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Design of small non-peptidic ligands that alter heteromerization between cannabinoid CB1 and serotonin 5HT2A receptors
No full textActivation of cannabinoid CB1 receptors (CB1R) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CB1R and the serotonin 5HT2A receptor (5HT2AR). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CB1R, which are predicted to bind 5HT2AR and alter the stability of the CB1R-5HT2AR heteromer, have been shown to avert CB1R agonist-induced cognitive impairment while preserving analgesia. Using these peptides as templates, we have now designed nonpeptidic small molecules that prevent CB1R-5HT2AR heteromerization in bimolecular fluorescence complementation assays and the heteromerization-dependent allosteric modulations in cell signaling experiments. These results provide proof-of-principle for the design of optimized ligand-based disruptors of the CB1R-5HT2AR heteromer, opening new perspectives for in vivo studies.We acknowledge the financial support from the Spanish Ministry of Economy and Innovation with FEDER funds (projects PID2020-113938RB-I00, PID2022-140912OB-I00, and PID2023-146914OB-I00) and Generalitat de Catalunya (2021-SGR-00230 and 2021-SGR-00304). S.F. is funded with the intramural funds of the National Institute on Drug Abuse (ZIA DA000493). Work at MELIS-UPF is supported by the MCIN “María de Maeztu” program for units of excellence in R&D (CEX2018-000792-M). The authors thankfully acknowledge the computer resources at MareNostrum and the technical support provided by the Barcelona Supercomputing Center (RES-BCV-2024-2-0002)
The Cost of sybils
No full textThis thesis explores Sybil strategies in decentralized and anonymous systems,
focusing on blockchain technology. Combining blockchain insights with game
theory, mechanism design, and machine learning, the research analyzes Sybil
attacks and their implications. It establishes a theoretical foundation by formalizing
permissionless games and Sybil extension mechanisms and applies machine
learning to detect scams on decentralized exchanges, showcasing automated
methods for identifying Sybil-related activities.
A game-theoretical analysis of Miner Extractable Value (MEV) reveals Sybil
strategies’ impact on transaction ordering and economic outcomes. The research
examines cost-sharing mechanisms for public goods, highlighting vulnerabilities
to Sybil strategies and proposing Sybil-resistant solutions applicable to
blockchain technology.
This thesis enhances our understanding of Sybil strategies and their mitigation
in decentralized systems, offering insights for designing more secure
blockchain networks. It provides a comprehensive framework for analyzing
strategic behaviors in permissionless environments, contributing to efforts to
improve the robustness of decentralized systems against strategic manipulations.El nostre treball explora les estratègies de Sybil en sistemes descentralitzats i
anònims, amb un enfocament en la tecnologia blockchain. Combinant coneixements
de blockchain amb teoria de jocs, disseny de mecanismes i aprenentatge
automàtic, la investigaci´o analitza els atacs Sybil i les seves implicacions.
S’estableix una base teòrica formalitzant jocs sense permís i mecanismes
d’extensió Sybil i s’aplica l’aprenentatge automàtic per detectar estafes
en intercanvis descentralitzats, mostrant mètodes automatitzats per identificar
activitats relacionades amb Sybil.
Una anàlisi de teoria de jocs del Valor Extractable pel Miner (MEV) revela
l’impacte de les estratègies Sybil en l’ordre de les transaccions i els resultats
econòmics. La investigació examina mecanismes de repartiment de costos per
béns públics, destacant vulnerabilitats a les estratègies Sybil i proposant solucions
resistents a Sybil aplicables a la tecnologia blockchain.
