1,720,958 research outputs found
Electrophilic stress induction in macrophages and its application to disease models of immune hyperactivation
No full textInflammation, while necessary for repairing damage and preventing infection, can be pathological when it occurs at an inappropriate location or for a prolonged period; making the attenuation of inflammation an outstanding clinical need. Electrophiles are chemical species that readily accept an electron pair from nucleophiles to form a covalent bond and in the cellular context can initiate a stress state by interfering with basal function. Activating Transcription Factor 3 (ATF3) is upregulated in states of cellular stress but also has an orchestrating role in negatively regulating canonical pro-inflammatory pathways. In Chapter 1 I hypothesize that by upregulating ATF3 via exogenous electrophile treatment excessive inflammation can be attenuated. I use two electrophilic compounds to test this: 1) DMF, a cell permeable electrophile and 2) GDS, a novel compound (the adduct of reduced glutathione and DMF) – I theorize that GDS functions as a buffered electrophile that maintains a precise and stable amount of electrophile available to the cell. In Chapter 2 using cultured macrophages I demonstrate GDS’s buffered electrophile reaction dynamics, how it establishes a state of electrophilic stress resulting in ATF3 upregulation through putative succination of NRF2, its inflammation attenuatory effect, and how it differs from DMF. In Chapter 3 I use transcriptomics, epigenomics, and metabolomics to characterize the phenotype of GDS treated macrophages, interrogate the contribution of ATF3 to these altered phenotype, and comprehensively contrast its effect to that of DMF. In Chapter 4 I use GDS in vivo for the first time, establish its tolerability, and demonstrate its therapeutic efficacy in a mouse model of multiple sclerosis. Finally, in Chapter 5 I describe buffered electrophiles’ properties mathematically, propose the utility and future development of novel buffered electrophiles, and end by revisiting the hypothesis.Medicine, Faculty ofGraduat
Hypoxia mimicry for enhancing regeneration and functional recovery following peripheral nerve injury
No full textPeripheral nerve injuries (PNIs) occur in 1-3% of patients with any trauma. While peripheral axons have the ability to regenerate at ~1-3 mm/day, the distance over which they must do so means lengthy recovery times associated with regenerative failure due to a decline in supporting cells’ ability to maintain axon growth. Successful axonal regeneration depends heavily upon the neuronal response to injury, and that of myeloid cells recruited to the damaged nerve. In injured regeneration-competent neurons, the transcriptomic changes that occur mirror those observed in hypoxia; hypoxia inducible factors (HIFs) effect some of these. HIF activity is governed in turn by the HIF-hydroxylases, prolyl hydroxylase domain (PHD) proteins and factor inhibiting HIF (FIH). Under normoxic conditions, HIF-hydroxylases act as master regulators of the hypoxia response, targeting HIFs for proteasomal degradation. I hypothesized that deleting any or all of the PHDs (PHD1, 2, and 3), or inhibiting PHDs pharmacologically, would induce a hypoxia response and enhance axonal regeneration and functional recovery following PNI. I used global PHD1 knockout, global PHD3 knockout, and heterozygous PHD2 transgenic mice, as well as non-transgenic mice treated with dimethyloxalylglycine (DMOG), a pan-HIF-hydroxylase inhibitor. Using sciatic nerve models of injury, I assessed functional recovery at various time points post-injury using behavioural assays. I characterized macrophage and axon densities in the nerves after injury and assessed DMOG-induced changes in macrophage phenotype using FACS, RT-PCR and immunohistochemistry. I found that deletion of PHD1 or PHD3, or inhibition of all three PHDs resulted in earlier functional recovery after injury, increased macrophage infiltration in the injured nerve, an M2-skewed macrophage phenotype, and enhanced axonal regrowth. Additionally, deletion of any of the PHDs, or their inhibition by DMOG, resulted in improved electromyographical responses of the nerve one-month post-injury. These findings suggest that nerve repair can be aided by hypoxia-independent induction of the hypoxia response.Science, Faculty ofZoology, Department ofGraduat
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
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
Towards a translatable approach to the inhibition of regeneration-impeding molecules following spinal cord injury
No full textThe full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty ofGraduat
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
- …
