1,721,076 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
Functional characterisation of dyslexia-susceptibility candidate genes KIAA0319 and KIAA0319L
Get PDFThe capacity for language is one of the key features underlying human cognition and evolution. However, little is known about the neurobiological mechanisms underlying normal or impaired linguistic ability. Developmental dyslexia refers to a specific impairment in reading performance and it is one of the most common neurodevelopmental disabilities in school-aged children. It has a well-established genetic component and KIAA0319 is one of the prime susceptibility candidate genes associated with it, also showing some genetic overlap with other language-related disorders. Its paralogous gene, KIAA0319L (or KIAA0319-Like), is the only other member of this gene family and has also been linked to dyslexia. This thesis interrogates the function of the mouse homologs of KIAA0319 and KIAA0319L at the molecular, cellular, electrophysiological and behavioural levels in order to uncover the mechanisms through which they may underlie the neural architecture of language, and susceptibility to dyslexia and related disorders.
Both KIAA0319 and KIAA0319L have been implicated in neuronal migration in the developing neocortex following in utero knockdown in rats using shRNA. However, our laboratories have recently shown that genetic ablation of KIAA0319 does not affect cortical migration. Given functional redundancy between paralogous genes is a well-known source of compensation in biological systems, I hypothesised that this may derive from compensation between KIAA0319 and AU040320, the mouse homolog of KIAA0319L. Using a range of anatomical methods to investigate AU040320 and double Kiaa0319;AU040320 KOs, I have found no evidence for a role of these proteins in cell migration in the mouse brain, in contrast to previous reports.
To interrogate other putative functions of KIAA0319 and AU040320, I performed a series of behavioural experiments on Kiaa0319;AU040320 KO mice to examine potential deficits in their behaviour. Despite a largely normal behavioural profile, these animals displayed impaired auditory processing in a gap detection task and in auditory brainstem recordings (ABRs) due to a potential reduction in neural activity in the early central auditory pathway - with similar deficits observed in AU040320 single KOs. These results raise the possibility these genes mediate the normal structure/function of the auditory system, in line with auditory-related deficits being one of the hallmarks of dyslexia.
Given the paucity of knowledge on the AU040320 protein, I interrogate its function at the cellular level by examining the male infertility observed in AU040320 KO mice. Spermatozoa in these mice were found to have round heads lacking the sperm secretory organelle called acrosome, features which mimic those of globozoospermia - a rare genetic condition affecting humans. Ultrastructural analyses revealed that acrosome formation in AU040320-deficient males resulted from an impairment in the fusion of proacrosomic vesicles during the early stages. Preliminary molecular analyses revealed that the AU040320 protein may interact with AP-1, AP-2 and ASAP1, key proteins in intracellular trafficking which regulate vesicle transport and function, suggesting a pathway which could be involved in the malformations observed in AU040320 KOs.</p
Characterisation of neuroserpin protein expression throughout development and investigation of putative neuroprotective properties in rodent models of neonatal hypoxia ischaemia
Get PDFNeonatal hypoxia ischaemia remains the most common cause of infant mortality globally, accounting for persistent motor and cognitive disorders in a substantial proportion of survivors. Currently, there is only one licensed treatment which aims to reduce brain damage and improve cognitive function: hypothermia. Increased understanding of the infant brainâs response to hypoxic ischaemic injury and novel treatment design are of utmost importance. This thesis characterises expression of neuronally- secreted serine protease inhibitor neuroserpin, previously established as a protective factor in rodent models of adult stroke, throughout development and in rodent models of mild-to-moderate neonatal hypoxic ischaemic injury.
The expression profile of neuroserpin protein was examined in the developing mouse and human brain using immunohistochemistry. Results closely corresponded with published mRNA expression patterns, demonstrating an enrichment of neuroserpin-immunoreactive neurons in Layer V and the transitory deep layer known as subplate in murine cerebral cortex. Within the subplate, neuroserpin- immunoreactive neurons formed an early-born subpopulation, partially overlapping conserved subplate molecular markers. Expression peaked at the murine brain development stage equivalent to birth in human, suggesting a potential developmental function for neuroserpin. Investigations in human foetal brain tissue confirmed neuroserpin-immunoreactivity within the deep layers of the cortical plate.
Neuroserpin expression patterns were also quantified in rodent models of neonatal hypoxia ischaemia, adapted from the Rice-Vannucci method. In a preterm rat model and a neonatal mouse model, the number of neuroserpin-immunoreactive neurons within the subplate underwent a statistically significant increase in the hypoxic-ischaemic hemisphere compared to the control hemisphere and sham-operated brains, with no significant change in any other cortical layer. However, semi- quantitative Western blot detected no significant difference in total cortical neuroserpin protein between hypoxic-ischaemic and control hemispheres in neonatal mouse brains. It is possible that neuroserpin contributes to a highly anatomically-localised or time-point specific endogenous response to neonatal hypoxia ischaemia.
The proposed neuroprotective properties of neuroserpin were investigated in two models of neonatal hypoxia ischaemia, yielding inconclusive results. Oxygen glucose deprivation experiments in cultured Neuro-2-A neuroblastoma cells and primary cortical neurons in vitro demonstrated a modest but statistically significant increase in staining for metabolic viability marker 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) when treated with exogenous neuroserpin. The functional significance of this effect remains to be evaluated.
