Corrosion resistance of TiAlVCuN coatings deposited by co-sputtering technique

ilustraciones, graficasEn este trabajo se depositaron recubrimientos de TiAlVCuN sobre sustratos de acero inoxidable 316 L usando un sistema de cosputtering reactivo con fuentes HIPIMS y magnetrón. Como material de depósito se usó un blanco de titanio/aluminio y un blanco de vanadio/cobre. Los recubrimientos obtenidos fueron caracterizados química, microestructural y morfológicamente. La variación del voltaje de deposición en el blanco de V/Cu (con 5 niveles entre 510 V y 580 V), generó un cambio en la composición química representado principalmente en la variación de la cantidad de V, cambiando entre 3% y 12%. Estos recubrimientos exhibieron un crecimiento columnar, sin precipitaciones de Cu en la superficie. Además, se encontró una estructura cúbica tipo FCC, correspondiente con la formación de una solución sólida de TiAlVN sin presencia de Cu en estado metálico, por lo cual este probablemente podría estar disuelto en los bordes de grano de la matriz. Por otro lado, se evalúo la resistencia a la corrosión de los recubrimientos y el sustrato en dos tipos de electrolitos (Solución 3.5 wt. % de NaCl y Lactato de Ringer) a través de las técnicas de polarización potenciodinámica (TAFEL) y espectroscopia de impedancia electroquímica (EIS). El comportamiento frente a la corrosión mostrado por los recubrimientos fue similar al reportado para el sustrato. Sin embargo, el valor de la resistencia a la polarización disminuye con el aumento del voltaje de deposición. Lo anterior puede estar relacionado con un aumento en la cantidad de defectos presentes en el recubrimiento y la generación esfuerzos residuales que comprometen la adherencia de este al sustrato. (Texto tomado de la fuente)In this work TiAlVCuN coatings were deposited on 316 L stainless steel substrates using a reactive cosputtering system with magnetron and HIPIMS power sources. Titanium/aluminum and vanadium/copper blanks were used as deposit materials. The coatings obtained were chemically, microstructurally and morphologically characterized. The variation of the deposition voltage on the V/Cu target (with 5 levels between 510 V and 580 V), generated a change in the chemical composition represented mainly in the variation of the amount of V, changing between 3% and 12%. These coatings exhibited columnar growth, without Cu precipitation on the surface. In addition, an FCC-type cubic structure was found, corresponding to the formation of a TiAlVN solid solution without the presence of Cu in the metallic state, for which it could probably be dissolved at the grain boundaries of the matrix. On the other hand, coatings and substrate corrosion resistance was evaluated through the techniques of potentiodynamic polarization (TAFEL) and electrochemical impedance spectroscopy (EIS) using two types of electrolytes (3.5 wt. % NaCl NaCl solution and Ringer's Lactate). The corrosion behavior shown by the coatings was similar to that reported for the substrate. However, the polarization resistance value decreases with increasing deposition voltage. This could be related to an increase in the number of defects present in the coating and the generation of residual stresses that compromise its adherence to the substrate.MaestríaMagíster en Ingeniería - Materiales y ProcesosIngeniería de superficie

Porous Titanium for Biomedical Applications: Evaluation of the Conventional Powder Metallurgy Frontier and Space-Holder Technique

Titanium and its alloys are reference materials in biomedical applications because of their desirable properties. However, one of the most important concerns in long-term prostheses is bone resorption as a result of the stress-shielding phenomena. Development of porous titanium for implants with a low Young’s modulus has accomplished increasing scientific and technological attention. The aim of this study is to evaluate the viability, industrial implementation and potential technology transfer of different powder-metallurgy techniques to obtain porous titanium with stiffness values similar to that exhibited by cortical bone. Porous samples of commercial pure titanium grade-4 were obtained by following both conventional powder metallurgy (PM) and space-holder technique. The conventional PM frontier (Loose-Sintering) was evaluated. Additionally, the technical feasibility of two different space holders (NH4HCO3 and NaCl) was investigated. The microstructural and mechanical properties were assessed. Furthermore, the mechanical properties of titanium porous structures with porosities of 40% were studied by Finite Element Method (FEM) and compared with the experimental results. Some important findings are: (i) the optimal parameters for processing routes used to obtain low Young’s modulus values, retaining suitable mechanical strength; (ii) better mechanical response was obtained by using NH4HCO3 as space holder; and (iii) Ti matrix hardening when the interconnected porosity was 36–45% of total porosity. Finally, the advantages and limitations of the PM techniques employed, towards an industrial implementation, were discussed.Ministry of Economy and Competitiveness of Spain Grant MAT2015-71284-PJunta de Andalucía Grant P12-TEP-1401Comisión Nacional de Investigación, Científica y Tecnológica (CONICYT) of the Chilean government project FONDECYT 1116086

Amelioration of BPSD-like phenotype and cognitive decline in SAMP8 mice model accompanied by molecular changes after treatment with I2-imidazoline receptor ligand MCR5

