1,721,026 research outputs found
sGC modulators as cognitive enhancers: neuronal and/ or vascular?
No full textO1 Applying translational approaches for the nonclinical and clinical evaluation of the sGC stimulator CY6463 in CNS diseases Christopher J. Winrow Cyclerion Therapeutics, Cambridge Massachusetts, USA Correspondence: Christopher J. Winrow ([email protected]) J Transl Med 2022, 21(1):O1 Introduction: The NO-sGC-cGMP pathway plays a critical role in central nervous system (CNS) function and is impacted across a range of neurological and psychiatric diseases. NO is recognized as a key neu-rotransmitter that is produced on-demand within the CNS and can act through sGC and cGMP to govern a range of downstream effects. We have identified CY6463, a CNS-penetrant sGC stimulator, with demonstrated pharmacological effects in nonclinical and clinical studies. By acting as a selective positive allosteric modulator of sGC, CY6463 can amplify endogenous NO signaling while maintaining upstream spatial and temporal regulation. This enables the on-demand production of cGMP and propagation of downstream signals within the CNS. Methods: A range of nonclinical studies were conducted to understand the in vitro and in vivo properties of CY6463 and supported advancement into clinical development. Phase 1 clinical studies included single-ascending dose, multiple-ascending dose and food interaction studies along with a translational pharmacology study in healthy elderly participants. Results: This presentation will describe the nonclinical pharmacology of CY6463, along with clinical data from Phase 1 studies including the pharmacokinetic, safety, and pharmacodynamic results of our clinical translational pharmacology study in elderly participants. Furthermore, we will discuss our translational biomarker strategy that has been carried through into clinical studies in three separate patient populations and provide outlines of these clinical studies and updates on progress to date. Conclusions: Applying a translational biomarker based approach to the development of CY6463 has enabled advancement of clinical studies in well-defined patient populations to help understand the potential opportunity for modulating sGC function in neuropsychiatric and neurodegenerative diseases. Acknowledgements: CJW is an employee of Cyclerion Therapeutics and gratefully acknowledges the contributions of the Cyclerion team members and collaborators to this project. O2 sGC modulators as cognitive enhancers: neuronal and/ or vascular? Correspondence: Jos Prickaerts ([email protected]) J Transl Med 2022, 21(1):O2 Introduction: Cognitive impairment is one of the main symptoms of Alzheimer's disease or Vascular dementia, which negatively impacts the quality of life of patients. Therefore, a pharmacological intervention that has memory enhancing effects would be beneficial to patients. Vascular dementia is characterized by impairments in cer-ebral blood flow, endothelial function and blood-brain barrier integrity. These processes are all physiologically regulated by the soluble guanylate cyclase (sGC)-cGMP signaling pathway in blood vessel cells. Additionally, neuronal cGMP signaling plays an important role in long-term potentiation underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating neuronal-and/or vascular-based dementias. Methods: sGC stimulators acting on heme-bound sGC and one sGC activator acting on heme-free sGC were tested in the object location task (OLT) on acquisition memory processes, in healthy rodents and in deficit models. Vascular function and neuroplasticity were assessed.Funding was in part supported by a restricted grant from Bayer AG and Merck Sharp & Dohme Corp
sGC modulators as cognitive enhancers: neuronal and/ or vascular?
No full textO1 Applying translational approaches for the nonclinical and clinical evaluation of the sGC stimulator CY6463 in CNS diseases Christopher J. Winrow Cyclerion Therapeutics, Cambridge Massachusetts, USA Correspondence: Christopher J. Winrow ([email protected]) J Transl Med 2022, 21(1):O1 Introduction: The NO-sGC-cGMP pathway plays a critical role in central nervous system (CNS) function and is impacted across a range of neurological and psychiatric diseases. NO is recognized as a key neu-rotransmitter that is produced on-demand within the CNS and can act through sGC and cGMP to govern a range of downstream effects. We have identified CY6463, a CNS-penetrant sGC stimulator, with demonstrated pharmacological effects in nonclinical and clinical studies. By acting as a selective positive allosteric modulator of sGC, CY6463 can amplify endogenous NO signaling while maintaining upstream spatial and temporal regulation. This enables the on-demand production of cGMP and propagation of downstream signals within the CNS. Methods: A range of nonclinical studies were conducted to understand the in vitro and in vivo properties of CY6463 and supported advancement into clinical development. Phase 1 clinical studies included single-ascending dose, multiple-ascending dose and food interaction studies along with a translational pharmacology study in healthy elderly participants. Results: This presentation will describe the nonclinical pharmacology of CY6463, along with clinical data from Phase 1 studies including the pharmacokinetic, safety, and pharmacodynamic results of our clinical translational pharmacology study in elderly participants. Furthermore, we will discuss our translational biomarker strategy that has been carried through into clinical studies in three separate patient populations and provide outlines of these clinical studies and updates on progress to date. Conclusions: Applying a translational biomarker based approach to the development of CY6463 has enabled advancement of clinical studies in well-defined patient populations to help understand the potential opportunity for modulating sGC function in neuropsychiatric and neurodegenerative diseases. Acknowledgements: CJW is an employee of Cyclerion Therapeutics and gratefully acknowledges the contributions of the Cyclerion team members and collaborators to this project. O2 sGC modulators as cognitive enhancers: neuronal and/ or vascular? Correspondence: Jos Prickaerts ([email protected]) J Transl Med 2022, 21(1):O2 Introduction: Cognitive impairment is one of the main symptoms of Alzheimer's disease or Vascular dementia, which negatively impacts the quality of life of patients. Therefore, a pharmacological intervention that has memory enhancing effects would be beneficial to patients. Vascular dementia is characterized by impairments in cer-ebral blood flow, endothelial function and blood-brain barrier integrity. These processes are all physiologically regulated by the soluble guanylate cyclase (sGC)-cGMP signaling pathway in blood vessel cells. Additionally, neuronal cGMP signaling plays an important role in long-term potentiation underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating neuronal-and/or vascular-based dementias. Methods: sGC stimulators acting on heme-bound sGC and one sGC activator acting on heme-free sGC were tested in the object location task (OLT) on acquisition memory processes, in healthy rodents and in deficit models. Vascular function and neuroplasticity were assessed.Funding was in part supported by a restricted grant from Bayer AG and Merck Sharp & Dohme Corp
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
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
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
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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