Novel application assigned to toluquinol: inhibition of lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signalling pathway

BACKGROUND AND PURPOSE Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphoedema and other inflammatory disorders. The development of new drugs that block lymphangiogenesis has become a promising therapeutic strategy. In this study, we investigated the ability of toluquinol, a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004, to inhibit lymphangiogenesis in vitro, ex vivo and in vivo. EXPERIMENTAL APPROACH We used human lymphatic endothelial cells (LECs) to analyse the effect of toluquinol in 2D and 3D in vitro cultures and in the ex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, mouse ear sponges and cornea models were used. Western blotting and apoptosis analyses were carried out to search for drug targets. KEY RESULTS Toluquinol inhibited LEC proliferation,migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol induced apoptosis of LECs after 14 h of treatment in vitro, blocked the development of the thoracic duct in zebrafish and reduced the VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we demonstrated that this drug attenuates VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependentmanner and suppresses the phosphorylation of Akt and ERK1/2. CONCLUSIONS AND IMPLICATIONS Based on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment of lymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications in vascular ocular pathologies.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This work has been supported by personal funding by FP7-PEOPLE-2013-IEF Marie Curie Postdoctoral Fellowship (MGC). Acknowledged are the supporting grants from the Action de Recherche Concertée (ARC) (Université de Liège), the Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS), the Foundation Against Cancer (foundation of public interest), the Centre Anticancéreux près l’Université de Liège, the Fonds Léon Fredericq (University of Liège), the Interuniversity Attraction Poles Programme-Belgian Science Policy (all from Belgium) and the Plan National Cancer (« Service Public Federal » from Belgium). Research in the lab of A.R.Q. and M.A.M. was supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER)

Linear Invariant Systems Theory for Signal Enhancement

This paper discusses a linear time invariant (LTI) systems approach to signal enhancement via projective subspace techniques. It provides closed form expressions for the frequency response of data adaptive finite impulse response eigenfilters. An illustrative example using speech enhancement is also presented.Este artigo apresenta a aplicação da teoria de sistemas lineares invariantes no tempo (LTI) na análise de técnicas de sub-espaço. A resposta em frequência dos filtros resultantes da decomposição em valores singulares é obtida aplicando as propriedades dos sistemas LTI

"Guess what I'm doing": Extending legibility to sequential decision tasks

In this paper we investigate the notion of legibility in sequential decision tasks under uncertainty. Previous works that extend legibility to scenarios beyond robot motion either focus on deterministic settings or are computationally too expensive. Our proposed approach, dubbed PoL-MDP, is able to handle uncertainty while remaining computationally tractable. We establish the advantages of our approach against state-of-the-art approaches in several simulated scenarios of different complexity. We also showcase the use of our legible policies as demonstrations for an inverse reinforcement learning agent, establishing their superiority against the commonly used demonstrations based on the optimal policy. Finally, we assess the legibility of our computed policies through a user study where people are asked to infer the goal of a mobile robot following a legible policy by observing its actions

Situación y perspectivas de la truficultura en España

En este trabajo se presenta un panorama de la situación de la truficultura en España, desde sus comienzos en los años 50 a la actualidad, y sus perspectivas de futuro. Se destacan la actividad científica y técnica, desarrolladas en Centros de Investigación y Universidades españolas, en aspectos diversos: micorrización en vivero, certificación de planta micorrizada, ecología de la trufa, recuperación de truferas naturales, cultivo y seguimiento de plantaciones truferas, taxonomía química, control de las especies de trufa, reforestación y selvicultura trufera. Se aprecia un aumento en el apoyo que se le da al sector desde las Administraciones Públicas, tanto desde la perspectiva forestal, la agraria o la, ya indicada, de la investigación. Se aportan datos de produccion, precios, áreas de recogida, mercados, investigación, plantaciones truferas. Se da un breve resumen de las perspectivas del sector trufero en España. SUMMARY The objective of this work is to provide a overview of truffle cultivation in Spain from its beginnings in the 1950s to the present, and its prospects for the future. At the moment, truffle cultivation in Spain is a reality. There is a great deal of activity on the part of farmers as well as on the part of scientific researchers in universities and specialised centres who are investigating a wide range of aspects on the subject: mycorrhization in nurseries, mycorrhized plant certification, ecology, recuperation of wild truffle stands, monitoring of truffle plantations, chemical taxonomy, control of truffle species, and reforestation and truffle cultivation. A growing support for the truffle sector from the Public Administration can be observed, as much from the agrarian and forestry perspective as from the mentioned research perspective. Data on production, prices, collection areas, markets, publications, truffle plantations and research are given. Finally, we give a brief summary of future prospects for the truffle sector in Spain

Porphyria Cutanea Tarda in a Patient with Myelofibrosis

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Learning from Tradition: Vernacular Built Heritage of Madeira (Portugal), a Sustainable Proposal

The archipelago of Madeira (Portugal), of volcanic origin and situated in the intraplate region of the African plate, was formed during the Miocene and seats in a full oceanic domain. Since the settlement of the island (15th century), several destructive landslides have happened. In the Island of Madeira, housing is an important expression of the action of man over nature, thus creating a harmonious landscape between the built and its surroundings. In response to the accentuated Topography, terraced platforms appeared to soften this inclination. Vernacular building traditions are repeatedly cited in the academic literature as exemplary models of environmental practice. Therefore, research that addresses the vernacular traditions of the Island of Madeira may emphasize its potential for continuity and viability for maintenance and rehabilitation. Sustainability is indissolubly linked to vernacular architecture and the lessons learned from this architecture of the past can teach us which knowledge to apply in the future. The demand for sustainable buildings with minimal environmental impact is increasing, thus leading the construction industry to adopt new technologies for building design. Achieved for generations, this architecture shows us the art of a population in the construction. The rural housing of Madeira revealed itself as a wise design, where the masters of the craft created a perfect communion between the space, utility, comfort and the volumetric balance, thus creating a new artificial element that connects perfectly with the natural space. Passive strategies have been used around the world for centuries. In the last decades, inhabitants became dependent on mechanical systems with rising economic and environmental impacts. Learning from the past to understand how houses evolved to respond to the surrounding environment is important. The analysis of the local vernacular dwellings will provide insight into well-adapted popular solutions to deal with the local climatic conditions in order to promote responsive passive building technologies and a sustainable proposal is also presented.info:eu-repo/semantics/publishedVersio

Enhanced detection of tuberculous mycobacteria in animal tissues using a semi-nested probe-based real-time PCR

Bovine tuberculosis has been tackled for decades by costly eradication programs in most developed countries, involving the laboratory testing of tissue samples from allegedly infected animals for detection of Mycobacterium tuberculosis complex (MTC) members, namely Mycobacterium bovis. Definitive diagnosis is usually achieved by bacteriological culture, which may take up to 6-12 weeks, during which the suspect animal carcass and herd are under sanitary arrest. In this work, a user-friendly DNA extraction protocol adapted for tissues was coupled with an IS6110-targeted semi-nested duplex real-time PCR assay to enhance the direct detection of MTC bacteria in animal specimens, reducing the time to achieve a diagnosis and, thus, potentially limiting the herd restriction period. The duplex use of a novel β-actin gene targeted probe, with complementary targets in most mammals, allowed the assessment of amplification inhibitors in the tissue samples. The assay was evaluated with a group of 128 fresh tissue specimens collected from bovines, wild boars, deer and foxes. Mycobacterium bovis was cultured from 57 of these samples. Overall, the full test performance corresponds to a diagnostic sensitivity and specificity of 98.2% (CIP95% 89.4-99.9%) and 88.7% (CIP95% 78.5-94.7%), respectively. An observed kappa coefficient was estimated in 0.859 (CI P95% 0.771-0.948) for the overall agreement between the semi-nested PCR assay and the bacteriological culture. Considering only bovine samples (n = 69), the diagnostic sensitivity and specificity were estimated in 100% (CI P95% 84.0-100%) and 97.7% (CIP95% 86.2-99.9%), respectively. Eight negative culture samples exhibiting TB-like lesions were detected by the semi-nested real-time PCR, thus emphasizing the increased potential of this molecular approach to detect MTC-infected animal tissues. This novel IS6110-targeted assay allows the fast detection of tuberculous mycobacteria in animal specimens with very high sensitivity and specificity, being amenable and cost effective for use in the routine veterinary diagnostic laboratory with further automation possibilities.publishersversionpublishe

Human gingival fibroblasts response to different endodontic sealers: an in vitro study

Endodontic treatment aims to eliminate infection of the root canals and fill the dental pulp space. The biocompatibility studies of the sealers used in root canals obturation are crucial since they are applied in direct contact with periradicular tissues. Objective: The aim of this study was to evaluate the cytotoxicity of three root canal sealers—AH Plus, Bio MTA+, and Bio C sealer—on immortalized human gingival fibroblasts. Methods: AH Plus, Bio MTA+, and Bio C sealers were evaluated through incubation in real-time and material-conditioned media. Cells were incubated for 24 h and 72 h, at three different concentrations (1, 10, and 100 mg/mL) of each sealer. The cytotoxic activity of the sealers was assessed by Methyl tetrazolium (MTT) and Sulforhodamine B (SRB) assays. Cell morphology and cytogenetic alterations were studied microscopically. Results: MTT and SRB assays revealed similar results within both approaches. Cell culture exposed to sealers through incubation in real-time revealed a cytotoxic effect of AH Plus at 100 mg/mL. Material- conditioned media study revealed a cytotoxic effect of Bio MTA+ and Bio C, increasing with higher compound concentration and reaching 50% with 100 mg/mL. Regarding the cell’s morphology, Bio C sealer revealed a decrease in cell confluence and several morphological changes. AH Plus and Bio MTA+ did not seem to affect the cell confluence however morphology alterations were observed. In the cytogenetic study, a severe decrease of the mitotic index and a large number of chromosomal aberrations were observed. The present study represents an advance in the understanding of the biocompatibility of AH Plus, Bio MTA+, and Bio C sealers. These sealers demonstrated some cytotoxicity, depending on the concentration used. Although more validation studies are still needed, this study brings very relevant results in terms of cytotoxicity, cell morphology, and cytogenetic alterations. Conclusions: These results could help in the selection of the most appropriate compounds to be used in clinical practice as well as to determine the maximum recommended amounts of each sealer. Clinical Relevance: This study highlights the potential cytotoxic effects of three commonly used root canal sealers on human gingival fibroblasts, with varying degrees of impact depending on the concentration used. The results emphasize the importance of careful consideration when selecting and applying these materials in clinical practice.info:eu-repo/semantics/publishedVersio