Small molecule inhibitors of the response regulator ArsR exhibit bactericidal activity against Helicobacter pylori

Helicobacter pylori is considered the most prevalent bacterial pathogen in humans. The increasing antibiotic resistance evolved by this microorganism has raised alarm bells worldwide due to the significant reduction in the eradication rates of traditional standard therapies. A major challenge in this antibiotic resistance crisis is the identification of novel microbial targets whose inhibitors can overcome the currently circulating resistome. In the present study, we have validated the use of the essential response regulator ArsR as a novel and promising therapeutic target against H. pylori infections. A high-throughput screening of a repurposing chemical library using a fluorescence-based thermal shift assay identified several ArsR binders. At least four of these low-molecular weight compounds noticeably inhibited the DNA binding activity of ArsR and showed bactericidal effects against antibiotic-resistant strains of H. pylori. Among the ArsR inhibitors, a human secondary bile acid, lithocholic acid, quickly destroyed H. pylori cells and exhibited partial synergistic action in combination with clarithromycin or levofloxacin, while the antimicrobial effect of this compound against representative members of the normal human microbiota such as Escherichia coli and Staphylococcus epidermidis appeared irrelevant. Our results enhance the battery of novel therapeutic tools against refractory infections caused by multidrug-resistant H. pylori strains

Web Design Attributes in Building User Trust, Satisfaction, and Loyalty for a High Uncertainty Avoidance Culture

In this study, we attempt to evaluate the user pref6 erences for web design attributes (i.e., typography, color, content 7 quality, interactivity, and navigation) to determine the trust, sat8 isfaction, and loyalty for uncertainty avoidance cultures. Content 9 quality and navigation have been observed as strong factors in 10 building user trust with e-commerce websites. In contrast, inter11 activity, color, and typography have been observed as strong de12 terminants of user satisfaction. The most relevant and interesting 13 finding is related to typography, which has been rarely discussed 14 in e-commerce literature. A questionnaire was designed to collect 15 data to corroborate the proposed model and hypotheses. Further16 more, the partial least-squares method was adopted to analyze the 17 collected data from the students who participated in the test (n 18 = 558). Finally, the results of this study provide strong support to 19 the proposed model and hypotheses. Therefore, all the web design 20 attributes were observed as important design features to develop 21 user trust and satisfaction for uncertainty avoidance cultures. Al22 though both factors seem to be relevant, the relationship between 23 trust and loyalty was observed to be stronger than between satis24 faction and loyalty; thus, trust seems to be a stronger determinant 25 of loyalty for risk/high uncertainty avoidance culture

Inhibición de la actividad biológica del regulador transcripcional HsrA de Helicobacter pylori mediante el empleo de ligandos de bajo peso molecular y estudio de la capacidad antimicrobiana de estos compuestos

