Publications by authors named "Félix Hernández"

348 Publications

Ecological risk assessment of pesticides in the Mijares River (eastern Spain) impacted by citrus production using wide-scope screening and target quantitative analysis.

J Hazard Mater 2021 Jun 2;412:125277. Epub 2021 Feb 2.

IMDEA Water Institute, Science and Technology Campus of the University of Alcalá, Avenida Punto Com 2, Alcalá de Henares, Madrid 28805, Spain; Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, c/ Catedrático José Beltrán 2, Paterna, Valencia 46980, Spain.

The widespread use of pesticides, especially in agricultural areas, makes necessary to control their presence in surrounding surface waters. The current study was designed to investigate the occurrence and ecological risks of pesticides and their transformation products in a Mediterranean river basin impacted by citrus agricultural production. Nineteen sites were monitored in three campaigns distributed over three different seasons. After a qualitative screening, 24 compounds was selected for subsequent quantitative analysis. As expected, the lower section of the river was most contaminated, with total concentration >5 µg/L in two sites near to the discharge area of wastewater treatment plants. The highest concentrations were found in September, after agricultural applications and when the river flow is reduced. Ecological risks were calculated using two mixture toxicity approaches (Toxic Unit and multi-substance Potentially Affected Fraction), which revealed high acute and chronic risks of imidacloprid to invertebrates, moderate-to-high risks of diuron, simazine and 2,4-D for primary producers, and moderate-to-high risks of thiabendazole for invertebrates and fish. This study shows that intensive agricultural production and the discharge of wastewater effluents containing pesticide residues from post-harvest citrus processing plants are threatening freshwater biodiversity. Further actions are recommended to control pesticide use and to reduce emissions.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125277DOI Listing
June 2021

A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer's disease.

Acta Neuropathol 2021 May 2. Epub 2021 May 2.

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM). Nicolás Cabrera, 1. Cantoblanco, 28049, Madrid, Spain.

Tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer's patients' brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer's disease and other tauopathies.
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http://dx.doi.org/10.1007/s00401-021-02317-zDOI Listing
May 2021

Changes in drug use in European cities during early COVID-19 lockdowns - A snapshot from wastewater analysis.

Environ Int 2021 Mar 26;153:106540. Epub 2021 Mar 26.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, Castellón, Spain; Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, the Netherlands. Electronic address:

The COVID-19 outbreak has forced countries to introduce severe restrictive measures to contain its spread. In particular, physical distancing and restriction of movement have had important consequences on human behaviour and potentially also on illicit drug use and supply. These changes can be associated with additional risks for users, in particular due to reduced access to prevention and harm reduction activities. Furthermore, there have been limitations in the amount of data about drug use which can be collected due to restrictions. To goal of this study was to obtain information about potential changes in illicit drug use impacted by COVID-19 restrictions. Wastewater samples were collected in seven cities in the Netherlands, Belgium, Spain and Italy at the beginning of lockdowns (March-May 2020). Using previously established and validated methods, levels of amphetamine (AMP), methamphetamine (METH), MDMA, benzoylecgonine (BE, the main metabolite of cocaine) and 11-nor-9-carboxy-Δ-tetrahydrocannabinol (THC-COOH, main metabolite of tetrahydrocannabinol (THC)) were measured and compared with findings from previous years. Important differences in levels of consumed drugs were observed across the considered countries. Whilst for some substances and locations, marked decreases in consumption could be observed (e.g., 50% decrease in MDMA levels compared to previous years). In some cases, similar or even higher levels compared to previous years could be found. Changes in weekly patterns were also observed, however these were not clearly defined for all locations and/or substances. Findings confirm that the current situation is highly heterogeneous and that it remains very difficult to explain and/or predict the effect that the present pandemic has on illicit drug use and availability. However, given the current difficulty in obtaining data due to restrictions, wastewater analysis can provide relevant information about the situation at the local level, which would be hard to obtain otherwise.
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http://dx.doi.org/10.1016/j.envint.2021.106540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997602PMC
March 2021

Use of ion mobility-high resolution mass spectrometry in metabolomics studies to provide near MS/MS quality data in a single injection.

J Mass Spectrom 2021 Mar 10;56(5):e4718. Epub 2021 Mar 10.

Analytical Chemistry and Public Health, Research Institute for Pesticides and Water (IUPA). Avda. Sos Baynat, s/n. University Jaume I, Castellón, Spain.