The Serpini1 knock-out mouse, which does not manufacture functional neuroserpin protein, was used to assess the vulnerability of neurons to hypoxic-ischaemic brain damage in the absence of neuroserpin in vivo. Serpini1 knock-out mouse pups and wild-type littermates underwent adapted Rice-Vannucci neonatal hypoxia ischaemia, before being perfused with metabolic activity marker 2,3,5- triphenyltetrazolium chloride (TTC) 48 hours after injury. No significant difference in staining intensity was detected between genotypes, although methodological refinement is required. Immunohistochemistry for glial inflammatory markers also found mixed results, with only one of three markers investigated demonstrating a significant difference in immunoreactivity between genotypes.
This thesis examines putative neuroprotective protein neuroserpin expression and reports a neuron- specific expression enrichment around term. Any endogenous upregulation of neuroserpin expression following rodent neonatal hypoxia ischaemia is modest, and evidence for substantial variability in injury severity in the absence of neuroserpin from these initial investigations is weak.</p
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
The development of corticothalamic and corticotectal connections in the murine visual system
Get PDFAll peripheral sensory information is represented in the thalamus before being transmitted to the cortex, with the exception of olfaction. The thalamus projects to all areas of the neocortex and all neocortical areas project to the thalamus. I am interested in the development of three corticothalamic populations which are anatomically and functionally distinct; they project to different thalamic nuclei and generate different post-synaptic responses. Layer V fibres project exclusively to higher order thalamic nuclei. These projections drive thalamic neuron activity and mediate a trans-thalamic cortico-cortical relay. Layer VI and VIb fibres project to both first order and higher order thalamic nuclei. These projections modulate thalamic neuron activity and mediate feedback to the thalamus. Using three transgenic mouse lines I demonstrate that developing corticothalamic fibres target the specific groups of thalamic nuclei to which they project in adulthood. Rbp4-Cre::tdTomato labels layer V; Ntsr1-Cre::tdTomato labels layer VI; Golli-τ-eGFP labels layer VI and VIb. By P4 layer V fibres arborise densely in higher order nuclei but do not innervate the first order nuclei at any age. In contrast, at this age VI and VIb fibres densely innervate the first order ventral posterior-medial nucleus (VPM), as well as higher order nuclei. Layer VI and VIb fibres accumulate outside the dorsal Lateral Geniculate Nucleus (dLGN) from P2 before entering at P6. During this waiting period, retinal fibres transmit spontaneous waves of activity to the dLGN. To assess whether retinal input regulates corticothalamic circuit development I performed monocular enucleation. I demonstrate that after loss of retinal input, layer VI and VIb fibres enter the dLGN prematurely, by P2. Furthermore layer V fibres which target the retino-recipient superior colliculus also enter prematurely following enucleation. These results suggest there may be a retinal mechanism which regulates the timing of corticofugal ingrowth to joint retinal/cortical targets. The loss of retinal driver input to the dLGN also induces layer V driver fibres to aberrantly enter the first order dLGN. These results are the first to show cross-hierarchical rewiring after losing peripheral sensory input. The role of peripheral activity in the developing nervous system is underscored by activity dependent molecular mechanisms. I therefore performed a microarray gene expression experiment to systematically analyse molecular changes in the dLGN following enucleation. The expression of numerous genes is altered following enucleation including potassium channels Kcnk9 and Kcnn3, kinase pathway mediators, Shc3 and Dgkk, and immediate early genes BDNF, Egr1 and Egr2. The majority of genes regulated by enucleation are regulated in the opposite direction over development indicating that the loss of the retinal input delays maturation of the dLGN transcriptome. In this thesis I demonstrate that early corticothalamic development targets specific thalamic nuclei. Using the visual system as a model I demonstrate that retinal input regulates corticothalamic development and contributes to the transcriptome of thalamic nuclei
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
Characterization of VIP+ interneurons in the mouse whisker barrel cortex during development
Get PDFGABAergic interneurons (INs) are thought to be important players in normal cortical circuit development, with a body of data highlighting the role of two major IN classes – parvalbumin and somatostatin-positive (PV+ and SST+) subtypes – in neonatal mouse sensory cortices (Marques-Smith et al., 2016;
Takesian and Hensch, 2013; Tuncdemir et al., 2016). More recent evidence supports a developmental role for a third class of IN, defined by the expression of vasoactive intestinal peptide (VIP+ INs) (Batista-Brito et al., 2017; Goff and Goldberg, 2019; Mossner et al., 2017). This IN subtype has been shown to play a role in sensorimotor integration via preferential targeting of SST+ cells and consequent disinhibition of pyramidal cells in the mature cortex (e.g., Lee et al., 2013). However, it is unknown how and when VIP+ INs integrate into the local and long-range circuitry during early development.
To address this, I first investigated the integration of VIP+ cells into the local circuit in postnatal whisker barrel cortex (S1BF). Data show that, while VIP+ INs acquire mature electrophysiological properties and integrate in the local glutamatergic network over the first two postnatal weeks, they engage with other INs and pyramidal cells already in the first postnatal week.
Second, I employed a viral optogenetic strategy to test the emergence of long-range inputs from anterior-motor areas onto S1BF VIP+ cells. Data show that VIP+ INs start to be recruited already in the first postnatal week, but they are fully integrated in the long-range circuitry only at the end of the second postnatal
week.
Finally, I have used the VIP-Cre;Prox1c/c conditional knockout model (Miyoshi et al., 2015) to investigate whether genetic perturbation of VIP+ INs has an impact on synaptic integration and in vivo activity. Data suggest that conditional deletion
of Prox1 leads to reorganisation of the local but not long-range glutamatergic input, and increased activity upon whisker stimulation.
These findings define the emergence of the VIP+ circuitry and show their early influence in circuit maturation, further supporting the importance of IN signalling in cortical development
- …