Aquesta tesi millora la nostra comprensió de les estratègies Sybil i la seva
mitigació en sistemes descentralitzats, oferint coneixements per dissenyar xarxes
blockchain més segures. Proporciona un marc comprensiu per analitzar comportaments
estratègics en entorns sense permís, contribuint als esfor¸cos per millorar
la robustesa dels sistemes descentralitzats contra manipulacions estratègiques.Programa de Doctorat en Tecnologies de la Informació i les Comunicacion
The pathways of secretory cargo export at the endoplasmic reticulum
No full textPalade's original model proposed that secretory cargo is transported between stable compartments via vesicles. However, recent findings challenge this view, suggesting that secretory pathway compartments are dynamic, with cargo itself dictating whether transfer occurs via vesicles or through the continuity and maturation of compartmental structures. At the heart of this process is TANGO1, a key component of a molecular machine that works in concert with COPII proteins to construct export routes tailored to the size and quantity of secretory cargo.I extend my heartfelt gratitude to Jeremy Thorner and Ishier Raote for their invaluable assistance in refining this text. I thank Agustin Lujan (Malhotra Lab, CRG) for providing Fig. 1 in this document. I acknowledge financial support from the following sources: Ministerio de Economía y Competitividad (IJCSEV-2012-0208, BFU2013-649 44188-P, and CSD2009-00016 to V.M.) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 951146)
The Legal Regulation Framework for the Artificial General Intelligence
No full textThis research addresses the problem of what legal regulation framework
would ensure the trustworthiness of artificial general intelligence? It
aims to develop such a legal regulation framework by employing
interdisciplinary research methods and under the assumption of the
singularity scenario. To achieve the aim and address the scientific
problem, six objectives are implemented within the six parts of this thesis.
The theoretical part of this thesis begins with validating the singularity
scenario assumption, continues with a summary of the genesis and
content of the AI Act, and concludes with an explanation of the
foundations of neo-institutional analysis. Having done this, the following
three chapters answer the “what, who, and how” questions. It starts with
the content analysis of systematically selected literature to map the AGI
risks landscape, continues with the discourse on the application of
electronic legal personhood in AGI regulation, and concludes with
developing a legal regulation framework for the AGI.Aquesta recerca persegueix identificar quin marc regulatori podria
assegurar una intel·ligència artificial general (AGI) més fiable. Amb la
finalitat de desenvolupar aquest marc de regulació jurídica, s’usen
mètodes de recerca interdisciplinaris i es parteix de l’assumpció de
l'escenari de la singularitat. Per assolir aquesta finalitat i abordar el
problema científic, s’han desplegat sis objectius dins de les sis parts que
composen aquesta tesi. La part teòrica d'aquesta tesi comença amb la
validació de l’assumpció de l'escenari de la singularitat, continua amb un
resum de la gènesi i el contingut del Reglament d'IA, i conclou amb una
explicació dels fonaments de l'anàlisi neoinstitucional. A continuació, els
tres capítols següents responen les preguntes "què, qui i com". Comença
amb l'anàlisi sistemàtica de contingut de literatura seleccionada per a
mapar les diferents constel·lacions de riscos associats a l'AGI, continua
amb el discurs sobre l'aplicació de la personalitat jurídica electrònica en
la regulació de l'AGI, i conclou amb el desenvolupament d'un marc de
regulació jurídica per a l'AGI.Esta investigación persigue identificar qué marco regulatorio podría
asegurar una inteligencia artificial general (AGI) más fiable. Con el fin
de desarrollar este marco de regulación jurídica, se usan métodos de
investigación interdisciplinares y se parte de la asunción del escenario de
la singularidad. Para lograr este fin y abordar el problema científico, se
han desplegado seis objetivos en las seis partes que componen esta tesis.
La parte teórica de esta tesis comienza con la validación de la asunción
del escenario de la singularidad, continúa con un resumen de la génesis
y contenido del Reglamento de IA, y concluye con una explicación de
los fundamentos del análisis neoinstitucional. A continuación, los tres
capítulos siguientes responden a las preguntas "qué, quién y cómo".
