1,720,970 research outputs found
Modulation of mitochondrial energy balance in health and disease
No full textMitochondria are highly dynamic organelles and their function is crucial for the maintenance of cellular homeostasis. Alterations in mitochondrial homeostasis has emerged as a hallmark of several diseases, like cancer and genetic disorders. Mitochondrial fitness and its energetic state can impact cell viability and proliferation, and its modulation via pharmacological tools can be used to treat several mitochondria-related diseases.
The potassium channel Kv1.3 is a voltage-gated potassium channel emerged as a novel oncological target. It is overexpressed in several tissues compared to normal ones, enhance cell proliferation, cell migration and metastasis. Direct inhibition of Kv1.3 using its known membrane-permeant inhibitor PAP-1 alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death. We generated two classes of PAP-1 derivatives in order to improve its effect. The first class comprises the mitochondria-targeted compounds PAPTP and PCARBTP. These molecules have a positively charged triphenyl-phosphonium group linked to the PAP-1 structure, so they can reach mitochondria in a more efficient way and can be used at lower concentrations compared to their precursor. We have demonstrated that these drugs selectively kill cancer cells in vitro, ex vivo and in vivo. The mechanism of selectivity involves both the overexpression of Kv1.3 and the high basal ROS level, present mainly in cancer cells. On the other hand, low, sub-lethal concentrations of PAPTP and PCARBTP cause a mild increase in mitochondrial ROS production, favoring cell survival and proliferation through the modulation of mitochondrial homeostasis. The second class of PAP-1 derivatives comprises the more soluble compounds PEGME and PTGME. Recapitulating the molecular mechanism of the mitochondria-targeted compounds, these more soluble derivatives act in vitro, ex vivo and in vivo. Moreover, PEGME and PTGME inhibited respiratory chain complex I (CI). To clarify this aspect, we revealed for the first time that mitoKv1.3 likely localizes in proximity of CI in the IMM, at the level of the supercomplexes.
To detect what else the new mitochondria-targeted derivatives of PAP-1 make inside cancer cells at sub-lethal concentrations, we investigated the effects of mitoKv1.3 inhibition on Wnt signaling. We demonstrated that the reduction of mitochondrial ATP due to the use of mitochondria-affecting drugs or to genetic dysfunction due to complex III (CIII) deficiency, decreases calcium uptake into the endoplasmic reticulum (ER), leading to ER stress and to impaired Wnt signaling. Importantly, both the recovery of ATP level or the inhibition of ER stress restored Wnt activity downregulated by mitochondria-affected compounds. This research revealed for the first time an unexpected mechanism related to the control of Wnt signaling by mitochondrial ATP, opening a new possibility to use compounds affecting mitochondrial homeostasis to fight tumors, or to use mitochondrial ATP-increasing drugs to ameliorate patients’ symptoms.
In the context of genetic dysfunction, we focused also on the use of the bacterial redox cycler to ameliorate CIII related disease. This redox cycler can mimic CIII activity, by accepting electrons from ubiquinol and reducing cytochrome c in vitro. We observed that sub-lethal doses of the drug recovers mitochondrial function both by increasing mitochondrial ATP production and by promoting mitohormesis, in vitro in CIII deficient cells from patients with CIII disease. Importantly, this redox cycler can increase also in vivo ATP production, and rescue respiration rate and locomotor ability in flies and zebrafish models of CIII deficiency. These results strongly suggest that the application of this drug in the sublethal concentration range might be a promising therapeutic tool against complex III diseases
Mitochondrial potassium channels in cell death
No full textMitochondria are intracellular organelles involved in several processes from bioenergetics to cell death. In the latest years, ion channels are arising as new possible targets in controlling several cellular functions. The discovery that several plasma membrane located ion channels have intracellular counterparts, has now implemented this consideration and the number of studies enforcing the understanding of their role in different metabolic pathways. In this review, we will discuss the recent updates in the field, focusing our attention on the involvement of potassium channels during mitochondrial mediated apoptotic cell death. Since mitochondria are one of the key organelles involved in this process, it is not surprising that potassium channels located in their inner membrane could be involved in modulating mitochondrial membrane potential, ROS production, and respiratory chain complexes functions. Eventually, these events lead to changes in the mitochondrial fitness that prelude to the cytochrome c release and apoptosis. In this scenario, both the inhibition and the activation of mitochondrial potassium channels could cause cell death, and their targeting could be a novel pharmacological way to treat different human diseases
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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