A New Highly Selective Chromogenic and Fluorogenic Chemosensor for Copper (II)

[EN] A new fluorogenic and chromogenic probe (L) for the selective, sensitive and naked-eye detection of Cu2+ is reported. Complexation constant, complex stoichiometry and quantum chemical (DFT) calculation for Cu2+ complex has been determined. Also, detection limits and the selectivity in front of other divalent and trivalent cations have been evaluated.This research was supported by the Agencia Nacional de Ciencia y Tecnologia (ANCyT) of Argentina-PICT 2014 No. 1587 and by the Universidad Nacional del Litoral, Santa Fe, Argentina.Quindt, MI.; Gutiérrez, LG.; Kneeteman, MN.; Mancini, P.; Parra Alvarez, M.; Gil Grau, S.; Costero, AM. (2018). A New Highly Selective Chromogenic and Fluorogenic Chemosensor for Copper (II). Letters in Organic Chemistry. 15(8):659-664. https://doi.org/10.2174/1570178615666180102155804S65966415

NO2-controlled cargo delivery from gated silica mesoporous nanoparticles

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ChemistryOpen, 4(4), 418-437. doi:10.1002/open.201500053Casasús, R., Aznar, E., Marcos, M. D., Martínez-Máñez, R., Sancenón, F., Soto, J., & Amorós, P. (2006). New Methods for Anion Recognition and Signaling Using Nanoscopic Gatelike Scaffoldings. Angewandte Chemie International Edition, 45(40), 6661-6664. doi:10.1002/anie.200602045Coll, C., Casasús, R., Aznar, E., Marcos, M. D., Martínez-Máñez, R., Sancenón, F., … Amorós, P. (2007). Nanoscopic hybrid systems with a polarity-controlled gate-like scaffolding for the colorimetric signalling of long-chain carboxylates. Chem. Commun., (19), 1957-1959. doi:10.1039/b617703dÖzalp, V. C., & Schäfer, T. (2011). Aptamer-Based Switchable Nanovalves for Stimuli-Responsive Drug Delivery. Chemistry - A European Journal, 17(36), 9893-9896. doi:10.1002/chem.201101403Climent, E., Marcos, M. D., Martínez-Máñez, R., Sancenón, F., Soto, J., Rurack, K., & Amorós, P. (2009). The Determination of Methylmercury in Real Samples Using Organically Capped Mesoporous Inorganic Materials Capable of Signal Amplification. Angewandte Chemie International Edition, 48(45), 8519-8522. doi:10.1002/anie.200904243Wen, Y., Xu, L., Li, C., Du, H., Chen, L., Su, B., … Song, Y. (2012). DNA-based intelligent logic controlled release systems. Chemical Communications, 48(67), 8410. doi:10.1039/c2cc34501cZhang, Z., Balogh, D., Wang, F., & Willner, I. (2013). Smart Mesoporous SiO2 Nanoparticles for the DNAzyme-Induced Multiplexed Release of Substrates. Journal of the American Chemical Society, 135(5), 1934-1940. doi:10.1021/ja311385yZhou, Y., Tan, L.-L., Li, Q.-L., Qiu, X.-L., Qi, A.-D., Tao, Y., & Yang, Y.-W. (2014). Acetylcholine-Triggered Cargo Release from Supramolecular Nanovalves Based on Different Macrocyclic Receptors. Chemistry - A European Journal, 20(11), 2998-3004. doi:10.1002/chem.201304864Chen, M., Huang, C., He, C., Zhu, W., Xu, Y., & Lu, Y. (2012). A glucose-responsive controlled release system using glucose oxidase-gated mesoporous silica nanocontainers. Chemical Communications, 48(76), 9522. doi:10.1039/c2cc34290aCliment, E., Bernardos, A., Martínez-Máñez, R., Maquieira, A., Marcos, M. D., Pastor-Navarro, N., … Amorós, P. (2009). Controlled Delivery Systems Using Antibody-Capped Mesoporous Nanocontainers. Journal of the American Chemical Society, 131(39), 14075-14080. doi:10.1021/ja904456dYang, S., Li, N., Liu, Z., Sha, W., Chen, D., Xu, Q., & Lu, J. (2014). Amphiphilic copolymer coated upconversion nanoparticles for near-infrared light-triggered dual anticancer treatment. Nanoscale, 6(24), 14903-14910. doi:10.1039/c4nr05305bSchloßbauer, A., Sauer, A. M., Cauda, V., Schmidt, A., Engelke, H., Rothbauer, U., … Bein, T. (2012). Cascaded Photoinduced Drug Delivery to Cells from Multifunctional Core-Shell Mesoporous Silica. Advanced Healthcare Materials, 1(3), 316-320. doi:10.1002/adhm.201100033Mackowiak, S. A., Schmidt, A., Weiss, V., Argyo, C., von Schirnding, C., Bein, T., & Bräuchle, C. (2013). Targeted Drug Delivery in Cancer Cells with Red-Light Photoactivated Mesoporous Silica Nanoparticles. Nano Letters, 13(6), 2576-2583. doi:10.1021/nl400681fSilveira, G. Q., Vargas, M. D., & Ronconi, C. M. (2011). Nanoreservoir operated by ferrocenyl linker oxidation with molecular oxygen. Journal of Materials Chemistry, 21(16), 6034. doi:10.1039/c0jm03738aColl, C., Bernardos, A., Martínez-Máñez, R., & Sancenón, F. (2012). Gated Silica Mesoporous Supports for Controlled Release and Signaling Applications. Accounts of Chemical Research, 46(2), 339-349. doi:10.1021/ar3001469El Sayed, S., Milani, M., Milanese, C., Licchelli, M., Martínez-Máñez, R., & Sancenón, F. (2016). Anions as Triggers in Controlled Release Protocols from Mesoporous Silica Nanoparticles Functionalized with Macrocyclic Copper(II) Complexes. 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(2016). 3-Formyl-BODIPY Phenylhydrazone as a Chromo-Fluorogenic Probe for Selective Detection of NO2(g). Chemistry - A European Journal, 22(25), 8448-8451. doi:10.1002/chem.20160092

