Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Psychiatry ; 22(3): 430-440, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27240532

RESUMO

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.


Assuntos
Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Japão , Masculino , Polimorfismo de Nucleotídeo Único/genética
3.
Clin Exp Immunol ; 160(3): 386-93, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20089077

RESUMO

Recent studies have demonstrated that the complement system participates in the regulation of T cell functions. To address the local biosynthesis of complement components in inflammatory bowel disease (IBD) mucosa, we investigated C3 and interleukin (IL)-17 mRNA expression in mucosal samples obtained from patients with IBD. The molecular mechanisms underlying C3 induction were investigated in human colonic subepithelial myofibroblasts (SEMFs). IL-17 and C3 mRNA expressions in the IBD mucosa were evaluated by real-time polymerase chain reaction. The C3 levels in the supernatant were determined by enzyme-linked immunosorbent assay. IL-17 and C3 mRNA expressions were elevated significantly in the active lesions from ulcerative colitis (UC) and Crohn's disease (CD) patients. There was a significant positive correlation between IL-17 and C3 mRNA expression in the IBD mucosa. IL-17 stimulated a dose- and time-dependent increase in C3 mRNA expression and C3 secretion in colonic SEMFs. The C3 molecules secreted by colonic SEMFs were a 115-kDa alpha-chain linked to a 70-kDa beta-chain by disulphide bonds, which was identical to serum C3. The IL-17-induced C3 mRNA expression was blocked by p42/44 mitogen-activated protein kinase (MAPK) inhibitors (PD98059 and U0216) and a p38 MAPK inhibitor (SB203580). Furthermore, IL-17-induced C3 mRNA expression was inhibited by an adenovirus containing a stable mutant form of I kappaB alpha. C3 and IL-17 mRNA expressions are enhanced, with a strong correlation, in the inflamed mucosa of IBD patients. Part of these clinical findings was considered to be mediated by the colonic SEMF response to IL-17.


Assuntos
Colite Ulcerativa/imunologia , Complemento C3/imunologia , Doença de Crohn/imunologia , Regulação da Expressão Gênica/imunologia , Interleucina-17/imunologia , Mucosa Intestinal/imunologia , RNA Mensageiro/imunologia , Adenoviridae , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Complemento C3/biossíntese , Complemento C3/genética , Doença de Crohn/genética , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Flavonoides , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/imunologia , Proteínas I-kappa B/metabolismo , Imidazóis/farmacologia , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucina-17/farmacologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Mutação , Inibidor de NF-kappaB alfa , Piridinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo , Transdução Genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
J Mol Cell Cardiol ; 33(2): 197-207, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11162126

RESUMO

Numerous mutations in KCNQ1, a gene encoding the alpha -subunit of cardiac delayed rectifier potassium channels, have been found in long QT syndrome (LQTS). Among them, several mutations in the C terminus have been shown to cause autosomal recessive or subclinical autosomal dominant LQTS. Here, we report a heterozygous mutation, T587M, which is also in the KCNQ1 C-terminal domain. The same mutation was found in three independent probands that were clearly symptomatic with family history of cardiac sudden death. Functional assay using a heterologous expression system with a mammalian cell line (COS7 cells) revealed that the mutant displayed neither functional channels when expressed alone nor dominant-negative effect when co-expressed with wild-type (WT) KCNQ1. To examine the cellular trafficking of KCNQ1, green fluorescent protein (GFP) was tagged to the cytoplasmic C terminus of WT or mutant KCNQ1. This procedure did not affect the essential properties of expressed WT KCNQ1 channels. On confocal microscopic images, GFP-tagged WT KCNQ1 showed a plasma membrane fluorescence pattern, whereas the GFP-tagged mutant showed a perinuclear fluorescence pattern. Co-expression of the mutant with GFP-tagged WT KCNQ1 did not influence its normal cellular transport. Therefore, the T587M mutant cannot traffic to the plasma membrane and may form no subunit assembly with WT KCNQ1. These findings provide a novel molecular basis for the clinical finding that this C-terminal mutation produced a severe form of RWS-type LQTS.


Assuntos
Mutação , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/biossíntese , Canais de Potássio/genética , Adolescente , Adulto , Animais , Células COS , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Análise Mutacional de DNA , Eletrofisiologia , Saúde da Família , Feminino , Proteínas de Fluorescência Verde , Heterozigoto , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Síndrome do QT Longo/genética , Síndrome do QT Longo/metabolismo , Proteínas Luminescentes/metabolismo , Masculino , Microscopia Confocal , Mutação de Sentido Incorreto , Fenótipo , Canais de Potássio/química , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/metabolismo , Transfecção
5.
Nucleic Acids Res Suppl ; (1): 29-30, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-12836248

RESUMO

The substitution effect on hydrogen bond energy of the Watson-Crick type base pair between 9-methylguanine (G) and chemically modified 1-methylcytosine (CX) derivatives was evaluated by ab initio molecular orbital theory. A remarkable trend was observed in the substitution effect of the hydrogen bond stability: Cytosine derivatives possessing an electron-donating group form stable base pairs with guanine. However, both the hydrogen bond distance and the charge distribution were not good indexes for the hydrogen bond status in CX-G base pairing.


