1,720,953 research outputs found
Parkinson's Disease: Therapeutic Targeting of Toll-Like Receptor
No full textBackground: Microglia play opposing roles in Parkinson's disease (PD) pathogenesis: in early stage they exert neuroprotection via alpha-synuclein (α-syn) phagocytosis, while as the disease progresses, they fail in α-syn clearance and induce neuroinflammation and neurodegeneration. Both α-syn clearance and inflammation are TLR-mediated: specific TLRs promote α-syn clearance in the early stage, while the same TLRs chronically activated by accumulated α-syn initiate a pro-inflammatory cascade leading to degenerative changes in neurons. These emerging knowledges allow to select specific immunomodulators, which, acting as agonists or antagonists to specific TLRs, can lead to the stop of the neuroinflammatory cascade. Among the different immunomodulators TLR-targeting, there are specific molecules, including neutralizing nanobodies or smallest molecules, able to cross the blood brain barrier (BBB). These immunomodulators could represent a promising approach, since they exhibit high affinity to TLRs, can be given to patients as an inhaled drug, a skin patch or a pill. Recently, small interfering RNA-selective compounds have proved significant inpredictive models for new therapeutic approaches. In addition, small interfering RNA-selective compounds, studied in predictive modeling, could successfully be used in PD therapy. These TLR-targeting drugs have shown fewer side effects and lower or no toxicity compared to drugs with anti-inflammatory effects commonly used in PD treatment. Results: Agonists There are currently many TLR agonists in clinical trials either alone or in combination with specific antigens to treat cancer, allergies, and viral infections. Among these: TLR2, TLR3 and TLR4 Agonists MPLA (TLR4) licensed for use as a vaccine adjuvant. It acts stimulating TRAM/TRIF transduction pathway, and deactivating Mal/MyD88 signalling, therefore acting as a partial agonist of the receptor; AMPLIGEN, (TLR3) which is a synthetic mismatched polyI:polyC dsRNA (polyI:poly C12U). It is in Phase III for chronic fatigue syndrome and in Phase II for HIV and cancer treatment. This compound induces the up-regulation of various proteins in CFS, including interferon; PolyI:C pretreatment (TLR3) in simulated cerebral ischemia models has been shown to exert neuroprotective and antiinflammatory effects, even though it also shows side effects; TLR7, TLR8 and TLR9 Agonists IMIQUIMOD and GARDIQUIMOD, which acta s selective TLR7 ligands, and autophagy inducers; IMO-2125, in clinical assessment to prevent and treat α-syn deposition (TLR9). Antagonists Amplification of neuroinflammation is also due to the upregulation of TLRs in response to extracellular α-syn. It has been shown that α-syn, acting as a DAMP for microglia, increases the expression of TLR1,-2,-3 and 7. Some of the several classes of TLR antagonists developed could be used to limit specific or excessive inflammatory response in the late stages of PD.  TLR2 and TLR4 Antagonists IBUDILAST, which is considered as a phosphodiesterase-4 inhibitor, capable of antagonizing TLR4 activity, could suppress production of proinflammatory cytokines, such as TNF-alpha and IL-6, and induce the anti-inflammatory cytokine IL-10. The anti-inflammatory properties of this compound have been shown to lead to inhibition of glial cell activation and, subsequently, to attenuation of neuroinflammation, even if the exact mechanism of IL-10 induction is unknown; CPN10 (chaperonin 10) molecule, able to inhibit TLR4 downstream signalling cascade, is in Phase II clinical trial for RA treatment, psoriasis and MS. Further studies indicate that Cpn10 inhibits TLR4-mediated production of Nf-kB, as well as TNF-alpha and IL-6. Discussion: The main feature of PD is rappresented by the progressive decline of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the presence of eosinophilic intracellular proteinaceous and lipidic inclusions, called "Lewy Bodies"(LBs), in surviving neurons. The basic components of LBs are misfolded alpha-synuclein (α-syn), neurofilament proteins, and ubiquitin. Recent evidence has shown that misfolded α-syn directly activates microglia, triggering the production of proinflammatory molecules and oxidative stress resulting in neurodegeneration. Microglia are considered "the brain macrophages", able to shift from a surveillance mode to a reactive mode, thus acting as immune effectors cells, producing proinflammatory cytokines. Microglial activation is, in part, induced by Pattern Recognition Receptors (PRRs), such as Toll-like Receptors (TLRs), that are expressed in immune cells, including microglia and astrocytes. TLRs are capable of detecting microbial products Pathogen Associated Molecular Patterns (PAMPs) or endogenous molecules Damage Associated Molecular Patterns (DAMPs), initiating the inflammatory response and contributing to oxidative stress, mediated by the release of cytokines, nitric oxide (NO) and other reactive oxygen species (ROS), which, in turn, may adversely impact on nearby neurons.. All of this may adversely impact on nearby neurons. In PD, TLR-dependent microglial activation plays a neuroprotective role in the early stages, whereas it can play a detrimental, proinflammatory role, in the late stages. More specifically, in the early stages of PD, TLRs play a physiological role, in clearing α-sin, by phagocytosis. However, as the disease progresses, misfolded α-syn begins to accumulate to form aggregates, which prevent α-syn degradation and turnovee, through the impairment of microglial clearance and this also induces microglia-mediated production of proinflammatory citokines, NO and ROS, which may be toxic to neurons. Conclusions: In PD, both α-syn clearance and neuroinflammation are TLR-mediated, anti-inflammatory agents targeting TLR could have neuroprotective effects in the middle-late stages of the disease. Another winning point of TLR-targeting drugs is that they show fewer side effects and lower or no toxicity, compared with that of commonly used drugs in PD treatment. In conclusion, although there has not been a new drug approved for PD treatment in many years, current investigation regarding TLR targeting shows promising expectations. Further research is needed to finally reach the objective of blocking neuroinflammation and progression of the disease
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
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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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