Empieza con el análisis sistemático de contenido de literatura
seleccionado para mapear las diferentes constelaciones de riesgos
asociados a la AGI, continúa con el discurso sobre la aplicación de la
personalidad jurídica electrónica en la regulación de la AGI, y concluye
con el desarrollo de un marco de regulación jurídica para la AGI.Programa de Doctorat en Dre
Mutual coupling in holographic MIMO: physical modeling and information-theoretic analysis
No full textThis paper presents a comprehensive framework for holographic multiantenna communication, a paradigm that integrates both wide apertures and closely spaced antennas relative to the wavelength. The presented framework is physically grounded, enabling information-theoretic analyses that inherently incorporate correlation and mutual coupling among the antennas. This establishes the combined effects of correlation and coupling on the information-theoretic performance limits across SNR levels. Additionally, it reveals that, by suitably selecting the individual antenna patterns, mutual coupling can be harnessed to either reinforce or counter spatial correlations as appropriate for specific SNRs, thereby improving the performance.This work was supported in part by the MICIU under the Maria de Maeztu Units of Excellence Programme under Grant CEX2021-001195-M; in part by ICREA; and in part by AGAUR (Catalan Government)
Transforming the legal landscape with blockchain: an examination of kleros as a decentralised dispute resolution system
No full textThis research investigates the transformative potential of blockchain technology within the legal landscape, with a specific focus on Kleros as a decentralised dispute resolution system. By examining the theoretical foundations, technological aspects, and legal implications of blockchain, this study provides critical insights into how this technology can reshape legal processes. It highlights the limitations of traditional legal systems and explores how blockchain’s inherent features—such as transparency, immutability, and efficiency—can effectively address these challenges. The research delves into Kleros as an innovative alternative for dispute resolution, underscoring its advantages in terms of transparency, cost-effectiveness, and accessibility. It also addresses significant legal issues related to blockchain implementation, including privacy, data protection, and regulatory compliance. Furthermore, the potential of smart contracts is explored as a means to enhance contractual relationships and mitigate legal concerns. This study emphasises the urgent need for balanced regulatory frameworks that can effectively govern four key areas: cryptocurrency transactions, smart contracts, blockchain-based data storage, and Initial Coin Offerings (ICOs). Through an analysis of international conventions, the research advocates for concrete regulatory proposals aimed at fostering innovation, protecting user rights, and ensuring legal compliance within the dynamic realm of blockchain technology.Esta investigación examina el potencial transformador de la tecnología blockchain en el ámbito jurídico, centrándose en Kleros como un sistema descentralizado de resolución de disputas. A través del análisis de los fundamentos teóricos, los aspectos tecnológicos y las implicaciones legales del blockchain, este estudio ofrece perspectivas críticas sobre cómo esta tecnología puede reconfigurar los procesos legales. Se destacan las limitaciones de los sistemas legales tradicionales y se explora cómo las características intrínsecas del blockchain—como la transparencia, la inmutabilidad y la eficiencia—pueden abordar eficazmente estos desafíos. La investigación profundiza en Kleros como una alternativa innovadora para la resolución de disputas, resaltando sus ventajas en términos de transparencia, coste-efectividad y accesibilidad. También se abordan cuestiones legales significativas relacionadas con la implementación del blockchain, incluyendo la privacidad, la protección de datos y el cumplimiento normativo. Además,
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se investiga el potencial de los contratos inteligentes para mejorar las relaciones contractuales y mitigar preocupaciones legales. Este estudio enfatiza la urgente necesidad de marcos regulatorios equilibrados que puedan gestionar de manera efectiva cuatro áreas clave: transacciones de criptomonedas, contratos inteligentes, almacenamiento de datos basado en blockchain y Ofertas Iniciales de Monedas (ICOs). A través de un análisis de convenios internacionales, la investigación aboga por propuestas regulatorias concretas destinadas a fomentar la innovación, proteger los derechos de los usuarios y garantizar el cumplimiento legal dentro del dinámico ámbito de la tecnología blockchain.Programa de Doctorat en Dre
Aplicación de sistemas de IA en un trabajo de final de máster universitario: presentación de un caso
