1,721,081 research outputs found
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
Use of lentiviral vectors for modelling and treating Parkinson's disease
No full textParkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway and the abnormal appearance of intracellular inclusions named Lewy bodies (LBs). Over the past few years, the discovery of genes involved in hereditary forms of the disease led to new insights into the pathogenesis of PD. Mutations in the α-synuclein gene have been associated with autosomal dominant PD, and mutations in parkin with autosomal recessive-juvenile parkinsonism (AR-JP). α-synuclein has emerged as a key protein in the pathogenesis of PD, as it appears to be the major structural component of LBs and its accumulation seems to play a prominent role in sporadic PD. To date, genetic PD models based on α-synuclein conventional transgenesis in rodents have been unsuccessful in recapitulating the main features of the human pathology, especially the loss of nigral dopamine neurons. The lack of clear dopaminergic cellular degeneration in these transgenic animal models is likely to be attributed to insufficient expression levels of α-synuclein in the substantia nigra. Injection of viral vectors constitutes an alternative approach for the development of genetic models, as viral vectors allow high gene expression levels in a localized brain region and can be applied in mammalian species other than mice. In the present study, the viral-mediated expression of different α-synuclein forms (normal or mutated) was explored in the substantia nigra of rats. Following the full characterization of this new genetic model, several neuroprotective strategies based on the delivery of potential neuroprotective factors such as the neurotrophic factor GDNF (glial cell line-derived neurotrophic factor), the E3 ligase parkin or the chaperone Hsp104 were evaluated in this α-synuclein rat model. As HIV-1-derived lentiviral vectors can efficiently transduce neurons in the brain, these retroviral vectors were used to overexpress normal or mutated forms of α-synuclein in the substantia nigra of adult rats. In contrast to α-synuclein transgenic mice, the lentiviral-based model developed a progressive and selective loss of nigral dopaminergic neurons associated with a dopaminergic denervation of the striatum in animals expressing either wild-type or mutant forms of human α-synuclein. The neuronal degeneration correlated with the appearance of ?α-synuclein-positive inclusions. This viral-based model thus constitutes an excellent genetic model for testing molecules that can interfere with the neurodegenerative process induced by α-synuclein. Delivery of GDNF, a potent neuroprotective factor for the survival of dopaminergic neurons, is currently the most promising strategy for the treatment of PD. The neuroprotective properties of GDNF were therefore evaluated in the lentiviral-based model expressing mutated human α-synuclein. Although a robust expression of GDNF was observed in the whole nigrostriatal pathway due to retrograde and/or anterograde transport, nigral GDNF delivery did not prevent the α-synuclein-induced neurodegeneration. As loss of function of parkin leads to dopaminergic cell loss in Autosomal Recessive-Juvenile Parkinsonism (AR-JP) patients, parkin may represent a critical survival factor for dopaminergic neurons. The neuroprotective role of the E3 ubiquitin ligase parkin was assessed in the viral-based model overexpressing mutated human α-synuclein. Co-expression of parkin with α-synuclein prevented the nigrostriatal degeneration and increased the number of hyperphosphorylated α-synuclein inclusions. These results suggest that parkin may also play a key role in the formation of aggregates. Abnormal folding and aggregation of α-synuclein is now recognized as a critical issue in the pathology of PD. Chaperones can block or reverse the incorrect folding of misfolded proteins, and increase the clearance of aggregates. To enhance the elimination of aggregated α-synuclein and to understand the importance of inclusions in the α-synuclein pathogenesis, we expressed a protein disaggregase, the yeast chaperone Hsp104, in the lentiviral-based model of PD. This chaperone can facilitate the clearance of misfolded proteins from an aggregate state. Expression of Hsp104 reduced the dopaminergic cell loss induced by lentiviralmediated expression of PD-linked mutated α-synuclein. This neuroprotective effect correlated with a reduction in the formation of hyperphosphorylated α-synuclein inclusions, indicating that enhancing clearance of protein aggregates through the disaggregase activity of Hsp104 may constitute a novel therapeutic strategy for PD and other diseases caused by misfolded protein accumulation. The present thesis demonstrates that lentiviral vectors expressing human α-synuclein constitute a powerful and flexible tool to mimic the neuropathological features of PD. Although not effective in the lentiviral-based model of PD, GDNF may still represent a promising molecule to promote the sprouting of dopaminergic axons. On the contrary, the E3 ligase parkin and the chaperone Hsp104 have demonstrated potent neuroprotective properties against the accumulation of the toxic mutated α-synuclein. Therapeutic approaches aiming at increasing parkin or chaperone levels in the brain may therefore open new perspectives for the treatment of PD.LE
Intrathecal implants of bovine chromaffin cells alleviate mechanical allodynia in a rat model of neuropathic pain
No full textModeling Parkinson's Disease in Adult Rats Using Viral Vectors as Gene Delivery Tools
