidroxilase/metabolismo , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Linhagem Celular , Modelos Animais de Doenças , Regulação para Baixo , Masculino , MicroRNAs/genética , Interferência de RNA , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Insuficiência Renal Crônica/genética , Transfecção , Regulação para Cima , Uremia/genética , Deficiência de Vitamina D/enzimologia , Deficiência de Vitamina D/genética , Vitamina D3 24-Hidroxilase/genéticaRESUMO
OBJECTIVE: To assess the synergistic effects of gene polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on essential hypertension (EH) in Kazakhs in Xinjiang. METHODS: A cross-sectional case-control association study was conducted in 52 1 hypertensive and 623 normotensive subjects of Kazakh ethnicity on eight common single nucleotide polymorphisms (SNPs) interspersed over five genes of the RAAS. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Interactions among the SNPs were analyzed by the multifactor dimensionality reduction method (MDR). RESULTS: In single-locus analysis, subjects with AGT -6G, ACE D, and CYP11B2 -344C had increased susceptibility to EH (OR: 1.249; 1.425; 1.201). When subgrouped by sex, males with the t allele of REN Taq I had decreased risk for EH (OR: 0.529), and those with AGT -6G and CYP11B2 -344 C had increased risk for EH (OR: 1.498; 1.449). In females, carrying ACE D increased the risk for EH. (OR: 1.327). In six AGT haplotypes, H1 was protective, while H3 increased susceptibility to EH (OR: 0.683; 2.025). Interaction analysis by MDR showed that there was a strong synergistic effect between ACE I/D and CY11B2 (T-344C) and a moderate interaction between both ACE I/D and CY11B2 T-344C and AGT A-6G. CONCLUSIONS: There was a strong synergistic effect between ACE I/D and CY11B2 T-344C and a moderate effect between both ACE I/D and CY11B2 T-344C and AGT A-6G. AGT -6G, ACE D, and CY11B2 -344C increased susceptibility to EH. REN Taq I, AGT -6G, CY11B2 -344 C and ACE D were associated with male and female EH, respectively. H1 and H3 of AGT were protective and risk haplotypes, respectively.
Assuntos
Angiotensinogênio/genética , Pressão Sanguínea/genética , Citocromo P-450 CYP11B2/genética , Hipertensão , Peptidil Dipeptidase A/genética , Adulto , Alelos , China/epidemiologia , Estudos Transversais , Hipertensão Essencial , Etnicidade/genética , Feminino , Predisposição Genética para Doença/etnologia , Haplótipos , Humanos , Hipertensão/diagnóstico , Hipertensão/etnologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , Sistema Renina-Angiotensina/genéticaRESUMO
PURPOSE: The purpose of this study was to apply next-generation sequencing (NGS) technology to identify chromosomally normal embryos for transfer in preimplantation genetic diagnosis (PGD) cycles for translocations. METHODS: A total of 21 translocation couples with a history of infertility and repeated miscarriage presented at our PGD clinic for 24-chromosome embryo testing using copy number variation sequencing (CNV-Seq). RESULTS: Testing of 98 embryo samples identified 68 aneuploid (69.4 %) and 30 (30.6 %) euploid embryos. Among the aneuploid embryos, the most common abnormalities were segmental translocation imbalances, followed by whole autosomal trisomies and monosomies, segmental imbalances of non-translocation chromosomes, and mosaicism. In all unbalanced embryos resulting from reciprocal translocations, CNV-Seq precisely identified both segmental imbalances, extending from the predicted breakpoints to the chromosome termini. From the 21 PGD cycles, eight patients had all abnormal embryos and 13 patients had at least one normal/balanced and euploid embryo available for transfer. In nine intrauterine transfer cycles, seven healthy babies have been born. In four of the seven children tested at 18 weeks gestation, the karyotypes matched with the original PGD results. CONCLUSION: In clinical PGD translocation cycles, CNV-Seq displayed the hallmarks of a comprehensive diagnostic technology for high-resolution 24-chromosome testing of embryos, capable of identifying true euploid embryos for transfer.
