45,684 research outputs found
Dispelling the Myths Behind First-author Citation Counts
No full textWe 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
Investigation of inflammatory and oxidative stress mechanisms in the disruption of white matter structure and function following chronic cerebral hypoperfusion
No full textVascular cognitive impairment (VCI) describes a heterogeneous condition caused
by cerebrovascular disease and disturbances in cerebral blood flow delivery. It is the
second leading form of dementia and vascular factors such as hypertension, diabetes
and obesity are associated with an increased risk of developing VCI. White matter
alterations are a prominent pathological feature observed in patients with VCI thought
to underlie cognitive impairment. Neuroimaging studies show a positive correlation
between the burden of white matter alterations and progressive cognitive impairment.
Similarly associated both with white matter alterations and cognitive impairment is
chronic cerebral hypoperfusion, sustained subtle reductions in cerebral blood flow.
Cerebral hypoperfusion is observed before the onset of cognitive decline in humans
and reducing cerebral blood flow in animal models replicates important aspects of
VCI, suggesting hypoperfusion is an early driver of white matter disruption and VCI.
Human neuropathology and preclinical animal models of chronic cerebral
hypoperfusion studies have repeatedly identified increased inflammation and
oxidative stress. This led to the hypothesis for this thesis; that inflammation and
oxidative stress are key drivers of structural and functional white matter disruption
when cerebral blood flow is reduced.
The studies reported in this thesis were developed to investigate mechanisms
involving inflammation and oxidative stress that can inform future treatments aimed
at preventing the disruption of white matter and cognitive impairment in VCI. One such
mechanism is the Nrf2 (Nuclear factor erythroid 2-related factor 2) signalling pathway.
Nrf2 is a transcription factor that acts to detect and resolve inflammation and oxidative
stress via induction of over 200 antioxidant and anti-inflammatory genes. Studies
have shown that modulation of Nrf2 alters levels of inflammation and oxidative stress
which impact on disease progression in models of Alzheimer’s disease, Parkinson’s
disease and multiple sclerosis. To date, no one has investigated the direct role of Nrf2
in cerebral hypoperfusion-induced white matter disruption. While Nrf2 represents a
promising network approach, another targeted mechanism of interest is microglial
proliferation. Many neurodegenerative diseases including human VCI demonstrate
increases in microglia, a sign of chronic neuroinflammation thought to be detrimental
to cells, tissues and synapses. Work by our group has found an association between
increasing numbers of microglia and the progressive disruption of white matter
structure and function when cerebral blood flow is reduced in a mouse model,
however, whether this is cause or consequence has yet to be determined. The first study of this thesis aimed to test the hypothesis that deficiency of Nrf2
exacerbates white matter pathology and cognitive decline when cerebral blood flow
is reduced. Using wild type and Nrf2 knockout mice the study investigated cortical
perfusion, white matter disruption and gliosis, cognitive impairment and white matter
gene changes following sham or surgically-induced cerebral hypoperfusion (bilateral
carotid artery stenosis). There were no differences in the severity of blood flow
reductions between genotypes initially, however, wild type mice displayed improved
recovery compared to Nrf2 deficient mice. Hypoperfusion induced white matter
disruption and microgliosis in the corpus callosum and the optic tract in both
genotypes, exacerbated by the absence of Nrf2. Further, hypoperfusion induced white
matter astrogliosis and upregulated pro-inflammatory gene signalling in the optic tract
and induced an impairment in spatial working memory. However, these measures
were not affected by Nrf2 deficiency. The results demonstrate that the absence of
Nrf2 exacerbates white matter pathology and microgliosis following cerebral
hypoperfusion but does not impact on functional outcome.
