1,721,108 research outputs found
Exploiting Chemical Modulation of Mitochondrial Dynamics during Melanogenesis
No full textMitochondria participate in many intracellular processes: they are known for ATP production, but also for their roles in controlling lipid metabolism, calcium cation homeostasis, metabolism, and apoptosis. To handle all these functions, they are characterized by a particular structure that dynamically changes in response to cell needs. Interactions with other organelles play a role in adaptation to intracellular changes.
In particular, the interaction between mitochondria and endoplasmic reticulum, called MERCs, has been recognized as a fundamental player in several signaling pathways, as Ca2+ transfer, phospholipid synthesis and exchange, mitochondrial fission and unfolded protein response (UPR). Consequently, MERCs impairment contributes to many diseases, such as neurodegenerative disorders, insulin resistance, and cancer. Considering this evidence, MERCs start to be considered as possible pharmacological targets. The molecules able to change the distance between the two organelles (chemical MERCs modulators) can exert their action through different mechanisms.
Aim of this work was to identify some chemical MERCs modulators and define their mechanisms of action. We performed a chemical compound screen based on high content imaging to study mitochondrial dynamics. After validation, our approach revealed five molecules able to change MERCs independently from the mitochondrial morphology.
In parallel, we developed a methodology for high throughput quantification of mitochondrial membrane potential in 2D and 3D models using the TMRM dye. By combining automated image analysis and machine learning we were able to distinguish melanoma cells from macrophages in co-culture, and to analyze the subpopulations separately. We also applied this approach to human fibroblasts, neural stem cells, spheroids, and isolated muscle fibers.
Then, we decided to apply our knowledge to a process whose molecular mechanisms are still unclear: melanogenesis, the process of melanin synthesis. Melanogenesis occurs in lysosome-related organelles called melanosomes, present within cells of the epidermis called melanocytes. Melanin is a biopolymer with pleiotropic roles in the cell, ranging from UV light photoprotection to ion chelation and ROS modulation.
Considering melanogenesis as a protective cell response from stress factors, and the pivotal role of MERCs during the stress response, we hypothesized that the interplay between mitochondria and endoplasmic reticulum could contribute to melanogenesis as well. We observed that extrinsic factors, like UV, inducing melanogenesis impact also on mitochondrial dynamics. To study melanogenesis we also designed a high throughput approach to analyze several properties of melanosomes, such as their number, intensity and morphological parameters.
In summary, this work contributes to the development of several methodologies for the study of mitochondrial biology (e.g., functionality, morphology, MERCs, interactions with melanosomes), but also new knowledge on the molecular pathways and on the pharmacology that regulate MERCs. Moreover, it also provides for the first time an analysis of the crosstalk between melanogenesis and mitochondria dynamics
Study of the Photoinduced Fate of Selected Contaminants in Surface Waters by HPLC‐HRMS
Full text linkRationale: Photoinduced transformation of contaminants of emerging concern (CECs) can occur in aquatic environment and could lead to the formation of transformation products (TPs) of greater concern than the parent compounds. For such, the fate of epoxiconazole, hymecromone, and coumarin in water was investigated by simulating photoinduced abiotic transformations to assess the toxicity of their TPs and which CEC may be of greatest concern. Methods: Heterogeneous photocatalysis with TiO2 and direct photolysis of selected CECs were exploited to simulate their TPs. The TPs were assessed by means of HPLC coupled with an Orbitrap MS analyser in ESI positive mode, while their toxicity was evaluated through a Vibrio fischeri bioluminescence assay, and ECOSAR tool. Results: The formation of numerous TPs via different photoinduced pathways was noticed (27 for epoxiconazole, 6 for coumarin, and 8 for hymecromone, some of which are in the form of structural isomers). Toxicity assessment via V. fischeri assay showed that, unlike coumarin species, epoxiconazole transformation proceeds through the formation of toxic compounds. By means of ECOSAR software, the formation of predominant more noxious TPs of epoxiconazole was proved than the parent compound for both acute and chronic toxicities. Instead, most TPs of coumarin and hymecromone generally exhibited "harmful" and "toxic" levels of acute and chronic toxicities. Conclusions: A probable structural identification was assigned to the monitored TPs via HPLC-HRMS to recognize the several transformation pathways, of which the hydroxylation reaction was predominant, and which compound may be more hazardous in the aquatic system due to its TPs. Epoxiconazole transformation brought to potentially toxic TPs, whereas photoinduced degradation of coumarin and hymecromone resulted in less hazardous TPs. The most significant aspect of this work is the ability of this overall approach to identify the formation of photoinduced TPs that are potentially more toxic than the original CEC
