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2020
Mendes, MJ.  2020.  Colloidal lithography for transparent electronics and light trapping in thin film flexible solar cells, 3-4 Nov.. Encontro Ciência 2020. , Lisbon, Portugal: Fundação para a Ciência e a Tecnologia
Almeida, APC, Oliveira J, Fernandes SN, Godinho MH, Canejo JP.  2020.  All-cellulose composite membranes for oil microdroplet collection, 2020. 27(8):4665-4677. AbstractWebsite

Oil spills on ocean waters represent a major threat to marine ecosystems. A significant part of the spilled oil is dispersed in microdroplets that are not recovered by traditional oil-removing methods. In this work, we report on the manufacture of cellulose acetate (CA) electrospun non-woven membranes, stamped with different cellulose nanocrystal (CNC) patterns. We demonstrate the use of the membranes produced as selective oil microdroplets removal from water emulsions with an efficiency up to 80%. Screenprinting was used to imprint different CNC designs on the CA surface membranes. To promote the adhesion between the CNCs and the CNCs with the CA fibers the membrane was subjected to a thermal and chemical treatments. Oil droplets were collected under water in the oleophilic CNC pattern while the water could flow through the hydrophilic CA electrospun non-woven membrane.

Kordestani, N, Rudbari HA, Fernandes AR, Raposo LR, Baptista PV, Ferreira D, Bruno G, Bella G, Scopelliti R, Braun JD, Herbert DE, Blacque O.  2020.  Antiproliferative Activities of Diimine-Based Mixed Ligand Copper(II) Complexes, 2020. ACS Comb Sci. 22(2):89-99. AbstractWebsite

A series of Cu(diimine)(X-sal)(NO3) complexes, where the diimine is either 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen) and X-sal is a monoanionic halogenated salicylaldehyde (X = Cl, Br, I, or H), have been synthesized and characterized by elemental analysis and X-ray crystallography. Penta-coordinate geometries copper(II) were observed for all cases. The influence of the diimine coligands and different halogen atoms on the antiproliferative activities toward human cancer cell lines have been investigated. All Cu(II) complexes were able to induce a loss of A2780 ovarian carcinoma cell viability, with phen derivatives more active than bpy derivatives. In contrast, no in vitro antiproliferative effects were observed against the HCT116 colorectal cancer cell line. These cytotoxicity differences were not due to a different intracellular concentration of the complexes determined by inductively coupled plasma atomic emission spectroscopy. A small effect of different halogen substituents on the phenolic ring was observed, with X = Cl being the most highly active toward A2780 cells among the phen derivatives, while X = Br presented the lowest IC50 in A2780 cells for bpy analogs. Importantly, no reduction in normal primary fibroblasts cell viability was observed in the presence of bpy derivatives (IC50 > 40 muM). Mechanistically, complex 1 seems to induce a stronger apoptotic response with a higher increase in mitochondrial membrane depolarization and an increased level of intracellular reactive oxygen species (ROS) compared to complex 3. Together, these data and the low IC50 compared to cisplatin in A2780 ovarian carcinoma cell line demonstrate the potential of these bpy derivatives for further in vivo studies.

Portela, PC, Dantas JM, Salgueiro CA.  2020.  Backbone, side chain and heme resonance assignment of the triheme cytochrome PpcA from Geobacter metallireducens in the oxidized state, 2020. Biomol NMR Assign. 14(1):31-36. AbstractWebsite

The bacterium Geobacter metallireducens is capable of transferring electrons to the cell exterior, a process designated extracellular electron transfer. This mechanism allows the microorganism to reduce extracellular acceptors such as Fe(III) (hydr)oxides and water toxic and/or radioactive contaminants including Cr(VI) and U(VI). It is also capable of oxidizing waste water aromatic organic compounds being an important microorganism for bioremediation of polluted waters. Extracellular electron transfer also allows electricity harvesting from microbial fuel cells, a promising sustainable form of energy production. However, extracellular electron transfer processes in this microorganism are still poorly characterized. The triheme c-type cytochrome PpcA from G. metallireducens is abundant in the periplasm and is crucial for electron transfer between the cytoplasm and the cell’s exterior. In this work, we report near complete assignment of backbone, side chain and heme resonances for PpcA in the oxidized state that will permit its structure determination and identification of interactions with physiological redox partners.

