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1. Integrating justice in Nature-Based Solutions to avoid nature-enabled dispossession

Author: Anguelovski, Isabelle, Corbera, Esteve, and Institució Catalana de Recerca i Estudis Avançats (ICREA)
Subjects: Climate adaptation policy, Climate justice, Climate mitigation policy, Land rights, Conservation, Privatized nature
Abstract: Acord transformatiu CRUE-CSIC Heavily featured over the last few years in global research and policy agreements, Nature-Based Solutions (NBS) remain however exposed to much debate over the ways their current design and ability to achieve both environmental goals and social needs. As they become mainstream climate mitigation and adaptation options, their capacity to deliver expected benefits, especially when contemplating equity and justice, is at least uncertain. Through a critical review of existing debates and perspectives on NBS, this paper questions their uptake and points at the frequent embeddedness of NBS in speculative and elite-based development paths in both urban and rural areas. We present an alternative, justice-oriented approach to NBS so that projects can avoid nature-enable dispossession and instead build nature-inspired justice that prioritizes the needs, identities, and livelihoods of the most ecologically and socially vulnerable residents. © 2022, The Author(s).
Published: 2022

2. The Trial of 1240 against the Talmud : A Reassessment of the Christian Account plus a New Edition

Author: Fidora, Alexander and Institució Catalana de Recerca i Estudis Avançats (ICREA)
Subjects: Critical Edition, Interrogatorio eclesiástico, Ecclesiastical Inquiry, Edición crítica, Burning of the Talmud, Polémica anti-judía, Quema del Talmud, Anti-Jewish Polemic, Disputa del Talmud, Talmud Disputation
Abstract: We are in a position to consult two reports regarding the trial against the Talmud that took place in Paris during the year 1240, a trial which led to the burning of several Talmudic manuscripts. One such report is in Latin, while the other is in Hebrew. The former, namely, the Depositiones or Confessiones, presents itself as a record detailing the interrogation of two rabbis by an assortment of high-ranking ecclesiastics; the Hebrew Vikkuah, on the other hand, describes a public dispute held at the French royal court between the Jewish convert Nicholas Donin and a group of rabbis. In this article, alongside a critical edition of the Depositiones, I provide a reassessment of the relationship between the above two documents and their divergent description of events. Disponemos de dos informes sobre el proceso contra el Talmud que tuvo lugar en París durante el año 1240 y que llevó a la quema de varios manuscritos talmúdicos, a saber, un informe en latín y otro en hebreo. El primero de ellos, las Depositiones o Confessiones, se presenta como el acta de un interrogatorio de dos rabinos por parte de un grupo de eclesiásticos de alto rango; la Vikkuah, en cambio, describe una disputa pública que protagoniza el converso judío Nicolás Donin con un grupo de rabinos en la corte real. Junto con la edición crítica de las Depositiones, ofrecemos en este artículo una revisión de la relación entre ambos documentos y sus respectivas descripciones de los hechos.
Published: 2022

3. Adsorption and reaction of methanol on supported palladium catalysts: microscopic-level studies from ultrahigh vacuum to ambient pressure conditions.

Author: Marcus Bäumer, Jörg LibudaPresent address: Lehrstuhl für Physikalische Chemie II, Universität Erlangen-Nürnberg, Egerlandstr. 3, D-91058 Erlangen, Germany., Konstantin M. NeymanPresent address: Institució Catalana de Recerca i Estudis Avançats (ICREA), E-08010 Barcelona and Departament de Química Física, Universitat de Barcelona, E-08028 Barcelona, Spain., Notker Rösch, Günther RupprechterPresent address: Institut für Materialchemie, Technische Universität Wien, Veterinärplatz 1, A-1210 Wien, Austria., and Hans-Joachim Freund
Abstract: We investigated the decomposition and (partial) oxidation of methanol on Pd based catalysts in an integrated attempt, simultaneously bridging both the pressure and the materials gap. Combined studies were performed on well-defined Pd model catalysts based on ordered Al2O3 and Fe3O4 thin films, on well-defined particles supported on powders and on Pd single crystals. The interaction of Pd nanoparticles and Pd(111) with CH3OH and CH3OH/O2 mixtures was examined from ultrahigh vacuum conditions up to ambient pressures, utilizing a broad range of surface specific vibrational spectroscopies which included IRAS, TR-IRAS, PM-IRAS, SFG, and DRIFTS. Detailed kinetic studies in the low pressure region were performed by molecular beam methods, providing comprehensive insights into the microkinetics of the reaction system. The underlying microscopic processes were studied theoretically on the basis of specially designed 3-D nanocluster models containing ∼102 metal atoms. The efficiency of this novel modelling approach was demonstrated by rationalizing and complementing pertinent experimental results. In order to connect these results to the behavior under ambient conditions, kinetic and spectroscopic investigations were performed in reaction cells and lab reactors. Specifically, we focused on (1) particle size and structure dependent effects in methanol oxidation and decomposition, (2) support effects and their relation to activity and selectivity, (3) the influence of poisons such as carbon, and (4) the role of oxide and surface oxide formation on Pd nanoparticles. [ABSTRACT FROM AUTHOR]
Published: 2007
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4. In Vitro Antibacterial Activity of Silver Nanoparticles Conjugated with Amikacin and Combined with Hyperthermia against Drug-Resistant and Biofilm-Producing Strains