The use of ion mobility separations (IMSs) in metabolomics approaches has started to be deeply explored in the last years. In this work, the use of liquid chromatography (LC) coupled to IMS-quadrupole time-of-flight mass spectrometry (QTOF MS) has been evaluated in a metabolomics experiments using single injection of the samples. IMS has allowed obtaining cleaner fragmentation spectra, of nearly tandem MS quality, in data-independent acquisition mode. This is much useful in this research area as a second injection, generally applied in LC-QTOF MS workflows to obtain tandem mass spectra, is not necessary, saving time and evading possible compound degradation. As a case study, the smoke produced after combustion of herbal blends used to spray synthetic cannabinoids has been selected as study matrix. The smoke components were trapped in carbon cartridges, desorbed and analyzed by LC-IMS-QTOF MS using different separation mechanisms (reversed phase and HILIC) and acquiring in both positive and negative mode to widen the chemical domain. Partial Least Squares-Discriminant Analysis highlighted several compounds, and ratio between N-Isopropyl-3-(isoquinolinyl)-2-propen-1-amine and quinoline allowed differentiating between tobacco and herbal products. These two compounds were tentatively identified using the cleaner fragmentation spectra from a single injection in the IMS-QTOF MS, with additional confidence obtained by retention time (Rt) and collisional cross section (CCS) prediction using artificial neural networks. Data from this work show that LC-IMS-QTOF is an efficient technique in untargeted metabolomics, avoiding re-injection of the samples for elucidation purposes. In addition, the prediction models for Rt and CCS resulted of help in the elucidation process of potential biomarkers.
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http://dx.doi.org/10.1002/jms.4718DOI Listing
March 2021

The embodiment of wastewater data for the estimation of illicit drug consumption in Spain.

Sci Total Environ 2021 Jun 26;772:144794. Epub 2021 Jan 26.

Department of Analytical Chemistry, Nutrition and Food Sciences, Institute of Research in Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. Electronic address:

Data obtained from wastewater analysis can provide rapid and complementary insights in illicit drug consumption at community level. Within Europe, Spain is an important country of transit of both cocaine and cannabis. The quantity of seized drugs and prevalence of their use rank Spain at the top of Europe. Hence, the implementation of a wastewater monitoring program at national level would help to get better understanding of spatial differences and trends in use of illicit drugs. In this study, a national wastewater campaign was performed for the first time to get more insight on the consumption of illicit drugs within Spain. The 13 Spanish cities monitored cover approximately 6 million inhabitants (12.8% of the Spanish population). Untreated wastewater samples were analyzed for urinary biomarkers of amphetamine, methamphetamine, MDMA, cocaine, and cannabis. In addition, weekend samples were monitored for 17 new psychoactive substances. Cannabis and cocaine are the most consumed drugs in Spain, but geographical variations showed, for instance, comparatively higher levels of methamphetamine in Barcelona and amphetamine in Bilbao, with about 1-fold higher consumption of these two substances in such metropolitan areas. For amphetamine, an enantiomeric profiling was performed in order to assure the results were due to consumption and not to illegal dumping of production residues. Furthermore, different correction factors for the excretion of cannabis were used to compare consumption estimations. All wastewater results were compared with previously reported data, national seizure data and general population survey data, were a reasonable agreement was found. Daily and yearly drug consumption were extrapolated to the entire Spanish population with due precautions because of the uncertainty associated. These data was further used to estimate the retail drug market, where for instance cocaine illicit consumption alone was calculated to contribute to 0.2-0.5% of the Spanish gross domestic product (ca. 3000-6000 million Euro/year).
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http://dx.doi.org/10.1016/j.scitotenv.2020.144794DOI Listing
June 2021

New psychoactive substances in several European populations assessed by wastewater-based epidemiology.

Water Res 2021 May 27;195:116983. Epub 2021 Feb 27.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Environmental Sciences, Via Mario Negri 2, 20156, Milan, Italy.

Wastewater-based epidemiology (WBE) can be a useful tool to face some of the existing challenges in monitoring the use of new psychoactive substances (NPS), as it can provide objective and updated information. This Europe-wide study aimed to verify the suitability of WBE for investigating the use of NPS. Selected NPS were monitored in urban wastewater by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The main classical illicit drugs were monitored in the same samples to compare their levels with those of NPS. Raw composite wastewater samples were collected in 2016 and 2017 in 14 European countries (22 cities) following best practice sampling protocols. Methcathinone was most frequent (>65% of the cities), followed by mephedrone (>25% of the cities), and only mephedrone, methcathinone and methylone were found in both years. This study depicts the use of NPS in Europe, confirming that it is much lower than the use of classical drugs. WBE proved able to assess the qualitative and quantitative spatial and temporal profiles of NPS use. The results show the changeable nature of the NPS market and the importance of large WBE monitoring campaigns for selected priority NPS. WBE is valuable for complementing epidemiological studies to follow rapidly changing profiles of use of drugs.
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http://dx.doi.org/10.1016/j.watres.2021.116983DOI Listing
May 2021

Home visiting: A lifeline for families during the COVID-19 pandemic.

Arch Psychiatr Nurs 2021 02 22;35(1):129-133. Epub 2020 Oct 22.

Mary's Center, Washington, DC, United States of America.

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http://dx.doi.org/10.1016/j.apnu.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581421PMC
February 2021

Treatment of wastewater effluents from Bogotá - Colombia by the photo-electro-Fenton process: Elimination of bacteria and pharmaceutical.

Sci Total Environ 2021 Jun 29;772:144890. Epub 2021 Jan 29.