Behavioural and Psychological Symptoms of Dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer's disease (AD), together with memory decline. I2-imidazoline receptors (I2-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I2-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I2-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I2-IR ligand MCR5 (5mg/kg/day for four weeks) in 10-month SAMP8 mice ameliorated both BPSD-like phenotype and cognitive decline by attenuating depressive-like behaviour, reducing fear-anxiety-like behaviour and improving cognitive performance using different tasks. Interaction of I2-IR ligand MCR5 with serotoninergic system did not account for behavioral or cognitive improvement, although changes in molecular pathways underlying depression and anxiety phenotype were observed. MCR5 increased levels of p-AKT, phosphorylated Glycogen synthase kinase 3 β (GSK3β) at Ser9 and phosphorylated mammalian target of rapamycin complex 1 (mTORC1) levels in SAMP8 treated mice compared to SAMP8 control. Moreover, MCR5 treatment altered NMDA2B phosphorylation, and decreased the protein levels of phosphorylated Cyclin-Dependent Kinase 5 (p-CDK5) and dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa phosphorylated at Thr75 (p-DARPP32), with a parallel increase in PKA and p-CREB levels. Consistent with these changes MCR5 attenuated neuroinflammation by decreasing expression of pro-inflammatory markers such as Tumor necrosis factor-alpha (Tnf-α), Interleukin 1β (Il-1β), Interleukin 6 (Il-6), and promoted synaptic plasticity by increasing levels of Postsynaptic density protein 95 (PSD95) as well as ameliorating Tropomyosin-related kinase B (TrkB) and Nerve growth factor receptor (NGFR) signalling. Collectively, these results increase the potential of highly selective I2-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations

Synthesis, Characterization and HPLC Analysis of the (1 S,2 S,5 R)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512

Abstract: AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512

Dibenzylxanthines as PPEPCK-M inhibitors for cancer therapy

Phosphoenolpyruvate carboxykinase (PEPCK) is the key enzyme in gluconeogenesis/glyceroneogenesis, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. In eukaryotes, there are two isozymes present either in the cytosol (PEPCKC, PCK1) or the mitochondria (PEPCK-M, PCK2). While PCK1 is found in gluconeogenic tissues and has a very clear metabolic function, PCK2 is expressed in non-gluconeogenic cell types, where its role remains largely unknown. For example, PCK2 is highly expressed in most cancer cells, where it provides a growth advantage to cancer cells in nutrient-poor environments

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca2+/ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the metabolite directly into the cell increased cytosolic calcium and NFAT activity. PEP-stirred cytosolic calcium was also responsible for the calmodulin (CaM) dependent phosphorylation of c-Myc at Ser62, resulting in increased activity, probably through enhanced stabilization of the protein. Protein expression of several c-Myc targets also correlated with PEP levels. Finally, the participation of PEPCK in this axis was interrogated as it should directly contribute to PEP through cataplerosis from TCA cycle intermediates, especially in glucose starvation conditions. Inhibition of PEPCK activity showed the expected regulation of PEP and calcium levels and consequential downstream modulation of NFAT and c-Myc activities. Collectively, these results suggest that glucose and PEPCK can regulate NFAT and c-Myc activities through their influence on the PEP/Ca2+ axis, advancing a role for PEP as a second messenger communicating metabolism, calcium cell signaling, and tumor biology

La Medicina General Integral desde la perspectiva y el pensamiento del Comandante en Jefe Fidel Castro Ruz

The creation of the Integral General Medicine specialty and the doctor's and nurse's family Program it was a political decision of the Cuban state, from the Commandant's idea in Boss Fidel Castro Ruz. A new concept it was made, the generality became into a specialty: the integral general medicine, a concept associated to the idea of the family's doctor. It was carried out a wide bibliographical revision in printed books and databases of available scientific bibliographies (BVS-BIREME, PubMed, LILACS, SciELO, EBSCO) as well as in Academic Google with the objective of get deeper in the history of the Integral General Medicine specialty from the perspective and the Commandant's thought in Boss Fidel Castro Ruz. It could verify that the Integral General Medicine specialty was created with the objective of creating a different kind of doctor, capable to catch up with new levels of health and to offer the population bigger satisfaction. It exists an insufficient knowledge and an insufficient bibliography where the history of the emergence of the Integral General Medicine as a specialty.La creación de la especialidad Medicina General Integral y del Programa del médico y la enfermera de la familia fue una decisión política del Estado cubano, a partir de la idea del Comandante en Jefe Fidel Castro Ruz. Se creó un nuevo concepto, se convirtió la generalidad en una especialidad: la Medicina General Integral, un concepto asociado a la idea del médico de la familia. Se realizó una amplia revisión bibliográfica en libros impresos y en las bases de datos de bibliografías científicas disponibles (BVS-BIREME, PubMed, LILACS, SciELO, EBSCO) y en Google Académico con el objetivo de profundizar en la historia de la especialidad de Medicina General Integral desde la perspectiva y el pensamiento del Comandante en Jefe Fidel Castro Ruz. Se pudo constatar que la especialidad Medicina General Integral Integral fue creada con el objetivo de formar un médico diferente capaz de alcanzar nuevos niveles de salud y brindar mayor satisfacción a la población. Existe insuficiente conocimiento y bibliografía en la que se desarrolle la historia del surgimiento de la Medicina General Integral como especialidad

