1,720,968 research outputs found
Microphthalmia with linear skin lesions (MLS) syndrome, an unconventional mitochondrial disorder
No full textThe HOPS Complex Subunit VPS39 controls ciliogenesis through autophagy
No full textPrimary cilia are microtubule-based organelles that assemble and protrude from the surface of most mammalian cells during quiescence. The biomedical relevance of cilia is indicated by disorders ascribed to cilia dysfunction, known as ciliopathies, that display distinctive features including renal cystic disease. In this report, we demonstrate that VPS39, a component of the homotypic fusion and vacuole protein sorting (HOPS) complex, acts as a negative regulator of ciliogenesis in human renal cells, by controlling the localization of the intraflagellar transport 20 (IFT20) protein at the base of cilia through autophagy. Moreover, we show that VPS39 controls ciliogenesis through autophagy also in vivo in renal tubules of Medaka fish. These observations suggest a direct involvement of the HOPS complex in the regulation of autophagy-mediated ciliogenesis and eventually in target selection. Interestingly, we show that the impact of autophagy modulation on ciliogenesis is cell-type dependent and strictly related to environmental stimuli. This report adds a further tile to the cilia-autophagy connection and suggests that VPS39 could represent a new biological target for the recovery of the cilia-related phenotypes observed in the kidneys of patients affected by ciliopathies
A medaka model to study the the molecular basis of Microphthalmia with Linear Skin defects (MLS) syndrome
No full textThe Microphthalmia with linear skin defects (MLS) syndrome is an X- linked dominant male-lethal neuro-developmental disorder associated to mutations in the holocytochrome c-type synthetase (HCCS) transcript. Female patients display unilateral or bilateral microphthalmia and linear skin defects, additional features include central nervous system (CNS) malformation and mental retardation. HCCS codifies a mitochondrial protein that catalyzes the attachment of heme to both apocytochrome c and c1, necessary for proper functioning of the mitochondrial respiratory chain. Although mutation analysis clearly indicates a role for HCCS in the pathogenesis of this genetic condition, the molecular mechanisms underlying the developmental anomalies in the presence of HCCS dysfunction are still unknown. Previous studies demonstrated the early lethality of mouse embryonic Hccs knock-out stem cells. To overcome the problem of the possible embryonic lethality, we decided to generate an animal model for MLS syndrome in the medaka fish (Oryzia latipes) using a morpholino-based technology. Fish models (zebrafish and medaka) are considered good models to study developmental biology processes and in particular eye developmental defects.
Three specific morpholinos directed against different portions of the olhccs transcript have been designed and injected and our data indicated that all morpholinos effectively downregulate the expression of the olhccs gene. The injection of the three different morpholinos resulted in a pathological phenotype, which resembles the human condition. Morphants displayed microphthalmia, coloboma, and microcephaly associated to a severe cardiac pathology. To date, this is the only animal model that recapitulates the phenotype observed in MLS syndrome. Analysis with markers for specific retinal cell types showed defects in differentiation of the ventral neural retina. Characterization of morphants revealed that hccs down-regulation results in impairment of mitochondrial functions, overproduction of reactive oxygen species (ROS) and a strong increase of apoptosis mediated by activation of the mitochondrial-dependent cell death pathway in the CNS and in the eyes. Our results clearly indicate that HCCS plays a critical role in mitochondria and imply that MLS should be considered a mitochondrial disease.
It is well established that the intrinsic mitochondrial dependent apoptotic pathway rely on the formation of apoptosomes, which require the presence and/or the activity of cytochrome c, Apaf1, and caspase 9. Detailed studies of the mechanisms that underlie intrinsic apoptosis have shown that the heme group of cytochrome c is necessary for Apaf1 activation, apoptosome formation and activation of caspase 9. Interestingly, our data indicate that, in our model, the mitochondrial dependent apoptosis is triggered by caspase 9 activation and occur in a Bcl-dependent but apoptosome-independent manner suggesting that at least in some tissues the apoptosis can occur in a non-canonical way. Our data support the evidence of an apoptosome-indipendent activation of caspase 9 and suggest the possibility that this event might be tissue specific. Our study shed new light into the functional role of HCCS in the mitochondria. In addition, we provide strong evidences that mitochondrial mediated apoptotic events underlie microphtalmia providing new insights into the mechanisms of this developmental defect
Synthetic long non-coding RNAs [SINEUPs] rescue defective gene expression in vivo
Full text linkNon-coding RNAs provide additional regulatory layers to gene expression as well as the potential to being exploited as therapeutic tools. Non-coding RNA-based therapeutic approaches have been attempted in dominant diseases, however their use for treatment of genetic diseases caused by insufficient gene dosage is currently more challenging. SINEUPs are long antisense non-coding RNAs that up-regulate translation in mammalian cells in a gene-specific manner, although, so far evidence of SINEUP efficacy has only been demonstrated in in vitro systems. We now show that synthetic SINEUPs effectively and specifically increase protein levels of a gene of interest in vivo. We demonstrated that SINEUPs rescue haploinsufficient gene dosage in a medakafish model of a human disorder leading to amelioration of the disease phenotype. Our results demonstrate that SINEUPs act through mechanisms conserved among vertebrates and that SINEUP technology can be successfully applied in vivo as a new research and therapeutic tool for gene-specific up-regulation of endogenous functional proteins
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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