No full textAnimal models of human pathologies remain invaluable tools for unraveling disease mechanisms and evaluating potential therapeutic strategies. For a number of diseases, the lack of a reliable animal model represents an important limiting step towards the development of efficient treatments. This holds particularly true for Parkinson's disease (PD), a major neurodegenerative disorder for which only symptomatic treatments currently exist. The difficulties encountered by researchers to reproduce PD pathology in animals stem primarily from an incomplete understanding of the disease. Indeed, the cause of the disease remains unknown in 90% of cases, referred to as sporadic or idiopathic. The discovery of familial forms of the disease, however, has led to the development of a large number of transgenic mice models based on genetic modifications that play a direct causative role in a significant proportion of human PD cases. Unfortunately, these transgenic mice fail to recapitulate the robust neurodegeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc) and concomitant loss of DAergic projections to the striatum, the neuropathological hallmark of the human condition. The lack of nigral pathology severely limits the usefulness of such models for pre-clinical evaluation of potential therapeutics. Viral vector gene delivery tools represent an interesting alternative to classical transgenesis as they allow for targeted and high-level transgene expression in the nigrostriatal system of adult animals. During the course of this thesis we have developed two new viral vector-based rodent models of PD. In our first model, we have used a recombinant adeno-associated virus (rAAV) vector, with a high tropism towards nigral DAergic neurons, to drive overexpression of the parkin-associated endothelin receptor-like receptor (Pael-R) in the SNpc of adult rats. Indeed, accumulation of Pael-R is implicated in the pathogenesis of autosomal-recessive juvenile parkinsonism (AR-JP), a young-onset familial form of PD. We show that insoluble accumulation of Pael-R in rats induces a rapidly progressing degeneration of nigral DAergic neurons and a loss of DAergic fibers and terminals in the striatum. Lesioned animals also displayed spontaneous behavioral abnormalities linked to depletion of striatal dopamine (DA) and persisting up to 6 months post-injection. Chronic accumulation of Pael-R in the nigrostriatal system of adult rats therefore represents a robust and highly reproducible model of PD, recapitulating key pathological and phenotypical features of the human condition. The second model developed was based on nigral delivery of the PD-associated mutant G2019S leucine-rich repeat kinase 2 (LRRK2) protein. Indeed, the G2019S mutation in the LRRK2 gene is the most important genetic determinant of PD, accounting for a significant proportion of both familial and sporadic PD cases. Due to the large size of the LRRK2 coding sequence, an adenoviral system with a high packaging capacity was used to drive expression of the protein. Recombinant adenoviral (rAd) vectors are potentially pro-inflammatory and less efficient tools as rAAV vectors for long-term gene delivery to the SNpc. Nevertheless, through retrograde axonal delivery of rAd-LRRK2 particles, we achieved robust and neuron-specific expression of full-length wild-type or mutant G2019S human LRRK2 in nigral DAergic neurons of adult rats. Expression persisted up to 6 weeks post-injection, with no visible signs of inflammation in the SNpc. We demonstrate that the wild-type form of LRRK2 does not induce neuronal loss when expressed in the SNpc. In contrast, under the same conditions and levels of expression as the wild-type form, the PD-associated G2019S mutation in LRRK2 is sufficient to cause a progressive loss of nigral dopaminergic neurons. This is the first demonstration of frank dopaminergic neuronal degeneration in rodents induced by the expression of G2019S mutant LRRK2. Our data also provide a new rodent model of LRRK2-linked PD which recapitulates one of the cardinal pathological features of the disease. In the absence of a clear understanding of human PD pathogenesis, the development of multiple transgenic models may help to identify common disease mechanisms and drug targets. A potential treatment identified in one model may be effective only in the corresponding subset of PD patients, carrying this particular genetic modification. On the other hand, the pathogenic pathway targeted may also be activated in sporadic PD. Ultimately, whether or not these models stand the test of time will depend on how effective newly-identified drugs will be, not only on AR-JP or LRRK2-linked PD patients, but above all on sporadic PD, which represents the vast majority of PD patients.LE
DJ-1 as a neuroprotective protein in models of Parkinson's disease
No full textParkinson's disease (PD) is a common progressive neurodegenerative disorder characterized clinically by the combination of motor symptoms like bradykinesia, tremor, rigidity and postural instability. The pathology of PD is related to the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) leading to the deficiency of dopamine in the striatal projection areas of these neurons. The pathogenesis of PD is not fully elucidated yet, however there is strong evidence that protein aggregation, mitochondrial dysfunction and oxidative stress play a primary role in the etiology of the disease. Most of PD cases are sporadic, however, several genes have been characterized to cause familial forms of the disease. Among them, mutations in DJ-1 were identified in families with autosomal-recessive early-onset PD and account for 2% of inherited PD cases. The DJ-1 protein was identified as an important player in cellular defense against oxidative stress as it possibly acts as an oxidative stress-induced chaperone and inhibits the formation of inclusions of α-synuclein, another protein related to PD. Alpha-synuclein mutations cause an autosomal dominant form of the disease. Moreover, this protein is a main component of Lewy Bodies, a pathological hallmark of PD. The goal of the experiments during my thesis was to investigate