No full textEn el contexto académico actual, el uso de herramientas de inteligencia artificial (IA) se ha convertido en una estrategia emergente para mejorar la eficiencia y calidad de los trabajos de investigación. La IA permite a los investigadores optimizar la búsqueda de literatura, sistematizar información y facilitar la construcción de marcos teóricos y metodológicos. A medida que estas tecnologías avanzan, su implementación en la academia plantea nuevas oportunidades y desafíos, lo que requiere un análisis crítico de sus ventajas y limitacionesEste informe forma parte de las publicaciones de metodología, innovación docente y transferencia del proyecto "Parámetros y estrategias para incrementar la relevancia de los medios y la comunicación digital en la sociedad: curación, visualización y visibilidad (CUVICOM)” financiado por MICIU/AEI/PID2021-123579OB-I00 y por FEDER/UE
Ambient air pollution and childhood obesity from infancy to late childhood: An individual participant data meta-analysis of 10 European birth cohorts
No full textAmbient air pollution may contribute to childhood obesity through various mechanisms. However, few longitudinal studies examined the relationship between pre- and postnatal exposure to air pollution and obesity outcomes in childhood. We aimed to investigate the association between pre- and postnatal exposure to air pollution and body mass index (BMI) and the risk of overweight/obesity throughout childhood in European cohorts. This study included mother-child pairs from 10 European birth cohorts (n = 37111 (prenatal), 33860 (postnatal)). Exposure to nitrogen dioxide (NO2) and fine particulate matter with aerodynamic diameter < 2.5 µm (PM2.5) was estimated at the home addresses during pre- and postnatal periods (year prior outcome assessment). BMI z-scores (continuous) and overweight/obesity status (categorical: zBMI≥+2 (<5 years) or ≥+1 (≥5 years) standard deviations) were derived at 0-2, 2-5, 5-9, 9-12 years. Associations between air pollution exposure and zBMI were estimated separately for each pollutant and cohort using linear and logistic longitudinal mixed effects models, followed by a random-effects meta-analysis. The overweight/obesity prevalence ranged from 12.3-40.5 % between cohorts at 0-2 years, 16.7-35.3 % at 2-5 years, 12.5-40.7 % at 5-9 years, and 10.7-43.8 % at 9-12 years. Results showed no robust associations between NO2 exposure and zBMI or overweight/obesity risk. Exposure to PM2.5 during pregnancy was associated with 23 % (95%CI 1.05;1.37) higher overweight/obesity risk across childhood, and higher zBMI and overweight/obesity risk at 9-12 years. Heterogeneity between cohorts was considerable (I2:25-89 %), with some cohort-specific associations; e.g., pre- and postnatal exposure to PM2.5 was associated with lower zBMI across age periods in UK cohorts (ALSPAC and BiB), while postnatal exposure to PM2.5 and NO2 was associated with higher zBMI in one Dutch cohort (Generation R). Overall, this large-scale meta-analysis suggests that prenatal PM2.5 exposure may be associated with adverse childhood obesity outcomes, but provides no evidence to support an effect of postnatal air pollution exposure, although cohort-specific associations were observed.The LifeCycle project received funding from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 733,206 LifeCycle). This study was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874583 (ATHLETE project). ABCD: Core funding of the ABCD-study was provided by the Amsterdam University Medical center, Amsterdam, the Public Health Services, Amsterdam, and the Dutch Organization for Health Research and Development (ZonMw). ALSPAC: Core funding for the Avon Longitudinal Study of Parents and Children (ALSPAC) is provided by the UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol. A comprehensive list of grants funding is available on the ALSPAC website (https://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). BiB: Born in Bradford receives funding from by a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) [MR/N024391/1]; the British Heart Foundation [CS/16/4/32482]; a Wellcome Infrastructure Grant [WT101597MA]; the National Institute for Health Research under its Applied Research Collaboration for Yorkshire and Humber [NIHR200166]; and was supported by UK Research and Innovation for the Healthy Urban Places consortium (grant reference MR/Y022785/1) as part of Population Health Improvement UK (PHI-UK), a national research network which works to transform health and reduce inequalities through change at the population level. The views expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. DNBC: The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation and other minor grants. The DNBC Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. Follow-up of mothers and children have been supported by the Danish Medical Research Council (SSVF 0646, 271-08-0839/06-066023, O602-01042B, 0602-02738B), the Lundbeck Foundation (195/04, R100-A9193), The Innovation Fund Denmark 0603-00294B (09-067124), the Nordea Foundation (02-2013-2014), Aarhus Ideas (AU R9-A959-13-S804), University of Copenhagen Strategic Grant (IFSV 2012), and the Danish Council for Independent Research (DFF – 4183-00594 and DFF − 4183-00152). EDEN: The EDEN study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale a complementary health insurance (MGEN), French national agency for food security, French speaking association for the study of diabetes and metabolism (ALFEDIAM).