The second study aimed to test the hypothesis that enhancing astrocytic Nrf2-
signalling preserves white matter structure and cognitive decline when cerebral blood
flow is reduced. Astrocytes have larger antioxidant capacity than other cell types in
the brain and overexpressing Nrf2 in astrocytes is associated with reduced white
matter damage in a model of multiple sclerosis, as well as improved outcome in
models of Parkinson’s and Huntington’s disease. Similar to the first study, wild type
mice and mice overexpressing Nrf2 in astrocytes (GFAP-Nrf2) were subjected to
bilateral carotid artery stenosis and cortical perfusion, white matter disruption and
gliosis, cognitive impairment and white matter gene changes were assessed. There
were no differences in the severity of blood flow reductions between genotypes. Akin
to the first study, hypoperfusion induced white matter disruption, micro- and
astrogliosis and pro-inflammatory gene signalling in the optic tract. The majority of
these alterations were ameliorated in GFAP-Nrf2 mice. In addition, the impairment in
spatial working memory induced by cerebral hypoperfusion was modestly improved
in GFAP-Nrf2 mice compared to wild type controls. These findings support the
hypothesis that astrocytic Nrf2 preserves white matter structure and function following
cerebral hypoperfusion.
The first two studies identified structural and functional consequences of altered
inflammation mediated via alterations in Nrf2 signalling. To thoroughly investigate the
Nrf2 signalling pathway following cerebral hypoperfusion the next step would ideally have been to study microglial Nrf2, however due to the lack of a suitable animal
model, the third and final study instead aimed to test the hypothesis that microglial
colony-stimulating factor 1 receptor (CSF1R) signalling is a driver of white matter
disruption and cognitive decline when cerebral blood flow is reduced. Wild type mice
treated with a pharmacological inhibitor of CSF1R (GW2580) or vehicle control, as an
oral gavage or in diet, were studied by a similar experimental protocol as the first two
studies. There were no differences in the severity of cerebral hypoperfusion between
GW2580- or vehicle-treated animals either at one or six weeks following bilateral
carotid artery stenosis. One week of GW2580 treatment was shown to modulate
microglial proliferation and pro-inflammatory signalling in white matter. Remarkably,
treatment with GW2580 for six weeks completely rescued impairments in spatial
learning, protected against white matter disruption and prevented increased both
white matter micro- and astrogliosis compared to wild type controls. These results
suggest that CSF1R signalling in microglia is an important driver of the
pathophysiological mechanisms that lead to white matter disruption and cognitive
impairment when cerebral blood flow is reduced, and importantly, that targeted
inhibition of this improves functional outcome.
In conclusion, the work described in this thesis provides evidence of the
contribution of inflammation and oxidative stress to the disruption and functional
impairment of cerebral white matter. The results indicate that these mechanisms are
amenable to alteration, and that direct microglial inflammatory mechanisms play an
important role in the pathogenesis of white matter disruption and cognitive decline.
The results demonstrate that targeted inhibition of CSF1R signalling in microglia and
increased astrocytic Nrf2 expression leads to improved structural and functional
outcome and as such represent a basis for potential treatment which warrants further
investigation
Stem cell marker olfactomedin 4: critical appraisal of its characteristics and role in tumorigenesis
No full textOlfactomedin 4 (OLFM4), a member of the olfactomedin domain-containing proteins, is a glycoprotein with molecular weight of approximately 64 kDa. The protein is a "robust marker" of Lgr5+ stem cells and has been localised to mitochondria, nuclei and cell membranes. The bulk of OLFM4 exists in a polymeric form which is held together by disulfide bonds and carbohydrate interactions. Earlier studies revealed that the protein binds to lectins and cadherins, and facilitates cell-cell adhesion. Recent data demonstrated that the protein possesses several hallmarks of carcinogenesis. OLFM4 has also been purported to be an inducible resistance factor to apoptotic stimuli such as radiation and anticancer drugs. Here, we review its synonyms and classification, gene structure, protein structure, intracellular and tissue distribution, adhesive and antiapoptotic; mitotic; migratory and cell cycle regulatory characteristics. We also critically evaluate recent advances in understanding of the transcriptional regulation of OLFM4 and its upstream signalling pathways with special emphasis on carcinogenesis and outline future perspectives in the field.Phulwinder K. Grover, Jennifer E. Hardingham, Adrian G. Cummin
