1,720,961 research outputs found
Deregulated FGF signaling substantially contributes to early osteogenic defects in Mucopolysaccharidosis type II
Full text linkFGF signaling is a key pathway strictly involved in many stages of ossification and gain of function mutations of many FGF pathway components have been associated with bone diseases like craniosynostosis and chondrodysplasia. The fine-tuning of the FGF signaling pathway is achieved at different levels, both intracellularly and by extracellular glycosaminoglycans (GAGs), which play a critical role in ligand and receptor binding. In this work, I show that the deficiency of iduronate 2-sulfatase (IDS), which is involved in GAGs catabolism, perturbs FGF signaling leading to early bone defects before the onset of evident massive GAGs storage.
A defective IDS activity causes a rare lysosomal storage disease called Mucopolysaccharidosis type II, in which skeletal abnormalities represent one of the major disabling aspects. Enzyme replacement therapy (ERT) is the currently available therapeutic option, which, however, suffer from limited efficacy.
To better elucidate early alterations of bone development occurring in MPSII, I took advantage of the zebrafish model, given its easy genetic manipulation and the evolutionary conserved mechanisms and signaling pathways regulating bone formation. In particular, I generated zebrafish models for MPSII, using a morpholino-based knock down technology and CRISPR/Cas9 technique, respectively. Using different approaches, including in situ hybridization and transgenesis, I demonstrated that the altered IDS function affects the expression of key FGF signaling markers and bone differentiation markers at early life stages, before any massive glycosaminoglycans accumulation is detectable.
The involvement of the FGF signaling downstream to the IDS loss of function was also detected in cranial and appendicular bones of IDS knockout mice and in Hunter patient fibroblasts. Therefore, the results of this study suggest that in MPSII an early FGF signaling impairment, due to IDS deficit, may cause a dysregulated expression of genes involved in bone development before the occurrence of lysosomal GAGs accumulation
Loss of lysosomal iduronate sulfatase function perturbs FGF signaling and the expression of downstream key osteogenic factors.
No full textMucopolisaccaridosis II (MPSII), also called Hunter syndrome, is a rare X-linked lysosomal storage disease caused by defects in the activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). IDS is an ubiquitously expressed hydrolase that catalyses the removal of O-linked sulfates from glycosaminoglycans heparan and dermatan sulfate. The disease is multi-systemic and patients exhibit a wide spectrum of clinical features with a distinct early childhood-onset and chronic progressive course. Clinical manifestations include severe skeletal abnormalities, a marked cardiomyopathy and cardiac valve alterations.
The current hypothesis suggests that loss of IDS function is tightly associated toa progressive accumulation of partially degraded glycosaminoglycans, which in turn is responsible for the multi-organ failure. However, the cascade of pathogenetic mechanisms is not well understood yet. We recently demonstrated that iduronate-2-sulfatase activity is critical during early vertebrate development (Moro et al.; 2010). We, therefore, hypothesize that major skeletal defects may occur during early development, before the onset of GAG accumulation.
To explore this hypothesis we generated a fish model for Hunter syndrome in order to assess early molecular defects occurring as a consequence of IDS loss of function. To shed light on bone impairments we have analyzed several key markers on fish morphants at different developmental stages. Moreover, we carried out IDS loss of function analysis in transgenic reporter lines for major developmental signaling pathways.
We found a significant decrease of FGF signaling in morphants, and altered expression of key transcription factors during osteogenesis. Therefore, our preliminary results support the hypothesis that IDS deficiency causes an early dysregulation of the FGF signaling pathway which may be associated with impaired expression of genes involved in bone development
Decreased canonical Wnt signaling is a hallmark of impaired lysosomal function in a fish model for Gaucher disease
No full textThe lysosome is the final destination compartment to which the content of multivesicular endosomes (MVEs) release their content. Many target proteins, including the Wnt signaling modulator, Glycogen-synthase-kinase 3 (GSK3), have been tightly associated with the activity of MVEs, so that upon Wnt ligand binding to its receptors, GSK3 is sequestered into the MVEs. How a deficient lysosomal function could be related to altered Wnt signaling has never been elucidated before.
Type I Gaucher disease (GD; OMIM #230800) is caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). Impaired enzymatic activity leads to considerable lysosomal amassment of undegraded glucocerebroside (GC) and a subsequent massive inflammatory response. However, accumulation of uncleaved GC is limited to few cell types and does not explain major organ abnormalities.
Using a morpholino-based GBA knockdown approach and an available genetic mutant we have analyzed the effects of GBA loss of function on different cell signaling pathways. Our results suggest that the impaired GBA function leads to canonical Wnt signaling activity decrease, which in turn severely affect fish osteogenesis. These observations establish a new paradigm in the pathogenesis of Gaucher disease and define a possible relation of lysosomal compartment function and the Wnt signaling pathway
A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models
No full textBone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3' untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function
A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models
No full textBone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3′ untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function
The zebrafish model as a novel tool to uncover the complex bone pathogenesis of type I Gaucher disease
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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