1,720,954 research outputs found
Modulating immune system activation in neurodegenerative disease
No full text2024In Alzheimer’s disease and related dementias (ADRD), chronic neuroinflammation contributes to cellular dysfunction and neurodegeneration. During cellular stress, RNA-binding proteins (RBPs) interact with tau and other disease-related proteins to promote toxic protein aggregation. We hypothesize that modulating these stress pathways can alleviate the contribution of RBPs to disease pathology in models of ADRD. In this dissertation, two different approaches to modulating the immune system were explored. In the first study, the RBP T-cell intracellular 1 (TIA1) was selectively knocked out in microglia of P301S tauopathy mice. TIA1 decreases inflammation in the peripheral immune system; therefore, we hypothesized that TIA1 could regulate inflammation in the central immune system. To explore this, P301S tauopathy mice overexpressing human microtubule associated protein tau (MAPT) with P301S mutation were bred with TIA1 conditional knockout mice in microglia using a CX3CR1 cre recombinase (P301S/TIA1cKO). We assessed the effect of conditionally mutating TIA1 in microglia on immune system activation and tau pathology using immunoblot, transcriptional assays, and immunohistochemistry. TIA1 is required in microglia for activation of the microglial sensome and transcription of immune receptors. Receptors that respond to tau pathology (TREM2, CLEC7A, TYROBP) and inflammatory cytokines (TNFα, IL-1β) were significantly downregulated in P301S/TIA1cKO mice compared to P301S mice. This was corroborated by a distinct lack of microglial morphological changes and CD68+ microgliosis. P301S/TIA1cKO mice also had significantly less tau pathology than P301S mice. In response to lipopolysaccharide stimulation, TIA1 null microglia exhibited decreased microglial activation, in contrast with peripheral TIA1 null macrophages which have exacerbated immune activation. In conclusion, microglial TIA1 is critical for transcription of the microglial sensome and mutating microglial TIA1 reduces tau aggregation.
In the second project, the integrated stress response (ISR) was inhibited using the viral protein open reading frame 57 (ORF57) from Human herpesvirus-8. Activation of the ISR is one of the precipitating events for protein aggregation in ADRDs. The ISR is activated by many stressors, including protein aggregation, dsRNA, viruses, and oxidative stress. In the ISR, protein kinase R (PKR) phosphorylates eIF2α which halts global translation, facilitates stress granule (SG) assembly, and induces apoptosis. Chronic activation of the ISR leads to protein aggregation of TAR DNA-binding protein 43kDa (TDP-43) through this SG pathway. ORF57 binds to and inhibits protein kinase R (PKR), preventing PKR from phosphorylating eIF2α and affecting translation. We hypothesized that ORF57 would inhibit TDP-43 aggregation through this blockade of PKR activation. To study this, the viral protein, ORF57, was optimized for expression in human neuroblastoma cells overexpressing TDP-43. These cells were treated with sodium arsenite oxidative stress causing TDP-43 to form insoluble aggregates. The impact of ORF57 on immune activation and TDP-43 aggregation was explored using immunofluorescence, immunoblot, and proteomics. ORF57 reduced phosphorylation of eIF2α, improved protein synthesis rates, and decreased SG assembly. ORF57 also affected TDP-43 pathology by altering TDP-43 aggregate morphology and increasing solubility of those aggregates. TDP-43 aggregates in cells with ORF57 disassembled at a significantly higher rate and had a faster recovery after photobleaching than those without ORF57. Proteomics revealed that ORF57 interacts with TDP-43, and other RBPs, in the presence of stress. In conclusion, my work demonstrates how the anti-stress functions of viral proteins can be re-engineered to inhibit disease processes. ORF57 blocks the ISR and reduces insoluble TDP-43 aggregation, demonstrating a novel approach to decreasing immune activation in disease. Together these two projects support a benefit of modulating immune activation in ADRDs
Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress
Full text linkAlzheimer’s disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance–based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network–based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology
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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