the potential protective effect of DJ-1 in toxin-based [6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)] as well as genetic models of PD in vivo. Towards this goal, the DJ-1 protein was over-expressed in rodent SNpc through the injections of recombinant adeno-associated viral vector (rAAV). In the first study, the DJ-1 over-expression led to significant protection of dopaminergic cells and spontaneous motor behavior in 6-OHDA-lesioned animals. However, this effect of DJ-1 was not confirmed when DJ-1 was over-expressed in the brains of mice lesioned with MPTP. In the third part of the study, the nigral over-expression of mutated a-synuclein (A30P mutation found in familial PD cases) was chosen as the genetic model of PD, already developed in our lab. Interestingly, significant preservation of spontaneous behavior was obtained when a-synuclein (A30P) was co-injected with DJ-1. However, this was accompanied by a modest protection of dopaminergic cells, suggesting the implication of other, subtle mechanisms regulating DJ-1-related basal ganglia output. Although the DJ-1 protection of dopaminergic cells was not always achieved, the effect of DJ-1 on the spontaneous behavior implies the interesting capacity of this protein. Our results suggest that DJ-1 is one of key factors playing role in maintenance of dopaminergic function. For a possible clinical application, DJ-1 may have to be linked with another neuroprotecting factor to assure a stronger protection effect.LE
Impact of phosphorylation of alpha-synuclein in Parkinson's disease
No full textParkinson's disease (PD) is characterized by the degeneration of dopamineric neurons of the substantia nigra pars compacta projecting to the striatum, and by the deposition of cytoplasmic protein inclusions. It is further defined by the persistent presence of the α-synuclein (α-syn) protein in these inclusions. Moreover, mutations of α-syn as well as a triplication of the α-syn gene have been identified as a cause of inherited PD. These rare familial cases indicate that modifications in the sequence and in the level of expression have a tremendous impact on the protein's properties. In both familial and sporadic PD, post-translational modifications of α-syn have been reported. In particular, phosphorylation of α-syn Serine at position 129 is found to be a major modification, tightly associated with pathogenesis in human PD. Whether it be through changes in the protein's folding properties or through aberrant interactions with other proteins and lipids, these modifications transform α-syn into toxic species. In the present work, we unilaterally injected one hemisphere of the substantia nigra of rats with recombinant adeno-associated vectors (rAAV) mediating the expression of human wild-type α-syn or of human α-syn bearing the familial A30P mutation. In both cases, we engineered the human α-syn gene to replace its Serine 129 either with an Alanine (S129A), in order to prevent the attachment of a phosphate, or with an Aspartate (S129D) with the objective of mimicking the negative charge of a bound phosphate at this site. In our experimental design, rAAV-mediated human α-syn expression levels in the substantia nigra were roughly equivalent to those of the rat endogenous protein. Eight weeks after injection, we measured a significant, dose-dependent decline in the number of dopaminergic neurons injected with the wild-type form or with A30P, as compared to the non-injected side. Thus a single amino-acid modification at position 129 caused marked differences in the patterns of toxicity. Notably, expression of the S129A variant dramatically increased the pathology in rats, while expression of the S129D appeared to protect against neuronal loss. This response was the exact opposite of that obtained following expression of the S129A and S129D variants in transgenic Drosophila. We then showed that the enhanced dopaminergic loss triggered by S129A was accompanied by extensive presence of α-syn- and β-pleated sheet-positive, proteinase K-resistant small aggregates. Immuno-electron microscopy revealed that these electro-dense cytoplasmic aggregates were frequently associated with lysosomes and with a phagosome-like glassy body with vesicular content. α-syn S129A was also extensively present in intracytoplasmic tubulo-membranous systems, in the outer membrane of mitochondria, in the nucleus, and was associated with neurofilaments within neuritic fibers. The nuclei of cells exhibiting these aggregates were lobulated, and aggregates were particularly present in the indented regions of the nucleus. In addition to the morphological characteristics of apoptosis, such as nucleus condensation and lobulation, markers of apoptotic pathways were activated. Strikingly, despite the absence of dopaminergic cells loss, aggregates were present also in the S129D-injected brains, although to a much lesser extent, and apoptotic markers were also activated in these rats. The present study did not report any substantial differences that can be attributed to the expression of wild-type α-syn versus that of the A30P mutant, whether these were mutated at Serine 129 or not. However, the divergence of our results from those of the Drosophila raises the question of the adequacy of the fly as a model for PD, in view of its nervous system and its lack of any endogenous homologue to α-syn. The fact that cellular mechanisms of death were triggered by the expression of all variants, despite their significant differences in terms of induced nigral degeneration, indicates that discrepancies between variants mostly reside in the dynamics of the pathogenesis and/or in the toxic potential of the aggregated proteins. Therefore this work also brings new perspective to the current efforts to modulate kinases/phosphatases activity directed towards α-syn as a therapeutic tool.LE
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