Assuntos
Aberrações Cromossômicas/embriologia , Variações do Número de Cópias de DNA/genética , Transferência Embrionária/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Diagnóstico Pré-Implantação/métodos , Adulto , Feminino , Humanos , Cariotipagem , Projetos Piloto , Gravidez , Taxa de Gravidez , Translocação Genética/genética , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the synergistic effects of gene polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on essential hypertension (EH) in Kazakhs in Xinjiang. METHODS: A cross-sectional case-control association study was conducted in 52 1 hypertensive and 623 normotensive subjects of Kazakh ethnicity on eight common single nucleotide polymorphisms (SNPs) interspersed over five genes of the RAAS. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Interactions among the SNPs were analyzed by the multifactor dimensionality reduction method (MDR). RESULTS: In single-locus analysis, subjects with AGT -6G, ACE D, and CYP11B2 -344C had increased susceptibility to EH (OR: 1.249; 1.425; 1.201). When subgrouped by sex, males with the t allele of REN Taq I had decreased risk for EH (OR: 0.529), and those with AGT -6G and CYP11B2 -344 C had increased risk for EH (OR: 1.498; 1.449). In females, carrying ACE D increased the risk for EH. (OR: 1.327). In six AGT haplotypes, H1 was protective, while H3 increased susceptibility to EH (OR: 0.683; 2.025). Interaction analysis by MDR showed that there was a strong synergistic effect between ACE I/D and CY11B2 (T-344C) and a moderate interaction between both ACE I/D and CY11B2 T-344C and AGT A-6G. CONCLUSIONS: There was a strong synergistic effect between ACE I/D and CY11B2 T-344C and a moderate effect between both ACE I/D and CY11B2 T-344C and AGT A-6G. AGT -6G, ACE D, and CY11B2 -344C increased susceptibility to EH. REN Taq I, AGT -6G, CY11B2 -344 C and ACE D were associated with male and female EH, respectively. H1 and H3 of AGT were protective and risk haplotypes, respectively.
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PURPOSE: The goals of our study were to develop a noninvasive prenatal test for autosomal recessive monogenic conditions and to prove its overall feasibility and potential for clinical integration. METHODS: We recruited a pregnant woman and her spouse, who had a proband child suffering from congenital deafness, and obtained the target-region sequencing data from a semicustom array that used genomic and maternal plasma DNA from three generations of this family. A haplotype-assisted strategy was developed to detect whether the fetus inherited the pathogenic mutations in the causative gene, GJB2. The parental haplotype was constructed using a trio strategy through two different processes, namely, the grandparent-assisted haplotype phasing process and the proband-assisted haplotype phasing process. The fetal haplotype was deduced afterward based on both the maternal plasma sequencing data and the parental haplotype. RESULTS: The accuracy levels of paternal and maternal haplotypes obtained by grandparent-assisted haplotype phasing were 99.01 and 97.36%, respectively, and the proband-assisted haplotype phasing process yielded slightly lower accuracies of 98.73 and 96.79%, respectively. Fetal inheritance of the pathogenic gene was deduced correctly in both processes. CONCLUSION: Our study indicates that the strategy of haplotype-based noninvasive prenatal testing for monogenic conditions has potential applications in clinical practice.
Assuntos
Surdez/sangue , Surdez/congênito , Surdez/genética , Diagnóstico Pré-Natal/métodos , Algoritmos , Alelos , Conexina 26 , Conexinas/genética , Feminino , Biblioteca Gênica , Genes Recessivos , Haplótipos , Humanos , Masculino , Cadeias de Markov , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Gravidez , Reprodutibilidade dos Testes , Análise de Sequência de DNARESUMO
PURPOSE: This article demonstrates a prominent noninvasive prenatal approach to assist the clinical diagnosis of a single-gene disorder disease, maple syrup urine disease, using targeted sequencing knowledge from the affected family. METHODS: The method reported here combines novel mutant discovery in known genes by targeted massively parallel sequencing with noninvasive prenatal testing. RESULTS: By applying this new strategy, we successfully revealed novel mutations in the gene BCKDHA (Ex2_4dup and c.392A>G) in this Chinese family and developed a prenatal haplotype-assisted approach to noninvasively detect the genotype of the fetus (transmitted from both parents). CONCLUSION: This is the first report of integration of targeted sequencing and noninvasive prenatal testing into clinical practice. Our study has demonstrated that this massively parallel sequencing-based strategy can potentially be used for single-gene disorder diagnosis in the future.
