1,720,969 research outputs found
Forkhead box R1-mediated stress response linked to a case of human microcephaly and progressive brain atrophy
Get PDFForkhead box (Fox) family transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. This family was named after the ectopic head structures observed in mutants of the Drosophila gene forkhead (fkh). Since the discovery of fkh, hundreds of Fox genes have been identified in organisms ranging from yeasts to humans, making it one of the largest but least explored families of higher eukaryotic transcription factors. The NIH Undiagnosed Diseases Program (NIH UDP), a clinical site of the NIH Undiagnosed Diseases Network (UDN), identified a variant (p.M280L) in a single allele of the FOXR1 gene in an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy, and global developmental delay. The de novo missense variant in FOXR1 converts a highly conserved methionine residue at amino acid 280 to leucine and was predicted to contribute to the individual’s disease. The goal of this research is to investigate the biological role of FOXR1 and to determine how the M280L mutant leads to disease pathogenesis.
At the protein level, the M280L mutant impaired FOXR1 expression and induced a nuclear aggregate phenotype when overexpressed in HEK 293T and COS7 cells due to protein misfolding and proteolysis. A FOXR1 C-terminal truncation mutant mimicked the M280L phenotype, suggesting that the C-terminal sequences of FOXR1 are important for FOXR1 protein stability. RNAseq and pathway analysis in HEK 293T cells indicated that FOXR1 acts as both transcriptional activator and repressor, playing central roles in heat shock response, chaperone cofactor-dependent protein refolding, and cellular response to stress. Indeed, FOXR1 expression is increased in HEK 293T in response to cellular stress, a process in which FOXRI directly controls HSPA6, HSPA1A and DHRS2 transcription. In contrast, the ability of the M280L mutant to respond to stress is compromised, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Combined, these results suggest that FOXR1 plays a role in cellular stress and that impairment of these functions may contribute to the disease phenotypes seen in the individual with the FOXRI M280L variant
Aging destabilizes egocentric boundary cells in the retrosplenial cortex of mice
Get PDFThe retrosplenial cortex is involved in generating spatial representations from specialized cells within an egocentric frame. Within the retrosplenial cortex, egocentric boundary cells encode this spatial information and it is known that these cells show tuning to boundaries and that they also exhibit spatial stability. However, the spatial properties of egocentric boundary cells with aging has not been fully characterized and understood. In order to identify and characterize the spatial properties of egocentric boundary cells with aging, this study took in vivo one-photon calcium imaging recordings in the retrosplenial cortex as mice explored an open field arena. This study imaged young wild-type mice, old wild-type mice, as well as young PS19 mice. Young PS19 mice show spatial impairments at a young age and, therefore, were used to examine if any similarities exist between these mice and old wild-type mice. The results of this study qualitatively validate the identification and characterization of egocentric boundary cells as their spatial properties showed robust tuning and spatial stability for young wild-type mice. As expected, loss of tuning and spatial instability was illustrated with old wild-type mice and young PS19 mice and they show similar tuning and spatial instability patterns
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Apolipoprotein E in Alzheimer's disease
No full textAlzheimer's disease (AD) is the most important cause of dementia, but the mechanism of pathogenesis remains unknown. The epsilon4 allele of apolipoprotein E (apoE) has been confirmed as the most important genetic risk factor for most cases of AD and is associated with Abeta-containing senile plaques, one of the neuropathological hallmarks of AD. We determined the neuronal binding, internalization and degradation of human apoE isoforms apoE3 and apoE4 in the presence and absence of Abeta peptides using primary hippocampal neurons from rat. The findings demonstrate apoE binding and internalization in neurons without endogenous synthesis. Increased apoE3 degradation was observed relative to the apoE4 isoform. Lipophilic Abeta peptides increased apoE binding to hippocampal neurons; the increase was greater for the apoE4 isoform than for the apoE3 isoform. Abeta uptake by hippocampal neurons was increased in the presence of apoE, more so in the presence of the apoE4 than apoE3 isoform. Further, apoE was shown to reduce the extracellular level of Abeta in hippocampal cultures. We also find that all three major apoE isoforms were equally potent inhibitors of Abeta fibril formation, which is thought to be necessary for in vitro neurotoxicity and possibly the neuronal degeneration observed in AD. Further, when apoE was associated with cholesterol-containing liposomes or very low density lipoproteins, its ability to prevent Abeta fibril formation was diminished. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Abeta levels were increased. Levels of apoE and Abeta1--40 were found to be apoE genotype dependent, with lowest levels of apoE and highest levels of Abeta occurring in epsilon4 allele carriers, suggesting that a reduction in apoE levels may give rise to increased deposition of amyloid peptides in AD brain. The low density lipoprotein receptor-related protein, an important neuronal a
Variations on the Author
Get PDF“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
Get PDFWe 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
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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