1,720,958 research outputs found
Characterizing novel protease activated receptor 2 compounds for potential use in examining depression-like behavior
No full textAims: Globally, depression is considered to be one of the leading causes of disability. Recently, it has been proposed that neuroinflammation is a key process underlying the pathology of depression, especially given the well-established increase in pro-inflammatory cytokines observed in depressed patients. Particularly, the G-protein coupled receptor (GPCR) protease activated receptor 2 (PAR2) has received interest towards its link with depression, as this has shown to play a pro-inflammatory role in disorders of the central nervous system (CNS). However, previously it has remained a challenge to examine PAR2 involvement in depression-like behavior due to the limited agonists and antagonists available. To address this issue, we aimed to investigate the selectivity of the proposed PAR2 small molecule agonist AC264613, which induces depression-like behavior in mice, by testing and comparing this to another GPCR, Mas-related G-protein coupled receptor C11 (MrgprC11), which has been proposed to underlie certain off-target effects of PAR2 activators. In addition, we also planned to characterize the selectivity of the recently developed PAR2 negative allosteric modulator (NAM) AZ8838.;Methods: The selectivity of SLIGRL-NH2 and AC264613 was examined by transfecting tsA201 cells with either PAR2-YFP or MrgprC11-YFP, which were then exposed to the proposed activators and imaged using the epifluorescence microscope. Receptor internalization ratios were performed on individual cells and all statistical analysis was carried out using one-way analysis of variance (ANOVA) followed by a Tukey post-hoc test where appropriate, with P ≤ 0.05 representing a statistical significance.;Results: SLIGRL-NH2 induced receptor internalization for both PAR2-YFP and MrgprC11-YFP. Similarly, AC264613 induced PAR2 internalization but was without effect on the MrgprC11-YFP receptor. Due to COVID-19, characterization of AZ8838 was not undertaken.;Conclusions: In this study, we report successful receptor expression of PAR2-YFP and MrgprC11-YFP in tsA201 cells. Consistent with previous studies, we show that SLIGRL-NH2 is non-specific for PAR2 whereas we confirmed that AC264613 is PAR2 selective. Thus, we conclude that the depression-like behavior, observed following AC264613 administration are mediated via PAR2 mediated signalling. Keywords: Depression, neuroinflammation, PAR2, MrgprC11, AC264613, SLIGRL-NH2, receptor internalizationAims: Globally, depression is considered to be one of the leading causes of disability. Recently, it has been proposed that neuroinflammation is a key process underlying the pathology of depression, especially given the well-established increase in pro-inflammatory cytokines observed in depressed patients. Particularly, the G-protein coupled receptor (GPCR) protease activated receptor 2 (PAR2) has received interest towards its link with depression, as this has shown to play a pro-inflammatory role in disorders of the central nervous system (CNS). However, previously it has remained a challenge to examine PAR2 involvement in depression-like behavior due to the limited agonists and antagonists available. To address this issue, we aimed to investigate the selectivity of the proposed PAR2 small molecule agonist AC264613, which induces depression-like behavior in mice, by testing and comparing this to another GPCR, Mas-related G-protein coupled receptor C11 (MrgprC11), which has been proposed to underlie certain off-target effects of PAR2 activators. In addition, we also planned to characterize the selectivity of the recently developed PAR2 negative allosteric modulator (NAM) AZ8838.;Methods: The selectivity of SLIGRL-NH2 and AC264613 was examined by transfecting tsA201 cells with either PAR2-YFP or MrgprC11-YFP, which were then exposed to the proposed activators and imaged using the epifluorescence microscope. Receptor internalization ratios were performed on individual cells and all statistical analysis was carried out using one-way analysis of variance (ANOVA) followed by a Tukey post-hoc test where appropriate, with P ≤ 0.05 representing a statistical significance.;Results: SLIGRL-NH2 induced receptor internalization for both PAR2-YFP and MrgprC11-YFP. Similarly, AC264613 induced PAR2 internalization but was without effect on the MrgprC11-YFP receptor. Due to COVID-19, characterization of AZ8838 was not undertaken.;Conclusions: In this study, we report successful receptor expression of PAR2-YFP and MrgprC11-YFP in tsA201 cells. Consistent with previous studies, we show that SLIGRL-NH2 is non-specific for PAR2 whereas we confirmed that AC264613 is PAR2 selective. Thus, we conclude that the depression-like behavior, observed following AC264613 administration are mediated via PAR2 mediated signalling. Keywords: Depression, neuroinflammation, PAR2, MrgprC11, AC264613, SLIGRL-NH2, receptor internalizatio
Sex-dependent mitochondrial function in the right ventricle in pulmonary arterial hypertension
No full textBackground: Pulmonary arterial hypertension (PAH) has a female predominance with a ~4:1 female-to-male ratio. However, female PAH patients exhibit better right ventricular (RV) compensation in the face of increased pulmonary arterial pressures and thus better survival than the males. The sex differences and the associated mechanism in RV in PAH are not well characterised. Additionally, the mitochondria become dysfunctional in PAH, which involves a
glycolytic shift in the mitochondrial metabolism. The mitochondria also undergo excessive fission in PAH, losing their filamentous structure and becoming fragmented. These key mitochondrial dysfunctional features have been shown to contribute to RV dysfunction, and within PAH, the status of the RV serves as the main determinant of survival. Hence, we aim to explore whether there are any sex differences in mitochondrial function and RV
remodelling in a Sugen-hypoxia (SuHx) induced PAH rat model. The work in this thesis also describes the impact of a mitochondria-targeted antioxidant, Mitoquinone (MitoQ), in vivo and whether MitoQ is able to exhibit protective activity with regard to RV status in PAH.
