1,720,969 research outputs found
The Role of INPP5D in Microglial Function and Amyloid Pathogenesis
No full textIndiana University-Purdue University Indianapolis (IUPUI)Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Genetic studies implicate the involvement of microglia-mediated immune responses during disease progression. Importantly, inositol polyphosphate-5-phosphatase D (INPP5D) serves as a regulator of microglial functions and its variants have been identified as risk of late-onset AD. The primary object of this thesis was to study the role of INPP5D in AD pathogenesis.
First, increased levels of INPP5D were detected in brain regions of LOAD patients, and a positive association was noted between INPP5D expression and amyloid plaque density. Importantly, increased INPP5D expression was also observed in the amyloidogenic 5xFAD mouse model, with a similar pattern of elevated expression predominately in plaque-associated microglia. These results demonstrated that INPP5D plays an important role in AD.
Second, we determined the effect of Inpp5d haplodeficiency on amyloid pathology and microglial functions in 5xFAD mice. The results revealed that Inpp5d haploinsufficiency reduced amyloid plaque burdens and reversed behavioral deficits in 5xFAD mice. Inpp5d haploinsufficiency enhanced microglial engagement to plaques while increasing amyloid plaque compaction in the brains. Furthermore, Inpp5d haploinsufficiency activates TREM2 signaling and suppresses proinflammatory cytokines release in cortical tissues. Spatial transcriptomic analysis highlights that Inpp5d haploinsufficiency modulated the functional pathways including immune cell activation, cytokines production, protein degradation, memory, and synaptic plasticity. Our study suggests that reducing INPP5D expression alters microglial responses and mitigates amyloid pathology during AD progression.
Finally, we prepared primary microglial cultures from the wild-type and Inpp5d-haplodeficient mice. The microglial cultures were treated with fibrillar beta-amyloid (fAβ) to investigate the effect of INPP5D inhibition on microglial signaling. Our results demonstrate an increased fAβ uptake and decreased fAβ cytotoxicity in the Inpp5d-deficient microglia. Inpp5d haplodeficiency alters microglial functional pathways, including phagocytosis, apoptosis, cytokines production, and the complement system. Importantly, Inpp5d haplodeficiency elevates the expression of homeostatic microglia signatures. Furthermore, treatment of microglia with INPP5D antagonist (TAD32, 1 μM) showed similar effect as the Inpp5d deficiency in microglia. Collectively, our study validates the hypothesis that INPP5D inhibition may help protect against AD pathology. Treatments utilizing INPP5D antagonists to target microglia-mediated immune responses may be beneficial as an AD therapy
The Role of INPP5D in Microglial Function and Amyloid Pathogenesis
No full textIndiana University-Purdue University Indianapolis (IUPUI)Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Genetic studies implicate the involvement of microglia-mediated immune responses during disease progression. Importantly, inositol polyphosphate-5-phosphatase D (INPP5D) serves as a regulator of microglial functions and its variants have been identified as risk of late-onset AD. The primary object of this thesis was to study the role of INPP5D in AD pathogenesis.
First, increased levels of INPP5D were detected in brain regions of LOAD patients, and a positive association was noted between INPP5D expression and amyloid plaque density. Importantly, increased INPP5D expression was also observed in the amyloidogenic 5xFAD mouse model, with a similar pattern of elevated expression predominately in plaque-associated microglia. These results demonstrated that INPP5D plays an important role in AD.
Second, we determined the effect of Inpp5d haplodeficiency on amyloid pathology and microglial functions in 5xFAD mice. The results revealed that Inpp5d haploinsufficiency reduced amyloid plaque burdens and reversed behavioral deficits in 5xFAD mice. Inpp5d haploinsufficiency enhanced microglial engagement to plaques while increasing amyloid plaque compaction in the brains. Furthermore, Inpp5d haploinsufficiency activates TREM2 signaling and suppresses proinflammatory cytokines release in cortical tissues. Spatial transcriptomic analysis highlights that Inpp5d haploinsufficiency modulated the functional pathways including immune cell activation, cytokines production, protein degradation, memory, and synaptic plasticity. Our study suggests that reducing INPP5D expression alters microglial responses and mitigates amyloid pathology during AD progression.
Finally, we prepared primary microglial cultures from the wild-type and Inpp5d-haplodeficient mice. The microglial cultures were treated with fibrillar beta-amyloid (fAβ) to investigate the effect of INPP5D inhibition on microglial signaling. Our results demonstrate an increased fAβ uptake and decreased fAβ cytotoxicity in the Inpp5d-deficient microglia. Inpp5d haplodeficiency alters microglial functional pathways, including phagocytosis, apoptosis, cytokines production, and the complement system. Importantly, Inpp5d haplodeficiency elevates the expression of homeostatic microglia signatures. Furthermore, treatment of microglia with INPP5D antagonist (TAD32, 1 μM) showed similar effect as the Inpp5d deficiency in microglia. Collectively, our study validates the hypothesis that INPP5D inhibition may help protect against AD pathology. Treatments utilizing INPP5D antagonists to target microglia-mediated immune responses may be beneficial as an AD therapy
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
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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