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1.
Nat Commun ; 8: 14364, 2017 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-28232668

RESUMO

Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Fatores Etários , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Fenda Labial/etnologia , Fissura Palatina/etnologia , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
2.
Proc Natl Acad Sci U S A ; 112(23): 7327-32, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-26015571

RESUMO

Glycosylation, the most abundant posttranslational modification, holds an unprecedented capacity for altering biological function. Our ability to harness glycosylation as a means to control biological systems is hampered by our inability to pinpoint the specific glycans and corresponding biosynthetic enzymes underlying a biological process. Herein we identify glycosylation enzymes acting as regulatory elements within a pathway using microRNA (miRNA) as a proxy. Leveraging the target network of the miRNA-200 family (miR-200f), regulators of epithelial-to-mesenchymal transition (EMT), we pinpoint genes encoding multiple promesenchymal glycosylation enzymes (glycogenes). We focus on three enzymes, beta-1,3-glucosyltransferase (B3GLCT), beta-galactoside alpha-2,3-sialyltransferase 5 (ST3GAL5), and (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (ST6GALNAC5), encoding glycans that are difficult to analyze by traditional methods. Silencing these glycogenes phenocopied the effect of miR-200f, inducing mesenchymal-to-epithelial transition. In addition, all three are up-regulated in TGF-ß-induced EMT, suggesting tight integration within the EMT-signaling network. Our work indicates that miRNA can act as a relatively simple proxy to decrypt which glycogenes, including those encoding difficult-to-analyze structures (e.g., proteoglycans, glycolipids), are functionally important in a biological pathway, setting the stage for the rapid identification of glycosylation enzymes driving disease states.


Assuntos
MicroRNAs/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Inativação Gênica , Glicosilação , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Transferases/genética , Transferases/metabolismo
3.
Proc Natl Acad Sci U S A ; 111(11): 4338-43, 2014 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-24591635

RESUMO

Cell surface glycans form a critical interface with the biological milieu, informing diverse processes from the inflammatory cascade to cellular migration. Assembly of discrete carbohydrate structures requires the coordinated activity of a repertoire of proteins, including glycosyltransferases and glycosidases. Little is known about the regulatory networks controlling this complex biosynthetic process. Recent work points to a role for microRNA (miRNA) in the regulation of specific glycan biosynthetic enzymes. Herein we take a unique systems-based approach to identify connections between miRNA and the glycome. By using our glycomic analysis platform, lectin microarrays, we identify glycosylation signatures in the NCI-60 cell panel that point to the glycome as a direct output of genomic information flow. Integrating our glycomic dataset with miRNA data, we map miRNA regulators onto genes in glycan biosynthetic pathways (glycogenes) that generate the observed glycan structures. We validate three of these predicted miRNA/glycogene regulatory networks: high mannose, fucose, and terminal ß-GalNAc, identifying miRNA regulation that would not have been observed by traditional bioinformatic methods. Overall, our work reveals critical nodes in the global glycosylation network accessible to miRNA regulation, providing a bridge between miRNA-mediated control of cell phenotype and the glycome.


Assuntos
Vias Biossintéticas/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Redes Reguladoras de Genes/genética , MicroRNAs/metabolismo , Polissacarídeos/biossíntese , Western Blotting , Linhagem Celular , Regulação Enzimológica da Expressão Gênica/genética , Glicômica/métodos , Glicosilação/efeitos dos fármacos , Humanos , Luciferases , MicroRNAs/farmacologia , Análise em Microsséries , Microscopia de Fluorescência , Reação em Cadeia da Polimerase em Tempo Real , Biologia de Sistemas/métodos
5.
Chemphyschem ; 14(5): 982-9, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23436755