Grupo de Investigación en Ciencias Biológicas y Químicas (GIBIQS), Facultad de Ciencias, Universidad Antonio Nariño (UAN), Bogotá, Colombia. Electronic address:

In this work, the occurrences of bacteria families and relevant pharmaceuticals in municipal wastewater effluents from Bogotá (Colombia), and their treatment by the photo-electro-Fenton process were studied. Twenty-five representative pharmaceuticals (azithromycin, carbamazepine, ciprofloxacin, clarithromycin, diclofenac, enalapril, gabapentin, iopromide, metoprolol, sulfamethoxazole, trimethoprim, valsartan, clindamycin, erythromycin, levamisole, lincomycin, norfloxacin, oxolinic acid, phenazone, primidone, salbutamol, sulfadiazine, tetracycline, tramadol, and venlafaxine) were quantified in the effluent by LC-MS/MS analysis. Four of these target compounds (azithromycin, diclofenac, trimethoprim, norfloxacin) were found at concentrations that represent an environmental risk. In addition, several bacteria families related to water and foodborne diseases were identified in such effluents (e.g., Pseudomonadaceae, Campylobacteraceae, Aeromonadaceae, Enterobacteriaceae, and Bacteroidaceae), via shotgun-metagenomic technique. Then, a bench-scale photo-electro-Fenton (PEF) system equipped with a DSA anode (Ti/IrO-SnO) and a GDE cathode was applied to treat such effluents. After 60 min, this treatment led to a decrease in the ratio of the bacterial content in the original samples, ~150 thousand times, and a pondered removal of 66.12% for the pharmaceuticals. The study of the process pathways indicated that the bacteria and pharmaceuticals elimination mainly occurred through attacks of hydroxyl and chlorine radicals. Interestingly, in the case of pharmaceuticals, their environmental risk quotients were diminished after the PEF application. Furthermore, the prolonged action of this electrochemical process induced ~15% of mineralization and a significant reduction of the total DNA (removal >85%). Hence, the photo-electro-Fenton process showed to be a promising alternative to deal with municipal effluents for limiting the waterborne diseases, pollution by pharmaceuticals, and mobility/availability of genetic material coming from microorganisms.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144890DOI Listing
June 2021

Treatment of two sartan antihypertensives in water by photo-electro-Fenton using BDD anodes: Degradation kinetics, theoretical analyses, primary transformations and matrix effects.

Chemosphere 2021 May 30;270:129491. Epub 2020 Dec 30.

Grupo de Investigación en Ciencias Biológicas y Químicas, Facultad de Ciencias, Universidad Antonio Nariño (UAN), Bogotá D.C., Colombia. Electronic address:

Degradation of two representative antihypertensives, losartan (LOS) and valsartan (VAL) in water by photo-electro-Fenton (PEF), using a BDD anode in presence of sulfate anion was evaluated. PEF showed a fast elimination of these pollutants (>95% at 30 and 60 min of treatment for LOS and VAL, respectively). The main elimination route was the attacks of radicals produced in the system, having pseudo-first-order rate constants of 0.154 and 0.054 min for LOS and VAL, correspondingly. Theoretical analyses of atomic charges were performed to rationalize the antihypertensives reactivity toward the electrogenerated degrading agents. Afterwards, the primary transformation products were assessed. The transformation products revealed that the degrading species attack the biphenyl-tetrazole, imidazole, and alcohol moieties on LOS. Meanwhile, carboxylic and amide groups, plus the central nucleus, were modified on VAL. These moieties corresponded well with the electron-rich sites indicated by the theoretical calculations. Also, the PEF process removed between 33 and 38% of total organic carbon after 5 h of electrolysis. Finally, it was considered LOS treatment in presence of oxalic acid (a typical organic waste of pharmaceutical industry), in addition to the pollutant degradation in effluents from municipal sewage treatment plants by PEF at pH ∼5. Oxalic acid accelerated LOS degradation. Meanwhile, in the effluent, the process led to 64% of LOS removal after 120 min of treatment, indicating the high potentiality of PEF to degrade antihypertensives in water containing organic and inorganic substances.
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http://dx.doi.org/10.1016/j.chemosphere.2020.129491DOI Listing
May 2021

Glycolysis and gluconeogenesis: A teaching view.

J Biol Chem 2020 Dec 8;296:100016. Epub 2020 Dec 8.

Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CBMSO, CSIC-UAM, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jbc.2020.100016DOI Listing
December 2020

Safety in the use of ultrasound in rheumatology during the COVID-19 Pandemic. Spanish Society of Rheumatology positioning paper.

Reumatol Clin 2021 May 2;17(5):284-289. Epub 2020 Dec 2.

Servicio de Reumatología, Hospital Universitario Fundación Jiménez Díaz, Madrid, España.

Ultrasound is a widely implemented imaging modality in rheumatology practice that implies a great interaction between patient and professional. The COVID-19 pandemic requires a change in our clinical practice, through the adoption of new strategies that allow comprehensive care for our patients, guaranteeing the safety of both patients and healthcare professionals.

Objetive: Our objective was to develop practical recommendations, agreed among a panel of experts, on the use and safety of rheumatological ultrasound during the COVID-19 pandemic.

Methods: We performed a narrative review of the available literature. Based on the literature review, we produced preliminary recommendations that were subsequently agreed among a panel of experts using the Delphi methodology with a 1-5 Likert scale. Agreement for each recommendation was considered if 75% of the panel members scored the item ≥4 on the Likert scale.