Ferreira, P, Cerqueira NSMFA, Fernandes PA, Romão MJ, Ramos MJ.  2020.  Catalytic Mechanism of Human Aldehyde Oxidase, 2020. ACS CatalysisACS Catalysis. 10(16):9276-9286.: American Chemical Society AbstractWebsite

The mechanism of oxidation of N-heterocycle phthalazine to phthalazin-1(2H)-one and its associated free energy profile, catalyzed by human aldehyde oxidase (hAOX1), was studied in atomistic detail using QM/MM methodologies. The studied reaction was found to involve three sequential steps: (i) protonation of the substrate’s N2 atom by Lys893, (ii) nucleophilic attack of the hydroxyl group of the molybdenum cofactor (Moco) to the substrate, and (iii) hydride transfer from the substrate to the sulfur atom of the Moco. The free energy profile that was calculated revealed that the rate-limiting step corresponds to hydride transfer. It was also found that Lys893 plays a relevant role in the reaction, being important not only for the anchorage of the substrate close to the Moco, but also in the catalytic reaction. The variations of the oxidation state of the molybdenum ion throughout the catalytic cycle were examined too. We found out that during the displacement of the products away from the Moco, the transfer of electrons from the catalytic site to the FAD site was proton-coupled. As a consequence, the most favorable and fastest pathway for the enzyme to complete its catalytic cycle was that with MoV and a deprotonated SH ligand of the Moco with the FAD molecule converted to its semiquinone form, FADH•.The mechanism of oxidation of N-heterocycle phthalazine to phthalazin-1(2H)-one and its associated free energy profile, catalyzed by human aldehyde oxidase (hAOX1), was studied in atomistic detail using QM/MM methodologies. The studied reaction was found to involve three sequential steps: (i) protonation of the substrate’s N2 atom by Lys893, (ii) nucleophilic attack of the hydroxyl group of the molybdenum cofactor (Moco) to the substrate, and (iii) hydride transfer from the substrate to the sulfur atom of the Moco. The free energy profile that was calculated revealed that the rate-limiting step corresponds to hydride transfer. It was also found that Lys893 plays a relevant role in the reaction, being important not only for the anchorage of the substrate close to the Moco, but also in the catalytic reaction. The variations of the oxidation state of the molybdenum ion throughout the catalytic cycle were examined too. We found out that during the displacement of the products away from the Moco, the transfer of electrons from the catalytic site to the FAD site was proton-coupled. As a consequence, the most favorable and fastest pathway for the enzyme to complete its catalytic cycle was that with MoV and a deprotonated SH ligand of the Moco with the FAD molecule converted to its semiquinone form, FADH•.

Terao, M, Garattini E, Romão MJ, Leimkühler S.  2020.  Evolution, expression, and substrate specificities of aldehyde oxidase enzymes in eukaryotes, 2020. Journal of Biological ChemistryJournal of Biological Chemistry. 295(16):5377-5389.: Elsevier AbstractWebsite

Aldehyde oxidases (AOXs) are a small group of enzymes belonging to the larger family of molybdo-flavoenzymes, along with the well-characterized xanthine oxidoreductase. The two major types of reactions that are catalyzed by AOXs are the hydroxylation of heterocycles and the oxidation of aldehydes to their corresponding carboxylic acids. Different animal species have different complements of AOX genes. The two extremes are represented in humans and rodents; whereas the human genome contains a single active gene (AOX1), those of rodents, such as mice, are endowed with four genes (Aox1-4), clustering on the same chromosome, each encoding a functionally distinct AOX enzyme. It still remains enigmatic why some species have numerous AOX enzymes, whereas others harbor only one functional enzyme. At present, little is known about the physiological relevance of AOX enzymes in humans and their additional forms in other mammals. These enzymes are expressed in the liver and play an important role in the metabolisms of drugs and other xenobiotics. In this review, we discuss the expression, tissue-specific roles, and substrate specificities of the different mammalian AOX enzymes and highlight insights into their physiological roles.Aldehyde oxidases (AOXs) are a small group of enzymes belonging to the larger family of molybdo-flavoenzymes, along with the well-characterized xanthine oxidoreductase. The two major types of reactions that are catalyzed by AOXs are the hydroxylation of heterocycles and the oxidation of aldehydes to their corresponding carboxylic acids. Different animal species have different complements of AOX genes. The two extremes are represented in humans and rodents; whereas the human genome contains a single active gene (AOX1), those of rodents, such as mice, are endowed with four genes (Aox1-4), clustering on the same chromosome, each encoding a functionally distinct AOX enzyme. It still remains enigmatic why some species have numerous AOX enzymes, whereas others harbor only one functional enzyme. At present, little is known about the physiological relevance of AOX enzymes in humans and their additional forms in other mammals. These enzymes are expressed in the liver and play an important role in the metabolisms of drugs and other xenobiotics. In this review, we discuss the expression, tissue-specific roles, and substrate specificities of the different mammalian AOX enzymes and highlight insights into their physiological roles.

