Hybrid computational models of multicellular tumour growth considering glucose metabolism

Cancer cells metabolize glucose through metabolic pathways that differ from those used by healthy and differentiated cells. In particular, tumours have been shown to consume more glucose than their healthy counterparts and to use anaerobic metabolic pathways, even under aerobic conditions. Nevertheless, scientists have still not been able to explain why cancer cells evolved to present an altered metabolism and what evolutionary advantage this might provide them. Experimental and computational models have been increasingly used in recent years to understand some of these biological questions. Multicellular tumour spheroids are effective experimental models as they replicate the initial stages of avascular solid tumour growth. Furthermore, these experiments generate data which can be used to calibrate and validate computational studies that aim to simulate tumour growth. Hybrid models are of particular relevance in this field of research because they model cells as individual agents while also incorporating continuum representations of the substances present in the surrounding microenvironment that may participate in intracellular metabolic networks as concentration or density distributions. Henceforth, in this review, we explore the potential of computational modelling to reveal the role of metabolic reprogramming in tumour growth

Neurorosettes: a novel computational modelling framework to investigate the Homer-Wright rosette formation in neuroblastoma

Cancer deregulates the interactions between cells and their microenvironment, leading to disrupted architectures. Homer-Wright rosettes, observed in neuroblastoma, comprise radial arrangements of neurons surrounding a meshwork of fibres. Currently, scientists believe that the presence of Homer-Wright rosettes reflects aberrant neuronal differentiation. Nonetheless, additional understanding of how these structures develop is required since neither experimental nor computational research has characterised this mechanism properly. In this work, we propose a mechanics-based computational framework to investigate Homer-Wright rosette formation. Our model depicts neurons as a combination of spherical (cell bodies) and cylindrical (neurites) agents, and it includes proliferation, neuronal differentiation, and adhesion/repulsion dynamics between neurons. We implemented our framework as an open-source user-friendly Python package called neurorosettes that provides real-time rendering of simulation results, making it adequate for general researchers to test and visualize hypotheses of Homer-Wright rosette formation. Furthermore, we present three example use-cases to replicate the emergence of this rosette subtype and investigate how mechanical interactions between neurons and neuronal differentiation may regulate its architecture. Due to the spare amount of experimental data on the formation of these histological patterns, our applications serve primarily as preliminary examples of how our tool can be used and extended. Although our preliminary results show the relevance of mechanical interactions and poor neuronal differentiation to Homer-Wright rosette formation, these factors appear to only predict the initial stages of rosette formation. Overall, our tool can improve the theoretical knowledge on this process and drive the design of new experimental studies to validate model results

Legionella pneumophila

Legionella pneumophila is an intracellular pathogen, ubiquitous in the environment and considered opportunistic. It is the leading cause of legionellosis, which can be present in its nonpneumonic form (Pontiac fever) and acute pneumonic form (Legionnaires` disease – LD). In the soil and aquatic systems, L. pneumophila can invade and survive intracellularly in various protozoans. The ability to proliferate within biofilms provides additional protection from environmental stresses, such as disinfection. Human infection by L. pneumophila occurs after the inhalation or aspiration of aerosols containing the pathogen. Upon infection, alveolar macrophages can be invaded and used by L. pneumophila for replication, resembling the infection of protozoan hosts in the environment. The ability of L. pneumophila to overcome the killing mechanisms of phagocytes depends on the Dot/Icm type IV secretion system – a specialized protein translocation system vital for the intracellular survival of the pathogen and for establishing a replicative niche known as the Legionella-containing vacuole. Following host cell lysis, the released bacteria infect other host cells, beginning a new cycle of infection.This work was financially supported by Base Funding – UIDB/00511/2020 of LEPABE and funded by national funds through the FCT/MCTES (PIDDAC); Project Biocide_for_Biofilm – PTDC/BII-BTI/30219/2017 – POCI-01-0145-FEDER-030219, pBio4.0 – POCI-01-0247-FEDER-033298, funded by FEDER funds through COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI) and by national funds (PIDDAC) through FCT/MCTES; Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit and BioTecNorte operation (NORTE 01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 – Programa Operacional Regional do Norte.info:eu-repo/semantics/publishedVersio

Development of products with Shiitake mushroom: chemical, physical and sensory characterization