Results: 5 overarching principles and 28 recommendations were issued and agreed among the panel. Group consensus was achieved in 100% of items.

Conclusions: The document provides useful information about preventive measures in the practice of ultrasound in rheumatology in times of a COVID-19 pandemic based on the experience and literature available to date.
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http://dx.doi.org/10.1016/j.reuma.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709584PMC
May 2021

Understanding the pharmacokinetics of synthetic cathinones: Evaluation of the blood-brain barrier permeability of 13 related compounds in rats.

Addict Biol 2020 Dec 2:e12979. Epub 2020 Dec 2.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, Jaume I University, Castellón, Spain.

Synthetic cathinones are the second most commonly seized new psychoactive substance family in Europe. These compounds have been related to several intoxication cases, including fatalities. Although the pharmacological effects, metabolism, and pharmacokinetics of cathinones have been studied, there is little information about the permeability of these compounds through the blood-brain barrier (BBB). This is an important parameter to understand the behavior and potency of cathinones. In this work, 13 selected cathinones have been analyzed in telencephalon tissue from Sprague-Dawley rats intraperitoneally dosed at 3 mg/kg. Our results revealed a direct relationship between compound polarity and BBB permeability, with higher permeability for the more polar cathinones. The chemical moieties present in the cathinone had an important impact on the BBB permeability, with lengthening of the α-alkyl chain or functionalization of the aromatic ring with alkyl moieties resulting in lower concentration in telencephalon tissue. Our data suggest that transport of cathinones is a carrier-mediated process, similar to cocaine transport across the BBB.
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http://dx.doi.org/10.1111/adb.12979DOI Listing
December 2020

Gas chromatography-mass spectrometry based untargeted volatolomics for smoked seafood classification.

Food Res Int 2020 11 18;137:109698. Epub 2020 Sep 18.

Enviromental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), University Jaume I, Av. Sos Baynat S/N, 12071 Castellón de la Plana, Spain.

With the increase of the demand of low flavouring smoked seafood products, there is a need of methodologies able to distinguish between different seafood treatments, as not all of them are allowed in all markers. Following this objective, in the present work an untargeted volatolomics approach was applied to identify volatile markers that demonstrate that Cold smoked products can be distinguished from Tasteless smoke neither Carbon monoxide treated seafood, which are prohibited in the European Union. The use of dynamic headspace for the volatile extraction followed by thermal desorption in combination with Gas Chromatography (GC) coupled to single quadrupole Mass Spectrometry (MS) has been employed for the determination of volatile composition of smoked fish. Data processing consisted on the use of PARADISe software, applied for GC/MS data treatment, followed by the multivariate analysis with PLS_Toolbox (MATLAB), and finally the creation and validation of statistical classification model. All 107 variables obtained allowed the construction of a model reaching the correct classification of 97% of the blind samples, while a simplified model with only 11 variables correctly classified up to 93% of the blind samples. These 11 compounds were elucidated to develop subsequent target volatolomics approaches, if needed. Ordered according to the importance in the classification model, the elucidated compounds were: 3-methyl-cyclopentanone, ethylbenzene, 2-methyl-2-cyclopenten-1-one, 2-methyl-benzofuran, furfuryl alcohol, 2-acetylfuran, acetophenone, guaiacol, 1-hydroxy-2-butanone, 4-vinylguaicol and acetoin. The results demonstrated the great potential of untargeted volatolomics for smoked seafood treatments classification.
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http://dx.doi.org/10.1016/j.foodres.2020.109698DOI Listing
November 2020

Identification of new, very long-chain polyunsaturated fatty acids in fish by gas chromatography coupled to quadrupole/time-of-flight mass spectrometry with atmospheric pressure chemical ionization.

Anal Bioanal Chem 2021 Feb 18;413(4):1039-1046. Epub 2020 Nov 18.

Research Institute for Pesticides and Water (IUPA), University Jaume I, Av. Sos Baynat S/N, 12071, Castellón, Spain.

The characterization of very long-chain (>C24) polyunsaturated fatty acids (VLC-PUFAs), which are essential in the vision, neural function, and reproduction of vertebrates, is challenging because of the lack of reference standards and their very low concentrations in certain lipid classes. In this research, we have developed a new methodology for VLC-PUFA identification based on gas chromatography coupled to quadrupole/time-of-flight mass spectrometry with an atmospheric pressure chemical ionization source (GC-APCI-QTOF MS). The mass accuracy attainable with the innovative QTOF instrument, together with the soft ionization of the APCI source, provides valuable information on the intact molecule, traditionally lost with electron ionization sources due to the extensive fragmentation suffered. We have identified, for the first time, VLC-PUFAs with chains up to 44 carbons in eyes, brain, and gonads of gilthead sea bream, a commercially important fish in the Mediterranean. The added value of ion mobility-mass spectrometry (IMS), recently developed in combination with GC-QTOF MS, and the contribution of the collisional cross section (CCS) parameter in the characterization of novel VLC-PUFAs (for which reference standards are not available) have been also evaluated. The methodology developed has allowed assessing qualitative differences between farmed and wild fish, and opens new perspectives in a still scarcely known field of research.
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http://dx.doi.org/10.1007/s00216-020-03062-0DOI Listing
February 2021

Improving Target and Suspect Screening High-Resolution Mass Spectrometry Workflows in Environmental Analysis by Ion Mobility Separation.

