Effect of dielectric constant on estimation of properties of ionic liquids: an analysis of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide

A series of different cationic structures based on 1-alkyl-3-methylimidazolium were combined with a single anion, bis(trifluoromethylsulfonyl)imide (CnmimNTf2, n = 1 to 12) for analyzing the quality of COSMO-RS based estimations. For this purpose, we have studied the structure as well as the estimations of several properties of one ionic liquid (IL). These estimations are obtained from polarization charge distribution in which the IL is embedded. Special attention has been paid to the effect of the dielectric constant value in the predictions. For this purpose, polarization charge density has been modeled using several values of dielectric constant, and properties have been estimated in each case. Thus, σ-profiles and, σ-potentials have been computed and used with COSMO-RS for estimating vapor pressure, as a function of temperature, as well as theoretical values of vaporization enthalpy, density, and viscosity at 298.15 K. The influence of the length of the alkyl chain of ionic liquid in the estimation of these properties has also been tested. Finally, the results have been compared with experimental dataThe authors thank the “Ministerio de Ciencia e Innovación” (Project: CTQ2010-19232) and “Comunidad de Madrid” (Project: LIQUORGAS-S2013/MAE-2800) financial suppor

Preparation and characterization of fluorescent CdS quantum dots used for the direct detection of GsT fusion proteins

Advances in the life sciences are now closely linked to the availability of new experimental tools that allow for the manipulation of biomolecules and the study of biological processes at the molecular level. In this context, we have optimized a synthesis process to obtain glutathione-capped fluorescent CdS nanoparticles to specifically detect Glutathione S-Transferase (GST) -tagged proteins. Using our method, based on five different heating steps, brightly fluorescent and biocompatible CdS quantum dots of different sizes can be obtained. QD optical behaviour has been evaluated studying both absorbance and fluorescence. For all the samples, the excitonic absorption onset clearly shows a blue shift at 512nm in comparison with that of bulk CdS, due to the quantum confinement effect. At increased average sizes of the nanocrystal, the emission fluorescent band shows a red shift, from 440nm to 540nm. Among different QD solutions, we demonstrate an expansion of the emission range up to ~100 nm, thus improving their features as biomarkers. Moreover we show that optimized glutathione-capped quantum dots can directly bind GST blotted onto polyvinylidene difluoride (PVDF) membranes, and thus are suitable for the direct detection of GST fusion proteins.Proyectos del Ministerio de Innovación y Ciencia (PN/PETRI/PR/2007‐019) y Junta de Andalucía (P08‐CTS‐04348

Generation of Molecular Diversity from Amino Acids. A Source for the Discovery of New TRP Channel Modulators

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.Ion channels are central and challenging targets in medicinal chemistry but, because of the scarce structural knowledge, rational approaches to ion channel modulators are still rare. Moreover, the multimodal activation of some channels, like TRPs, complicates still more the scenario for rational discovery programs. Due to these facts, most strategies directed to identify ion channel modulators rely on the screening of peptide and small-molecule libraries. In this context, we have been involved in the development of synthetic pathways for the generation of diverse, chiral, highly functionalized linear and heterocyclic scaffolds from amino acids, and in the production of discrete libraries from them. The screening of these libraries on different TRP channels has allowed the discovery of some innovative hits that have progressed to hit-to-lead optimization programs. This communication will deal with the synthesis, structural characterization, and biological evaluation of a collection of β,γ–diaminoester derivatives that display significant activity at TRPV1, TRPM8 and TRPA1 channels. Compound RGM04-7, a selective.Supported by MICINN grants: Consolider-Ingenio 2010 (CSD2008-00005 and CSD2006-00015), SAF2009-09323 and BFU2009-08346, and the Generalitat Valenciana (PROMETEO/2010/046)

Discovery of New Antagonists for TRPM8 Channel by High Throughput Assay

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.TRP ion channels family is represented by 85 members that can be organized by their sequence homology into seven subfamilies. Some members of these subfamilies play an important role in detecting temperature changes. Within TRPV (vanilloid) subfamily, TRPV1 is the most studied member, and has been related with chronic pain, furthermore its pharmacological blockade and genetic deletion experiments have validated TRPV1 as a therapeutic target. Another member of the TRP family is TRPA1, which is activated by noxious cold and chemical compounds including allyl isothiocyanate (AITC), the pungent principle of wasabi and other mustard oils. TRPA1 appears to have a central role in the pain response but also it has been demonstrated that is essential for asthma [1]. TRP melastatin 8 (TRPM8) is activated by chemical cooling agents (such as menthol) or by temperatures between 28-15 ºC, mediating the detection of innocuous cold thermal stimuli. TRPM8 expression up-regulates has been suggested to play an important role in carcinogenesis and related with prostate cancer [2]. In this study was evaluated the biological activity of a new chemical library, through high throughput screening. We report here the identification of compounds presented a high blockade activity on TRPM8 and share common structure. These hits with notorious antagonistic effect were selected and observed in patch-clamp experiments performed in stable cell lines that expressed TRPV1, TRPM8 and TRPA1 to characterize more accurately their properties. These new pharmacophoric scaffolds can be used as a hit to develop new compounds with better modulator properties interesting to the clinical field or as a research tool.Supported by Consolider-Ingenio 2010 (CSD2008-00005), MICINN (BFU2009- 08346), MICCIN (BES-2010-037112), La Fundacion La Marato de TV3, PrometeoGVA and SAF2009-09323Peer reviewe

Unusual hydrogen bond patterns contributing to supramolecular assembly: conformational study, Hirshfeld surface analysis and density functional calculations of a new steroid derivative

