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1.
Ann Rheum Dis ; 78(9): 1269-1273, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177096

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc. METHODS: Expression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models. RESULTS: The expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-ß (TGFß)/SMAD-dependent manner. Knockdown of HHAT reduced TGFß-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis. CONCLUSION: HHAT is regulated in SSc in a TGFß-dependent manner and in turn stimulates TGFß-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.

2.
Nat Commun ; 9(1): 3259, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108215

RESUMO

Uncontrolled activation of TGFß signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFß-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFß stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFß promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFß-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.

3.
Child Dev ; 89(6): 1996-2009, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29736962

RESUMO

Previous work suggests that key factors for replicability, a necessary feature for theory building, include statistical power and appropriate research planning. These factors are examined by analyzing a collection of 12 standardized meta-analyses on language development between birth and 5 years. With a median effect size of Cohen's d = .45 and typical sample size of 18 participants, most research is underpowered (range = 6%-99%; median = 44%); and calculating power based on seminal publications is not a suitable strategy. Method choice can be improved, as shown in analyses on exclusion rates and effect size as a function of method. The article ends with a discussion on how to increase replicability in both language acquisition studies specifically and developmental research more generally.

5.
Ann Rheum Dis ; 77(3): 459, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29311148

RESUMO

OBJECTIVES: Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC-cyclic guanosine monophosphate (cGMP) in SSc. METHODS: Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823. RESULTS: PKG1 and 2 are upregulated in SSc in a transforming growth factor-ß1 (TGFß1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC-cGMP-PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice. CONCLUSIONS: Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFß signalling. TGFß1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFß1-induced ERK phosphorylation.

6.
Ann Rheum Dis ; 77(1): 150-158, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29070530

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis. METHODS: JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP. RESULTS: The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFß)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFß. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2. CONCLUSION: We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.


Assuntos
Fibroblastos/enzimologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Escleroderma Sistêmico/enzimologia , Adulto , Idoso , Animais , Bleomicina , Estudos de Casos e Controles , Células Cultivadas , Ativação Enzimática , Feminino , Fibrose/induzido quimicamente , Fibrose/enzimologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
8.
Nat Commun ; 8(1): 1130, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066712

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFß-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFß. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.


Assuntos
Fibrose/metabolismo , Fator de Transcrição STAT3/metabolismo , Escleroderma Sistêmico/metabolismo , Adolescente , Adulto , Idoso , Ácidos Aminossalicílicos/química , Animais , Benzenossulfonatos/química , Biópsia , Bleomicina/química , Colágeno/química , Ativação Enzimática , Feminino , Fibroblastos/metabolismo , Humanos , Inflamação , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Fosforilação , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Pele/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
9.
Ann Rheum Dis ; 76(8): 1467-1475, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28478401

RESUMO

OBJECTIVES: Janus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-ß. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts. METHODS: The antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance. RESULTS: The antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis. CONCLUSION: Fibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.


Assuntos
Fibroblastos/efeitos dos fármacos , Janus Quinase 1/efeitos dos fármacos , Janus Quinase 2/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Fibrose Pulmonar/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Escleroderma Sistêmico , Sulfonamidas/farmacologia , Adulto , Animais , Antibióticos Antineoplásicos/toxicidade , Benzoquinonas/farmacologia , Bleomicina/toxicidade , Western Blotting , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Imuno-Histoquímica , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Lactamas Macrocíclicas/farmacologia , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta/farmacologia
10.
Epigenomics ; 9(4): 463-477, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28343418

RESUMO

Prolonged activation of fibroblasts is a central hallmark of fibrosing disorders such as systemic sclerosis (SSc). Fibroblasts are the key effector cells. They differentiate into an activated myofibroblast phenotype. In contrast to normal wound healing with transient activation, myofibroblasts persist in fibrosing disorders. Current hypothesis suggests that profibrotic cytokines might trigger epigenetic changes which contribute to the persistently activated fibroblast phenotype. In the last years, several epigenetic alterations have been described in SSc and have been linked to different pathogenic aspects of the disease, in particular to aberrant fibroblast activation and tissue fibrosis, but also to vascular manifestations and inflammation. The focus of this review is the current knowledge on epigenetic changes in fibroblast activation in SSc.