Oliveira, B, Veigas B, Fernandes AR, Aguas H, Martins R, Fortunato E, Baptista PV.  2020.  Fast Prototyping Microfluidics: Integrating Droplet Digital Lamp for Absolute Quantification of Cancer Biomarkers, 2020. Sensors (Basel). 20(6) AbstractWebsite

Microfluidic (MF) advancements have been leveraged toward the development of state-of-the-art platforms for molecular diagnostics, where isothermal amplification schemes allow for further simplification of DNA detection and quantification protocols. The MF integration with loop-mediated isothermal amplification (LAMP) is today the focus of a new generation of chip-based devices for molecular detection, aiming at fast and automated nucleic acid analysis. Here, we combined MF with droplet digital LAMP (ddLAMP) on an all-in-one device that allows for droplet generation, target amplification, and absolute quantification. This multilayer 3D chip was developed in less than 30 minutes by using a low-cost and extremely adaptable production process that exploits direct laser writing technology in "Shrinky-dinks" polystyrene sheets. ddLAMP and target quantification were performed directly on-chip, showing a high correlation between target concentration and positive droplet score. We validated this integrated chip via the amplification of targets ranging from five to 500,000 copies/reaction. Furthermore, on-chip amplification was performed in a 10 microL volume, attaining a limit of detection of five copies/microL under 60 min. This technology was applied to quantify a cancer biomarker, c-MYC, but it can be further extended to any other disease biomarker.

Germano, GCM, Machado YDR, Martinho L, Fernandes SN, Costa AMLM, Pecoraro E, Gomes ASL, Carvalho ICS.  2020.  Flexible random lasers in dye-doped bio-degradable cellulose nanocrystalline needles, 2020. Journal of the Optical Society of America BJournal of the Optical Society of America B. 37(1):24-29.: OSA AbstractWebsite

In this work, we developed and investigated a random laser based on rhodamine6G (Rh6G) in ethylene glycol (EG) solution with varying cellulose nanocrystalline (CNC) needles as scatterers in the lasing media. Besides the suspension-in-cuvette scheme, an alternative configuration was also employed: a dye-CNC flexible self-supported thick-film (70 µm) random laser made by drop casting of the ${\rm CNCs}+{\rm Rh6G}+{\rm hydroxypropyl}$CNCs+Rh6G+hydroxypropyl cellulose suspension. In relation to conventional scatterers, the biodegradable cellulose nanocompounds showed a comparable reduction in both the spectral full width at half-maximum and the energy threshold values, with an optimal concentration of 5 mg [CNC]/ml[EG] in suspension. Its performance was also compared with other cellulose-based random lasers, presenting advantages for some parameters. The flexible film configuration showed similar results, but contained 10% less Rh6G than the suspension.

Vidossich, P, Castañeda Moreno LE, Mota C, de Sanctis D, Miscione GP, De Vivo M.  2020.  Functional Implications of Second-Shell Basic Residues for dUTPase DR2231 Enzymatic Specificity, 2020. ACS CatalysisACS Catalysis. 10(23):13825-13833.: American Chemical Society AbstractWebsite