Antiarrhythmic efficacy of anakinra in a young patient with autoimmune lymphocytic myocarditis
No full textIL-1 inhibition with anakinra suppressed ventricular arrhythmias refractory to conventional therapies in severe myocarditis
Mass spectrometric fragmentation and photocatalytic transformation of nicotine and cotinine
No full textRATIONALE: Nicotine and cotinine are, respectively, alkaloids produced mainly by the Solanaceae plant family, especially tobacco, and its most important human metabolite. These compounds are frequently found as contaminants in wastewater or landfill samples and they could be used to evaluate pollution by tobacco use. The aim of this study is to improve the knowledge about possible transformation pathways of nicotine and cotinine. This would help the identification of degradants by using HPLC coupled with a high resolving power mass analyzer (LTQ-Orbitrap). In addition, we evaluated toxicity on bioluminescent photobacteria to indicate possible relationships between the formation of transformation products and their toxic effects.METHODS: The transformation of nicotine and cotinine and the formation of intermediate products were evaluated adopting titanium dioxide as photocatalyst. The structural identification of photocatalytic transformation products of these two alkaloids was based on LC/multistage MS experiments. High-resolution MS allowed the elemental composition of these products to be hypothesized. The evolution of toxicity as a function of the irradiation time was also studied using a bioluminescent photobacterium (Vibrio fischeri) test.RESULTS: Several products were formed and characterized using HPLC/HRMSn. The main photocatalytic pathways involving nicotine and cotinine appear to be hydroxylation, demethylation and oxidation. Nine degradants were formed from nicotine, including cotinine. Seven degradants were generated from cotinine. There is no transformation product in common between the two studied molecules.CONCLUSIONS: The study of photocatalytic degradation allowed us to partially simulate human metabolism and the environmental transformation of the bioactive alkaloid nicotine. We searched for some of the identified transformation products in river water and landfill percolate by solid-phase extraction and HPLC/HRMS and eventually their presence was confirmed. These new findings could be of interest in further metabolism and environmental pollution studies. Copyright (C) 2016 John Wiley & Sons, Ltd
Rapid high performance liquid chromatography-high resolution mass spectrometry methodology for multiple prenol lipids analysis in zebrafish embryos
No full text
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
Biologics for eosinophilic granulomatosis with polyangiitis
No full textPurpose of review: The link between severe asthma and eosinophilic granulomatosis with polyangiitis (EGPA) in terms of pathophysiological background, clinical manifestations and disease evolution has leaded to investigate the relevance of anti T2 monoclonal antibodies licensed for severe asthma patients as a treatment option for EGPA. The present review aimed to provide un update on EGPA pathophysiology and to critically summarize the most robust evidence coming from trials and real-life setting on the use of anti T2 biologics in EGPA patients. Recent findings: Mepolizumab, an anti-interleukin-5 monoclonal antibody, is the only biologic drug targeting eosinophilic inflammation currently approved for EGPA treatment at the dose of 300 mg/4 weeks. Its use is restricted by the American College of Rheumatology guidelines to specific diseases phases and severity grades. However the most appropriate mepolizumab positioning and dose is still under investigation in the real life practice, which is providing an increasing amount of evidence confirming its efficacy, alone or in combination with other options in different disease stages. The relevance of other monoclonal antibodies interfering with T2 inflammation, including omalizumab and benralizumab, is under investigation but the evidence is still scarce. Summary: Taking into account the suboptimal medium-long term safety profile of conventional EGPA treatments, the opportunity of selectively targeting eosinophilic inflammation certainly represents a revolutionary approach. However, further real-word evidence is required to effectively position the new treatments in the light of the disease complexity, including different immunological drivers, and individual variability
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
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