Methods: Male and female Sprague-Dawley rats were injected with Sugen (25 mg/kg) and exposed to hypoxia for 3 weeks followed by up to 5 weeks in normoxia. Control rats received vehicle (CMC) and were kept in normoxia for up to 8 weeks. RV haemodynamics were measured via pressure-volume (PV) loop measurement using the open chest method.
Confocal imaging was performed on fresh RV tissue stained with mitochondrial dyes to examine mitochondrial properties. RV fibrosis, myocyte size, and right coronary artery (RCA) remodelling were assessed by staining the RV tissue with picrosirius red. Mitochondria-linked biogenesis, dynamics and oxidative stress genes were examined in both the RV and lung tissue by quantitative polymerase chain reaction (qPCR). The effect of MitoQ (300 nM) and estradiol (E2; 10 nM) on mitochondrial superoxide levels, cell proliferation and protein expression were examined in vitro in male and female human cardiac fibroblasts (HCF) and primary RV fibroblasts isolated from male monocrotaline (MCT) rats. MitoQ (5 mg/kg) was given by intraperitoneal injection (IP) injection to male and female SuHx rats twice a week from week
5 post Sugen injection. The rats were assessed in vivo using the PV loop method to obtain the hemodynamic parameters. RV from these rats were then examined histologically for collagen deposition and myocyte size.
Results: SuHx caused significant increases in RV systolic pressure (RVSP), RV hypertrophy, RV fibroblast proliferation, and RV myocyte size in both sexes. Although SuHx did not cause differences in the RVSP and effective arterial elastance (Ea) between the sexes, it caused a slightly greater increase in RV end-systolic elastance (Ees) in females vs. males, leading to a
preserved RV-pulmonary artery coupling (Ees/Ea) in females and a significant decrease in Ees/Ea in males. SuHx caused a significant increase in RV end diastolic pressure (RVEDP) only in males, which was associated with a significantly higher amount of RV interstitial fibrosis and increased expression of fibrotic gene expression in males vs. females. The male SuHx rats had more severe RCA remodelling in their smaller vessels (diameter of 15-50 μm) which was not detected in the females. SuHx caused a significant decrease in mitochondrial membrane potential and fusion in RV from male SuHx rats only. Within the lung, SuHx reduced mitochondrial biogenesis and mitochondrial fusion gene expression in only the male SuHx rats. E2 (10 nM) and MitoQ (300 nM) were able to mediate protective effects by reducing
mitochondrial superoxide levels, fibroblast proliferation in male and female HCF cells and male MCT RV fibroblasts. Both MitoQ and E2 were able to reduce markers of fibrosis protein expression and increase mitochondrial biogenesis protein expression. In vivo, MitoQ (5mg/kg) was not able to reduce RVSP, RVEDP, RV hypertrophy, and Ea or increase Ees in the SuHx rats of both sexes. However, MitoQ reduced RV interstitial fibrosis and increased RVpulmonary artery coupling (Ees/Ea) in male SuHx rats.
Conclusion: Overall, this project shows that the male SuHx rats have worse RV hemodynamic parameters, which correlate with worse interstitial collagen production. Mitochondrial function in the RV and lung displayed sexual dimorphisms, with the male RV associated with more impaired mitochondrial properties compared to the females. We show that both E2 and MitoQ are protective in vitro by reducing MitoSOX, cell proliferation, and collagen expression.
