1,721,130 research outputs found
Recommended from our members
In Vivo Characterization of CLR01, an Aggregation and Toxicity Inhibitor, with an Alzheimer's Disease Focus
Get PDFAberrant protein self-assembly underlies over 30 human diseases called amyloidoses, for which there are no cures. In these diseases, particular proteins misfold and self-assemble into toxic oligomers that disrupt cellular function, and proceed to form insoluble amyloid fibrils that deposit in specific tissues. A promising strategy for preventing and treating amyloidoses is inhibition or modulation of the self-assembly process to disrupt the formation of the toxic oligomers. In practice, this has proven immensely difficult because the oligomer structures are unknown, are metastable, and do not have distinct binding sites. In this dissertation, three primary studies are presented that evaluate and characterize a small molecule, CLR01, which utilizes a novel strategy circumventing these challenges and has been found to be efficacious as an aggregation and toxicity inhibitor in vitro and in vivo. In the first study, CLR01 was evaluated for its ability to rescue synaptic toxicity in cell culture and brain slices. Additionally, it was tested in a transgenic mouse model of AD for its ability to reduce the pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles. This study found positive results in all domains tested; a rescue from amyloid β-protein (Aβ)-induced depletion of synaptic spine density, a rescue of Aβ-induced disruption of basal synaptic transmission and long-term potentiation, and reduction of brain Aβ, hyperphosphorylated tau, and microglia burden. CLR01 also showed low propensity for causing metabolic toxicity or drug-drug interaction, indicating favorable drug-like characteristics. In the second study, CLR01's safety and pharmacological profile were characterized in mice. CLR01 was found not to disrupt normal protein assembly, to have a high safety margin in mice, and to penetrate the blood-brain barrier (BBB) at 1-3%. Interestingly, brain levels of CLR01 remained stable for 72 hours following administration despite rapid clearance from the plasma. These results suggest a large safety margin for CLR01 and a pharmacokinetic profile that allows reaching high levels in the brain by administering relatively low doses. The third study delineates a detailed optimization of behavioral testing of mice for detection of memory deficits using the Barnes maze, and validates for the first time memory deficits in a triple-transgenic mouse model of AD at the youngest age described in the literature. The study provides a framework for analysis of CLR01's influence on learning and memory deficits in this triple transgenic model. Additionally, the study provides specific and detailed guidelines for optimizing both the performance and the analysis of the Barnes maze in a manner that increases the likelihood of detecting subtle changes in future studies using mouse models of AD. The work described in this dissertation provides a strong foundation supporting formal pre-clinical development of CLR01 as a promising disease-modifying therapeutic drug for AD
The recent failure of the PROMESA clinical trial for multiple system atrophy raises the question—are polyphenols a viable therapeutic option against proteinopathies?
Get PDF
Chapter Fifteen Disease-modifying therapy for proteinopathies: Can the exception become the rule?
Get PDFDisease-modifying therapies for proteinopathies are urgently needed yet clinical trials for the major neurodegenerative diseases, Alzheimer's and Parkinson's, have been failing at an alarming rate leaving patients and caregivers scrambling for any sign of hope. At the same time, for one family of proteinopathies, the rare TTR amyloidoses, disease-modifying therapy has existed for almost 3 decades and two new types of disease-modifying therapy have become available more recently. In this chapter, I discuss those therapies, examine to what extent they can be generalized for other diseases, and consider what we may learn from their relative success
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
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
Effects of different forms of amyloid β-peptide on synaptic function.
No full textIntroduction: In early stages of Alzheimer’s disease, that precede plaque formation and neuronal death, cognitive deficits are likely the result of synaptic function impairment. The key initiating pathogenic event is the accumulation of neurotoxic aggregates of amyloid β-peptide (Aβ) in hippocampus and cortex. We previously demonstrated that the redox state of methionine in position 35 (Met35) plays a critical role in Aβ toxicity.
Objective: To determine whether oxidation of Met35 also influences Aβ synaptotoxicity we investigated the effects of 20-min lasting perfusion with 200 nM AβWT and its oxidized analogues (AβMet35(O), AβMet35(O2)) on synaptic transmission and plasticity, and on synaptophysin (Syn) expression.
Methods: We performed electrophysiological experiment on hippocampal brain slices and autaptic neurons to study the long-term potentiation (LTP) and synaptic transmission. We also studied Syn density as the ratio between Syn fluorescence intensity and MAP2 labeled area by confocal microscopy.
Results: In control slices, 60 min after tetanus fEPSP amplitude (A) and slope (S) were increased by 138% and 132% of baseline, respectively. This potentiation was significantly lower after AβWT treatment (A: +72%; S: +68%; P<0.001) whereas no changes in LTP were observed in slices exposed to AβMet35(O). Surprisingly, AβMet35(O2) reduced the synaptic plasticity to the same level as AβWT. In autaptic microcultures, AβWT and AβMet35(O2) significantly reduced the amplitude of EPSCs evoked by action potentials and mEPSC frequency (P<0.05) whereas AβMet35(O) had no effects on basal synaptic transmission. Finally, AβWT and AβMet35(O2) significantly reduced Syn density while AβMet35(O) did not affect presynaptic terminals.
Conclusion: Our results indicate that the chemical state of Met35 plays a key role in Aβ- induced: (i) synaptic depression, (ii) inhibition of synaptic plasticity and (iii) alterations in the expression of proteins relevant for the synaptic function
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
- …