Environ Sci Technol 2020 12 19;54(23):15120-15131. Epub 2020 Nov 19.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellón, Spain.

Currently, the most powerful approach to monitor organic micropollutants (OMPs) in environmental samples is the combination of target, suspect, and nontarget screening strategies using high-resolution mass spectrometry (HRMS). However, the high complexity of sample matrices and the huge number of OMPs potentially present in samples at low concentrations pose an analytical challenge. Ion mobility separation (IMS) combined with HRMS instruments (IMS-HRMS) introduces an additional analytical dimension, providing extra information, which facilitates the identification of OMPs. The collision cross-section (CCS) value provided by IMS is unaffected by the matrix or chromatographic separation. Consequently, the creation of CCS databases and the inclusion of ion mobility within identification criteria are of high interest for an enhanced and robust screening strategy. In this work, a CCS library for IMS-HRMS, which is online and freely available, was developed for 556 OMPs in both positive and negative ionization modes using electrospray ionization. The inclusion of ion mobility data in widely adopted confidence levels for identification in environmental reporting is discussed. Illustrative examples of OMPs found in environmental samples are presented to highlight the potential of IMS-HRMS and to demonstrate the additional value of CCS data in various screening strategies.
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http://dx.doi.org/10.1021/acs.est.0c05713DOI Listing
December 2020

The key role of mass spectrometry in comprehensive research on new psychoactive substances.

J Mass Spectrom 2020 Oct 29:e4673. Epub 2020 Oct 29.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, Castellón, 12071, Spain.

New psychoactive substances (NPS) are a wide group of compounds that try to mimic the effects produced by the 'classical' illicit drugs, including cannabis (synthetic cannabinoids), cocaine and amphetamines (synthetic cathinones) or heroin (synthetic opioids), and which health effects are still unknown for most of them. Nowadays, more than 700 compounds are being monitored by official organisms, some of which have been recently identified in seizures and/or intoxication cases. Toxicological analysis plays a pivotal role in NPS research. A comprehensive investigation on NPS, from the first identification of a novel substance until its detection in drug users to help in diagnostics and medical treatment, requires the use of a wide variety of instruments and analytical strategies. This paper illustrates the key role of mass spectrometry (MS) along a comprehensive investigation on NPS. The synthetic cannabinoid XLR-11 and the synthetic cathinone 5-PPDi have been chosen as representative substances of the most consumed NPS families. Moreover, both compounds have been investigated at our laboratory in different stages of the three-step strategy considered in this article. The initial identification and characterisation of the compound in consumption products, the first reported metabolic pathway and the development of analytical methodologies for its determination (and/or their metabolites) in different toxicological samples are described. The analytical strategies and MS instruments are briefly discussed to show the reader the possibilities that MS instrumentation offer to analytical scientists. This publication aims to be a starting point for those interested on the NPS research field from an analytical chemistry point of view.
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http://dx.doi.org/10.1002/jms.4673DOI Listing
October 2020

In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice.

Stem Cell Reports 2020 11 22;15(5):1056-1066. Epub 2020 Oct 22.

Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CBMSO, CSIC-UAM, Madrid, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. Electronic address:

Post-translational epigenetic modifications take place in mouse neurons of the dentate gyrus (DG) with age. Here, we report that age-dependent reduction in H3K9 trimethylation (H3K9me3) is prevented by cyclic induction of the Yamanaka factors used for cell reprogramming. Interestingly, Yamanaka factors elevated the levels of migrating cells containing the neurogenic markers doublecortin and calretinin, and the levels of the NMDA receptor subunit GluN2B. These changes could result in an increase in the survival of newborn DG neurons during their maturation and higher synaptic plasticity in mature neurons. Importantly, these cellular changes were accompanied by an improvement in mouse performance in the object recognition test over long time. We conclude that transient cyclic reprogramming in vivo in the central nervous system could be an effective strategy to ameliorate aging of the central nervous system and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.stemcr.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663782PMC
November 2020

Overexpression of GSK-3β in Adult Tet-OFF GSK-3β Transgenic Mice, and Not During Embryonic or Postnatal Development, Induces Tau Phosphorylation, Neurodegeneration and Learning Deficits.

Front Mol Neurosci 2020 10;13:561470. Epub 2020 Sep 10.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.