Author: Marta Palau, Estela Muñoz, Muriel F. Gusta, Nieves Larrosa, Xavier Gomis, Joan Gilabert, Benito Almirante, Victor Puntes, Robert Texidó, Joan Gavaldà, Institut Català de la Salut, [Palau M, Almirante B, Gavaldà J] Laboratori de Resistència Microbiana, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Spanish Network for Research in Infectious Diseases (REIPI RD19/0016), Instituto de Salud Carlos III, Madrid, Spain. CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain. [Muñoz E] Laboratori de Resistència Microbiana, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Freixanet Gusta M] Institut Català de Nanociència i Nanotecnologia (ICN2), CSIC, The Barcelona Institute of Science and Technology (BIST), Campus UAB, Bellaterra, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain. [Larrosa N] Spanish Network for Research in Infectious Diseases (REIPI RD19/0016), Instituto de Salud Carlos III, Madrid, Spain. CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain. Servei de Microbiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Gomis X] Laboratori de Resistència Microbiana, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain. [Gilabert J] Tractivus SL, Barcelona, Spain i Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Puntes V] Institut Català de Nanociència i Nanotecnologia (ICN2), CSIC, The Barcelona Institute of Science and Technology (BIST), Campus UAB, Bellaterra, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Microbiology (medical), General Immunology and Microbiology, Ecology, Nanopartícules, Physiology, Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles::Metal Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], terapéutica::hipertermia inducida [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Cell Biology, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antiinfecciosos::antibacterianos [COMPUESTOS QUÍMICOS Y DROGAS], tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas::nanopartículas metálicas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Infectious Diseases, Medicaments antiinfecciosos, Genetics, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [CHEMICALS AND DRUGS], Therapeutics::Hyperthermia, Induced [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Calor - Efectes fisiològics
Abstract: Antibacterial activity; Biofilms; Silver nanoparticles Actividad antibacteriana; Biopelículas; Nanopartículas de plata Activitat antibacteriana; Biopel·lícules; Nanopartícules de plata In view of the current increase and spread of antimicrobial resistance (AMR), there is an urgent need to find new strategies to combat it. This study had two aims. First, we synthesized highly monodispersed silver nanoparticles (AgNPs) of approximately 17 nm, and we functionalized them with mercaptopoly(ethylene glycol) carboxylic acid (mPEG-COOH) and amikacin (AK). Second, we evaluated the antibacterial activity of this treatment (AgNPs_mPEG_AK) alone and in combination with hyperthermia against planktonic and biofilm-growing strains. AgNPs, AgNPs_mPEG, and AgNPs_mPEG_AK were characterized using a suite of spectroscopy and microscopy methods. Susceptibility to these treatments and AK was determined after 24 h and over time against 12 clinical multidrug-resistant (MDR)/extensively drug-resistant (XDR) isolates of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The efficacy of the treatments alone and in combination with hyperthermia (1, 2, and 3 pulses at 41°C to 42°C for 15 min) was tested against the same planktonic strains using quantitative culture and against one P. aeruginosa strain growing on silicone disks using confocal laser scanning microscopy. The susceptibility studies showed that AgNPs_mPEG_AK was 10-fold more effective than AK alone, and bactericidal efficacy after 4, 8, 24, or 48 h was observed against 100% of the tested strains. The combination of AgNPs_mPEG_AK and hyperthermia eradicated 75% of the planktonic strains and exhibited significant reductions in biofilm formation by P. aeruginosa in comparison with the other treatments tested, except for AgNPs_mPEG_AK without hyperthermia. In conclusion, the combination of AgNPs_mPEG_AK and hyperthermia may be a promising therapy against MDR/XDR and biofilm-producing strains. IMPORTANCE Antimicrobial resistance (AMR) is one of the greatest public health challenges, accounting for 1.27 million deaths worldwide in 2019. Biofilms, a complex microbial community, directly contribute to increased AMR. Therefore, new strategies are urgently required to combat infections caused by AMR and biofilm-producing strains. Silver nanoparticles (AgNPs) exhibit antimicrobial activity and can be functionalized with antibiotics. Although AgNPs are very promising, their effectiveness in complex biological environments still falls below the concentrations at which AgNPs are stable in terms of aggregation. Thus, improving the antibacterial effectiveness of AgNPs by functionalizing them with antibiotics may be a significant change to consolidate AgNPs as an alternative to antibiotics. It has been reported that hyperthermia has a large effect on the growth of planktonic and biofilm-producing strains. Therefore, we propose a new strategy based on AgNPs functionalized with amikacin and combined with hyperthermia (41°C to 42°C) to treat AMR and biofilm-related infections. This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162); la Marató TV3 (472/U/2018); the CaixaImpulse Program (Fundació LaCaixa); and the Spanish Network for Research in Infectious Diseases (REIPI RD19/0016).
Published: 2023

