1,720,963 research outputs found
Boosting NAD+ pathways to counteract Doxorubicin-induced cardiotoxicity
No full textCancer and cardiovascular diseases are among the main causes of death worldwide. Very powerful drugs have been developed in order to cure cancers, and among them we find anthracyclines, which include Doxorubicin (DOX). However, this chemotherapeutic has important side effects, which limit its usage. DOX’s most prevalent side effect is cardiotoxicity; thus, many efforts have been made to find drugs and therapeutic approaches to counteract it.
NAD+ is a fundamental coenzyme for the cell, both as a redox co-substrate and as a substrate for enzymes regulating different cellular processes, like post-translational modifications, epigenetic regulation, and so on. NAD+ levels are often decreased in pathologies and during aging, making their restoration a potential strategy to reverse these phenomena. This could be done either by decreasing its consumption, limiting the activity of the aforementioned enzymes, or by boosting its synthesis, by feeding precursors or analogues.
LGD SARL is interested in NAD+ boosting approaches to counteract different pathologies, including DOX-induced cardiotoxicity. They have already published that a physiological NAD+ precursor, Nicotinamide Mononucleotide (NMN), is able to counteract Doxorubicin-induced mortality, body weight loss, and cardiotoxicity in mice. Recently, they have become interested in another NAD+-related molecule, whose name and structure cannot be disclosed (called hereafter undisclosed compound, U.C.). Preliminary data in the DOX-induced cardiotoxicity mouse model show that this molecule exerted beneficial biological effects, comparable to those of NMN (which has consequently been used as a positive control).
This project aimed to characterize the mechanism of action of U.C., using in vivo and in vitro models and by finding potential U.C. interactors.
The first step was characterizing the mechanism underlying the cardioprotection observed in DOX-induced cardiotoxicity in vivo model. Therefore, we measured the levels of NAD+ and its related metabolites in blood, heart and kidneys collected from U.C.- or vehicle-treated animals exposed to DOX. While NMN co-treatment with DOX was able to increase the levels of NAD+ and of its downstream products, N1-Methyl-2-pyridone-5-carboxamide (2PY) and 1-MethylNicotinamide (1-MeNam), reversing the effects of DOX on these metabolites, U.C. co-treatment did not lead to such effects, suggesting a mechanism of action distinct from that of NMN. However, U.C. caused an increase in the levels of ATP and non-significant tendency toward restoring cyclic ADPR (cADPR) levels, suggesting a possible involvement of calcium signaling, which was not observed in NMN-treated animals. In the heart, kidneys and blood of animals treated with U.C. and DOX, a side product of U.C. (called U.C.+1) was formed, which could support U.C.’s mechanism of action.
The second aim was to mimic the effects observed in vivo in a cellular system, where we could study a higher number of parameters. We were able to recapitulate these effects in a primary murine cardiomyocyte cell line (mNVCM) treated with DOX, where we found that U.C. reversed the increase in Malondialdehyde (MDA), an oxidative stress biomarker. This suggests that U.C. is not just involved in NAD+ pathways, but also in protection from oxidative stress. Treatment of these cells with DOX and U.C.+1, instead of U.C. itself, showed similar effects, suggesting that it could indeed mediate U.C.’s observed effects. This was further supported in a primary cardiac fibroblast cell line, that massively produced the downstream product rapidly after U.C.’s administration, rather than raising levels of any of the NAD+-pathway classical metabolites.
Lastly, we focused on potential U.C.’s interactors, to determine which pathways could be activated after its administration. U.C. is not a substrate or modulator of several NAD+-related enzymes (NMNAT, CD38, SARM-1), as determined on the recombinant form of these enzymes (for NMNAT and SARM-1) or on a cell line (HUVECs) overexpressing CD38.
To deepen our understanding of U.C.’s mechanism of action, we administered it to DOX- and H2O2-treated murine myoblasts (C2C12 cell line), which is a non-cardiac muscle cell model. U.C. was not effective in counteracting DOX effects on these cells but successfully prevented H2O2 induced mortality. Thus, these results confirm the involvement of U.C. in protection against oxidative stress, consistently with the decreased levels of MDA measured in mNVCM upon U.C. treatment.
Altogether, U.C. appears to modulate cellular energetic and oxidative stress responses independently of NAD+ biosynthesis, potentially involving calcium-related signaling pathways, although the molecular mediator remains unidentified. These findings could provide fundamental insights into the prevention of DOX-induced cardiotoxicity
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
Diffusivity of E. coli -like microswimmers in confined geometries: the role of the tumbling rate
No full textWe analyzed the effect of confinement on the effective diffusion of a run-and-tumble E. coli-like flagellated microswimmer. We used a simulation protocol where the run phases are obtained via a fully resolved swimming problem, i.e., Stokes equations for the fluid coupled with rigid-body dynamics for the microorganism, while tumbles and collisions with the walls are modeled as random reorientation of the microswimmer. For weak confinement, the swimmer is trapped in circular orbits close to the solid walls. In this case, optimal diffusivity is observed when the tumbling frequency is comparable with the angular velocity of the stable orbits. For strong confinement, stable circular orbits disappear and the diffusion coefficient monotonically decreases with the tumbling rate. Our findings are generic and can be potentially applied to other natural or artificial chiral microswimmers that follow circular trajectories close to an interface or in confined geometries
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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