Assuntos
Epigênese Genética , Redes Reguladoras de Genes , Escleroderma Sistêmico/patologia , Animais , Citocinas/metabolismo , Metilação de DNA , Fibrose , Código das Histonas , Humanos , Miofibroblastos/imunologia , Miofibroblastos/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia
11.
Ann Rheum Dis ; 76(6): 1133-1141, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28209630

RESUMO

OBJECTIVES: To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc). METHODS: We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4. RESULTS: Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role. CONCLUSIONS: PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Citocinas/genética , Fibroblastos/metabolismo , Macrófagos/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Escleroderma Sistêmico/patologia , Pele/patologia , Animais , Bleomicina , Diferenciação Celular/efeitos dos fármacos , Colágeno/metabolismo , DNA Topoisomerases Tipo I/imunologia , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibrose , Expressão Gênica/efeitos dos fármacos , Doença Enxerto-Hospedeiro/complicações , Humanos , Interleucina-13/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Inibidores da Fosfodiesterase 4/uso terapêutico , RNA Mensageiro/metabolismo , Rolipram/farmacologia , Escleroderma Sistêmico/tratamento farmacológico , Pele/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/farmacologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta2/genética
12.
Lab Invest ; 96(2): 151-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26752744

RESUMO

Fibrosing disorders are characterized by abundant accumulation of extracellular matrix proteins such as collagen in a variety of organs, which results in structural changes and dysfunction of the affected organ. Thus fibrotic diseases are characterized by a high morbidity and mortality and also lead to major socioeconomic costs. Systemic sclerosis (SSc) is a prototypic multi-systemic fibrosing disease, which affects the skin and a variety of internal organs, including the lungs, heart and gastrointestinal tract. Targeted antifibrotic therapies are not yet available for clinical use in SSc. In recent years, canonical Wnt signaling has been profoundly characterized as an important mediator of sustained fibroblast activation in fibrotic diseases. In the present review, we will summarize current research on the canonical Wnt signaling pathway in SSc and discuss translational implications and potential limitations of prolonged Wnt inhibition.


Assuntos
Escleroderma Sistêmico , Via de Sinalização Wnt , Humanos
13.
Dev Sci ; 19(6): 901-917, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26353859

RESUMO

Infants start learning words, the building blocks of language, at least by 6 months. To do so, they must be able to extract the phonological form of words from running speech. A rich literature has investigated this process, termed word segmentation. We addressed the fundamental question of how infants of different ages segment words from their native language using a meta-analytic approach. Based on previous popular theoretical and experimental work, we expected infants to display familiarity preferences early on, with a switch to novelty preferences as infants become more proficient at processing and segmenting native speech. We also considered the possibility that this switch may occur at different points in time as a function of infants' native language and took into account the impact of various task- and stimulus-related factors that might affect difficulty. The combined results from 168 experiments reporting on data gathered from 3774 infants revealed a persistent familiarity preference across all ages. There was no significant effect of additional factors, including native language and experiment design. Further analyses revealed no sign of selective data collection or reporting. We conclude that models of infant information processing that are frequently cited in this domain may not, in fact, apply in the case of segmenting words from native speech.