Assuntos
Citosina/análogos & derivados , Citosina/química , Guanina/análogos & derivados , Guanina/química , Pareamento de Bases , Ligação de Hidrogênio
6.
Int Immunol ; 10(8): 1203-10, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9723707

RESUMO

Antigen stimulation via TCR in mature T cells provides rapid induction of tyrosine phosphorylation of intracellular substrates including ZAP-70. To study the potential involvement of tyrosine phosphorylation in CD4+CD8+ [double-positive (DP)] thymocytes in the positive selection process in vivo, we isolated and analyzed them in the presence of phosphatase inhibitor. DP thymocytes were obtained from TCR transgenic mice (TCR-Tg) expressing MHC class I- or class II-restricted TCR in selecting and non-selecting MHC backgrounds respectively. The phosphorylation of ZAP-70 in DP thymocytes of class I-restricted TCR-Tg was significantly higher in the positively selecting background than in the non-selecting one. However, such a phosphorylation difference between selecting and non-selecting TCR-Tg was found to be considerably less in class II-restricted TCR-Tg. A similar bias for ZAP-70 phosphorylation was also observed on selecting DP thymocytes when I-A(beta) deficient- and beta2-microglobulin-deficient mice were compared. These ex vivo studies suggest that TCR-mediated signaling on DP thymocytes induces ZAP-70 phosphorylation under a different manner of engagement of TCR to class I and class II molecules in the positive selection process.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Anticorpos Monoclonais , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Antígenos de Histocompatibilidade/imunologia , Isoenzimas/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Fosfolipase C gama , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Timo/metabolismo , Fosfolipases Tipo C/metabolismo , Vanadatos/farmacologia , Proteína-Tirosina Quinase ZAP-70 , Microglobulina beta-2/imunologia
7.
Ophthalmic Surg Lasers ; 28(6): 510-2, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9189957

RESUMO

In cases in which filtration surgery such as trabeculectomy is necessary, a flat anterior chamber postoperatively due to overfiltration may cause severe problems in the control of intraocular pressure. Once a broad synechia has formed between the iris and the corneal endothelium, this type of refractory, surgically induced angle closure can be difficult to manage. This article details a case of refractory angle-closure glaucoma secondary to a flat anterior chamber following trabeculectomy. Multiple surgical treatments were performed to control intraocular pressure and to reconstruct the anterior segment of the eye.


Assuntos
Câmara Anterior/patologia , Glaucoma de Ângulo Fechado/cirurgia , Glaucoma de Ângulo Aberto/cirurgia , Trabeculectomia/efeitos adversos , Vitrectomia/métodos , Câmara Anterior/cirurgia , Feminino , Glaucoma de Ângulo Fechado/etiologia , Glaucoma de Ângulo Fechado/patologia , Humanos , Pressão Intraocular , Lentes Intraoculares , Pessoa de Meia-Idade , Facoemulsificação/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/cirurgia , Reoperação , Retalhos Cirúrgicos/métodos
8.
Int Immunol ; 8(10): 1473-81, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8921426

RESUMO

In order to determine whether the cells immigrating into the thymus have been committed to the T cell lineage, we examined the gene expression of the TCR complex in fetal thymus (FT) and fetal liver (FL) precursors. We previously showed that c-kit bright-positive, Pgp-1 bright-positive and lineage markers negative fetal thymocytes (c-kit+ FT cells) are the most immature cells which do not undergo gene rearrangement of the TCR beta chain. In this study, we demonstrated that the gene rearrangement of TCR gamma as well as beta chains does not occur in c-kit+ FT cells, but that the germline transcript of their TCR beta was found in J-C regions. The TCR beta gene was demethylated in c-kit+ FT cells. CD3 gamma, delta and epsilon subunit genes were also expressed at the mRNA levels in c-kit+ FT cells, but cytoplasmic protein staining divided them into two populations: cytoplasmic CD3 epsilon positive and negative cells. These features were not observed in c-kit+ FL cells. Moreover, Ly-1 expression was found on c-kit+ FT cells but not on c-kit+ FL cells. These results indicate that DNA alteration on the TCR beta gene initiates with other phenotype expression determining the T cell lineage in the thymus prior to TCR gene rearrangement.