A structural and conformational study of 3β-acetoxy-17-chloro-16-formyl-5α-androstan-16-ene has been carried out by using X-ray analysis and M06-2X density functional calculations. The compound crystallizes with three independent molecules in the asymmetric unit. Natural Bond Order and Atoms in Molecules methods were used for a better understanding of the key factors that determine the stability of this steroidal molecule, particularly the role of C-H...Cl intramolecular interactions. A detailed investigation of C-H...Cl and C-H...O intermolecular interactions, in addition to the most important van der Waals contribution, are presented by means of Hirshfeld surface analysis. The crystal packing exhibits an unusual intra- and intermolecular hydrogen bond pattern, and shows the importance of non-classical interactions in the construction of the supramolecular assembly. Excellent agreement between the theoretical and experimental data is found.Ministerio de Economía y Competitividad (MINECO)ICTP/CLA

Engineering of III-Nitride Semiconductors on Low Temperature Co-fired Ceramics

This work presents results in the feld of advanced substrate solutions in order to achieve high crystalline quality group-III nitrides based heterostructures for high frequency and power devices or for sensor applications. With that objective, Low Temperature Co-fred Ceramics has been used, as a noncrystalline substrate. Structures like these have never been developed before, and for economic reasons will represent a groundbreaking material in these felds of Electronic. In this sense, the report presents the characterization through various techniques of three series of specimens where GaN was deposited on this ceramic composite, using diferent bufer layers, and a singular metal-organic chemical vapor deposition related technique for low temperature deposition. Other single crystalline ceramic-based templates were also utilized as substrate materials, for comparison purposes

HypoxamiRs Profiling Identify miR-765 as a Regulator of the Early Stages of Vasculogenic Mimicry in SKOV3 Ovarian Cancer Cells

Vasculogenic mimicry (VM) is a novel cancer hallmark in which malignant cells develop matrix-associated 3D tubular networks with a lumen under hypoxia to supply nutrients needed for tumor growth. Recent studies showed that microRNAs (miRNAs) may have a role in VM regulation. In this study, we examined the relevance of hypoxia-regulated miRNAs (hypoxamiRs) in the early stages of VM formation. Data showed that after 48 h hypoxia and 12 h incubation on matrigel SKOV3 ovarian cancer cells undergo the formation of matrix-associated intercellular connections referred hereafter as 3D channels-like structures, which arose previous to the apparition of canonical tubular structures representative of VM. Comprehensive profiling of 754 mature miRNAs at the onset of hypoxia-induced 3D channels-like structures showed that 11 hypoxamiRs were modulated (FC>1.5; p < 0.05) in SKOV3 cells (9 downregulated and 2 upregulated). Bioinformatic analysis of the set of regulated miRNAs showed that they might impact cellular pathways related with tumorigenesis. Moreover, overall survival analysis in a cohort of ovarian cancer patients (n = 485) indicated that low miR-765, miR-193b, miR-148a and high miR-138 levels were associated with worst patients outcome. In particular, miR-765 was severely downregulated after hypoxia (FC < 32.02; p < 0.05), and predicted to target a number of protein-encoding genes involved in angiogenesis and VM. Functional assays showed that ectopic restoration of miR-765 in SKOV3 cells resulted in a significant inhibition of hypoxia-induced 3D channels-like formation that was associated with a reduced number of branch points and patterned tubular-like structures. Mechanistic studies confirmed that miR-765 decreased the levels of VEGFA, AKT1 and SRC-α transducers and exerted a negative regulation of VEGFA by specific binding to its 3‘UTR. Finally, overall survival analysis of a cohort of ovarian cancer patients (n = 1435) indicates that high levels of VEGFA, AKT1 and SRC-α and low miR-765 expression were associated with worst patients outcome. In conclusion, here we reported a novel hypoxamiRs signature which constitutes a molecular guide for further clinical and functional studies on the early stages of VM. Our data also suggested that miR-765 coordinates the formation of 3D channels-like structures through modulation of VEGFA/AKT1/SRC-α axis in SKOV3 ovarian cancer cells

The Use of Corticosteroids or Tocilizumab in COVID-19 Based on Inflammatory Markers

SEMI-COVID-19 Network.[Background] The inflammatory cascade is the main cause of death in COVID-19 patients. Corticosteroids (CS) and tocilizumab (TCZ) are available to treat this escalation but which patients to administer it remains undefined.[Objective] We aimed to evaluate the efficacy of immunosuppressive/anti-inflammatory therapy in COVID-19, based on the degree of inflammation. .[Design] A retrospective cohort study with data on patients collected and followed up from March 1st, 2020, to May 1st, 2021, from the nationwide Spanish SEMI-COVID-19 Registry. Patients under treatment with CS vs. those under CS plus TCZ were compared. Effectiveness was explored in 3 risk categories (low, intermediate, high) based on lymphocyte count, C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and d-dimer values.[Patients] A total of 21,962 patients were included in the Registry by May 2021. Of these, 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ).[Main Measures] The primary outcome of the study was in-hospital mortality. Secondary outcomes were the composite variable of in-hospital mortality, requirement for high-flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), invasive mechanical ventilation (IMV), or intensive care unit (ICU) admission.[Key Results] A total of 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ). No significant differences were observed in either the low/intermediate-risk category (1.5% vs. 7.4%, p=0.175) or the high-risk category (23.1% vs. 20%, p=0.223) after propensity score matching. A statistically significant lower mortality was observed in the very high–risk category (31.9% vs. 23.9%, p=0.049).[Conclusions] The prescription of CS alone or in combination with TCZ should be based on the degrees of inflammation and reserve the CS plus TCZ combination for patients at high and especially very high risk.Peer reviewe