1,721,050 research outputs found
Interaction of anaesthetics with the carotid body glomus cell and the background potassium channel response to hypoxia
Full text linkThis thesis investigates the role anaesthetics play in the depression of the acute hypoxic and hypercapnic ventilatory response. Particular attention is paid to TASK (TWIK related acid sensitive potassium) channels that are known to be sensitive to both hypoxia and the volatile anaesthetics. After chapters relating to a general introduction and methods, chapter 3 describes studies into the hypoxic and hypercapnic responses of mice with genetic ablation of TASK 1 and/or TASK 3. By using whole animal unrestrained plethysmography, it was demonstrated that any loss of TASK channels resulted in a depression of ventilatory responses to hypoxia and hypercapnia. In isocapnic hypoxia, there is a genotype specific depression by anaesthetics of the remaining AHVR, depending on whether halothane or isoflurane is inspired. Chapter 4 establishes that propofol depresses the chemosensory responses of carotid body glomus cells. Using ratiometric flurimetry to measure the intracellular calcium concentration in isolated neonatal rat glomus cells, it was demonstrated that propofol depresses the normal cellular response to both hypoxia and hypercapnia. Using pharmacological modulators of GABA and nAChR, and single channel patch clamp electrophysiology of TASK, it is apparent that this depression is independent of these candidate mechanisms. Chapter 5 describes the effects of the anaesthetic dexmedetomidine at two levels of the hypoxic chemoreflex arc in rodents. Neither isolated rat glomus cells, nor unrestrained mice show significant depression of hypoxic responses when dexmedetomidine is present. Chapter 6 illustrates the potential role for specific antagonism of TASK channels in stimulating the carotid body. Two TASK channel blockers, A1899 (TASK 1 antagonist) and PK-THPP (TASK 3 antagonist) are shown to cause a significant influx of calcium into isolated glomus cells, and an augmentation in the glomus cell response to hypoxia, which persists in the presence of isoflurane. Overall, this thesis provides evidence that both TASK 1 and TASK 3 channels are essential for normal hypoxic chemosensitivity. It has extended the knowledge that anaesthetics depress glomus cell chemosensation, by demonstrating that propofol too causes this effect. It also proposes that dexmedetomidine may have greater utility in sparing of ventilatory reflexes. By selectively blocking TASK channels, glomus cells can be stimulated, and exploiting this mechanism would be useful in minimising anaesthetic-induced depression of ventilation
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
Regulation of the carotid body type-1 cell by lipid signalling pathways
Full text linkDespite several proposed theories, the precise mechanism underlying acute oxygen sensing in type-1 cells of the carotid body remains elusive. This thesis investigates the role of Gq- coupled receptors and PLC signalling molecules in the regulation of carotid body type-1 cells by utilizing Ca2+ measurements and single channel electrophysiology. This thesis investigates the involvement of these signalling molecules in hypoxia-induced [Ca2+]i rise and TASK channel inhibition in type-1 cells. In addition, this thesis examines the role of PLC signalling molecules in mediating the effects of metabolic poisons and volatile anaesthetics on TASK channels in type-1 cells. This thesis seeks to address the question as to whether there might be a common signalling pathway mediating all these effects. Specifically, it proposes that lipid signalling may ultimately be central to all these forms of TASK channel regulation.
Following the general introduction and methods chapters, chapter 3 examines the effects of Gq- coupled receptors and PLC signalling molecules on the hypoxia-induced [Ca2+]i rise in type-1 cell. The results show that hypoxia-induced [Ca2+]i rise was sensitive to alterations in Gq-coupled receptors and PLC-signalling molecules, suggesting that these signalling molecules are involved in mediating the hypoxia-induced [Ca2+]i rise in type-1 cells.
Chapter 4, further examines the role of these signalling molecules by looking at their effects on the activity of TASK channels in type-1 cells. This chapter presents novel findings demonstrating the involvement of PLC signalling molecules in mediating the hypoxic inhibition of TASK channels in type 1 cells. It proposes a model for acute oxygen sensing in these cells, incorporating findings from chapters 3 and 4.
Chapter 5 examines the role of PLC signalling molecules in mediating the effects of metabolic inhibitors on TASK channels. Metabolic inhibitors are known to inhibit TASK channels in type-1 cells and other cell types. We further confirmed this and showed that these effects are not likely to be mediated by PLC-produced DAG.
Chapter 6 examines the interactions between DAG and halothane on TASK channels in type-1 cells. We demonstrated that DiC8, a DAG analogue, induced a strong, reversible, and dose-dependent inhibition of TASK channels and inhibited the halothane-induced activation of these channels. These novel findings support the hypothesis that anaesthetics and endogenous ligands may compete for binding sites in sensitive proteins.
In conclusion, this thesis presents novel findings on the role of Gq-coupled receptors and PLC signalling molecules in the regulation of carotid body type-1 cells and suggests that these signalling molecules are involved in mediating the responses of type-1 cells to various endogenous and exogenous stimuli. Additionally, it posits that PLC signalling molecules establish a connection between metabolic function and the modulation of TASK channels by hypoxia in type-1 cells
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
Novel interactions of volatile anaesthetics on O2 sensing and TASK channels in carotid body type-1 cells
Full text linkHypoxia elicits a carotid body-mediated increase in minute ventilation, called the
chemoreflex. Volatile anaesthetics depress this chemoreflex, even at sub-anaesthetic doses.
The broad aim of this thesis is to explore how these anaesthetics act on carotid body
mechanisms to depress the chemoreflex. The agents studied in this thesis are halothane (a
potent depressant of this reflex), isoflurane (a less potent depressant) and sevoflurane (a weak
depressant).
Intracellular Ca2+ measurements, mitochondrial NADH and potential measurements, and
single channel electrophysiology studies were performed on a primary culture of rat carotid
body type-1 cells and HEK cells transiently expressing TASK channels. Cells were exposed
to hypoxia and/or volatile anaesthetics.
The results reveal that on all levels studied, the same order of potency of anaesthetics was
observed as seen in human ventilatory studies. Volatile anaesthetics depress the hypoxia
evoked Ca2+ entry in the carotid body and increase the activity of K+ background channels
both in glomus and HEK cells expressing TASK. Furthermore, on all levels studied, when
halothane and isoflurane were applied as a mixture, the effect evoked by the mix was of a
lesser magnitude than that of the halothane alone, revealing a novel sub-additive observation,
which has not been previously reported in the literature.
The anaesthetic action of glomus cells was not exclusive to the TASK channels as application
of all three anaesthetics evoked an increase in mitochondrial NADH and caused
mitochondrial depolarization in glomus cells. These effects of anaesthetics on mitochondria
mimics the effects of hypoxia, the implications of which are discussed in this thesis. Two
novel TASK blocking agents A1899 and PK-THPP were able to decrease glomus cell TASK
channel activity, even in the presence of a clinically relevant concentration of isoflurane.
These agents may be promising as future respiratory stimulants.</p
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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