1,720,972 research outputs found
Multifaceted roles of prokineticins and prokineticin receptors
No full textMore than two decades of research on the prokineticin system show that prokineticins (PKs) are involved in several physiological processes such as angiogenesis, neurogenesis, nociception, regulation of the circadian cycle, and reproduction by acting as angiogenic, anorectic and proinflammatory cytokines, hormones, and neuropeptides. Therefore, mutations, dysfunctions or dysregulations of PKs and their cognate receptors (PKRs) may be involved in various pathologies and trigger disease progression or promote their cure, depending on the pathological insults.
After reviewing the current knowledge on the functions of the PK system in health and disease and evidencing the promising effects of PKR non-peptide ligands in various preclinical models, in the present thesis I have highlighted the multifaceted roles of PK2 and PKRs in diseases with a strong neuroinflammatory component such as Parkinson’s disease (PD) and post-COVID-19 olfactory dysfunction (OD) as well as in cancer suggesting the potential of PK2 and PKRs as biomarkers and/or novel therapeutic targets in humans.
We investigated the dynamics of PK2 pathway, at both the mRNA and protein levels, in olfactory neurons of PD patients at different disease stages and determined the relationship between PK2 upregulation and clinicopathological features of PD. In particular, the increase in PK2 levels in early disease stages and in accordance with the severity of motor symptoms and the accumulation of α-synuclein suggests that PK2 is neuroprotective in PD where it may serve as both disease biomarker and novel therapeutic target. In addition, we also examined the expression profile of Substance P (SP), a neurotransmitter whose role in PD and olfaction has been extensively described by previous studies. We found a correlation between olfactory neuronal SP and gastrointestinal dysfunction in PD, confirming the reliability of olfactory neurons as a model to study PD progression.
Since both PK system and SP have been described as factors involved in olfaction pathophysiology, we evaluated their alterations in olfactory neurons of patients with post-COVID-19 OD compared to healthy controls. We found a significant upregulation of PK2 and, due to the role of PK2/PKR2 in driving the formation of olfactory bulb, we hypothesised that PK2 supports the recovery of the sense of smell following post-COVID-19 OD. In contrast, persistent activation of SP appears to maintain inflammation and contribute to olfactory impairment, counteracting the functions of PK2. These data highlight for the first time the promising role of PKR agonists as a disease-modifying therapy in both PD and post-COVID-19 OD.
Finally, we have developed an heterocellular spheroid model of human breast cancer that resemble in vivo tumour organisation to investigate the response of the cancer to doxorubicin (Dox) treatment and to explore the mechanisms involved in both the development of chemoresistance and the efficacy of the drug. We were able to show that hypoxia plays a central role in Dox resistance, while the increase in reactive oxygen species (ROS) is responsible for the achievement of Dox therapeutic effects. Furthermore, we found a direct correlation between ROS and PK2 levels, suggesting the upregulation of PK2 as a potential biomarker for Dox efficacy (pharmacodynamic biomarker).
However, despite these promising results that I have reported here, more detailed characterisation of the dynamics of the PK2 pathway in humans is required to validate its clinical value
Management to optimize organ procurement in brain dead donors
No full textThe demand for donor organs continues to exceed the number of organs available for transplantation. Many reasons may account for this discrepancy, such as the lack of consent, the absence of an experienced coordinator team able to solve logistical problems, the use of strict donor criteria, and suboptimal, unstandardized critical care management of potential organ donors. This has resulted in efforts to improve the medical care delivered to potential organ donors, so as to reduce organ shortages, improve organ procurement, and promote graft survival. The physiological changes that follow brain death entail a high incidence of complications jeopardizing potentially transplantable organs. Adverse events include cardiovascular changes, endocrine and metabolic disturbances, and disruption of internal homeostasis. Brain death also upregulates the release of pro-inflammatory molecules. Recent findings support the hypothesis that a preclinical lung injury characterized by an enhanced inflammatory response is present in potential donors and may predispose recipients to an adverse clinical prognosis following lung transplantation. In clinical practice, hypotension, diabetes insipidus, relative hypothermia, and natremia are more common than disseminated intravascular coagulation, cardiac arrhythmias, pulmonary oedema, acute lung injury, and metabolic acidosis. Strategies for the management of organ donors exist and consist of the normalization of donor physiology. Management has been complicated by the recent use of ''marginal'' donors and donors of advanced age or with ''extended'' criteria. Current guidelines suggest that the priority of critical care management for potential organ donors should be shifted from a ''cerebral protective'' strategy to a multimodal strategy aimed to preserve peripheral organ function
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
The balance of concentration between Prokineticin 2β and Prokineticin 2 modulates the food intake by STAT3 signaling
Full text linkThe secreted bioactive peptide prokineticin 2 (PK2) is a potent adipokine and its central and peripheral administration reduces food intake in rodents. The pk2 gene has two splice variants, PK2 and PK2L (PK2 long form), which is cleaved into an active peptide, PK2β, that preferentially binds prokineticin receptor 1 (PKR1). We investigated the role of PK2β in the regulation of food intake. We demonstrated that intraperitoneal injection of PK2β, in contrast to PK2, did not reduce food intake in mice. Exposure of hypotalamic explants to PK2, but not PK2β, induced phosphorylation of STAT3 and ERK. We also evidenced that in adipocytes from PKR1 knock-out mice, a model of obesity, there were higher PK2β levels than PK2 inducing a decreased activation of STAT3 and ERK. Our results suggest that variations in PK2 and PK2β levels, due to modulation of pk2 gene splicing processes, affect food intake in mice
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
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