Nucleotide-processing enzymes are key players in biological processes. They often operate through high substrate specificity for catalysis. How such specificity is achieved is unclear. Here, we dealt with this question by investigating all-α dimeric deoxyuridine triphosphate nucleotidohydrolases (dUTPases). Typically, these dUTPases hydrolyze either dUTP or deoxyuridine diphosphate (dUDP) substrates. However, the dUTPase enzyme DR2231 from Deinococcus radiodurans selectively hydrolyzes dUTP only, and not dUDP. By means of extended classical molecular dynamics simulations and quantum chemical calculations, we show that DR2231 achieves this specificity for dUTP via second-shell basic residues that, together with the two catalytic magnesium ions, contribute to properly orienting the γ-phosphate of dUTP in a prereactive state. This allows a nucleophilic water to be correctly placed and activated in order to perform substrate hydrolysis. We show that this enzymatic mechanism is not viable when dUDP is bound to DR2231. Importantly, in several other dUTPases capable of hydrolyzing either dUTP or dUDP, we detected that active site second-shell basic residues are more in number, anchoring the β-phosphate of the nucleotide substrate too, in contrast to what is observed in DR2231. Thus, strategically located basic second-shell residues mediate precise reactant positioning at the catalytic site, determining substrate specificity in dUTPases and possibly in other structurally similar nucleotide-processing metalloenzymes.Nucleotide-processing enzymes are key players in biological processes. They often operate through high substrate specificity for catalysis. How such specificity is achieved is unclear. Here, we dealt with this question by investigating all-α dimeric deoxyuridine triphosphate nucleotidohydrolases (dUTPases). Typically, these dUTPases hydrolyze either dUTP or deoxyuridine diphosphate (dUDP) substrates. However, the dUTPase enzyme DR2231 from Deinococcus radiodurans selectively hydrolyzes dUTP only, and not dUDP. By means of extended classical molecular dynamics simulations and quantum chemical calculations, we show that DR2231 achieves this specificity for dUTP via second-shell basic residues that, together with the two catalytic magnesium ions, contribute to properly orienting the γ-phosphate of dUTP in a prereactive state. This allows a nucleophilic water to be correctly placed and activated in order to perform substrate hydrolysis. We show that this enzymatic mechanism is not viable when dUDP is bound to DR2231. Importantly, in several other dUTPases capable of hydrolyzing either dUTP or dUDP, we detected that active site second-shell basic residues are more in number, anchoring the β-phosphate of the nucleotide substrate too, in contrast to what is observed in DR2231. Thus, strategically located basic second-shell residues mediate precise reactant positioning at the catalytic site, determining substrate specificity in dUTPases and possibly in other structurally similar nucleotide-processing metalloenzymes.

Roma-Rodrigues, C, Rivas-Garcia L, Baptista PV, Fernandes AR.  2020.  Gene Therapy in Cancer Treatment: Why Go Nano?, 2020 Pharmaceutics. 12(3) AbstractWebsite

The proposal of gene therapy to tackle cancer development has been instrumental for the development of novel approaches and strategies to fight this disease, but the efficacy of the proposed strategies has still fallen short of delivering the full potential of gene therapy in the clinic. Despite the plethora of gene modulation approaches, e.g., gene silencing, antisense therapy, RNA interference, gene and genome editing, finding a way to efficiently deliver these effectors to the desired cell and tissue has been a challenge. Nanomedicine has put forward several innovative platforms to overcome this obstacle. Most of these platforms rely on the application of nanoscale structures, with particular focus on nanoparticles. Herein, we review the current trends on the use of nanoparticles designed for cancer gene therapy, including inorganic, organic, or biological (e.g., exosomes) variants, in clinical development and their progress towards clinical applications.

Ferreira, D, Fontinha D, Martins C, Pires D, Fernandes AR, Baptista PV.  2020.  Gold Nanoparticles for Vectorization of Nucleic Acids for Cancer Therapeutics, 2020. Molecules. 25(15) AbstractWebsite

Cancer remains a complex medical challenge and one of the leading causes of death worldwide. Nanomedicines have been proposed as innovative platforms to tackle these complex diseases, where the combination of several treatment strategies might enhance therapy success. Among these nanomedicines, nanoparticle mediated delivery of nucleic acids has been put forward as key instrument to modulate gene expression, be it targeted gene silencing, interference RNA mechanisms and/or gene edition. These novel delivery systems have strongly relied on nanoparticles and, in particular, gold nanoparticles (AuNPs) have paved the way for efficient delivery systems due to the possibility to fine-tune their size, shape and surface properties, coupled to the ease of functionalization with different biomolecules. Herein, we shall address the different molecular tools for modulation of expression of oncogenes and tumor suppressor genes and discuss the state-of-the-art of AuNP functionalization for nucleic acid delivery both in vitro and in vivo models. Furthermore, we shall highlight the clinical applications of these spherical AuNP based conjugates for gene delivery, current challenges, and future perspectives in nanomedicine.

Roma-Rodrigues, C, Pombo I, Fernandes AR, Baptista PV.  2020.  Hyperthermia Induced by Gold Nanoparticles and Visible Light Photothermy Combined with Chemotherapy to Tackle Doxorubicin Sensitive and Resistant Colorectal Tumor 3D Spheroids, 2020. Int J Mol Sci. 21(21) AbstractWebsite