Helicobacter pylori es el patógeno bacteriano de mayor prevalencia mundial, infectando a más de la mitad de la población y estando relacionado con más del 90% de casos de cáncer gástrico. El incremento y acumulación de resistencias frente a la mayoría de los antibióticos convencionales ha determinado una disminución apreciable de la eficacia de los regímenes de erradicación empleados para este patógeno. En la actualidad resulta imperativa la búsqueda de nuevas dianas terapéuticas para la investigación y desarrollo de nuevas familias de antimicrobianos efectivas, que logren evadir los mecanismos de resistencia actuales. Nuestro grupo de investigación ha sido el primero en validar el regulador de respuesta esencial HsrA de H. pylori como diana molecular para el descubrimiento de nuevos fármacos con actividad bactericida frente a este microorganismo. Mediante cribados masivos de quimiotecas han sido identificados varios ligandos de HsrA que se unen al regulador, formando un complejo con mayor estabilidad térmica que la proteína. En el presente trabajo se evaluó la capacidad inhibitoria de 20 ligandos de bajo peso molecular y naturaleza química diversa sobre la actividad in vitro del HsrA mediante estudios de retardo en gel. Se estudió la interacción molecular proteína-inhibidores mediante acoplamiento (docking) molecular y se analizó la actividad antimicrobiana de los inhibidores de HsrA frente a diferentes cepas de H. pylori mediante la determinación de las concentraciones mínimas inhibitorias (CMI) y las concentraciones mínimas bactericidas (CMB). Seis de los ligandos estudiados inhibieron efectivamente la actividad biológica in vitro de la proteína HsrA a concentraciones iguales o inferiores a 2 mM. Todos los inhibidores de HsrA se unieron preferiblemente al dominio efector C-terminal de la proteína, interaccionando con residuos directamente implicados en la estructura del motivo HTH de unión al DNA o con residuos aparentemente imprescindibles para la estabilidad del dominio. Al menos 2 de estos inhibidores mostraron una alta capacidad antimicrobiana frente a H. pylori, con valores de CMI y CMB ≤ 8 mg/L. Los resultados obtenidos avalan el uso del regulador transcripcional HsrA como diana terapéutica e incrementan la batería de potenciales nuevas herramientas para el tratamiento de infecciones refractarias causadas por cepas de H. pylori resistentes a los antibióticos convencionales. ABSTRACTHelicobacter pylori is the most worldwide prevalent bacterial pathogen, infecting more than half of the world’s population and it has been associated with more than 90% of gastric cancer cases. The increase and accumulation in the resistance against most of the conventional antibiotics has determined a greatly and noticeable reduction in the efficacy of eradication therapies used for the treatment of infections caused by this pathogen. Currently, it is imperative to search for new therapeutic targets for the research and development of novel and effective antimicrobial families which can surpass current resistance mechanisms. Our research group has been the first one to validate the essential response regulator HsrA from H. pylori as a molecular target for the discovery of new drugs with bactericidal activity against this microorganism. Through high-throughput screening of some chemical libraries several HsrA ligands that bind to the response regulator were found, forming a complex with a higher thermal stability compared to the free protein. In the present work we studied the inhibitory capacity of 20 low-weight and structurally diverse ligands over the in vitro activity of HsrA by electrophoretic mobility shift assays. The molecular interaction between the protein and its inhibitors was studied by molecular docking and antimicrobial activity of HsrA inhibitors was analysed against different H. pylori strains by determining the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Six of the studied ligands effectively inhibited the in vitro biological activity of HsrA at concentration equal to or lower than 2 mM. All HsrA inhibitors bound preferably to the C-terminal effector domain in the protein, interacting with residues directly involved in the structure of the HTH DNA-binding motif or with residues apparently essential for the domain stability. At least two of these inhibitors showed a high antimicrobial activity against H. pylori, with MIC and MBC values ≤ 8 mg/L. The results obtained in this study support the use of response regulator HsrA as a therapeutic target and increase the battery of potential novel tools for the treatment of refractory infection caused by H. pylori strains resistant to conventional antibiotics.<br /

Wnt signaling alterations in the human spinal cord of amyotrophic lateral sclerosis cases: spotlight on Fz2 and Wnt5a

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure, and elucidation of the mechanisms mediating neuronal death in this neuropathology is crucial to develop effective treatments. It has recently been demonstrated in animal models that the Wnt family of proteins is involved in this neuropathology, although its potential involvement in case of humans is almost unknown. We analyzed the expression of Wnt signaling components in healthy and ALS human spinal cords by quantitative RT-PCR, and we found that most Wnt ligands, modulators, receptors, and co-receptors were expressed in healthy controls. Moreover, we observed clear alterations in the mRNA expression of different components of this family of proteins in human spinal cord tissue from ALS cases. Specifically, we detected a significant increase in the mRNA levels of Wnt3, Wnt4, Fz2, and Fz8, together with several non-significant increases in the mRNA expression of other genes such as Wnt2b, Wnt5a, Fz3, Lrp5, and sFRP3. Based on these observations and on previous reports of studies performed in animal models, we evaluated with immunohistochemistry the protein expression patterns of Fz2 and Fz5 receptors and their main ligand Wnt5a in control samples and ALS cases. No substantial changes were observed in Fz5 protein expression pattern in ALS samples. However, we detected an increase in the amount of Fz2+ astrocytes in the borderline between gray and white matter at the ventral horn in ALS samples. Finally, Wnt5a expression was observed in neurons and astrocytes in both control and ALS samples, although Wnt5a immunolabeling in astroglial cells was significantly increased in ALS spinal cords in the same region where changes in Fz2 were observed. Altogether, these observations strongly suggest that the Wnt family of proteins, and more specifically Fz2 and Wnt5a, might be involved in human ALS pathology