Assuntos
Percepção Auditiva/fisiologia , Desenvolvimento da Linguagem , Percepção da Fala/fisiologia , Fala , Humanos , Lactente , Linguagem
14.
PLoS One ; 10(7): e0132245, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26218504

RESUMO

During language acquisition, infants frequently encounter ambient noise. We present a computational model to address whether specific acoustic processing abilities are necessary to detect known words in moderate noise--an ability attested experimentally in infants. The model implements a general purpose speech encoding and word detection procedure. Importantly, the model contains no dedicated processes for removing or cancelling out ambient noise, and it can replicate the patterns of results obtained in several infant experiments. In addition to noise, we also addressed the role of previous experience with particular target words: does the frequency of a word matter, and does it play a role whether that word has been spoken by one or multiple speakers? The simulation results show that both factors affect noise robustness. We also investigated how robust word detection is to changes in speaker identity by comparing words spoken by known versus unknown speakers during the simulated test. This factor interacted with both noise level and past experience, showing that an increase in exposure is only helpful when a familiar speaker provides the test material. Added variability proved helpful only when encountering an unknown speaker. Finally, we addressed whether infants need to recognise specific words, or whether a more parsimonious explanation of infant behaviour, which we refer to as matching, is sufficient. Recognition involves a focus of attention on a specific target word, while matching only requires finding the best correspondence of acoustic input to a known pattern in the memory. Attending to a specific target word proves to be more noise robust, but a general word matching procedure can be sufficient to simulate experimental data stemming from young infants. A change from acoustic matching to targeted recognition provides an explanation of the improvements observed in infants around their first birthday. In summary, we present a computational model incorporating only the processes infants might employ when hearing words in noise. Our findings show that a parsimonious interpretation of behaviour is sufficient and we offer a formal account of emerging abilities.


Assuntos
Linguagem Infantil , Simulação por Computador , Modelos Biológicos , Percepção da Fala/fisiologia , Feminino , Humanos , Lactente , Masculino
16.
Perspect Psychol Sci ; 9(6): 661-5, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26186116

RESUMO

We present the concept of a community-augmented meta-analysis (CAMA), a simple yet novel tool that significantly facilitates the accumulation and evaluation of previous studies within a specific scientific field. A CAMA is a combination of a meta-analysis and an open repository. Like a meta-analysis, it is centered around a psychologically relevant topic and includes methodological details and standardized effect sizes. As in a repository, data do not remain undisclosed and static after publication but can be used and extended by the research community, as anyone can download all information and can add new data via simple forms. Based on our experiences with building three CAMAs, we illustrate the concept and explain how CAMAs can facilitate improving our research practices via the integration of past research, the accumulation of knowledge, and the documentation of file-drawer studies.


Assuntos
Bases de Dados como Assunto , Metanálise como Assunto , Acesso à Informação , Humanos , Psicologia/métodos
17.
Front Psychol ; 4: 676, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24109461

RESUMO

In this paper we use a computational model to investigate four assumptions that are tacitly present in interpreting the results of studies on infants' speech processing abilities using the Headturn Preference Procedure (HPP): (1) behavioral differences originate in different processing; (2) processing involves some form of recognition; (3) words are segmented from connected speech; and (4) differences between infants should not affect overall results. In addition, we investigate the impact of two potentially important aspects in the design and execution of the experiments: (a) the specific voices used in the two parts on HPP experiments (familiarization and test) and (b) the experimenter's criterion for what is a sufficient headturn angle. The model is designed to be maximize cognitive plausibility. It takes real speech as input, and it contains a module that converts the output of internal speech processing and recognition into headturns that can yield real-time listening preference measurements. Internal processing is based on distributed episodic representations in combination with a matching procedure based on the assumptions that complex episodes can be decomposed as positive weighted sums of simpler constituents. Model simulations show that the first assumptions hold under two different definitions of recognition. However, explicit segmentation is not necessary to simulate the behaviors observed in infant studies. Differences in attention span between infants can affect the outcomes of an experiment. The same holds for the experimenter's decision criterion. The speakers used in experiments affect outcomes in complex ways that require further investigation. The paper ends with recommendations for future studies using the HPP.