La Medicina General Integral desde la perspectiva y el pensamiento del Comandante en Jefe Fidel Castro Ruz

The creation of the Integral General Medicine specialty and the doctor's and nurse's family Program it was a political decision of the Cuban state, from the Commandant's idea in Boss Fidel Castro Ruz. A new concept it was made, the generality became into a specialty: the integral general medicine, a concept associated to the idea of the family's doctor. It was carried out a wide bibliographical revision in printed books and databases of available scientific bibliographies (BVS-BIREME, PubMed, LILACS, SciELO, EBSCO) as well as in Academic Google with the objective of get deeper in the history of the Integral General Medicine specialty from the perspective and the Commandant's thought in Boss Fidel Castro Ruz. It could verify that the Integral General Medicine specialty was created with the objective of creating a different kind of doctor, capable to catch up with new levels of health and to offer the population bigger satisfaction. It exists an insufficient knowledge and an insufficient bibliography where the history of the emergence of the Integral General Medicine as a specialty.La creación de la especialidad Medicina General Integral y del Programa del médico y la enfermera de la familia fue una decisión política del Estado cubano, a partir de la idea del Comandante en Jefe Fidel Castro Ruz. Se creó un nuevo concepto, se convirtió la generalidad en una especialidad: la Medicina General Integral, un concepto asociado a la idea del médico de la familia. Se realizó una amplia revisión bibliográfica en libros impresos y en las bases de datos de bibliografías científicas disponibles (BVS-BIREME, PubMed, LILACS, SciELO, EBSCO) y en Google Académico con el objetivo de profundizar en la historia de la especialidad de Medicina General Integral desde la perspectiva y el pensamiento del Comandante en Jefe Fidel Castro Ruz. Se pudo constatar que la especialidad Medicina General Integral Integral fue creada con el objetivo de formar un médico diferente capaz de alcanzar nuevos niveles de salud y brindar mayor satisfacción a la población. Existe insuficiente conocimiento y bibliografía en la que se desarrolle la historia del surgimiento de la Medicina General Integral como especialidad

(2-Imidazolin-4-yl)phosphonates: Green Chemistry and Biology Walk Together

2-Imidazoline-containing compounds constitute a valuable class of agents that modulate α2- adrenergic receptors and often show a high affinity for imidazoline I2-receptors (I2-IR). Moreover, 2- imidazolines are an important class of heterocyclic scaffolds found in natural product chemistry, coordination chemistry, and homogeneous catalysis. To meet the demand for 2-imidazolinecontaining compounds, different synthetic approximations were developed. In this work, we describe an efficient and user-friendly synthetic process involving the combination of isocyanidebased multicomponent reaction and microwave heating without the need of anhydrous atmosphere or additional solvents that generates unprecedented (2-imidazolin-4-yl)phosphonates [1]. We assessed the pharmacological profile and selectivity of the prepared compounds upon I2-IR. Owing to the outstanding high I2-IR affinity of one of the prepared compounds and high selectivity devoid to the α2-adrenoceptor of other compounds, markedly better than any described I2-IR ligand to date, (2-imidazolin-4-yl)phosphonates might be considered as a suitable scaffold for designing novel I2-IR ligands [2]. In addition, we demonstrated the effectiveness of two of the new I2-IR ligands in an in vivo female model for cognitive decline (SAMP8), and we analyzed the pathological biomarkers for neurodegeneration. This study is the first experimental evidence that demonstrates the possibility of using this receptor as a target for cognitive impairment [3]. Note, theoretical studies were carried out for designing compounds with enhanced activity and selectivity upon I2-IR based on created 3D-QSAR model. In this work, green chemistry to access an unprecedented scaffold and promising pharmacological results in the neurodegeneration field walked together.The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery, Barcelona, Spain, 15–17 May 201

Hydrophobic waters in bromodomains

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains due to their implication in cancer, inflammation, and a plethora of diseases. Several small-molecule inhibitors and degraders that target bromodomains have entered the clinic, and many more are increasingly being used as chemical probes to describe bromodomain biology. From a structural point of view, crystallographic studies of bromodomains describe, as a common feature, five water molecules as an integral part of the acetyl-lysine binding pocket. These water molecules are essential in druggability and are described as a functional part of the protein [1,2]. In this framework, we focused our attention on the description of the hydrophilic/hydrophobic character of these molecules, which seem to create a favorable environment for the recognition of hydrophobic groups. To this end, and following fragment-based drug design techniques, here we describe a new family of small molecules with a 5-phenylthiazolo[2,3-c][1,2,4]triazol nucleus and probe the water site with various substituents at the 3-position endowing hydrophilic or hydrophobic properties. In this work, we present the theoretical calculations, the synthesis of the new compounds, the results of differential scanning fluorimetry (DSF) and isothermal titration calorimetry (ITC), and the crystal structures of three of our compounds with the target protein. The study sheds light on the counterintuitive behavior of the water molecules in this particular environment