Current cancer therapies are frequently ineffective and associated with severe side effects and with acquired cancer drug resistance. The development of effective therapies has been hampered by poor correlations between pre-clinical and clinical outcomes. Cancer cell-derived spheroids are three-dimensional (3D) structures that mimic layers of tumors in terms of oxygen and nutrient and drug resistance gradients. Gold nanoparticles (AuNP) are promising therapeutic agents which permit diminishing the emergence of secondary effects and increase therapeutic efficacy. In this work, 3D spheroids of Doxorubicin (Dox)-sensitive and -resistant colorectal carcinoma cell lines (HCT116 and HCT116-DoxR, respectively) were used to infer the potential of the combination of chemotherapy and Au-nanoparticle photothermy in the visible (green laser of 532 nm) to tackle drug resistance in cancer cells. Cell viability analysis of 3D tumor spheroids suggested that AuNPs induce cell death in the deeper layers of spheroids, further potentiated by laser irradiation. The penetration of Dox and earlier spheroid disaggregation is potentiated in combinatorial therapy with Dox, AuNP functionalized with polyethylene glycol (AuNP@PEG) and irradiation. The time point of Dox administration and irradiation showed to be important for spheroids destabilization. In HCT116-sensitive spheroids, pre-irradiation induced earlier disintegration of the 3D structure, while in HCT116 Dox-resistant spheroids, the loss of spheroid stability occurred almost instantly in post-irradiated spheroids, even with lower Dox concentrations. These results point towards the application of new strategies for cancer therapeutics, reducing side effects and resistance acquisition.

Fernandes, AR, Mendonça-Martins I, Santos MFA, Raposo LR, Mendes R, Marques J, Romão CC, Romão MJ, Santos-Silva T, Baptista PV.  2020.  Improving the Anti-inflammatory Response via Gold Nanoparticle Vectorization of CO-Releasing Molecules, 2020. ACS Biomaterials Science & EngineeringACS Biomaterials Science & Engineering. 6(2):1090-1101.: American Chemical Society AbstractWebsite

CO-releasing molecules (CORMs) have been widely studied for their anti-inflammatory, antiapoptotic, and antiproliferative effects. CORM-3 is a water-soluble Ru-based metal carbonyl complex, which metallates serum proteins and readily releases CO in biological media. In this work, we evaluated the anti-inflammatory and wound-healing effects of gold nanoparticles–CORM-3 conjugates, AuNPs@PEG@BSA·Ru(CO)x, exploring its use as an efficient CO carrier. Our results suggest that the nanoformulation was capable of inducing a more pronounced cell effect, at the anti-inflammatory level and a faster tissue repair, probably derived from a rapid cell uptake of the nanoformulation that results in the increase of CO inside the cell.CO-releasing molecules (CORMs) have been widely studied for their anti-inflammatory, antiapoptotic, and antiproliferative effects. CORM-3 is a water-soluble Ru-based metal carbonyl complex, which metallates serum proteins and readily releases CO in biological media. In this work, we evaluated the anti-inflammatory and wound-healing effects of gold nanoparticles–CORM-3 conjugates, AuNPs@PEG@BSA·Ru(CO)x, exploring its use as an efficient CO carrier. Our results suggest that the nanoformulation was capable of inducing a more pronounced cell effect, at the anti-inflammatory level and a faster tissue repair, probably derived from a rapid cell uptake of the nanoformulation that results in the increase of CO inside the cell.

Fernandes, AR, Mendonça-Martins I, Santos MFA, Raposo LR, Mendes R, Marques J, Romão CC, Romão MJ, Santos-Silva T, Baptista PV.  2020.  Improving the Anti-inflammatory Response via Gold Nanoparticle Vectorization of CO-Releasing Molecules, 2020. ACS Biomaterials Science & Engineering. 6(2):1090-1101. AbstractWebsite
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Choroba, K, Raposo LR, Palion-Gazda J, Malicka E, Erfurt K, Machura B, Fernandes AR.  2020.  In vitro antiproliferative effect of vanadium complexes bearing 8-hydroxyquinoline-based ligands - the substituent effect, 2020. Dalton Trans. 49(20):6596-6606. AbstractWebsite