RESUMO

A set of terfluorenes and terfluorene-like molecules with different pendant substitutions or side groups were designed and synthesized, their photophysical properties and the excited-state geometries were studied. Dual fluorescence emissions were observed in compounds with rigid pendant groups bearing electron-donating N atoms. According to our earlier studies, in this set of terfluorenes, the blue emission is from the local π-π* transition, while the long-wavelength emission is attributed to a spiroconjugation-like through-space charge-transfer process. Herein, we probe further into how the molecular structures (referring to the side groups, the type of linkage between central fluorene and the 2,2'-azanediyldiethanol units, and-most importantly-the amount of pendant groups), as well as the excited-state geometries, affect the charge-transfer process of these terfluorenes or terfluorene-like compounds. 9-(9,9,9'',9''-tetrahexyl-9H,9'H,9''H-[2,2':7',2''-terfluoren]-9'-yl)-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolone (TFPJH), with only one julolidine pendant group, was particularly synthesized, which exhibits complete "perpendicular" conformation between julolidine and the central fluorene unit in the excited state, thus typical spiroconjugation could be achieved. Notably, its photophysical behaviors resemble those of TFPJ with two pendant julolidines. This study proves that spiroconjugation does happen in these terfluorene derivatives, although their structures are not in line with the typical orthogonal π fragments. The spiroconjugation charge-transfer emission closely relates to the electron-donating N atoms on the pendant groups, and to the rigid connection between the central fluorene and the N atoms, whereas the amount of pendant groups and the nature of the side chromophores have little effect. These findings may shed light on the understanding of the through-space charge-transfer properties and the emission color tuning of fluorene derivatives.

6.
Chem Commun (Camb) ; 46(36): 6666-8, 2010 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-20571695

RESUMO

We have synthesized a series of new terfluorene derivatives, and investigated their novel fluorescence emission behaviors. We have demonstrated a new intramolecular through-space charge transfer emission experimentally and theoretically. This is the first report on spiroconjugation-like caused fluorescence emission, which could be tuned by the electron nature of pendent groups without changing their absorption.

7.
Org Lett ; 11(18): 4132-5, 2009 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-19681581

RESUMO

A bent ladder-type hexaphenylene with a carbazole core and spiro-linkage is designed and synthesized by using the ortho-linked spirobifluorene. The design eliminates the possibility of forming a positional isomer. As a blue-emitter, the BLHPC shows good thermal and color stability. A simple light-emitting device fabricated from BLHPC exhibits a maximum current efficiency of 1.46 cd/A and a maximum luminance of 505 cd/m(2).

8.
Org Lett ; 11(12): 2607-10, 2009 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-19459696

RESUMO

4-Bromo-9,9'-spirobifluorene is facilely synthesized, and from this precursor, two ortho-linked oligo-9,9'-spirobifluorenes, 44BSF and 24TSF, are constructed. Devices with 24TSF as the full-hydrocarbon host material and Ir(ppy)(3) or (ppq)(2)Ir(acac) as the triplet emitter show maximum external quantum efficiencies of 12.6 and 10.5% for green and red electrophosphorescence, respectively.

9.
Artigo em Chinês | MEDLINE | ID: mdl-14663947

RESUMO

OBJECTIVE: To study the effects of jaw advancement in treating micromandibular deformity associated with obstructive sleep apnea syndrome (OSAS) by ramus osteotomy and genioplasty. METHODS: From April 1998 to February 2002, 12 patients with micromandibular deformity associated with OSAS (aged 14-36 years, 7 females and 5 males) were treated. Invert "L" shape ramus osteotomy and inverted replantation of posterior segment of ramus were performed to reconstruct the TMJ with the jaw advancement and genioplasty at the same time in 7 cases; mandibular angle osteotomy, bone grafts and genioplasty in 3 cases; and the jaw advancement by ramus sagittal osteotomy and genioplasty in 2 cases of the first branchial arch syndrome. RESULTS: The follow-up period was 6 months to 4 years. All the patients gained good appearance and had the distance of opening movement over 3.0 cm. Micromandible and facial asymmetries were corrected satisfactorily. The ratio of SaO2 was ascended from 82%-92% (preoperation) to 97%-99% (postoperation). OSAS was relieved. CONCLUSION: The jaw advancement by ramus osteotomy and genioplasty for treating micromandibular deformity associated with OSAS can correct the maxillofacial deformities and enlarge the upper airway space to relieve OSAS. This method has achieved satisfactory result.


Assuntos
Micrognatismo/cirurgia , Apneia Obstrutiva do Sono/etiologia , Adolescente , Adulto , Transplante Ósseo , Feminino , Seguimentos , Humanos , Masculino , Mandíbula/cirurgia , Avanço Mandibular , Micrognatismo/complicações , Procedimentos Cirúrgicos Bucais/métodos , Osteotomia , Apneia Obstrutiva do Sono/cirurgia , Transtornos da Articulação Temporomandibular/complicações , Transtornos da Articulação Temporomandibular/cirurgia
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