Meanwhile, MitoQ treatment in vivo was not able to reverse the RV hypertrophy in either sex. However, it did improve the RV-pulmonary artery coupling and lower RV collagen deposition in the male SuHx rats. Taken together, this provides preliminary evidence that male SuHx rats are associated with worse PAH characteristics and that MitoQ could potentially offer therapeutic value for RV, but only in the male sex in PAH.Background: Pulmonary arterial hypertension (PAH) has a female predominance with a ~4:1 female-to-male ratio. However, female PAH patients exhibit better right ventricular (RV) compensation in the face of increased pulmonary arterial pressures and thus better survival than the males. The sex differences and the associated mechanism in RV in PAH are not well characterised. Additionally, the mitochondria become dysfunctional in PAH, which involves a
glycolytic shift in the mitochondrial metabolism. The mitochondria also undergo excessive fission in PAH, losing their filamentous structure and becoming fragmented. These key mitochondrial dysfunctional features have been shown to contribute to RV dysfunction, and within PAH, the status of the RV serves as the main determinant of survival. Hence, we aim to explore whether there are any sex differences in mitochondrial function and RV
remodelling in a Sugen-hypoxia (SuHx) induced PAH rat model. The work in this thesis also describes the impact of a mitochondria-targeted antioxidant, Mitoquinone (MitoQ), in vivo and whether MitoQ is able to exhibit protective activity with regard to RV status in PAH.
Methods: Male and female Sprague-Dawley rats were injected with Sugen (25 mg/kg) and exposed to hypoxia for 3 weeks followed by up to 5 weeks in normoxia. Control rats received vehicle (CMC) and were kept in normoxia for up to 8 weeks. RV haemodynamics were measured via pressure-volume (PV) loop measurement using the open chest method.
Confocal imaging was performed on fresh RV tissue stained with mitochondrial dyes to examine mitochondrial properties. RV fibrosis, myocyte size, and right coronary artery (RCA) remodelling were assessed by staining the RV tissue with picrosirius red. Mitochondria-linked biogenesis, dynamics and oxidative stress genes were examined in both the RV and lung tissue by quantitative polymerase chain reaction (qPCR). The effect of MitoQ (300 nM) and estradiol (E2; 10 nM) on mitochondrial superoxide levels, cell proliferation and protein expression were examined in vitro in male and female human cardiac fibroblasts (HCF) and primary RV fibroblasts isolated from male monocrotaline (MCT) rats. MitoQ (5 mg/kg) was given by intraperitoneal injection (IP) injection to male and female SuHx rats twice a week from week
5 post Sugen injection. The rats were assessed in vivo using the PV loop method to obtain the hemodynamic parameters. RV from these rats were then examined histologically for collagen deposition and myocyte size.
Results: SuHx caused significant increases in RV systolic pressure (RVSP), RV hypertrophy, RV fibroblast proliferation, and RV myocyte size in both sexes. Although SuHx did not cause differences in the RVSP and effective arterial elastance (Ea) between the sexes, it caused a slightly greater increase in RV end-systolic elastance (Ees) in females vs. males, leading to a
preserved RV-pulmonary artery coupling (Ees/Ea) in females and a significant decrease in Ees/Ea in males. SuHx caused a significant increase in RV end diastolic pressure (RVEDP) only in males, which was associated with a significantly higher amount of RV interstitial fibrosis and increased expression of fibrotic gene expression in males vs. females. The male SuHx rats had more severe RCA remodelling in their smaller vessels (diameter of 15-50 μm) which was not detected in the females. SuHx caused a significant decrease in mitochondrial membrane potential and fusion in RV from male SuHx rats only. Within the lung, SuHx reduced mitochondrial biogenesis and mitochondrial fusion gene expression in only the male SuHx rats. E2 (10 nM) and MitoQ (300 nM) were able to mediate protective effects by reducing
mitochondrial superoxide levels, fibroblast proliferation in male and female HCF cells and male MCT RV fibroblasts. Both MitoQ and E2 were able to reduce markers of fibrosis protein expression and increase mitochondrial biogenesis protein expression. In vivo, MitoQ (5mg/kg) was not able to reduce RVSP, RVEDP, RV hypertrophy, and Ea or increase Ees in the SuHx rats of both sexes. However, MitoQ reduced RV interstitial fibrosis and increased RVpulmonary artery coupling (Ees/Ea) in male SuHx rats.
Conclusion: Overall, this project shows that the male SuHx rats have worse RV hemodynamic parameters, which correlate with worse interstitial collagen production. Mitochondrial function in the RV and lung displayed sexual dimorphisms, with the male RV associated with more impaired mitochondrial properties compared to the females. We show that both E2 and MitoQ are protective in vitro by reducing MitoSOX, cell proliferation, and collagen expression.
Meanwhile, MitoQ treatment in vivo was not able to reverse the RV hypertrophy in either sex. However, it did improve the RV-pulmonary artery coupling and lower RV collagen deposition in the male SuHx rats. Taken together, this provides preliminary evidence that male SuHx rats are associated with worse PAH characteristics and that MitoQ could potentially offer therapeutic value for RV, but only in the male sex in PAH
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
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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