1,721,226 research outputs found
Pathogenic mycobacteria achieve cellular persistence via lipid-mediated inhibition of the Niemann-Pick disease type C pathway
Full text linkM.tuberculosis, the causative agent of human tuberculosis, is able to achieve long-term persistence within host organism macrophages. This persistence is achieved via the ability of the mycobacterium to prevent phagosomal-lysosomal fusion. The mechanisms by which fusion is inhibited remain incompletely understood. Here we provide evidence supporting a mechanistic link between infection with pathogenic mycobacteria and the cellular pathway defective in the rare lysosomal storage disorder Niemann-Pick disease type C (NPC). We observed that NPC phenotypes, including lipid storage and reduced lysosomal calcium release, can be induced in wild-type murine and human macrophages by infection with pathogenic mycobacteria. This phenotype induction did not occur following infection with the non-pathogenic M.smegmatis. Phenotype induction could be achieved in the absence of the mycobacteria using lipids from the mycobacterial cell walls. The importance of mycobacterial cell wall lipids to mycobacterial virulence has been well-documented. This lipid-mediated inhibition likely occurs through the NPC1 protein. Susceptibility to phenotype induction was inversely proportional to levels of functional NPC1, whilst a pre-existing dysfunction in the NPC pathway (either stemming from mutation or pharmacological inhibition) rendered cells less able to clear non-pathogenic mycobacteria. Finally, we demonstrate that therapies for NPC, particularly curcumin, are able to promote clearance of mycobacteria from infected macrophages. NPC therapies may hold promise for a new approach to the treatment of tuberculosis
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
Lysosomal dysfunction and glycosphingolipid dysregulation in rare and common neurodegenerative diseases
Full text linkHistorically, the rare early-onset neurodegenerative lysosomal storage disorders (LSDs)
have been studied as discrete metabolic diseases in their own right. However, in recent
years links with more common late-onset neurodegenerative diseases, including
amyotrophic lateral sclerosis (ALS) and Parkinsonâs disease (PD), have emerged. For
example, lysosomal dysfunction, impaired autophagy, and protein aggregation are
shared features in these diseases. However, altered lipid homeostasis, especially
glycosphingolipid (GSL) dysregulation, is a relatively new research field of interest in PD
and even more so in ALS.
In this thesis, we provide evidence that GSL metabolism is altered during denervation,
in an ALS mouse model, and in ALS patients. We further show that pharmacological
modulation of GSL levels, especially the ganglioside GM1a, could be a therapeutic
approach for ALS.
Mutations in the Gaucher disease-linked lysosomal enzyme GBA are major genetic risk
factors for developing PD. In this thesis, we observed that a subset of sporadic PD
fibroblasts phenocopied characteristics of lysosomal dysfunction associated with GBA
mutations. Furthermore, ageing is the major non-genetic risk factor for adult-onset
neurodegenerative diseases. We show that levels of GSLs and activities of lysosomal
hydrolases, relevant to PD, are altered in the ageing brain of wildtype mice. Importantly,
we demonstrate, in human post-mortem substantia nigra and putamen, that levels of
GSLs, especially complex gangliosides such as GM1a, and multiple lysosomal
hydrolase activities are reduced during ageing and to a greater extent in sporadic PD.
However, these changes were not observed in mouse models of PD, questioning their
usefulness as models for PD. Finally, we demonstrate that ganglioside levels in
cerebrospinal fluid and serum from PD patients are potential biomarkers for PD.
Consequently, existing LSD therapies may hold promise as new therapeutic approaches
for treating PD.</p
Evaluation of new therapies in Niemann-Pick type C disease
Full text linkNiemann Pick type C (NPC) disease is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by a mutation in the NPC1 or NPC2 genes. The functions of the proteins these genes encode are not fully understood, but are thought to be involved in free cholesterol egress from the acidic compartment. The pathogenic cascade in proposed to begin with sphingosine accumulation followed by reduction of acidic store calcium levels. This results in impairing intracellular trafficking and storage of multiple lipid substrates in the late endosome/lysosomal compartment. In this thesis, multiple potential therapies have been tested in a mouse model of NPC1 disease including neuroprotective compounds. Positive effects were observed with some compounds, as reflected by increased life span and/or improved neurological function. In the course of these studies, I discovered another factor that affects the outcome of treatment with liver metabolised drugs. In the NPC1 mouse the cytochrome P450 system is impaired as is the case in the NPC1 cats and in patients. This thesis therefore sheds light on the impairment of this system at the genetic and functional level and presents data on why this aspect of pathology must be considered when designing therapeutics for this fatal neurodegenerative disease. This defect was partially corrected with bile acid supplementation, resulting in an unexpected functional improvement suggesting benefit in the CNS. Another aspect of NPC disease investigated was Crohn's-like intestinal inflammation that occurs in some NPC patients. This has been investigated in the Npc1-/- mouse model using two colitis models showing a partial protection by the Npc1 mutation with different infection kinetics and secretory cytokine profiles. Taken together, this thesis therefore provides insights into two novel aspects of pathogenesis (Crohn's-like intestinal inflammation and a drug metabolism defect) and provides new leads on treatments that target unique aspects of the pathogenic cascade
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
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