Assuntos
Aminoácidos de Cadeia Ramificada/genética , Doença da Urina de Xarope de Bordo/diagnóstico , Diagnóstico Pré-Natal , Análise de Sequência de DNA , Aminoácidos de Cadeia Ramificada/química , Povo Asiático/genética , Feminino , Humanos , Masculino , Doença da Urina de Xarope de Bordo/genética , Mutação de Sentido Incorreto , GravidezRESUMO
Large-scale genome-wide association studies (GWAS) have been conducted and reported the association between rs999737 polymorphism at 14q24.1 (RAD51L1) and breast cancer risk. Following studies investigated rs999737 polymorphism in European and Asian populations. However, some of these studies reported weak and no significant association. Here, we reevaluated this association using large-scale samples from previous 11 studies (n=395,793; 162,261 cases and 233,532 controls) from the PubMed database. We evaluated the genetic heterogeneity among the selected studies. The pooled odds ratio (OR) is calculated by the fixed effect model. All statistical tests for heterogeneity and meta-analysis were computed using R package. We did not identify significant heterogeneity among the included studies using the allele model (P=0.1314 and I (2)=33.4 %). We observed significant association between rs999737 and breast cancer using the allele model (P=2.47E - 35, OR=0.92, 95 % confidence interval (CI) 0.91-0.93). Our analysis further supports previous findings that the rs999737 polymorphism contributes to breast cancer susceptibility. We believe that our finding will be very useful for future genetic studies in breast cancer.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Polimorfismo Genético , Feminino , Estudo de Associação Genômica Ampla , Humanos , Viés de PublicaçãoRESUMO
In this study, we investigated the influence of ß-asarone, the major ingredient of Acorus tatarinowii Schott, on depressive-like behavior induced by the chronic unpredictable mild stresses (CUMS) paradigm and to clarify the underlying mechanisms. The results show that ß-asarone treatment partially reversed the CUMS-induced depression-like behaviors in both the forced swim and sucrose preference tests. The behavioral effects were associated with increased hippocampal neurogenesis indicated by bromodeoxyuridine (BrdU) immunoreactivity. ß-Asarone treatment significantly increased the expression of brain-derived neurotrophic factor (BDNF) at levels of transcription and translation. Moreover, CUMS caused significant reduction in ERK1/2 and CREB phosphorylation, both of which were partially attenuated by ß-asarone administration. It is important to note that ß-asarone treatment had no effect on total levels or phosphorylation state of any of the proteins examined in ERK1/2-CREB pathway in no stress rats, suggesting that ß-asarone acts in a stress-dependent manner to block ERK1/2-CREB signaling. We did not observe a complete reversal of depression-like behaviors to control levels by ß-asarone. To our knowledge, the present study is the first to demonstrate that adult neurogenesis is involved in the antidepressant-like behavioral effects of ß-asarone, suggesting that ß-asarone is a promising candidate for the treatment of depression.
Assuntos
Anisóis/administração & dosagem , Depressão/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Derivados de Alilbenzenos , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Humanos , Ratos , NataçãoRESUMO
The human leukocyte antigen G (HLA-G) is expressed on the fetal-maternal interface and plays a role in protecting fetal-derived trophoblasts from the maternal immune response, allowing trophoblasts to invade the uterus. However, HLA-G also possesses immune suppressing-independent functions. We found that HLA-G expressing BeWo choriocarcinoma cells increased cell-cell fusion compared to control BeWo cells under forskolin treatment. Regardless of forskolin treatment, the expression of fusogenic gene mRNAs, including syncytin-1, the transcription factor glial cell missing 1 (Gcm1), and beta human chorionic gonadotropin (ß-hCG) were elevated. HLA-G up-regulates ß-hCG production in human choriocarcinoma cells because HLA-G knockdown in JEG-3 cells induces a dramatic decrease in ß-hCG compared with control cells. The defect in ß-hCG production in HLA-G knocked-down cells could not be completely overcome by stimulating hCG production through increasing intracellular cAMP levels. HLA-G expressing cells have increased phosphorylation levels for extracellular signal-regulated kinase1/2 (Erk1/2) in BeWo cells. The Erk1/2 pathway is inactivated after the inhibition of HLA-G expression in JEG-3 cells. Finally, Erk1/2 inhibition was able to suppress the increased hCG production induced by HLA-G expression. Together, these data suggest novel roles for HLA-G in regulating ß-hCG production via the modulation of the Erk1/2 pathway and by inducing trophoblast cell fusion.
Assuntos
Fusão Celular , Coriocarcinoma/imunologia , Gonadotropina Coriônica/biossíntese , Antígenos HLA-G/imunologia , Sistema de Sinalização das MAP Quinases , Trofoblastos/citologia , Sequência de Bases , Western Blotting , Linhagem Celular Tumoral , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Primers do DNA , Imunofluorescência , Técnicas de Silenciamento de Genes , Antígenos HLA-G/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para CimaRESUMO
Until recently, the molecular pathogenesis of preeclampsia (PE) remained largely unknown. Reports have shown that circulating microRNAs (miRNAs) are promising novel biomarkers for cancer, pregnancy, tissue injury, and other conditions. The objective of this study was to identify differentially expressed miRNAs in plasma from severe preeclamptic pregnancies compared with plasma from normal pregnancies. By mature miRNA microarray analysis, 15 miRNAs, including 13 up- and two downregulated miRNAs, were screened to be differentially expressed in plasma from women with severe PE (sPE). Seven miRNAs, namely miR-24, miR-26a, miR-103, miR-130b, miR-181a, miR-342-3p, and miR-574-5p, were validated to be elevated in plasma from severe preeclamptic pregnancies by real-time quantitative stem-loop RT-PCR analysis. Gene ontology and pathway enrichment analyses revealed that these miRNAs were involved in specific biological process categories (including regulation of metabolic processes, regulation of transcription, and cell cycle) and signaling pathways (including the MAP kinase signaling pathway, the transforming growth factor-ß signaling pathway, and pathways in cancer metastasis). This study presents, for the first time, the differential expression profile of circulating miRNAs in sPE patients. The seven elevated circulating miRNAs may play critical roles in the pathogenesis of sPE, and one or more of them may become potential markers for diagnosing sPE.