Author, publisher and bookseller : a tripartite synergy in Nigerian book industry
No full textThis work is about the roles of Author, Publisher and Bookseller in Book development in
Nigeria. The paper started by delving into the history of Book Publishing in Nigeria after
which it proceeded by defining who an author, a publisher, and a bookseller is and
expatiated on the indispensable roles of these key actors in Nigerian Book Industry and in
the emerging Information Society. Furthermore, the various constraints to book
development were identified while the paper advised on how the Book Industry can be
further promoted in Nigeria. However, the paper concluded and made recommendations
on how the Book sector can help in enhancing scholarship in the country
Mining e-mail content for author identification forensics
No full textWe describe an investigation into e-mail content mining for author identification, or authorship attribution, for the purpose of forensic investigation. We focus our discussion on the ability to discriminate between authors for the case of both aggregated e-mail topics as well as across different email topics. An extended set of e-mail document features including structural characteristics and linguistic patterns were derived and, together with a Support Vector Machine learning algorithm, were used for mining the e-mail content. Experiments using a number of e-mail documents generated by different authors on a set of topics gave promising results for both aggregated and multi-topic author categorisation
Control of anti-apoptotic and antioxidant pathways in neural cells
No full textOxidative stress is a feature of many chronic neurodegenerative diseases as well as a
contributing factor in acute disorders including stroke. Fork head class of
transcription factors (Foxos) play a key role in promoting oxidative stress-induced
apoptosis in neurons through the upregulation of a number of pro-apoptotic genes.
Here I demonstrate that synaptic NMDA receptor activity not only promotes Foxos
nuclear exclusion but also suppresses the expression of Foxo1 in a PI3K-dependent
fashion. I also found that Foxo1 is in fact, a Foxo target gene and that it is subject to
a feed-forward inhibition by synaptic activity, which is thought to result in longerterm
suppression of Foxo downstream gene expression than previously thought. The
nuclear factor (erythroid 2-related) factor 2 (Nrf2) is another transcription factor
involved in oxidative stress and the key regulator of many genes, whose products
form important intrinsic antioxidant systems. In the CNS, artificial activation of Nrf2
in astrocytes has been shown to protect nearby neurons from oxidative insults.
However, the extent to which Nrf2 in astrocytes could respond to endogenous signals
such as mild oxidative stress is less clear. The data presented herein, demonstrate for
the first time that endogenous Nrf2 could be activated by mild oxidative stress and
that this activation is restricted to astrocytes. Contrary to the established dogma, I
found that mild oxidative stress induces the astrocytic Nrf2 pathway in a manner
distinct from the classical Keap1 antagonism employed by prototypical Nrf2
inducers. The mechanism was found to involve direct regulation of Nrf2's
transactivation properties. Overall these results advance our knowledge of the
molecular mechanism(s) associated with the control of endogenous antioxidant
defences by physiological signals
Un nuevo manuscrito de Chimalpahin.. Anales del Instituto Nacional de Antropología e Historia. Num. 50 Tomo II (1969) Séptima Época (1967-1976)
