Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors.

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase required for normal development and maintenance of neurons of the central and peripheral nervous systems. Deregulation of RET and hyperactivity of the RET kinase is intimately connected to several types of human cancers, most notably thyroid cancers, making it an attractive therapeutic target for small-molecule kinase inhibitors. Novel approaches, allowing external control of the activity of RET, would be key additions to the signal transduction toolbox. In this work, photoswitchable RET kinase inhibitors based on azo-functionalized pyrazolopyrimidines were developed, enabling photonic control of RET activity. The most promising compound displays excellent switching properties and stability with good inhibitory effect towards RET in cell-free as well as live-cell assays and a significant difference in inhibitory activity between its two photoisomeric forms. As the first reported photoswitchable small-molecule kinase inhibitor, we consider the herein presented effector to be a significant step forward in the development of tools for kinase signal transduction studies with spatiotemporal control over inhibitor concentration in situ

Synthesis and G-Quadruplex-Binding Properties of Defined Acridine Oligomers

The synthesis of oligomers containing two or three acridine units linked through 2-aminoethylglycine using solid-phase methodology is described. Subsequent studies on cell viability showed that these compounds are not cytotoxic. Binding to several DNA structures was studied by competitive dialysis, which showed a clear affinity for DNA sequences that form G-quadruplexes and parallel triplexes. The fluorescence spectra of acridine oligomers were affected strongly upon binding to DNA. These spectral changes were used to calculate the binding constants (K). Log K were found to be in the order of 4–6

ADMINISTRACIÓN PÚBLICA, CONSTITUCIÓN ESPAÑOLA Y PORTUGUESA Y DERECHOS FUNDAMENTALES EN LA PENÍNSULA IBÉRICA

RESUMEN La característica esencial de un Estado de Derecho es el sometimiento de los diferentes poderes públicos al imperio de la ley. Por ello, tanto el poder ejecutivo, como el legislativo y el judicial están sometidos a la ley. Aún así no son los únicos, puesto que los ciudadanos y la propia Administración Pública no son ajenos a ello y también están obligados a cumplir la ley. El propio término Estado de Derecho lleva implícito el de derechos fundamentales, pues sin ellos, no podríamos hablar de Estado de Derecho. PALABRAS CLAVE: Estado; Derechos Fundamentales; Derecho Administrativo; Derecho Constitucional; Gobierno; Derecho Público.  ABSTRACT The essential characteristic of a State of Right is the submission of the different public powers to the empire of the law. Thus, so much the executive power, as the legislative and the judicial are submitted to the law. Still like this are not the only, since the citizen and the proper Public Administration aren’t extraneous to this and also are forced to fulfill the law. The proper term Been of Right carries implicit the one of fundamental rights, so without them, couldn’t speak of State of Right. KEYWORDS: State; Fundamental Rights; Administrative Law; Constitutional Law; Govern; Public Law. RESUMOA característica essencial de um Estado de Direito é a submissão dos diferentes poderes públicos ao estado de direito. Portanto, ambos os poderes executivo, legislativo e judiciário estão sujeitos à lei. Mesmo assim, não são os únicos, pois os cidadãos e a própria Administração Pública não são alheios a isso e também são obrigados a cumprir a lei. O termo "Estado de Direito" em si implica o dos direitos fundamentais, porque sem eles, não poderíamos falar do Estado de Direito.PALAVRAS-CHAVE: Estado; Direitos fundamentais; Direito Administrativo; Direito Constitucional; Governo; Direito Público.

Administração pública, Constituição Espanhola e Portuguesa e direitos fundamentais da Península Ibérica