18.
Nat Commun ; 3: 735, 2012 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-22415826

RESUMO

The transforming growth factor-ß (TGF-ß) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-ß and the canonical Wnt pathway. TGF-ß stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-ß receptor type I signalling and also prevents fibrosis in other TGF-ß-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-ß-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.


Assuntos
Fibrose/patologia , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Adulto , Animais , Células Cultivadas , Matriz Extracelular/metabolismo , Feminino , Fibrose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Interferência de RNA , RNA Interferente Pequeno , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
J Child Lang ; 39(4): 777-803, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21914243

RESUMO

Pronouns seem to be acquired in an asymmetrical way, where children confuse the meaning of pronouns with reflexives up to the age of six, but not vice versa. Children's production of the same referential expressions is appropriate at the age of four. However, response-based tasks, the usual means to investigate child language comprehension, are very demanding given children's limited cognitive resources. Therefore, they might affect performance. To assess the impact of the task, we investigated learners of Dutch (three- and four-year-olds) using both eye-tracking, a non-demanding on-line method, and a typical response-based task. Eye-tracking results show an emerging ability to correctly comprehend pronouns at the age of four. A response-based task fails to indicate this ability across age groups, replicating results of earlier studies. Additionally, biases seem to influence the outcome of the response-based task. These results add new evidence to the ongoing debate of the asymmetrical acquisition of pronouns and reflexives and suggest that there is less of an asymmetry than previously assumed.


Assuntos
Compreensão , Desenvolvimento da Linguagem , Semântica , Aprendizagem Verbal , Atenção , Pré-Escolar , Feminino , Humanos , Masculino , Reconhecimento Visual de Modelos , Psicolinguística , Percepção da Fala , Comportamento Verbal
20.
Ann Rheum Dis ; 70(12): 2191-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21873331

RESUMO

OBJECTIVE: Glycogen synthase kinase 3ß (GSK-3) regulates the phosphorylation and subsequent degradation of ß-catenin, thereby preventing aberrant activation of the canonical Wnt pathway. A study was undertaken to define the role of GSK-3 in fibroblast activation and in experimental models of systemic sclerosis (SSc). METHODS: siRNA and specific inhibitors were used to inhibit GSK-3 in cultured fibroblasts and in mice. Activation of the canonical Wnt signalling was analysed by determining the levels of nuclear ß-catenin and by measuring the mRNA levels of the Wnt target gene Axin2. The effects of GSK-3 on the release of collagen were evaluated in human dermal fibroblasts and in the mouse model of bleomycin-induced skin fibrosis in tight-skin-1 (tsk-1) mice. RESULTS: Targeting GSK-3 potently activated the canonical Wnt pathway in fibroblasts in vitro and in vivo. Inactivation of GSK-3 dose-dependently stimulated the release of collagen from cultured fibroblasts in a ß-catenin-dependent manner and further resulted in progressive accumulation of collagen and dermal thickening in mice. Inhibition of GSK-3 aggravated experimental fibrosis in bleomycin-challenged mice and in tsk-1 mice. CONCLUSION: Inhibition of GSK-3 activates the canonical Wnt pathway in fibroblasts, stimulates the release of collagen from fibroblasts, exacerbates experimental fibrosis and is sufficient to induce fibrosis. GSK-3 is therefore a key regulator of the canonical Wnt signalling in fibroblasts and inhibition of GSK-3 results in fibroblast activation and increased release of collagen.


Assuntos
Quinase 3 da Glicogênio Sintase/fisiologia , Escleroderma Sistêmico/enzimologia , Pele/patologia , Via de Sinalização Wnt/fisiologia , Animais , Bleomicina , Células Cultivadas , Colágeno/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Fibroblastos/metabolismo , Fibrose , Técnicas de Silenciamento de Genes/métodos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Humanos , Indóis/farmacologia , Masculino , Maleimidas/farmacologia , Camundongos , Camundongos Endogâmicos DBA , RNA Interferente Pequeno/genética , Escleroderma Sistêmico/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
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