This is the first comprehensive study demonstrating the antiproliferative effect of vanadium complexes bearing 8-hydroxyquinoline (quinH) ligands, including the parent and -CH3 (Me), -NO2, -Cl and -I substituted ligands, on HCT116 and A2780 cancer cell lines. To determine the structure-cytotoxicity relationships seven six-coordinate oxovanadium(v) complexes [VO(OMe)(5,7-(Me)2-quin)2] (1), [VO(OMe)(5,7-Cl2-quin)2] (2), [VO(OMe)(5,7-Cl,I-quin)2] (3), [VO(OMe)(5,7-I2-quin)2] (4), [VO(OMe)(5-NO2-quin)2] (5), [VO(OMe)(5-Cl-quin)2] (6), and [VO(OMe)(quin)2] (7) were investigated. The cytotoxicity of 8-hydroxyquinoline oxovanadium(v) complexes is higher in the A2780 cell line (lower IC50) than that observed for the widely used chemotherapeutic agent, cisplatin, while displaying low cytotoxicity for normal human primary fibroblasts. Substituents introduced into the 8-hydroxyquinoline backbone reduced the antiproliferative effect of the vanadium complexes, and the complexes with the ligand substituted only in the 5 position (5 and 6) were more cytotoxic than those with substituents in the 5,7 positions of the quin backbone (1-4). Depending on the substituent type, the cytotoxicity of 1-4 followed the trend: -Cl > -CH3 > -I. Incubation of A2780 cancer cells with IC50 concentrations of complexes 5, 6 and 7 promoted cellular detachment, possibly through membrane destabilization, and triggered apoptosis and necrosis. ROS production might be responsible for the cell death mechanism observed particularly in the A2780 cells exposed to complexes 5 and 6.

Beola, L, Asin L, Roma-Rodrigues C, Fernandez-Afonso Y, Fratila RM, Serantes D, Ruta S, Chantrell RW, Fernandes AR, Baptista PV, de la Fuente JM, Grazu V, Gutierrez L.  2020.  The Intracellular Number of Magnetic Nanoparticles Modulates the Apoptotic Death Pathway after Magnetic Hyperthermia Treatment, 2020. ACS Appl Mater Interfaces. 12(39):43474-43487. AbstractWebsite

Magnetic hyperthermia is a cancer treatment based on the exposure of magnetic nanoparticles to an alternating magnetic field in order to generate local heat. In this work, 3D cell culture models were prepared to observe the effect that a different number of internalized particles had on the mechanisms of cell death triggered upon the magnetic hyperthermia treatment. Macrophages were selected by their high capacity to uptake nanoparticles. Intracellular nanoparticle concentrations up to 7.5 pg Fe/cell were measured both by elemental analysis and magnetic characterization techniques. Cell viability after the magnetic hyperthermia treatment was decreased to <25% for intracellular iron contents above 1 pg per cell. Theoretical calculations of the intracellular thermal effects that occurred during the alternating magnetic field application indicated a very low increase in the global cell temperature. Different apoptotic routes were triggered depending on the number of internalized particles. At low intracellular magnetic nanoparticle amounts (below 1 pg Fe/cell), the intrinsic route was the main mechanism to induce apoptosis, as observed by the high Bax/Bcl-2 mRNA ratio and low caspase-8 activity. In contrast, at higher concentrations of internalized magnetic nanoparticles (1-7.5 pg Fe/cell), the extrinsic route was observed through the increased activity of caspase-8. Nevertheless, both mechanisms may coexist at intermediate iron concentrations. Knowledge on the different mechanisms of cell death triggered after the magnetic hyperthermia treatment is fundamental to understand the biological events activated by this procedure and their role in its effectiveness.

Grey, P, Fernandes SN, Gaspar D, Deuermeier J, Martins R, Fortunato E, Godinho MH, Pereira L.  2020.  Ionically Modified Cellulose Nanocrystal Self-Assembled Films with a Mesoporous Twisted Superstructure: Polarizability and Application in Ion-Gated Transistors, 2020. ACS Applied Electronic MaterialsACS Applied Electronic Materials. 2(2):426-436.: American Chemical Society AbstractWebsite
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Vale, TM, Leitão J, Preguiça N, Rodrigues R, Dias RJ, Lourenço JM.  2020.  Lazy State Determination: More Concurrency for Contending Linearizable Transactions, 2020. , Lisboa: FCT-NOVAvl20_-_lsd.pdf
Amendoeira, A, García LR, Fernandes AR, Baptista PV.  2020.  Light Irradiation of Gold Nanoparticles Toward Advanced Cancer Therapeutics, 2020. 3(1):1900153. AbstractWebsite

Abstract Cancer is one of the leading causes of death in the world. To challenge this epidemic, there are growing demands for the development of new advanced and targeted therapeutics capable of effectively tackling cancer cells with improved selectivity. Nanomedicine has put forward several innovative therapeutics toward improving therapeutic efficacy while decreasing the deleterious side effects of current chemotherapy. Multifunctional gold nanoparticles (AuNPs) have been at the core of a plethora of advanced therapeutic strategies that provide selective targeting with their unique optical properties, capable to interact with the light of specific wavelength to deliver therapy with tremendous spatiotemporal precision. AuNPs have been exploited as photodynamic and photothermal therapeutic agents alone or in combination with other cancer treatment modalities with other cancer applications. Due to their exceptional physicochemical properties, they have been proven efficacious allies for photodynamic therapy and for photothermal therapy regimens. Herein, the rapidly progressing literature related to the use of these promising strategies against cancer is discussed, highlighting their possible future clinical translation.