GSK-3β or tau-kinase I is particularly abundant in the central nervous system (CNS), playing a key role in the pathogenesis of Alzheimer's disease (AD). Accordingly, transgenic mouse models overexpressing this kinase recapitulate some aspects of this disease, such as tau hyperphosphorylation, neuronal death, and microgliosis. These alterations have been studied in mouse models showing GSK-3β overexpression from birth. In this case, some of these alterations may be due to adaptations that occur during development. Here we explored the potential of the Tet-OFF conditional system in the murine CamKIIα-tTA/GSK-3β model to increase the activity of GSK-3β only during adulthood. To this end, the overexpression of GSK-3β remained OFF during embryonic and postnatal development by administration of doxycycline in drinking water for 6 months, while it was turned ON in adult animals by removal of the treatment for 6 months. In these conditions, the CamKIIα-tTA/GSK-3β mouse is characterized by an increase in phosphorylated tau, cell death, and microgliosis. Furthermore, the increase in GSK-3β expression in the adult animals triggered a cognitive deficit, as determined through the hippocampus-dependent object recognition test (OR). These results demonstrate that the GSK-3β plays a key role in AD and that previously published data with other transgenic models are neither caused by or a consequence of adaptations to high levels of the enzyme during development.
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http://dx.doi.org/10.3389/fnmol.2020.561470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511757PMC
September 2020

Protein Biomarkers for the Diagnosis of Alzheimer's Disease at Different Stages of Neurodegeneration.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain.

Mainly obtained from familial Alzheimer's disease patients' data, we know that some features of the neurodegenerative start several years before the appearance of clinical symptoms. In this brief review, we comment on some molecular and cellular markers appearing at different stages of the disease, before or once the clinical symptoms are evident. These markers are present in biological fluids or could be identified by image techniques. The combined use of molecular and cellular markers will be of interest to determine the development of the different phases of the disease.
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http://dx.doi.org/10.3390/ijms21186749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554800PMC
September 2020

Assessing alcohol consumption through wastewater-based epidemiology: Spain as a case study.

Drug Alcohol Depend 2020 10 19;215:108241. Epub 2020 Aug 19.

Water, Environmental, and Food Chemistry Unit (ENFOCHEM), Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Spain. Electronic address:

Background: In this study, an alternative and complementary method to those approaches currently used to estimate alcohol consumption by the population is described. This method, known as wastewater-based epidemiology (WBE), allows back-calculating the alcohol consumption rate in a given population from the concentrations of a selected biomarker measured in wastewater.

Methods: Composite (24-h) wastewater samples were collected at the inlet of 17 wastewater treatment plants located in 13 Spanish cities for seven consecutive days in 2018. The sampled area covered 12.8% of the Spanish population. Wastewater samples were analyzed to determine the concentration of ethyl sulfate, the biomarker used to back-calculate alcohol consumption.

Results: Alcohol consumption ranged from 4.5 to 46 mL/day/inhabitant. Differences in consumption were statistically significant among the investigated cities and between weekdays and weekends. WBE-derived estimates of alcohol consumption were comparable to those reported by its corresponding region in the Spanish National Health Survey in most cases. At the national level, comparable results were obtained between the WBE-derived annual consumption rate (5.7 ± 1.2 L ethanol per capita (aged 15+)) and that reported by the National Health Survey (4.7 L ethanol per capita (aged 15+)).

Conclusions: This is the largest WBE study carried out to date in Spain to estimate alcohol consumption rates. It confirms that this approach is useful for establishing spatial and temporal patterns of alcohol consumption, which could contribute to the development of health care management plans and policies. Contrary to established methods, it allows obtaining information in a fast and relatively economical way.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108241DOI Listing
October 2020

Occurrence and ecological risks of pharmaceuticals in a Mediterranean river in Eastern Spain.

Environ Int 2020 11 31;144:106004. Epub 2020 Jul 31.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), University Jaume I, Avda. Sos Baynat s/n, E-12071, Castellón, Spain. Electronic address:

Pharmaceuticals are biologically active molecules that may exert toxic effects to a wide range of aquatic organisms. They are considered contaminants of emerging concern due to their common presence in wastewaters and in the receiving surface waters, and the lack of specific regulations to monitor their environmental occurrence and risks. In this work, the environmental exposure and risks of pharmaceuticals have been studied in the Mijares River, Eastern Mediterranean coast (Spain). A total of 57 surface water samples from 19 sampling points were collected in three monitoring campaigns between June 2018 and February 2019. A list of 40 compounds was investigated using a quantitative target UHPLC-MS/MS method. In order to complement the data obtained, a wide-scope screening of pharmaceuticals and metabolites was also performed by UHPLC-HRMS. The ecological risks posed by the pharmaceutical mixtures were evaluated using species sensitivity distributions built with chronic toxicity data for aquatic organisms. In this study, up to 69 pharmaceuticals and 9 metabolites were identified, out of which 35 compounds were assessed using the quantitative method. The highest concentrations in water corresponded to acetaminophen, gabapentin, venlafaxine, valsartan, ciprofloxacin and diclofenac. The compounds that were found to exert the highest toxic pressure on the aquatic ecosystems were principally analgesic/anti-inflammatory drugs and antibiotics. These were: phenazone > azithromycin > diclofenac, and to a lower extent norfloxacin > ciprofloxacin > clarithromycin. The monitored pharmaceutical mixtures are expected to exert severe ecological risks in areas downstream of WWTP discharges, with the percentage of aquatic species affected ranging between 65% and 82% in 3 out of the 19 evaluated sites. In addition, five antibiotics were found to exceed antibiotic resistance thresholds, thus potentially contributing to resistance gene enrichment in environmental bacteria. This work illustrates the wide use and impact of pharmaceuticals in the area under study, and the vulnerability of surface waters if only conventional wastewater treatments are applied. Several compounds included in this study should be incorporated in future water monitoring programs to help in the development of future regulations, due to their potential risk to the aquatic environment.
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http://dx.doi.org/10.1016/j.envint.2020.106004DOI Listing
November 2020

Tau Protein as a New Regulator of Cellular Prion Protein Transcription.