La característica esencial de un Estado de Derecho es el sometimiento de los diferentes poderes públicos al imperio de la ley. Por ello, tanto el poder ejecutivo, como el legislativo y el judicial están sometidos a la ley. Aún así no son los únicos, puesto que los ciudadanos y la propia Administración Pública no son ajenos a ello y también están obligados a cumplir la ley. El propio término Estado de Derecho lleva implícito el de derechos fundamentales, pues sin ellos, no podríamos hablar de Estado de Derecho.The essential characteristic of a State of Right is the submission of the different public powers to the empire of the law. Thus, so much the executive power, as the legislative and the judicial are submitted to the law. Still like this are not the only, since the citizen and the proper Public Administration aren’t extraneous to this and also are forced to fulfill the law. The proper term Been of Right carries implicit the one of fundamental rights, so without them, couldn’t speak of State of Right.A característica essencial de um Estado de Direito é a submissão dos diferentes poderes públicos ao estado de direito. Portanto, ambos os poderes executivo, legislativo e judiciário estão sujeitos à lei. Mesmo assim, não são os únicos, pois os cidadãos e a própria Administração Pública não são alheios a isso e também são obrigados a cumprir a lei. O termo "Estado de Direito" em si implica o dos direitos fundamentais, porque sem eles, não poderíamos falar do Estado de Direito.info:eu-repo/semantics/publishedVersio

Specific loop modifications of the thrombin-binding aptamer trigger the formation of parallel structures

Guanine-rich sequences show large structural variability, with folds ranging from duplex to triplex and quadruplex helices. Quadruplexes are polymorphic, and can show multiple stoichiometries, parallel and antiparallel strand alignments, and different topological arrangements. We analyze here the equilibrium between intramolecular antiparallel and intermolecular parallel G-quadruplexes in the thrombin-binding aptamer (TBA) sequence. Our theoretical and experimental studies demonstrate that an apparently simple modification at the loops of TBA induces a large change in the monomeric antiparallel structure of TBA to yield a parallel G-quadruplex showing a novel T-tetrad. The present results illustrate the extreme polymorphism of G-quadruplexes and the ease with which their conformation in solution can be manipulated by nucleotide modification.This work was supported by the Spanish Ministry of Science and Innovation, MICINN (CTQ2010-20541, CTQ2012-38616, BIO2009-10964 and Consolider E-Science), the Generalitat de Catalunya, (2009/SGR/208), the University of Milano (PUR 2009 Funds), the funds de la Recherche ScientifiqueFNRS (VG research associate position and FRFC grant 2.4528.11) and PRIN09 (2009Prot- 2009J54YAP_005). RF is a recipient of a FPI predoctoral contract (MICINN) and a STSM from COST (G4net, MP0802). GP is a recipient of a Sara Borrell postdoctoral fellowship. Collaborative research was funded by a Cost action (G4net, MP0802) and an Italian-Spanish collaborative action (IT2009-0067). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Peer reviewe

Effect of nacl replacement by other salts on the quality of bísaro pork sausages (Pgi chouriça de vinhais)

Concerned about the trend to reduce salt consumption, the meat industry has been increasing the strategies to produce and commercialize products where the reduction or even the replacement of NaCl is an important goal. The aim of this study was to test the effect of partial NaCl replacement by KCl and Sub4Salt® on the quality of pork sausages. Three different formulations (NaCl + KCl, NaCl + Sub4Salt®, and KCl + Sub4Salt®) were considered and compared to the control (2% NaCl). Physicochemical properties, chemical composition, and microbiological and sensory characteristics were evaluated. The replacement of NaCl did not affect pH, water activity (aw) or its chemical composition after eight or 16 days ripening time, while a significant sodium reduction was achieved. The oxidation index expressed in TBARS was also not affected by the NaCl substitution and varied between 0.01 to 0.04 of malonaldehyde (MDA) per kg of sample. Similarly, the NaCl replacement did not change the microbiological quality of the sausages, and the production of healthier meat sausages had also no significant effect on their sensory characteristics. Therefore, according to the results obtained, it is viable and a good strategy for the meat industry to produce “reduced sodium content” sausages without affecting their traditional quality.The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support by national funds FCT/MCTES to CIMO (UIDB/00690/2020); to Bísaro-Salsicharia Tradicional industry and to Laboratory of Carcass and Meat Quality of Agriculture School of Polytechnic Institute of Bragança ‘Cantinho do Alfredo’. Thanks are extended to GAIN (Axencia Galega de Innovación) for supporting this work (grant number IN607A2019/01). The authors are members of the Healthy Meat network, funded by CYTED (ref. 119RT0568).info:eu-repo/semantics/publishedVersio

Assessment of Parkinson’s disease medication state through automatic speech analysis

