1,721,024 research outputs found
HYPERREFLECTIVE FOCI AS A PATHOGENETIC BIOMARKER IN CHOROIDEREMIA
No full textTo assess hyperreflective foci (HF) number and distribution in choroideremia (CHM) using spectral domain optical coherence tomography
Developing gene therapy for inherited retinal degenerations
No full textThe aim of this thesis was to evaluate the efficacy and safety of retinal gene therapy in a pre-clinical model of CDHR1-associated retinal degeneration – a hitherto untreatable, blinding disorder.
Deep phenotyping of the Cdhr1-/- murine model demonstrated severe early deficits in cone and rod photoreceptor function followed by progressive photoreceptor cell death – recapitulating CDHR1 cone-rod dystrophy. Two AAV8 vectors expressing the full-length human CDHR1 coding sequence were designed, manufactured, validated and titrated in vivo.
Sub-retinal injection of AAV8.GRK1.CDHR1.pA (1.5 x 108 vg) in Cdhr1-/- mice at 3-4 weeks of age resulted in functional rescue of cone and rod photoreceptors with improved response amplitudes and decreased implicit times to 12-months post-injection; a slowing of photoreceptor cell death with regeneration of full-length photoreceptor outer segments confirmed on ultrastructural analysis to 21-months post-injection; and a behavioural rescue effect on photopic and scotopic optomotor testing, sustained to 21-months post-injection. AAV8.GRK1.CDHR1.pA at 1.5 x 108 vg appeared safe in C57BL/6J mice by the same outcome measures to 22-months post-injection.
Genetic prevalence estimates presented herein suggest more than 200,000 affected individuals worldwide. We characterised 146 individuals with biallelic variants in CDHR1, describing the retinal phenotype, natural history, genotype-phenotype associations, with 25 novel pathological sequence variants.
This is the first therapy shown to improve retinal structure and function in a pre-clinical model of CDHR1-associated retinal degeneration. A patent to protect the vectors described herein has been filed on behalf of the University of Oxford, with commercial agreements obtained in preparation for an onward phase 1 clinical trial
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
The Abca4-/- mouse model of Stargardt disease – phenotype and therapeutic strategies
Full text linkStargardt disease is caused by mutations in the ABCA4 gene and is probably the commonest inherited cause for retinal degeneration in youth with progressive visual deterioration. The Abca4-/- mouse is an animal model mimicking certain aspects of the human disease, including an accumulation of autofluorescent lipofuscin in the retinal pigment epithelium (RPE). The model is therefore ideally suited for preclinical investigation of novel treatment approaches for Stargardt disease. Imaging of lipofuscin- and melanin-related fundus autofluorescence (AF) was optimized in mice, which subsequently allowed investigating the mouse ocular phenotype in vivo. The Abca4-/- mouse showed an age-related increase in lipofuscin- and melanin-related AF intensity, correlating to an increase of ex vivo assessed bis-retinoid-fluorophores and formation of melanolipofuscin granules, respectively. Retinal function remained largely unaffected by those changes within the RPE. Abca4-/- mice were fed with C20-deuterized vitamin A (C20dVitA) which had been shown to inhibit lipofuscin-formation in the RPE. The diet markedly reduced lipofuscin- and melanin-related AF intensity to levels measured in wild type animals on a normal diet. This treatment did not affect retinal function. The possibility of performing similar fundus AF measurements in humans may allow fast translation of this therapy into clinical trials. The only causative treatment approach for Stargardt disease will be gene replacement therapy. Investigation of various mutant adeno-associated viruses (AAVs) as vector for delivering ABCA4 revealed that photoreceptors in Abca4-/- mice were more difficult to transduce than photoreceptors in wild type mice. This indicates an influence of the diseased retina on gene delivery. Thus, very efficient viruses might be needed to achieve relevant ABCA4 expression in the retina of patients with Stargardt disease. In summary, application of a clinically relevant imaging method allows to assess the ocular phenotype of the mouse model for Stargardt disease and to investigate novel treatment strategies
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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