Mol Neurobiol 2020 Oct 18;57(10):4170-4186. Epub 2020 Jul 18.

Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), Baldiri and Reixac 15-21, 08028, Barcelona, Spain.

Cellular prion protein (PrP) is largely responsible for transmissible spongiform encephalopathies (TSEs) when it becomes the abnormally processed and protease resistant form PrP. Physiological functions of PrP include protective roles against oxidative stress and excitotoxicity. Relevantly, PrP downregulates tau levels, whose accumulation and modification are a hallmark in the advance of Alzheimer's disease (AD). In addition to the accumulation of misfolded proteins, in the initial stages of AD-affected brains display both increased reactive oxygen species (ROS) markers and levels of PrP. However, the factors responsible for the upregulation of PrP are unknown. Thus, the aim of this study was to uncover the different molecular actors promoting PrP overexpression. In order to mimic early stages of AD, we used β-amyloid-derived diffusible ligands (ADDLs) and tau cellular treatments, as well as ROS generation, to elucidate their particular roles in human PRNP promoter activity. In addition, we used specific chemical inhibitors and site-specific mutations of the PRNP promoter sequence to analyze the contribution of the main transcription factors involved in PRNP transcription under the analyzed conditions. Our results revealed that tau is a new modulator of PrP expression independently of ADDL treatment and ROS levels. Lastly, we discovered that the JNK/c-jun-AP-1 pathway is involved in increased PRNP transcription activity by tau but not in the promoter response to ROS.
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http://dx.doi.org/10.1007/s12035-020-02025-xDOI Listing
October 2020

Assessing population exposure to phthalate plasticizers in thirteen Spanish cities through the analysis of wastewater.

J Hazard Mater 2021 01 22;401:123272. Epub 2020 Jun 22.

Department of Analytical Chemistry, Institute of Research on Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

Phthalates are widely used plasticizers that produce endocrine-disrupting disorders. Quantifying exposure is crucial to perform risk assessments and to develop proper health measures. Herein, a wastewater-based epidemiology approach has been applied to estimate human exposure to six of the mostly used phthalates within the Spanish population. Wastewater samples were collected over four weekdays from seventeen wastewater treatment plants serving thirteen cities and ca. 6 million people (12.8 % of the Spanish population). Phthalate metabolite loads in wastewater were transformed into metabolite concentrations in urine and into daily exposure levels to the parent phthalates. Considering all the sampled sites, population-weighted overall means of the estimated concentrations in urine varied between 0.7 ng/mL and 520 ng/mL. Very high levels, compared to human biomonitoring data, were estimated for monomethyl phthalate, metabolite of dimethyl phthalate. This, together with literature data pointing to other sources of this metabolite in sewage led to its exclusion for exposure assessments. For the remaining metabolites, estimated concentrations were closer to those found in urine. Their 4-days average exposure levels ranged from 2 to 1347 μg/(day∙inh), exceeding in some sites the daily exposure thresholds set for di-i-butyl phthalate and di-n-buthyl phthalate by the European Food Safety Authority.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123272DOI Listing
January 2021

First nation-wide estimation of tobacco consumption in Spain using wastewater-based epidemiology.

Sci Total Environ 2020 Nov 20;741:140384. Epub 2020 Jun 20.

Department of Analytical Chemistry, Institute of Research on Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address:

Wastewater-based epidemiology (WBE) has become a very useful tool to monitor a population's drug consumption or exposure to environmental and food contaminants. In this work, WBE has been applied to estimate tobacco consumption in seven Spanish regions. To this end, 24 h composite wastewater samples were taken daily for one week in 17 wastewater treatment plants, covering altogether a population of ca. 6 million inhabitants. The samples were treated by enzymatic deconjugation and the wastewater content of two human-specific nicotine metabolites (namely, cotinine and trans-3'-hydroxycotinine) was measured to estimate the daily consumption of nicotine. The population-weighted average nicotine consumption in the seven analyzed regions was 2.2 g/(day∙1000 inh.), without any daily pattern. This average estimated nicotine consumption value agreed with the value derived from official tobacco sales data. Differences in consumption among the seven studied regions were found, being Galicia, the region with the lowest rate, and the Basque Country and Catalonia those with the highest rates. However, no conclusive correlation was found between those values and the prevalence data taken from two different national surveys, nor sociodemographic and health data. This study demonstrates that this tool can complement other indicators in order to accurately assess tobacco consumption rates at regional and national levels and provides the most extensive application of the approach in the Spanish territory.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140384DOI Listing
November 2020

ACE2 is on the X chromosome: could this explain COVID-19 gender differences?

Eur Heart J 2020 06;41(32):3095

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain.

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http://dx.doi.org/10.1093/eurheartj/ehaa521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337796PMC
June 2020

Focal cerebral ischemia induces changes in oligodendrocytic tau isoforms in the damaged area.

