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1.
J Immunol ; 204(6): 1607-1620, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32024700

RESUMO

Autoinflammatory diseases are characterized by dysregulation of the innate immune system, leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Because of the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1ß by neutrophil granulocytes. In this study, we show that in addition to IL-1ß, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1ß levels, and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.

2.
R Soc Open Sci ; 5(2): 171914, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29515893

RESUMO

The Tasmanian tiger or thylacine (Thylacinus cynocephalus) was an iconic Australian marsupial predator that was hunted to extinction in the early 1900s. Despite sharing striking similarities with canids, they failed to evolve many of the specialized anatomical features that characterize carnivorous placental mammals. These evolutionary limitations are thought to arise from functional constraints associated with the marsupial mode of reproduction, in which otherwise highly altricial young use their well-developed forelimbs to climb to the pouch and mouth to suckle. Here we present the first three-dimensional digital developmental series of the thylacine throughout its pouch life using X-ray computed tomography on all known ethanol-preserved specimens. Based on detailed skeletal measurements, we refine the species growth curve to improve age estimates for the individuals. Comparison of allometric growth trends in the appendicular skeleton (fore- and hindlimbs) with that of other placental and marsupial mammals revealed that despite their unique adult morphologies, thylacines retained a generalized early marsupial ontogeny. Our approach also revealed mislabelled specimens that possessed large epipubic bones (vestigial in thylacine) and differing vertebral numbers. All of our generated CT models are publicly available, preserving their developmental morphology and providing a novel digital resource for future studies of this unique marsupial.

3.
Development ; 144(12): 2212-2221, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28506989

RESUMO

The patterning of repeated structures is a major theme in developmental biology, and the inter-relationship between spacing and size of such structures is an unresolved issue. Fungiform papillae are repeated epithelial structures that house taste buds on the anterior tongue. Here, we report that FGF signaling is a crucial regulator of fungiform papillae development. We found that mesenchymal FGF10 controls the size of the papillary area, while overall patterning remains unchanged. Our results show that FGF signaling negatively affects the extent of canonical Wnt signaling, which is the main activation pathway during fungiform papillae development; however, this effect does not occur at the level of gene transcription. Rather, our experimental data, together with computational modeling, indicate that FGF10 modulates the range of Wnt effects, likely via induction of Sostdc1 expression. We suggest that modification of the reach of Wnt signaling could be due to local changes in morphogen diffusion, representing a novel mechanism in this tissue context, and we propose that this phenomenon might be involved in a broader array of mammalian developmental processes.


Assuntos
Fator 10 de Crescimento de Fibroblastos/metabolismo , Papilas Gustativas/embriologia , Papilas Gustativas/metabolismo , Via de Sinalização Wnt , Animais , Padronização Corporal/genética , Padronização Corporal/fisiologia , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Simulação por Computador , Feminino , Fator 10 de Crescimento de Fibroblastos/deficiência , Fator 10 de Crescimento de Fibroblastos/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Biológicos , Gravidez , Proteínas Serina-Treonina Quinases
4.
Proc Natl Acad Sci U S A ; 114(9): E1641-E1650, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28196895

RESUMO

The formation of mineralized tissues is governed by extracellular matrix proteins that assemble into a 3D organic matrix directing the deposition of hydroxyapatite. Although the formation of bones and dentin depends on the self-assembly of type I collagen via the Gly-X-Y motif, the molecular mechanism by which enamel matrix proteins (EMPs) assemble into the organic matrix remains poorly understood. Here we identified a Y/F-x-x-Y/L/F-x-Y/F motif, evolutionarily conserved from the first tetrapods to man, that is crucial for higher order structure self-assembly of the key intrinsically disordered EMPs, ameloblastin and amelogenin. Using targeted mutations in mice and high-resolution imaging, we show that impairment of ameloblastin self-assembly causes disorganization of the enamel organic matrix and yields enamel with disordered hydroxyapatite crystallites. These findings define a paradigm for the molecular mechanism by which the EMPs self-assemble into supramolecular structures and demonstrate that this process is crucial for organization of the organic matrix and formation of properly structured enamel.


Assuntos
Motivos de Aminoácidos/fisiologia , Esmalte Dentário/metabolismo , Proteínas Intrinsicamente Desordenadas/metabolismo , Amelogenina/metabolismo , Sequência de Aminoácidos , Animais , Evolução Biológica , Proteínas do Esmalte Dentário/metabolismo , Durapatita/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Masculino , Camundongos , Ligação Proteica/fisiologia
5.
PLoS One ; 11(4): e0153316, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27092776

RESUMO

INTRODUCTION: The aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA) and redundancy analysis (RDA). METHODS: A total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE) in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601), STAT4 G/T (rs7574865), CTLA4 A/G (rs3087243), TRAF1/C5 A/G (rs3761847), IRF5 T/C (rs10488631), TNFAIP3 C/T (rs5029937), AFF3 A/T (rs11676922), PADI4 C/T (rs2240340), CD28 T/C (rs1980422), CSK G/A (rs34933034) and FCGR3A A/C (rs396991), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and clinical status was analysed using the LDA and RDA. RESULTS: HLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002). The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001). The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA. CONCLUSIONS: The association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA.