Assuntos
Complexo CD3/análise , Metilação de DNA , Rearranjo Gênico do Linfócito T/imunologia , Proteínas Proto-Oncogênicas c-kit/análise , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/imunologia , Timo/imunologia , Transcrição Gênica/genética , Animais , Complexo CD3/biossíntese , Diferenciação Celular/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Proteínas Proto-Oncogênicas c-kit/biossíntese , Linfócitos T/metabolismo , Timo/citologia
9.
Int Immunol ; 6(9): 1451-4, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7819155

RESUMO

The effects of IL-7 on the growth and differentiation of thymocytes were analyzed using murine fetal thymus organ cultures (FTOC) in the presence of mAbs specific for the conventional IL-7 receptor (IL-7R) and for the common gamma (gamma c) chain. In FTOC, the development of CD4-CD8- double-negative thymocytes to CD4+CD8+ double-positive (DP) and CD4+ or CD8+ single-positive (SP) cells was not completely blocked by adding these mAbs, although cell growth was reduced by the treatment. To define a developing stage sensitive to the mAbs, most immature thymocytes, Pgp-1+ c-kit+ cells, were cultured in 2-deoxyguanosine treated fetal thymus. In the presence of both mAbs in the culture, neither DP nor SP thymocytes developed whereas either of the mAbs partially blocked their development. These results indicate that the gamma c chain is involved in early T cell development as an indispensable subunit of the functional IL-7 receptor complex.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores de Interleucina/imunologia , Timo/citologia , Animais , Anticorpos Monoclonais/imunologia , Diferenciação Celular , Feto , Citometria de Fluxo , Interleucina-7/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C3H , Receptores de Interleucina-7 , Timo/efeitos dos fármacos , Timo/embriologia
10.
Eur J Immunol ; 24(6): 1339-44, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7515811

RESUMO

Ten percent of 15-day fetal thymocytes of mice were Pgp-1+Thy-1lo cells. Half were strongly stained with monoclonal antibodies (mAb) recognizing the oncogene product, c-kit, but were not stained with mAb against non-T cell markers such as B220, Mac-1 and Gr-1. The isolated Pgp-1+c-kit+ thymocytes showed no rearranged bands for V-DJ and D-J of T cell receptor (TcR) beta, but Pgp-1(-)-c-kit- thymocytes showed D-J rearranged bands. Both cells expressed the RAG-2 gene which is required for the V(D)J recombination process. When Pgp-1+c-kit+ thymocytes were cultured in 2-deoxyguanosine-treated alymphocytic fetal thymus, they became TcR-expressing mature type T cells, but this differentiation was reduced by the addition of anti c-kit mAb. These data indicate that Pgp-1+c-kit+ thymocytes are pro-T cells with the potential to differentiate mature T cells in the thymic environment. This study also indicates that c-kit-mediated signals promote the differentiation of thymocytes during their early stages.


Assuntos
Proteínas de Ligação a DNA , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Receptores de Fator Estimulador de Colônias/biossíntese , Linfócitos T/metabolismo , Timo/embriologia , Animais , Sequência de Bases , Diferenciação Celular , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C3H , Dados de Sequência Molecular , Técnicas de Cultura de Órgãos , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-kit , Timo/citologia , Timo/metabolismo
11.
Nihon Yakurigaku Zasshi ; 90(6): 313-20, 1987 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-3443413

RESUMO

FUT-175 is a newly synthesized serine protease inhibitor. In the present study, we investigated the effects of FUT-175 on blood coagulation and experimental DIC. The effects on coagulation were examined in vitro by measuring the activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) of rat plasma in the presence of FUT-175. FUT-175 exhibited remarkable anticoagulative effects to prolong APTT at a plasma concentration of 3 x 10(-7) M, PT at 1 x 10(-5) M and TT at 3 x 10(-5) M. The anticoagulative effect of FUT-175 at 1 x 10(-6) M on APTT was almost similar to that of heparin at 0.3 U/ml or that of gabexate mesilate at 1 x 10(-3) M. Experimental DIC was induced by a four-hr sustained intravenous infusion of endotoxin. FUT-175 was administered intraperitoneally prior to the injection of endotoxin or infused intravenously with endotoxin. As a result, the prolongation of APTT and PT, the decreases of fibrinogen level, platelet counts and complement level, and the increase of FDP were remarkably improved by FUT-175. Furthermore, glomerular fibrin deposits were reduced by the infusion of FUT-175. These results indicate that FUT-175, having a potent inhibitory effect on blood coagulation, is clinically applicable to therapy for DIC.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Coagulação Intravascular Disseminada/tratamento farmacológico , Guanidinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Animais , Benzamidinas , Guanidinas/farmacologia , Masculino , Inibidores de Proteases/farmacologia , Ratos , Ratos Endogâmicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...