Parkinson’s disease (PD) is a progressive degenerative disorder of the central nervous system characterized by motor and nonmotor symptoms. As the disease progresses, patients alternate periods in which motor symptoms are mitigated due to medication intake (ON state) and periods with motor complications (OFF state). The time that patients spend in the OFF condition is currently the main parameter employed to assess pharmacological interventions and to evaluate the efficacy of different active principles. In this work, we present a system that combines automatic speech processing and deep learning techniques to classify the medication state of PD patients by leveraging personal speech-based bio-markers. We devise a speakerdependent approach and investigate the relevance of different acoustic-prosodic feature sets. Results show an accuracy of 90.54% in a test task with mixed speech and an accuracy of 95.27% in a semi-spontaneous speech task. Overall, the experimental assessment shows the potentials of this approach towards the development of reliable, remote daily monitoring and scheduling of medication intake of PD patients.info:eu-repo/semantics/publishedVersio

Culture, education and water resources management: a literature review highlighting new research opportunities

Given that water is a conditioning and irreplaceable element to the existence of life on Earth, equally present and future populations also depend on water to ensure their continuity and economic activities, biological and sociocultural factors that develop. Based on a review of the scientific literature available in EBSCO and Web of Science databases, this study aimed to investigate and discuss the existing relationships between culture and education in the context of water resources management. We conducted a systematic literature review technique in conjunction with a bibliometric analysis with the support of Rayyan, Microsoft Excel, and VOSviewer software. For the data collection, we evaluated the sample regarding the number of annual publications, the mapping of publications, and the relations network between the keywords created to identify new trends and a research agenda. The results highlighted the complexity of the relationship between culture, education, and water resources, revealing the need to deepen and advance research on the subject. In the analysis, we identified the need to consider man as the leading actor in a new structure in which education will be the leading mobilizer for constructing a new cultural perspective on water resource management

Effect of the inclusion of olive cake in the diet on the physicochemical characteristics of dry-cured loin and dry-cured "cachaço" of Bísaro pig

The purpose of the present study was to characterize the dry-cured loin and dry-cured “cachaço” of Bísaro pork and evaluate the effect of the inclusion of olive cake in the animals’ diet on the cured products. For this purpose, forty loins and forty “cachaços” were used, followed by a process of cold curing with controlled ventilation, without adding nitrites or synthetic additives. The dry-cured loin and “cachaço” chemical compositions were significantly different in moisture, total fat, protein, chlorides, ash, and haem pigments. The “cachaço” showed a much higher value of total fat and a lower protein value. Its chloride content was lower and was related to the lower ash percentage. Neither product differed significantly in the water activity and collagen content. The proportions of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids were significantly different between these products. The dry-cured “cachaço” showed higher values of SFA and PUFA, and the dry-cured loin had higher MUFA content. No significant effect of different olive cakes on diet was observed in the chemical compositions. Both products are of high quality and with good nutritional and physicochemical characteristics, and the introduction of olive cake in the diet did not affect any of the quality parameters analyzed.Axencia Galega de Innovación | Ref. IN607A2019/01Fundação para a Ciência e a Tecnologia | Ref. UIDB/00690/2020Fundação para a Ciência e a Tecnologia | Ref. UIDP/00690/202

Structure and stability of human telomeric G-quadruplex with preclinical 9-amino acridines

G-quadruplexes are higher-order DNA structures formed from guanine-rich sequences, and have been identified as attractive anticancer drug targets. Elucidating the three-dimensional structure of G-quadruplex with 9-amino acridines and the specific interactions involved in binding selectivity are the key to understanding their mechanism of action. Fluorescence titration assays, competitive dialysis and NMR studies have been used to study the binding specificity of 9-amino acridines to DNA. Structural models of the complexes with the telomeric DNA G-quadruplex based on NMR measurements were developed and further examined by molecular dynamics simulations and free energy calculations. Selective binding of 9-amino acridines for G-quadruplex sequences were observed. These compounds bind between A and G-tetrads, involving significant π-π interactions and several strong hydrogen bonds. The specific interactions between different moieties of the 9-amino acridines to the DNA were examined and shown to play a significant role in governing the overall stabilities of DNA G-quadruplex complexes. Both 9-amino acridines, with similar binding affinities to the G-quadruplex, were shown to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the two 9-amino acridines