dos Santos, R, Iria I, Manuel AM, Leandro AP, Madeira CAC, Goncalves J, Carvalho AL, Roque AC.  2020.  Magnetic Precipitation: A New Platform for Protein Purification, 2020. Biotechnology JournalBiotechnology Journal. n/a(n/a):2000151.: John Wiley & Sons, Ltd AbstractWebsite

One of the trends in downstream processing comprises the use of ?anything-but-chromatography? methods to overcome the current downfalls of standard packed-bed chromatography. Precipitation and magnetic separation are two techniques already proven to accomplish protein purification from complex media, yet never used in synergy. With the aim to capture antibodies directly from crude extracts, a new approach combining precipitation and magnetic separation was developed and named as affinity magnetic precipitation. A precipitation screening, based on the Hofmeister series, and a commercial precipitation kit were tested with affinity magnetic particles to assess the best condition for antibody capture from human serum plasma and clarified cell supernatant. The best conditions were obtained when using PEG3350 as precipitant at 4°C for 1h, reaching 80% purity and 50% recovery of polyclonal antibodies from plasma, and 99% purity with 97% recovery yield of anti-TNFα mAb from cell supernatants. These results show that the synergetic use of precipitation and magnetic separation can represent an alternative for the efficient capture of antibodies. This article is protected by copyright. All rights reserved

Leisico, F, Godinho LM, Gonçalves IC, Silva SP, Carneiro B, Romão MJ, Santos-Silva T, de Sá-Nogueira I.  2020.  Multitask ATPases (NBDs) of bacterial ABC importers type I and their interspecies exchangeability, 2020. 10(1):19564. AbstractWebsite

ATP-binding cassette (ABC) type I importers are widespread in bacteria and play a crucial role in its survival and pathogenesis. They share the same modular architecture comprising two intracellular nucleotide-binding domains (NBDs), two transmembrane domains (TMDs) and a substrate-binding protein. The NBDs bind and hydrolyze ATP, thereby generating conformational changes that are coupled to the TMDs and lead to substrate translocation. A group of multitask NBDs that are able to serve as the cellular motor for multiple sugar importers was recently discovered. To understand why some ABC importers share energy-coupling components, we used the MsmX ATPase from Bacillus subtilis as a model for biological and structural studies. Here we report the first examples of functional hybrid interspecies ABC type I importers in which the NBDs could be exchanged. Furthermore, the first crystal structure of an assigned multitask NBD provides a framework to understand the molecular basis of the broader specificity of interaction with the TMDs.

Restani, RB, Pires RF, Baptista PV, Fernandes AR, Casimiro T, Bonifácio VDB, Aguiar-Ricardo A.  2020.  Nano-in-Micro Sildenafil Dry Powder Formulations for the Treatment of Pulmonary Arterial Hypertension Disorders: The Synergic Effect of POxylated Polyurea Dendrimers, PLGA, and Cholesterol, 2020. 37(6):1900447. AbstractWebsite

Abstract POXylated polyurea dendrimer nanoparticles (PUREG4OOx48) are loaded with sildenafil (SDF) by a supercritical carbon dioxide–assisted (scCO2) impregnation. Further supercritical CO2-assisted spray drying (SASD) leads to hybrid nano-in-micro dry powder formulations that are investigated aiming at efficient pulmonary delivery of SDF in pulmonary arterial hypertension treatment. This is the first report of the production of poly(D,L-lactide-co-glycolide)-cholesterol (PLGA-Chol) microparticles processed by SASD. The optimized formulation of nano-in-microparticles is composed of PLGA, Chol, and PUREG4OOx48, loaded with SDF solutions in a 77:23 ratio (PLGA-Chol:dendrimer, w/w). The dry powders are fully characterized and found to be highly biodegradable and biocompatible, and the SDF release profile evaluates under different pH values. The median mass average diameter (MMAD) of the nano-in-micro systems varies between 2.57 and 5 µm and the fine particle fraction (FPF) between 36% and 29% for PUREG4OMeOx48[PLGA-Chol] and PUREG4OEtOx48[PLGA-Chol], respectively. The data validate the potential use of these new formulations in inhalation therapy. In vitro studies are also carried out in order to evaluate the effect of the free drug in cell viability and formulations cytotoxicity.