Glia 2020 12 9;68(12):2471-2485. Epub 2020 Jun 9.

Departamento de Biología (Fisiología Animal), Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.

Ischemic stroke is a major cause of death and the first leading cause of long-term disability worldwide. The only therapeutic strategy available to date is reperfusion and not all the patients are suitable for this treatment. Blood flow blockage or reduction leads to considerable brain damage, affecting both gray and white matter. The detrimental effects of ischemia have been studied extensively in the former but not in the latter. Previous reports indicate that preservation of white matter integrity reduces deleterious effect of ischemia on the brain. Oligodendrocytes are sensitive to ischemic damage, however, some reports demonstrate that oligodendrogenesis occurs after ischemia. These glial cells have a complex cytoskeletal network, including tau, that plays a key role to proper myelination. 4R-Tau/3R-Tau, which differ in the presence/absence of Exon 10, are found in oligodendrocytes; but the precise role of each isoform is not understood. Using permanent middle cerebral artery occlusion model and immunofluorescence, we demonstrate that cerebral ischemia induces an increase in 3R-Tau versus 4R-Tau in oligodendrocytes in the damaged area. In addition, cellular distribution of Tau undergoes a change after ischemia, with some oligodendrocytic processes showing positive staining for 3R-Tau. This occurs simultaneously with the amelioration of neurological damage in ischemic rats. We propose that ischemia triggers an endogenous mechanism involving 3R-Tau, that induces colonization of the ischemic damaged area by oligodendrocytes in an attempt to myelinate-injured axons. Understanding the molecular mechanism of this phenomenon could pave the way for the design of therapeutic strategies that exploit glial cells for the treatment of ischemia.
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http://dx.doi.org/10.1002/glia.23865DOI Listing
December 2020

Direct and Fast Screening of New Psychoactive Substances Using Medical Swabs and Atmospheric Solids Analysis Probe Triple Quadrupole with Data-Dependent Acquisition.

J Am Soc Mass Spectrom 2020 Jul 9;31(7):1610-1614. Epub 2020 Jun 9.

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, 12071 Castellón, Spain.

New psychoactive substances (NPS) have become a serious public health problem, as they are continuously changing their structures and modifying their potency and effects on humans, and therefore, novel compounds are unceasingly appearing. One of the major challenges in forensic analysis, particularly related to the problem of NPS, is the development of fast screening methodologies that allow the detection of a wide variety of compounds in a single analysis. In this study, a novel application of the atmospheric solids analysis probe (ASAP) using medical swabs has been developed. The swab-ASAP was coupled to a triple quadrupole mass analyzer working under a data-dependent acquisition mode in order to perform a suspect screening of NPS in different types of samples as well as on surfaces. The compounds were automatically identified based on the observed fragmentation spectra using an in-house built MS/MS spectra library. The developed methodology was applied for the identification of psychoactive substances in research chemicals and herbal blends. The sensitivity of the method, as well as its applicability for surface analysis, was also assessed by identifying down to 1 μg of compound impregnated onto a laboratory table. Another remarkable application was the identification of cathinones and synthetic cannabinoids on the fingers of potential consumers. Interestingly, our data showed that NPS could be identified on the fingers after being in contact with the product and even after cleaning their hands by shaking off with a cloth. The methodology proposed in this paper can be applied for routine analyses of NPS in different matrix samples without the need to establish a list of target compounds prior to analysis.
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http://dx.doi.org/10.1021/jasms.0c00112DOI Listing
July 2020

Metabolic profiling of four synthetic stimulants, including the novel indanyl-cathinone 5-PPDi, after human hepatocyte incubation.

J Pharm Anal 2020 Apr 28;10(2):147-156. Epub 2019 Dec 28.

Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, 12071, Castellón, Spain.

Synthetic cathinones are new psychoactive substances that represent a health risk worldwide. For most of the 130 reported compounds, information about toxicology and/or metabolism is not available, which hampers their detection (and subsequent medical treatment) in intoxication cases. The principles of forensic analytical chemistry and the use of powerful analytical techniques are indispensable for stablishing the most appropriate biomarkers for these substances. Human metabolic fate of synthetic cathinones can be assessed by the analysis of urine and blood obtained from authentic consumers; however, this type of samples is limited and difficult to access. In this work, the metabolic behaviour of three synthetic cathinones (4-CEC, 4-CPrC and 5-PPDi) and one amphetamine (3-FEA) has been evaluated by incubation with pooled human hepatocytes and metabolite identification has been performed by high-resolution mass spectrometry. This approach has previously shown its feasibility for obtaining excretory human metabolites. 4-CEC and 3-FEA were not metabolised, and for 4-CPrC only two minor metabolites were obtained. On the contrary, for the recently reported 5-PPDi, twelve phase I metabolites were elucidated. Up to our knowledge, this is the first metabolic study of an indanyl-cathinone. Data reported in this paper will allow the detection of these synthetic stimulants in intoxication cases, and will facilitate future research on the metabolic behaviour of other indanyl-based cathinones.
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http://dx.doi.org/10.1016/j.jpha.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192961PMC
April 2020