Assuntos
Artrite Reumatoide/genética , Antígenos CD28/genética , Predisposição Genética para Doença/genética , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Autoanticorpos/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/genética , Fatores de Risco
6.
Dev Cell ; 35(6): 713-24, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26702830

RESUMO

The proper positioning of organs during development is essential, yet little is known about the regulation of this process in mammals. Using murine tooth development as a model, we have found that cell migration plays a central role in positioning of the organ primordium. By combining lineage tracing, genetic cell ablation, and confocal live imaging, we identified a migratory population of Fgf8-expressing epithelial cells in the embryonic mandible. These Fgf8-expressing progenitors furnish the epithelial cells required for tooth development, and the progenitor population migrates toward a Shh-expressing region in the mandible, where the tooth placode will initiate. Inhibition of Fgf and Shh signaling disrupted the oriented migration of cells, leading to a failure of tooth development. These results demonstrate the importance of intraepithelial cell migration in proper positioning of an initiating organ.


Assuntos
Movimento Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Dente Molar/embriologia , Morfogênese/fisiologia , Dente/citologia , Animais , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Dente Molar/citologia , Dente Molar/metabolismo , Odontogênese/fisiologia , Dente/embriologia
7.
J Exp Zool B Mol Dev Evol ; 320(5): 307-20, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23606267

RESUMO

In mice, a toothless diastema separates the single incisor from the three molars in each dental quadrant. In the prospective diastema of the embryo, small rudimentary buds are found that are presumed to be rudiments of suppressed teeth. A supernumerary tooth occurs in the diastema of adult mice carrying mutations in either Spry2 or Spry4. In the case of Spry2 mutants, the origin of the supernumerary tooth involves the revitalization of a rudimentary tooth bud (called R2), whereas its origin in the Spry4 mutants is not known. In addition to R2, another rudimentary primordium (called MS) arises more anteriorly in the prospective diastema. We investigated the participation of both rudiments (MS and R2) in supernumerary tooth development in Spry2 and Spry4 mutants by comparing morphogenesis, proliferation, apoptosis, size and Shh expression in the dental epithelium of MS and R2 rudiments. Increased proliferation and decreased apoptosis were found in MS and R2 at embryonic day (ED) 12.5 and 13.5 in Spry2(-/-) embryos. Apoptosis was also decreased in both rudiments in Spry4(-/-) embryos, but the proliferation was lower (similar to WT mice), and supernumerary tooth development was accelerated, exhibiting a cap stage by ED13.5. Compared to Spry2(-/-) mice, a high number of Spry4(-/-) supernumerary tooth primordia degenerated after ED13.5, resulting in a low percentage of supernumerary teeth in adults. We propose that Sprouty genes were implicated during evolution in reduction of the cheek teeth in Muridae, and their deletion can reveal ancestral stages of murine dental evolution.


Assuntos
Evolução Biológica , Epitélio/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Dente/crescimento & desenvolvimento , Animais , Apoptose/genética , Incisivo/crescimento & desenvolvimento , Incisivo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Dente Molar/crescimento & desenvolvimento , Dente Molar/metabolismo , Mutação , Proteínas do Tecido Nervoso/genética , Odontogênese , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Dente Supranumerário/patologia
8.
J Morphol ; 271(10): 1204-18, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20623522

RESUMO

The tribosphenic molar is a dental apomorphy of mammals and the molar type from which all derived types originated. Its enamel coat is expected to be ancestral: a thin, evenly distributed layer of radial prismatic enamel. In the bat Myotis myotis, we reinvestigated the 3D architecture of the dental enamel using serial sectioning combined with scanning electron microscopy analyses, biometrics of enamel prisms and crystallites, and X-ray diffraction. We found distinct heterotopies in enamel thickness (thick enamel on the convex sides of the crests, thin on the concave ones), angularity of enamel prisms, and in distribution of particular enamel types (prismatic, interprismatic, aprismatic) and demonstrated structural relations of these heterotopies to the cusp and crest organization of the tribosphenic molar. X-ray diffraction demonstrated that the crystallites composing the enamel are actually the aggregates of much smaller primary crystallites. The differences among particular enamel types in degree of crystallite aggregation and the variation in structural microstrain of the primary crystallites (depending upon the duration and the mechanical context of mineralization) represent factors not fully understood as yet that may contribute to the complexity of enamel microarchitecture in a significant way.


Assuntos
Esmalte Dentário/ultraestrutura , Dente Molar/ultraestrutura , Esmalte Dentário/química , Humanos , Microscopia Eletrônica de Varredura , Dente Molar/química , Difração de Raios X
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