Electron Microscopy Structural Insights into CPAP Oligomeric Behavior:A Plausible Assembly Process of a Supramolecular Scaffold of the Centrosome

Centrosomal P4.1-associated protein (CPAP) is a cell cycle regulated protein fundamental for centrosome assembly and centriole elongation. In humans, the region between residues 897–1338 of CPAP mediates interactions with other proteins and includes a homodimerization domain. CPAP mutations cause primary autosomal recessive microcephaly and Seckel syndrome. Despite of the biological/clinical relevance of CPAP, its mechanistic behavior remains unclear and its C-terminus (the G-box/TCP domain) is the only part whose structure has been solved. This situation is perhaps due in part to the challenges that represent obtaining the protein in a soluble, homogeneous state for structural studies. Our work constitutes a systematic structural analysis on multiple oligomers of HsCPAP897−1338, using single-particle electron microscopy (EM) of negatively stained (NS) samples. Based on image classification into clearly different regular 3D maps (putatively corresponding to dimers and tetramers) and direct observation of individual images representing other complexes of HsCPAP897−1338 (i.e., putative flexible monomers and higher-order multimers), we report a dynamic oligomeric behavior of this protein, where different homo-oligomers coexist in variable proportions. We propose that dimerization of the putative homodimer forms a putative tetramer which could be the structural unit for the scaffold that either tethers the pericentriolar material to centrioles or promotes procentriole elongation. A coarse fitting of atomic models into the NS 3D maps at resolutions around 20 Å is performed only to complement our experimental data, allowing us to hypothesize on the oligomeric composition of the different complexes. In this way, the current EM work represents an initial step toward the structural characterization of different oligomers of CPAP, suggesting further insights to understand how this protein works, contributing to the elucidation of control mechanisms for centriole biogenesis.This work was supported by the Comunidad de Madrid through grant CAM (S2010/BMD- 2305) and the Spanish Ministry of Economy and Competitiveness through Grants AIC-A-2011-0638 and BIO2013-44647-R.Peer reviewedPeer Reviewe

Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine

[EN] A new hybrid organic-inorganic material for sensing spermine (Spm) and spermidine (Spd) has been prepared and characterized. The material is based on MCM-41 particles functionalized with an N-hydroxysuccinimide derivative and loaded with Rhodamine 6G. The cargo is kept inside the porous material due to the formation of a double layer of organic matter. The inner layer is covalently bound to the silica particles, while the external layer is formed through hydrogen and hydrophobic interactions. The limits of detection determined by fluorimetric titration are 27 mu M and 45 mu M for Spm and Spd, respectively. The sensor remains silent in the presence of other biologically important amines and is able to detect Spm and Spd in both aqueous solution and cells.This research was funded by Spanish Government (RTI2018-100910-B-C42 and RTI2018100910-B-C44 (MCUI/AEI/FEDER, UE) and grant GRISOLIAP/2019/023.Barros, M.; López-Carrasco, A.; Amorós, P.; Gil Grau, S.; Gaviña, P.; Parra Alvarez, M.; El Haskouri, J.... (2021). Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine. Nanomaterials. 11(3):1-12. https://doi.org/10.3390/nano1103081811211

Topo-Iberia Project: CGPS crustal velocity field in the Iberian Peninsula and Morocco