Recomendador inteligente de vestimenta

En la actualidad más que nunca, una imagen vale más que mil palabras. Esto coincide con una sociedad que cada vez valora más su tiempo y donde desde hace pocas décadas existe un auge de los grandes gigantes de moda, con millones de personas que quieren estar siempre atentos a las últimas tendencias. Este trabajo ha consistido en el desarrollo de una aplicación web que combina todo esto, ayudándonos a mejorar nuestra imagen, adecuándose siempre a cada evento y circunstancia, pero sin perder la esencia personal. Esta aplicación aprenderá de tus gustos y los ajustará a tu agenda, haciendo de esta aplicación una experiencia personal muy satisfactoria. Para ello, se tendrá en cuenta el fondo de armario del usuario, y analizando diversos factores como la meteorología de ese día, los eventos anotados en su agenda y la formalidad requerida, sus preferencias. . . se le dará un look acorde a todo ello. Así mismo, la app podrá hacer recomendaciones de looks que se asemejen a la tendencia de todos los usuarios de la aplicación en ese momento, utilizando prendas lo más parecidas de su armario. Una vez escogido el look, la aplicación aprenderá acerca de su elección

Soluble iron dust export in the high altitude Saharan Air Layer

Every summer huge amounts of desert dust particles are exported from the hyperarid subtropical Sahara to the North Atlantic the so-called Saharan Air Layer (SAL), a dry, warm and dust-laden corridor that expands from the North African coast (1-5 km.a.s.I.) to the Americas above the marine boundary layer. Because of the potential impact of the dust deposited on the ocean on marine biogeochemistry and climate, we studied the Fe solubility (in seawater) of atmospheric aerosols samples directly collected in the SAL off the North African coast, i.e, the fresh aerosols recently exported from the Sahara in the SAL. The aerosol sampling was performed at 2400 m.a.s.l. in Izana observatory in Tenerife island. In the total aerosols, we found low Fe concentrations and high fractional Fe solubility (FFS-2%) in the North Atlantic free troposphere airflows and high Fe concentrations and low FFS (-0.7%) within the SAL; the resulting FFS versus total dust (or total Fe) plot shows a hyperbolic trend attributed to the conservative mixing of 'fine combustion aerosols' and 'lithogenic mineral dust'. We then focused on the soluble Fe in the SAL Our results indicate that 70% of soluble Fe is associated with the dissolution of submicron dust particles, probably involving Fe-bearing clays. We found a FFS of submicron dust (-6%) higher than that typically observed in submicron particles of soil dust samples (<1%).This study is part of the project AEROATLAN e 2015-66229 -, funded by the Ministry of Economy and Competitiveness of Spain. M.I. García holds a research grant e TESIS20120054 e co-funded by the Canarian Agency for Research, Innovation and Information Society and the European Social Fund

REVIEW OF VEGETABLE NANOLUBRICANTS FOR TRIBOLOGICAL APPLICATIONS

About 40 million tons of lubricants are used every year for various industry purposes and applications, where most of them are petroleum based oils. These oils are difficult and expensive to dispose of, have low biodegradability and are contamination risks. Recent efforts have been focused on reducing the environmental impact of petroleum based lubricants through the use of vegetable oils since they are biodegradable and have good lubricity. A drawback of vegetable oils is their poor thermal stability and oxidation, which causes them to decrease their properties at higher loads. Nanoparticle (NP) additives have been explored for improving the tribological performance of vegetable. This literature review seeks to compare and analise the impact of the different NP types, concentrations and vegetable oil type on the coefficient of friction. The vegetable oils that have shown to provide the best tribological behaviour were coconut oil, sunflower oil, palm sesame oil, canola oil, among others. The NP with the best performance were SiO2 and CuO and the concentration with the highest improvement was between 0.01-3.0 wt.%. The results of this study provide an insight on the areas of opportunity for developing new lubricant formulations with vegetable oils and NP additives for industrial applications

Quantification of Ceftaroline in Human Plasma Using High-Performance Liquid Chromatography with Ultraviolet Detection: Application to Pharmacokinetic Studies

This study was conducted to develop a rapid, simple and reproducible method for the quantification of ceftaroline in plasma samples by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Sample processing consisted of methanol precipitation and then, after centrifugation, the supernatant was injected into the HPLC system, working in isocratic mode. Ceftaroline was detected at 238 nm at a short acquisition time (less than 5 min). The calibration curve was linear over the concentration range from 0.25 to 40 µg/mL, and the method appeared to be selective, precise and accurate. Ceftaroline in plasma samples was stable at −80 °C for at least 3 months. The method was successfully applied to characterize the pharmacokinetic profile of ceftaroline in two critically ill patients and to evaluate whether the pharmacokinetic/pharmacodynamic (PK/PD) target was reached or not with the dose regimen administered.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU 17/32)