Gen R: The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. This project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect grant agreement No 824989; ATHLETE, grant agreement No 874583; LongITools, grant agreement No 874739). VJ received funding from a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). INMA: This study was funded by grants from the Instituto de Salud Carlos III (Red INMA G03/176) and the Generalitat de Catalunya-CIRIT (1999SGR 00241). INMA-Valencia was funded by Grants from UE (FP7-ENV-2011 cod 282,957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249). INMA-Gipuzkoa was funded by grants from the Instituto de Salud Carlos III (FISFIS PI06/0867, FISPS09/0009) 0867, Red INMA G03/176) and the Departamento de Salud del Gobierno Vasco (2005111093 and 2009111069) and the Provincial Government of Guipúzcoa (DFG06/004 and FG08/001). INMA-Sabadell was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds; PI15/00118 incl. FEDER funds; CP16/00128 incl. FEDER funds; PI16/00118 incl. FEDER funds; PI16/00261 incl. FEDER funds; PI17/01340 incl. FEDER funds; PI18/00547 incl. FEDER funds), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació La marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securité Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010; EST-2016 RF-21), EU Commission (261357, 308333, 603,794 and 634453). Mònica Guxens was funded by a Miguel Servet II fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. We acknowledge support from the grant CEX2023-0001290-S funded by MCIN/AEI/https://doi.org/10.13039/501100011033, and support from the Generalitat de Catalunya through the CERCA Program.
MoBa: The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. This study includes data from the Norwegian Mother, Father and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. NINFEA: The NINFEA cohort was initially funded by the Compagnia SanPaolo Foundation and the Piedmont Region. It received funding from European projects: CHICOS (FP7 grant number HEALTH-FP7-2009-241604, LifeCycle (H2020 grant number 733206), ATHLETE (H2020 grant number 874583). RHEA: The “Rhea” project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 NV.2007.1.2.2.2. Project No 211,250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226,285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308,333 HELIX) and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15).
SW acknowledges receiving the funding by the Generalitat de Catalunya (Agency for Management of University and Research Grants) with a Beatriu de Pinós post-doctoral fellowship (Ref: 2021 BP 00058). SS is supported by the European Uniońs Horizon Europe Research and Innovation Programme under the Marie Sklodowska-Curie Postdoctoral Fellowship Grant Agreement No. 101,109,136 (URBANE).
The funders had no role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication
Pyarchinit at Castelseprio: progressive adoption of an integrated managing system for archaeological field data
No full textIn the framework of the project 'Castelseprio, centre of power', the authors began excavating the structure known as Casa Piccoli in 2021. The area, already investigated by Piccoli in the 1970s, presents itself as an interesting case study for the application of an open and integrated solution for the management of stratigraphic data, specifically pyArchInit. Being an academic excavation project and, therefore, characterized by both research and training issues, it was decided to progressively and incrementally include the use of pyArchInit within the documentation protocols on site and post-excavation, over the three years of the permit granted by the Ministry of Culture for the excavations. Master's degree students who participated in the excavation, at the end of the planned period, will have the basic skills to use the plugin also in a professional environment. At the end of the first two years of implementation, a SWOT analysis will show the results obtained within the site for both training and research purposes
Minimax rate for multivariate data under componentwise local differential privacy constraints
No full textOur research analyses the balance between maintaining privacy and preserving statistical accuracy when dealing with multivariate data that is subject to componentwise local differential privacy (CLDP). With CLDP, each component of the private data is made public through a separate privacy channel. This allows for varying levels of privacy protection for different components or for the privatization of each component by different entities, each with their own distinct privacy policies. It also covers the practical situations where it is impossible to privatize jointly all the components of the raw data. We develop general techniques for establishing minimax bounds that shed light on the statistical cost of privacy in this context, as a function of the privacy levels α1, . . . , αd of the d components.
We demonstrate the versatility and efficiency of these techniques by presenting various statistical applications. Specifically, we examine nonparametric density and joint moments estimation under CLDP, providing upper and lower bounds that match up to constant factors, as well as an associated data-driven adaptive procedure. Additionally, we conduct a detailed analysis of the effective privacy level, exploring how information about a private characteristic of an individual may be inferred from the publicly visible characteristics of the same individual.CA gratefully acknowledges financial support of ERC Consolidator Grant 815703 "STAMFORD: Statistical Methods for High Dimensional Diffusions"