No full textChimalpahin, Cuauhtlehuanitzin Francisco de San Antón Muñón 1965 Relaciones originales de Chalco Amaquemecan. Paleografía, traducción y glosa de Silvia Rendón. Fondo de Cultura Económica. México.Mengin, E. (Ed.) 1949 Diferentes historias originales de los Reynos de Culhuacan, y México, y de otras provincias. El autor de ellas dicho Don Domingo Chimalpahín. Manuscrito mexicano No. 74. Corpus Codicum Americanorum. Medii Aevi, vol. III. Copenhagen.Pompa y Pompa, A. 1964 La Biblioteca Nacional de Antropología e Historia. Boletín del Instituto Nacional de Antropología e Historia, No. 17, pp. 34-36. México.Simeón, R. 1899 Annales de Domingo Francisco de San Antón Muñón Chimalpahin Quauhtlehuanitzin. Sixième et septième Relations ( 1258-1612). Bibliothèque Linguistique Americaine, No. XII. Paris.Zimmerman, G. 1965 Die Relations Chimalpahin's zur Geschichte Mexico's. Das Jahrhundert nach der Conquista (1522-1615), Teil 2. Hamburg.Zimmerman, G. 1966 Chimalpahin y la iglesia de San Antón Abad en México. Traducciones Mesoamericanas, t. I. Sociedad Mexicana de Antropología. México
TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner
No full textAntagonists that are sufficiently selective to preferentially block GluN2A-containing N-methyl-d-aspartate receptors (NMDARs) over GluN2B-containing NMDARs are few in number. In this study we describe a pharmacological characterization of 3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide (TCN 201), a sulphonamide derivative, that was recently identified from a high-throughput screen as a potential GluN2A-selective antagonist. Using two-electrode voltage-clamp (TEVC) recordings of NMDAR currents from Xenopus laevis oocytes expressing either GluN1/GluN2A or GluN1/GluN2B NMDARs we demonstrate the selective antagonism by TCN 201 of GluN2A-containing NMDARs. The degree of inhibition produced by TCN 201 is dependent on the concentration of the GluN1-site co-agonist, glycine (or d-serine), and is independent of the glutamate concentration. This GluN1 agonist-dependency is similar to that observed for a related GluN2A-selective antagonist, N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide (TCN 213). Schild analysis of TCN 201 antagonism indicates that it acts in a non-competitive manner but its equilibrium constant at GluN1/GluN2A NMDARs indicates TCN 201 is around 30-times more potent than TCN 213. In cortical neurones TCN 201 shows only modest antagonism of NMDAR-mediated currents recorded from young (DIV 9-10) neurones where GluN2B expression predominates. In older cultures (DIV 15-18) or in cultures where GluN2A subunits have been over-expressed TCN 201 gives a strong block that is negatively correlated with the degree of block produced by the GluN2B-selective antagonist, ifenprodil. Nevertheless, while TCN 201 is a potent antagonist it must be borne in mind that its ability to block GluN2A-containing NMDARs is dependent on the GluN1-agonist concentration and is limited by its low solubility
Analytical study of contents of LANL physics and cross-listed e-print archives, 1994-2002
No full textThe frontiers of physics and cross-listed e-print archives posted during the years 1994-2002 at http://www.arxiv.org/archives/physics web service of Los Alamos National Laboratory (LANL) are explored from 7770 submissions. E-print archives posted to top most six physics-cross-listed research categories besides physics (5390) are: Condensed matter (754), Quantum physics (279), Astrophysics (222), Chemical physics (129), High energy physics - Phenomenology (118), and High energy physics-Theory (100). Prominent contributors are B.G. Sidharth (India), V.V. Flambaum (Australia), Antonina N. Fedorova (Russia), and Michael G. Zeitlin (Russia). Most preferred journals for rechannelising e-print archives are Physical Review Letters, Physical Review A, Physical Review E, Nuclear Instruments and Methods A, and Journal of Chemical Physics
Self-archiving practice and the influence of publisher policies in the social sciences
No full textAuthors in different disciplines exhibit very different behaviours on the so-called ‘green’ road to open access, i.e. self-archiving. This study looks at the self-archiving behaviour of authors publishing in leading journals in six social science disciplines. It tests the hypothesis that authors are self-archiving according to the norms of their respective disciplines rather than following self-archiving policies of publishers, and that, as a result, they are self-archiving significant numbers of publisher PDF versions. It finds significant levels of
self-archiving, as well as significant self-archiving of
the publisher PDF version, in all the disciplines
investigated. Publishers’ self-archiving policies have
no influence on author self-archiving practice
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