1,720,970 research outputs found
Developmental abnormalities and cancer predisposition in neurofibromatosis type 1
No full textNeurofibromatosis type 1 (NF1) is a developmental and cancer predisposing syndrome resulting from haploinsufficiency or alteration in neurofibromin, a multifunctional protein that acts in various signaling pathways affecting morphogenetic processes and cell proliferation. Neurofibromin deficiency deregulates Ras/Raf/MEK/ERK and Ras/PI3K/AKT/PKB/mTOR signaling networks and intersected pathways including the cAMP-dependent protein kinase A (PKA) and the Rho-cofillin which acts on actin cytoskeleton reorganization, cell motility and adhesion. As the neurofibromin-mediated pathways are associated with biological effects depending on the cell lineage, deregulation induced by NF1 mutation clearly has cell type-specific effects. This review summarizes our increasing knowledge of NF1 as a disease rooted in defective developmental mechanisms that can also influence the potential for malignant growth. The cardinal features of NF1 patients, at birth and during life involve the cardiovascular, connective/skeletal and central nervous systems, as they reflect the NF1 mutation sensitivity of cell lineages committed to specifying these systems during embryonic development. A switch to neoplastic transformation may also occur in both the prenatal and postnatal life in cancer initiating cells of defined lineages, with the cooperation of a genetically and epigenetically modified tumor microenvironment. We emphasize how much of our current knowledge of the pathomechanisms of NF1 clinical signs and cancer has come from engineered mouse models and in vitro primary cells and cell lines exposed to inhibitors of signaling molecules. Advances in our knowledge of the developmental defects primed by the loss neurofibromin should reveal further associations between given NF1 mutations and tissue-specific symptoms, thus improving the clinical management of the patients
Mutations and novel polymorphisms in coding regions and UTRs of CDK5R1 and OMG genes in patients with nonsyndromic mental retardation
Full text linkMental retardation (MR) is displayed by 57% of
NF1 patients with microdeletion syndrome as a result of
17q11.2 region haploinsufficiency. We considered the
cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1)
and oligodendrocyte-myelin glycoprotein (OMG) genes,
mapping in the NF1 microdeleted region, as candidate
genes for MR susceptibility. CDK5R1 encodes for a
neurone-specific activator of cyclin-dependent kinase 5
(CDK5) involved in neuronal migration during central
nervous system development. OMG encodes for an
inhibitor of neurite outgrowth by the binding to the
Nogo-66 receptor (RTN4R). CDK5R1 and OMG genes
are characterized by large 3′ and 5′ untranslated regions
(UTRs), where we predict the presence of several transcription/
translation regulatory elements. We screened
100 unrelated Italian patients affected by unspecific MR
for mutations in CDK5R1 and OMG coding regions and in
their 3′ or 5′ UTRs. Four novel mutations and two novel
polymorphisms for CDK5R1 and three novel mutations
for OMG were detected, including two missense changes
(c.323C>T; A108V in CDK5R1 and c.1222A>G; T408A
in OMG), one synonymous codon variant (c.532C>T;
L178L in CDK5R1), four variants in CDK5R1 3′UTR and
two changes in OMG 5′UTR. All the mutations were absent in 370 chromosomes from normal subjects. The
allelic frequencies of the two novel polymorphisms in
CDK5R1 3′UTR were established in both 185 normal and
100 mentally retarded subjects. Prediction of mRNA and
protein secondary structures revealed that two changes
lead to putative structural alterations in the mutated
c.2254C>G CDK5R1 3′UTR and in OMG T408A gene
product
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
The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis
Full text linkCyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, the main activatory subunit of cyclin-dependent kinase 5 (CDK5). The p35/CDK5 active complex plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). CDK5R1 displays a large and highly evolutionarily conserved 3′-untranslated region (3′-UTR), a fact that has suggested a role for this region in the post-transcriptional control of CDK5R1 expression. Our group has recently demonstrated that two miRNAs, miR-103 and miR-107, regulate CDK5R1 expression and affect the levels of p35. MiR-103 and miR-107 belong to the miR-15/107 family, a group of evolutionarily conserved miRNAs highly expressed in human cerebral cortex. In this work, we tested the hypothesis that other members of this group of miRNAs, in addition to miR-103 and miR-107, were able to modulate CDK5R1 expression. We provide evidence that several miRNAs belonging to the miR-15/107 family regulate p35 levels. BACE1 expression levels were also found to be modulated by different members of this family. Furthermore, overexpression of these miRNAs led to reduced APP phosphorylation levels at the CDK5-specific Thr668 residue. We also show that miR-15/107 miRNAs display reduced expression levels in hippocampus and temporal cortex, but not in cerebellum, of AD brains. Moreover, increased CDK5R1 mRNA levels were observed in AD hippocampus tissues. Our results suggest that the downregulation of the miR-15/107 family might have a role in the pathogenesis of AD by increasing the levels of CDK5R1/p35 and consequently enhancing CDK5 activity
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