Machado, JF, Sequeira D, Marques F, Piedade MFM, Villa de Brito MJ, Helena Garcia M, Fernandes AR, Morais TS.  2020.  New copper(I) complexes selective for prostate cancer cells, 2020. Dalton Trans. 49(35):12273-12286. AbstractWebsite

A new family of eighteen Cu(i) complexes of the general formula [Cu(PP)(LL)][BF4], where PP is a phosphane ligand and LL represents an N,O-heteroaromatic bidentate ligand, has been synthesized and fully characterized by classical analytical and spectroscopic methods. Five complexes of this series were also characterized by single crystal X-ray diffraction studies. The cytotoxicity of all compounds was evaluated in breast (MCF7) and prostate (LNCap) human cancer cells and in a normal prostate cell line (RWPE). In general, all compounds showed higher cytotoxicity for the prostate cancer cells than for the breast cells, with IC50 values in the range 0.2-2 muM after 24 h of treatment. The most cytotoxic compound, [Cu(dppe)(2-ap)][BF4] (16), where dppe = 1,2-bis(diphenylphosphano) ethane and 2-ap = 2-acetylpyridine, showed a high level of cellular internalization, generation of intracellular ROS and activation of the cell death mechanism via apoptosis/necrosis. Owing to its high cytotoxic activity for LNCap cells, being 70-fold higher than that for normal prostate cells (RWPE), complex (16) was found to be the most promising for further research in prostate cancer models.

Trindade, AC, Carreto M, Helgesen G, Knudsen KD, Puchtler F, Breu J, Fernandes S, Godinho MH, Fossum JO.  2020.  Photonic composite materials from cellulose nanorods and clay nanolayers, 2020. 229(17):2741-2755. AbstractWebsite

Cellulose nano crystals (CNCs) are promising materials for energy efficient buildings related to the control of reflectivity and heat absorption/reflection of light. In this sense it is important to improve CNCs films fire retardant properties, which can be achieved by adding clays. Cellulose nanocrystals (CNCs) and nanolayers obtained from Sodium Fluorohectorite (NaFh) synthetic clay are both known to form liquid crystalline phases in aqueous suspensions. CNCs form cholesteric phases, which structure is preserved after water evaporation, while dry NaFh nanolayers aligned films collapse. In this initial work, it is shown that CNCs are compatible with NaFh clay. We demonstrate that the liquid crystalline phase of CNCs in water is not destroyed by the presence of NaFh nanolayers. The NaFh nanolayers act as planar anchoring surfaces to the cellulose nanorods and, after evaporation of the water coloured films are obtained. The precursor solutions and the photonic films were investigated by Describe several techniques.

Chagas, R, Silva PES, Fernandes SN, Žumer S, Godinho MH.  2020.  Playing the blues, the greens and the reds with cellulose-based structural colours, 2020. Faraday Discussions. 223:247-260.: The Royal Society of Chemistry AbstractWebsite

Structural vivid colours can arise from the interference of light reflected from structures exhibiting periodicity on scales in the range of visible wavelengths. This effect is observed with light reflected from cell-walls of some plants and exoskeletons of certain insects. Sometimes the colour sequence observed for these structures consists of nearly circular concentric rings that vary in colour from Red, Orange, Yellow, Green, Cyan to Blue, from the periphery to the centre, similarly to the colour scheme sequence observed for the rainbow (ROYGB). The sequence of colours has been found for solid films obtained from droplets of aqueous cellulose nanocrystals (CNCs) suspensions and attributed to a “coffee ring” effect. In this work, coloured lyotropic solutions and solid films obtained from a cellulose derivative in the presence of trifluoroacetic acid (TFA), which acts as a “reactive solvent”, are revisited. The systems were investigated with spectroscopy, using circularly and linearly polarised light, coupled with a polarised optical microscope (POM) and scanning electron microscopy (SEM). The lyotropic cholesteric liquid crystalline solutions were confined in capillaries to simplify 1D molecular diffusion along the capillary where an unexpected sequence of the structural colours was observed. The development and reappearance of the sequence of vivid colours seem consistent with the reaction–diffusion of the “reactive solvent” in the presence of the cellulosic chains. The strong TFA acts as an auto-catalyst for the chemical reaction between TFA and the hydroxyl groups, existing along the cellulosic chain, and diffuses to the top and bottom along the capillaries, carrying dissolved cellulosic chains. Uncovering the precise mechanism of colour sequence and evolution over time in cellulosic lyotropic solutions has important implications for future optical/sensors applications and for the understanding of the development of cellulose-based structures in nature.

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