A new continuous GPS network was installed under the umbrella of a research project called 'Geociencias en Iberia: Estudios integrados de topografı´a y evolución 4D (Topo-Iberia)', to improve understanding of kinematic behavior of the Iberian Peninsula region. Here we present a velocity field based on the analysis of the 4 years of data from 25 stations constituting the network, which were analyzed by three different analysis groups contributing to the project. Different geodetic software packages (GIPSY-OASIS, Bernese and GAMIT) as well as different approaches were used to estimate rates of present day crustal deformation in the Iberian Peninsula and Morocco. In order to ensure the consistency of the velocity fields determined by the three groups, the velocities obtained by each analysis center were transformed into a common Eurasia Reference Frame. After that, the strain rate field was calculated. The results put in evidence more prominent residual motions in Morocco and southernmost part of the Iberian Peninsula. In particular, the dilatation and shear strain rates reach their maximum values in the Central Betics and northern Alboran Sea. A small region of high shear strain rate is observed in the east-central part of the peninsula and another deformation focus is located around the Strait of Gibraltar and the Gulf of Cadiz

Identification and functional analysis of the cyclopropane fatty acid synthase of Brucella abortus

The brucellae are facultative intracellular pathogens of mammals that are transmitted by contact with infected animals or contaminated materials. Several major lipidic components of the brucella cell envelope are imperfectly recognized by innate immunity, thus contributing to virulence. These components carry large proportions of acyl chains of lactobacillic acid, a long chain cyclopropane fatty acid (CFA). CFAs result from addition of a methylene group to unsaturated acyl chains and contribute to resistance to acidity, dryness and high osmolarity in many bacteria and to virulence in mycobacteria. We examined the role of lactobacillic acid in Brucella abortus virulence by creating a mutant in ORF BAB1_0476, the putative CFA synthase gene. The mutant did not incorporate [(14)C]methyl groups into lipids, lacked CFAs and synthesized the unsaturated precursors, proving that BAB1_0476 actually encodes a CFA synthase. BAB1_0476 promoter-luxAB fusion studies showed that CFA synthase expression was promoted by acid pH and high osmolarity. The mutant was not attenuated in macrophages or mice, strongly suggesting that CFAs are not essential for B. abortus intracellular life. However, when the mutant was tested under high osmolarity on agar and acid pH, two conditions likely to occur on contaminated materials and fomites, they showed reduced ability to grow or survive. Since CFA synthesis entails high ATP expenses and brucellae produce large proportions of lactobacillic acyl chains, we speculate that the CFA synthase has been conserved because it is useful for survival extracellularly, thus facilitating persistence in contaminated materials and transmission to new hosts

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC

Pilot multi-omic analysis of human bile from benign and malignant biliary strictures: a machine-learning approach

Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.This research was funded by: Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa, grant numbers: PI16/01126 (M.A.A.), PI19/00819 (M.J.M. and J.J.G.M.), PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129 (J.M.B.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation), grant name: Rare Cancers 2017 (J.M.U., M.L.M., J.M.B., M.J.M., R.I.R.M., M.G.F.-B., C.B., M.A.A.); Gobierno de Navarra Salud, grant number 58/17 (J.M.U., M.A.A.); La Caixa Foundation, grant name: HEPACARE (C.B., M.A.A.); AMMF The Cholangiocarcinoma Charity, UK, grant number: 2018/117 (F.J.C. and M.A.A.); PSC Partners US, PSC Supports UK, grant number 06119JB (J.M.B.); Horizon 2020 (H2020) ESCALON project, grant number H2020-SC1-BHC-2018–2020 (J.M.B.); BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia, grant numbers BIO15/CA/016/BD (J.M.B.) and BIO15/CA/011 (M.A.A.). Department of Health of the Basque Country, grant number 2017111010 (J.M.B.). La Caixa Foundation, grant number: LCF/PR/HP17/52190004 (M.L.M.), Mineco-Feder, grant number SAF2017-87301-R (M.L.M.), Fundación BBVA grant name: Ayudas a Equipos de Investigación Científica Umbrella 2018 (M.L.M.). MCIU, grant number: Severo Ochoa Excellence Accreditation SEV-2016-0644 (M.L.M.). Part of the equipment used in this work was co-funded by the Generalitat Valenciana and European Regional Development Fund (FEDER) funds (PO FEDER of Comunitat Valenciana 2014–2020). Gobierno de Navarra fellowship to L.C. (Leticia Colyn); AECC post-doctoral fellowship to M.A.; Ramón y Cajal Program contracts RYC-2014-15242 and RYC2018-024475-1 to F.J.C. and M.G.F.-B., respectively. The generous support from: Fundación Eugenio Rodríguez Pascual, Fundación Echébano, Fundación Mario Losantos, Fundación M Torres and Mr. Eduardo Avila are acknowledged. The CNB-CSIC Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0001 (F.J.C.). Comunidad de Madrid Grant B2017/BMD-3817 (F.J.C.).Peer reviewe

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC