Effects on Rotational Dynamics of Azo and Hydrazodicarboxamide-Based Rotaxanes

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This manuscript version is made available under the CC-BY 4.0 license https://creativecommons.org/licenses/by/4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in Molecules. To access the final edited and published work see https://doi.org/10.3390/molecules22071078The synthesis of novel hydrogen-bonded [2]rotaxanes having two pyridine rings in the macrocycle and azo- and hydrazodicarboxamide-based templates decorated with four cyclohexyl groups is described. The different affinity of the binding sites for the benzylic amide macrocycle and the formation of programmed non-covalent interactions between the interlocked components have an important effect on the dynamic behavior of these compounds. Having this in mind, the chemical interconversion between the azo and hydrazo forms of the [2]rotaxane was investigated to provide a chemically-driven interlocked system enable to switch its circumrotation rate as a function of the oxidation level of the binding site. Different structural modifications were carried out to further functionalize the nitrogen of the pyridine rings, including oxidation, alkylation or protonation reactions, affording interlocked azo-derivatives whose rotation dynamics were also analyzed

Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways

Emerging evidence indicates that early-life exposure to environmental factors may increase the risk for schizophrenia via inflammatory mechanisms. Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine pathways in the maternal immune activation (MIA) animal model of schizophrenia. The potential reversion exerted by long-term antipsychotic treatment was also evaluated. MIA was induced by prenatal administration of polyinosinic:polycytidylic acid (poly (I:C)) in mice. Expression of different proteins and the content of different metabolites involved in the function of serotonergic and kynurenine pathways was assessed by RT-PCR, immunoblot and ELISA analyses in frontal cortex of the offspring after puberty. MIA decreased tissue 5-HT content and promoted changes in the expression of serotonin transporter, 5-HT2A and 5-HT2C receptors. Expression of indoleamine 2,3-dioxygenase 2 (IDO2) and kynurenine 3-monooxygenase (KMO) was increased by poly (I:C) whereas kynurenine aminotransferase II and its metabolite kynurenic acid were not altered. Long-term paliperidone was able to counteract MIA-induced changes in 5-HT and KMO, and to increase tryptophan availability and tryptophan hydroxylase-2 expression in poly (I:C) mice but not in controls. MIA-induced increase of the cytotoxic risk ratio of kynurenine metabolites (quinolinic/kynurenic acid) was also reversed by paliperidone. MIA induces specific long-term brain effects on serotonergic activity. Such effects seem to be related with alternative activation of the kynurenine metabolic pathway towards a cytotoxic status. Atypical antipsychotic paliperodine partially remediates abnormalities observed after MIA.This work was supported by MINECO-FEDER Funds (SAF201675500-R to JL; SAF2017-88126-R to JM); Centro de Investigacion en Red de Salud Mental, CIBERSAM; and the Basque Government (IT1211-19). Editoria

Caracterización microambiental de la Cueva de Pozalagua (Vizcaya): aplicación a la gestión y protección de cavidades turísticas

There are summarized the data obtained after monitoring some microenvironmental parameters in the Pozalagua cave from 1st April 2001 to 1st july 2002. The singularity of this show cave is because the high amount of helictites type speleothems. Host rock, speleothems and infiltration waters have been analysed as well as the effect of the visits into the cave have been evaluated. It is stated that visits influence the temperature and CO2 levels inside the cave and the natural system need some time in recover from this changes. During massive visits increase in cave temperature is over the natural annual thermal oscillation. Management guidelines focused in visits schedule have been proposed in order to minimize the effects of the visits and to keep the cave microenvironment near the natural conditions.Se presentan los datos obtenidos tras el registro en continuo de diversos parámetros microambientales en la Cueva de Pozalagua (Vizcaya) durante el período del 1 de abril de 2001 al 1 de julio de 2002. La singularidad de esta cueva turística se debe a la alta presencia de espeleotemas tipo excéntricas o helictitas. Tras la caracterización de la roca encajante y diversos espeleotemas, así como de la hidroquímica de las aguas de infiltración que circulan por la misma, se ha evaluado el efecto que tienen las visitas turísticas en esta cavidad. Se constata que las visitas influyen claramente en la temperatura de la cavidad y en los niveles de CO2 de la misma, de lo que el sistema natural tarda tiempo en recuperarse. En períodos de visitas masivas se ha comprobado que el incremento de temperatura que se produce en la cavidad es superior a la oscilación térmica natural de la misma durante un ciclo anual. Se proponen medidas de gestión de la cavidad, principalmente enfocadas a optimizar el régimen de visitas, que minimicen el impacto de las mismas y que permitan mantener las condiciones microambientales de la cavidad cercanas a las condiciones originales naturales

The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil

<p>Abstract</p> <p>Background</p> <p>Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H⁺-ATPase (β-F1-ATPase). The <it>bioenergetic signature </it>is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the <it>bioenergetic signature </it>of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU).</p> <p>Methods</p> <p>The <it>bioenergetic signature </it>of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the <it>bioenergetic signature </it>and the cell death response. <it>In vivo </it>tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells.</p> <p>Results</p> <p>We demonstrate that the <it>bioenergetic signature </it>of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the <it>bioenergetic signature </it>directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the <it>in vitro </it>cell-death responses associated with 3BrP, IA and 5-FU, the <it>in vivo </it>tumor regression activities of these agents were comparable.</p> <p>Conclusions</p> <p>Overall, we suggest that the determination of the <it>bioenergetic signature </it>of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression.</p

Manganese oxides as biominerals in a granitic subterranean environment

Black coatings were detected on granite surfaces in groundwater catch work tunnels from Porto city (NW Portugal). XRD, FTIR, Micro-Raman, ICP-MS, TEM-EDS, SEM-EDS and SEM-FIB were the analytical procedures carried out to investigate the origin of the black coatings. In this subterranean environment, the enrichment in metals and other trace elements, such as Mn and Fe, and clay minerals characterize the black microbial mats, mainly composed of Mn/Fe-oxidising bacteria.Fundação para a Ciência e a Tecnologia (FCT

Síntesis de la cronoestratigrafía y evolución sedimentaria de los sistemas lacustres evaporíticos y carbonatados neógenos de la Cuenca de Calatayud-Montalbán.

La Cuenca terciaria de Calatayud-Montalbán consta de dos subcuencas diferentes separadas por el umbral de Daroca (Cuenca de Calatayud en el sector septentrional y Cuenca de Montalbán en el sector meridional). Estas cuencas presentan una evolución sedimentaria muy similar de los sistemas lacustres neógenos evaporíticos y carbonáticos, que generalmente ocupan los sectores centrales de ambas depresiones. En la Cuenca de Calatayud, se reconocen tradicionalmente en el Neógeno tres unidades sedimentarias mayores denominadas Unidad Inferior, Intermedia y Superior separadas por dos rupturas sedimentarias principales. Las dos primeras tienen carácter evaporítico, mientras que la última tiene un carácter fluviolacustre. En los sectores centrales de la Cuenca de Montalbán, el sondeo Barrachina-l y las secciones estratigráficas complementarias han permitido apreciar una evolución sedimentaria muy similar para las unidades neógenas, con facies evaporíticas y carbonáticas muy parecidas, aunque con una cronoestratigrafía diferente y la ausencia del registro sedimentario del Mioceno medio a Plioceno. En este trabajo también se describe por vez primera la presencia de un nivel volcanoclástico intercalado entre las facies evaporíticas del Mioceno inferior de la Cuenca de Montalbán. Las asociaciones minerales identificadas en los depósitos lacustres del Mioceno inferiormedio de ambos sectores de la cuenca, muestran una secuencia que evoluciona desde facies lacustres evaporíticas de alto grado de hipersalinidad, hacia facies lacustres evaporíticas de baja-moderada salinidad. Solamente, el registro sedimentario de la Cuenca de Calatayud permite asegurar que esta evolución sedimentaria se completa con la presencia de facies carbonáticas fluviolacustres características de aguas dulces en el Mioceno superior. Esta secuencia de precipitación salina responde a un cambio progresivo en la hidroquímica de los sistemas lacustres relacionado con un cambio gradual de las condiciones climáticas que comenzaría en el Rambliense y se extendería, al menos, durante todo el Mioceno medio. Las diferencias cronoestratigráficas entre los dos sectores de la misma depresión deben estar relacionados con los diferentes condicionantes tectónicos y/o geomorfológicos a los que se han visto sometidas ambas cuencas durante el Mioceno. [ABSTRACT] The Tertiary Calatayud-Montalbán Basin consists of two distinct sub-basins separated by the Daroca High (Calatayud Basin in the northern sector and Montalbán Basin in the southern sector). These basins present a quite similar sedimentary evolution of the Neogene evaporitic and carbonatic lacustrine systems, that generally occupy central locations in both basins. Three main sedimentary units (Lower, Intermediate and Upper units) divided by two main sedimentary breaks are traditionally described in the Calatayud Basin. The Lower and Intermediate units have evaporitic sedimentation, whilst the Upper Unit is tipically freshwater fluviolacustrine sedimentation. In the central areas of the Montalbán basin, the Barrachina-l drill hole and complementary stratigraphic sections showed a very similar sedimentary evolution of the Neogene units, with similar evaporitic and carbonatic facies, but different chronostratigraphy. The Upper MiocenePliocene sedimentary record of the Montalbán Basin is absent. In addition, this work presents the first occurrence of a volcanoclastic layer interbedded in the Lower Miocene evaporitic facies of the Montalbán Basin. The identified mineral assemblages of the lacustrine deposits of both sectors of the basin, show an evolutionary sequence during the Lower-Middle Miocene from hypersaline to lower moderated salinity lacustrine facies. This evolutionary trend is only complete in the sedimentary record of the Calatayud Basin, where freshwater carbonatic fluviolacustrine facies are described in the Upper Miocene. This precipitation sequence is the result of a progressive hydrochemical change of the lacustrine systems related to a climatic change from the Ramblian to the Middle Miocene. Differences in the chronostratigraphy of both basins should be related to distinct tectonic scenarios and/or geomorphologic features during the Miocene

A study on the state of conservation of the Roman Necropolis of Carmona (Sevilla, Spain)

The Roman Necropolis of Carmona (Sevilla, Spain) has experienced a severe deterioration since the accidental discovery in 1868 and subsequent archaeological excavations starting in 1882. To this deterioration contributed the location in a soft calcarenite rock quarry, the adverse environmental conditions and the numerous and extensive wrong archaeological and managing interventions along more than a century. The cultural, artistic and religious importance of this Necropolis converts the protection and conservation of this archaeological site in a major issue. This work present the data obtained in a multidisciplinary research were geology, geomorphology, micro-environmental and climatic monitoring, rock petrophysical characterization, description of weathering forms and biological colonization were considered in order to propose corrective measures to minimize deterioration

Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Human Molecular Genetics 22.16 (2013): 3296-3305 is available online at http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=23604518X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous system characterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA. In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. We have formerly shown that an excess of the VLCFA C26:0 induces oxidative damage, which underlies the axonal degeneration exhibited by the Abcd1(-) mice. In the present study, we sought to investigate the noxious effects of C26:0 on mitochondria function. Our data indicate that in X-ALD patients' fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) triggering mitochondrial ROS production from electron transport chain complexes. This correlates with impaired complex V phosphorylative activity, as visualized by high-resolution respirometry on spinal cord slices of Abcd1(-) mice. Further, we identified a marked oxidation of key OXPHOS system subunits in Abcd1(-) mouse spinal cords at presymptomatic stages. Altogether, our results illustrate some of the mechanistic intricacies by which the excess of a fatty acid targeted to peroxisomes activates a deleterious process of oxidative damage to mitochondria, leading to a multifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALDThis study was supported by grants from the European Commission (FP7-241622), the European Leukodystrophy Association (ELA2009-036C5; ELA2008-040C4), the Spanish Institute for Health Carlos III (FIS PI080991 and FIS PI11/01043), the Autonomous Government of Catalonia (2009SGR85) to A.P. and the Spanish Institute for Health Carlos III (Miguel Servet program CP11/00080) to S.F. The CIBER on Rare Diseases (CIBERER) is an initiative of the ISCIII. The study was developed under the COST action BM0604 (to A.P.). J.L.-E. was a fellow of the Department of Education, Universities and Research of the Basque Country Government (BFI07.126). S.F. was a fellow of the European Leukodystrophy Association (ELA 2010-020F1). The studies conducted at the Department of Experimental Medicine were supported in part by R&D grants from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI), the Spanish Ministry of Health (PI11/1532), the Autonomous Government of Catalonia (2009SGR735), the ‘La Caixa’ Foundation and COST B35 Action of the European Union. D.C. is a fellow from the Spanish Ministry of Health (FI08-00707). The studies conducted at the Department of Biochemistry and Molecular Biology, University of Barcelona, were supported by grants SAF2008-01896 and SAF2011-23636 from the Spanish Ministry of Science and Innovatio