Shiitake mushrooms are much appreciated and therefore their production has increased. However, an important quantity of by-products and residues, are also generated and which are considered as waste materials. In this way, the aim of this work was to develop new foods incorporating shiitake mushrooms that do not comply with standards for commercialization, thus providing additional sources of income for the farmers. For this, a filling with mushroom was produced for rissoles and pies, and the final products were analysed for their chemical composition, colour, texture and sensorial attributes. The results showed that the shiitake products presented an interesting chemical composition, rich in protein and minerals, and poor in salt. It was also observed that the frying operation induced more colour changes in the rissoles than the oven baking of the pies. The textural measurements indicated that the rissoles were much softer when compared to the pies, being also more cohesive and elastic. The sensory panel attributed high scores to both products (around 4.5, on a scale from 1 to 5), thus indicating that these may constitute an additional source of income to the farmers and at the same time reducing waste.info:eu-repo/semantics/publishedVersio

Synthesis, photophysical characterisation and photostability studies of NIR probes with aliphatic, aromatic and chlorinated terminals in 5- and 9-amino positions of benzo[a]phenoxazines

A new series of benzo[a]phenoxazinium chlorides possessing mono- or disubstituted amines with 3-chloropropyl groups at the 9-position, isopropyl, cyclohexyl and phenyl groups as terminals at 5-postion was synthesised. Photophysical studies were performed in dry ethanol and aqueous solutions. The terminals at the 5-amino position were found to influence the acid-base equilibrium. The presence of hydroxyl functionality at 2-position was found to introduce an additional basic form that is the one in equilibrium with the cationic acid form in dry ethanol solutions. The photostability of these compounds in different media was also investigated and a high resistance to photobleaching in model biological membranes was observed. In proteins a moderate of 20% photobleaching occurs in 1h 30min, while in water more than 60% of the compound molecules are photodegraded during the same time interval.Thanks are due to the Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to Research Centres CQ/UM [PEst-C/QUI/UI0686/2013 (FCOMP-01-0124-FEDER-037302)] and CFUM [PEst-C/FIS/UI0607/2013 (F-COMP-01-0124-FEDER-022711)]. Post-doctoral grant to B. R. Raju (SFRH/BPD/62881/2009) is also acknowledged to FCT, POPH-QREN, FSE

Benzo[a]phenoxazinium chlorides functionalized with chloride atoms and/or ester groups

Proceedings of the 19th Int. Electron. Conf. Synth. Org. Chem.With the aim of contributing to the development of fluorescent near-infrared (NIR) probes with applications in biomedicine, our research group is committed to the development of new water-soluble benzo[a]phenoxazine derivatives and the evaluation of their photophysical and biological potential. Herein we report the photophysical behaviour in anhydrous ethanol of four synthesised benzo[a]phenoxazinium chlorides, possessing the (3-chloropropyl)amino and/or (4-ethoxy-4- oxobutyl)amino groups at 5- and 9-positions of the polycyclic system.Thanks are due to the Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to the Research Centres CFUM [PEst-C/FIS/UI0607/2011 (F-COMP-01-0124-FEDER-022711)] and CQ/UM [PEstC/QUI/UI0686/2013(FCOMP-01-0124-FEDER-022716)]. A post-doctoral grant to B. R. Raju (SFRH/BPD/62881/2009) is also acknowledged to FCT, POPH-QREN, FSE.info:eu-repo/semantics/publishedVersio

New benzo[a]phenoxazines bearing the (4,6-dichloro-1,3,5-triazin-2-yl)amino group: synthesis and photophysical properties

Synthesis of new benzo[a]phenoxazinium chlorides possessing the (4,6-dichloro-1,3,5- triazin-2-yl)amino at 5-amino function of the heterocycles is described. The preliminary photophysical properties of these compounds in anhydrous ethanol when acidified with TFA or basified with TEAH is also investigated, as well as their response in aqueous media. These benzo[a]phenoxazinium chlorides exhibited fluorescence with maximum emission wavelengths between 628 and 676 nm, in anhydrous ethanol and water.Thanks are due to the Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to the Research Centres CFUM [PEst-C/FIS/UI0607/2011 (F-COMP-01-0124-FEDER-022711)] and CQ/UM [PEst-C/QUI/UI0686/2013(FCOMP-01-0124-FEDER-022716)]. A post-doctoral grant to B. R. Raju (SFRH/BPD/62881/2009) is also acknowledged to FCT, POPH-QREN, FSE.info:eu-repo/semantics/publishedVersio

Synthesis and photophysical studies of new benzo[a]phenoxazinium chlorides as potential antifungal agents

A set of four new benzo[a]phenoxazinium chlorides possessing ethyl, propyl, decyl and tetradecyl groups at the 9-amino function of the heterocycle along with a propyl group at the 5-amino position was efficiently synthesised. These compounds displayed fluorescence with maximum emission wavelengths of 673 and 685 nm, in anhydrous ethanol and water. All the benzo[a]phenoxazines were evaluated against the yeast Saccharomyces cerevisiae in a broth microdilution assay. It was found that their antifungal activity depended on the variation in the lengths of the aliphatic chains. The highest MIC activity of 1.56 µM was obtained for compound 7 comprising a di-alkylated propyl substituent at 9-amino position and a propyl chain at the 5-amino position of the heterocycle core.FEDER-COMPETE-QREN-EUFSEThanks are due to the Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to the Research Centres CFUM [PEst-C/FIS/UI0607/2011 (F-COMP-01-0124-FEDER-022711)] and CQ/UM [PEst-C/QUI/UI0686/2011 (FCOMP-01-0124-FEDER-022716)]. A post-doctoral grant to B. R. Raju (SFRH/BPD/62881/2009) is also acknowledged to FCT, POPH-QREN, FSE. This work was supported by the strategic programme UID/BIA/04050/2013 (POCI-01- 0145-FEDER-007569) funded by national funds through the FCT I.P. and by the ERDF through the COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI).ERDFPOPH-QRENCOMPETE202

Left atrial abnormal mechanics by speckle tracking as an early subclinical manifestation in patients with systemic sclerosis

© The European Society of Cardiology 2018. All rights reserved.Introduction: Heart involvement in systemic sclerosis (SSc) affects the prognosis of the disease when clinically evident. SSc may be associated with myocardial microvascular obstruction and micronecrosis is a presumible determinant of ventricular dysfunction, heart failure and sudden death. The aim of this study was to assess whether there were early changes of left atrial (LA) deformation by speckle tracking in patients with normal ejection fraction.info:eu-repo/semantics/publishedVersio

Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming

Funding Information: Funding. This research was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) (Ph.D. ProRegeM program, Ref: PD/BD/105893/2014; FCT individual Ph.D. fellowship Ref: 2020.06956.BD) and iNOVA4 Health (Project 4 and Project 21). iNOVA4Health-UID/Multi/04462/2013 is a program financially supported by Funda??o para a Ci?ncia e Tecnologia/ Minist?rio da Educa??o e Ci?ncia, through national funds. The authors would like to acknowledge the Instituto Portugu?s de Oncologia de Lisboa Francisco Gentil (IPOLFG) for partially funding the project. Publisher Copyright: © Copyright © 2021 Nunes, Ramos, Santos, Mendes, Silva, Vicente, Pereira, Félix, Gonçalves and Serpa.Among gynecologic malignancies, ovarian cancer is the third most prevalent and the most common cause of death, especially due to diagnosis at an advanced stage together with resistance to therapy. As a solid tumor grows, cancer cells in the microenvironment are exposed to regions of hypoxia, a selective pressure prompting tumor progression and chemoresistance. We have previously shown that cysteine contributes to the adaptation to this hypoxic microenvironment, but the mechanisms by which cysteine protects ovarian cancer cells from hypoxia-induced death are still to be unveiled. Herein, we hypothesized that cysteine contribution relies on cellular metabolism reprogramming and energy production, being cysteine itself a metabolic source. Our results strongly supported a role of xCT symporter in energy production that requires cysteine metabolism instead of hydrogen sulfide (H2S) per se. Cysteine degradation depends on the action of the H2S-synthesizing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and/or 3-mercaptopyruvate sulfurtransferase (MpST; together with cysteine aminotransferase, CAT). In normoxia, CBS and CSE inhibition had a mild impact on cysteine-sustained ATP production, pointing out the relevance of CAT + MpST pathway. However, in hypoxia, the concomitant inhibition of CBS and CSE had a stronger impact on ATP synthesis, thus also supporting a role of their hydrogen sulfide and/or cysteine persulfide-synthesizing activity in this stressful condition. However, the relative contributions of each of these enzymes (CBS/CSE/MpST) on cysteine-derived ATP synthesis under hypoxia remains unclear, due to the lack of specific inhibitors. Strikingly, NMR analysis strongly supported a role of cysteine in the whole cellular metabolism rewiring under hypoxia. Additionally, the use of cysteine to supply biosynthesis and bioenergetics was reinforced, bringing cysteine to the plateau of a main carbon sources in cancer. Collectively, this work supports that sulfur and carbon metabolism reprogramming underlies the adaptation to hypoxic microenvironment promoted by cysteine in ovarian cancer.publishersversionpublishe