5. Variations in Biodistribution and Acute Response of Differently Shaped Titania Nanoparticles in Healthy Rodents

Author: Martina B. Violatto, Giovanni Sitia, Laura Talamini, Annalisa Morelli, Ngoc Lan Tran, Qian Zhang, Atif Masood, Beatriz Pelaz, Indranath Chakraborty, Daxiang Cui, Wolfgang J. Parak, Mario Salmona, Neus G. Bastús, Victor Puntes, Paolo Bigini, Institut Català de la Salut, [Violatto MB, Talamini L, Morelli A] Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy. [Sitia G, Tran NL] Experimental Hepatology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy. [Zhang Q] Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Jiao Tong University, Shanghai, China. [Bastús NG] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Puntes V] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas CSIC and the Barcelona Institute of Science and Technology (BIST), Campus UAB, Bellaterra, Barcelona, Spain. CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], Nanopartícules, Pulmons - Efecte dels medicaments, General Chemical Engineering, titanium dioxide nanomaterial, physico-chemical properties, biodistribution, nanotoxicity, tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Otros calificadores::/efectos de los fármacos [Otros calificadores], Respiratory System::Lung [ANATOMY], sistema respiratorio::pulmón [ANATOMÍA], General Materials Science, Ratolins, Other subheadings::/drug effects [Other subheadings], Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Mice [ORGANISMS], Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratones [ORGANISMOS]
Abstract: Biodistribution; Nanotoxicity; Physico-chemical properties Biodistribución; Nanotoxicidad; Propiedades fisicoquímicas Biodistribució; Nanotoxicitat; Propietats fisicoquímiques Titanium dioxide nanoparticles (TiO2 NPs) are one of the main sources of the nanoparticulate matter exposure to humans. Although several studies have demonstrated their potential toxic effects, the real nature of the correlation between NP properties and their interaction with biological targets is still far from being fully elucidated. Here, engineered TiO2 NPs with various geometries (bipyramids, plates, and rods) have been prepared, characterized and intravenously administered in healthy mice. Parameters such as biodistribution, accumulation, and toxicity have been assessed in the lungs and liver. Our data show that the organ accumulation of TiO2 NPs, measured by ICP-MS, is quite low, and this is only partially and transiently affected by the NP geometries. The long-lasting permanence is exclusively restricted to the lungs. Here, bipyramids and plates show a higher accumulation, and interestingly, rod-shaped NPs are the most toxic, leading to histopathological pulmonary alterations. In addition, they are also able to induce a transient increase in serum markers related to hepatocellular injury. These results indicate that rods, more than bipyramidal and spherical geometries, lead to a stronger and more severe biological effect. Overall, small physico-chemical differences can dramatically modify both accumulation and safety. This research was funded by National Key Research and Development Program of China (No. 2017FYA0205301), Projects of International Cooperation and Exchanges NSFC (No. 82020108017), National Natural Science Foundation of China (No. 82272821); MCIN/AEI (PID2019-111218RB-I00 and RYC-2017-23457) and Centro Singular De Investigación de Galicia Accreditation 2019−2022, and ED431G 2019/03. Moreover, parts of this work were funded by the Cluster of Excellence ‘Advanced Imaging of Matter’ of the Deutsche Forschungsgemeinschaft (DFG)-EXC 2056-project ID 390715994; by Deutscher Akademischer Austauschdienst (DAAD); and by an Alexander von Humboldt fellowship. G.S. is supported by the Italian Association for Cancer Research (AIRC), grants 22820 and 22737. NGB and VP receive financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER, UE) proyectos de I + D + i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436), co-funded by the European Union. P.B. is supported by the CONCORD project (EuroNanoMed III).
Published: 2023

6. Nanoceria dissolution at acidic pH by breaking off the catalytic loop

Author: Dmitry Galyamin, Lena M. Ernst, Aina Fitó-Parera, Guillem Mira-Vidal, Neus G. Bastús, Neus Sabaté, Victor Puntes, European Research Council, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Universidad Autónoma de Barcelona, Institut Català de la Salut, [Galyamin D, Fitó-Parera A] Institut de Microelectrònica de Barcelona, IMB-CNM (CSIC). C/dels Til·lers, Campus Universitat Autònoma de Barcelona, Bellaterra, Spain. [Ernst LM] Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Mira-Vidal G, Bastús NG] Instiut Català de Nanociència I Nanotecnologia (ICN2), CSIC and The Barcelona Institute of Science and Technology (BIST). Campus UAB, Barcelona, Spain. [Sabaté N] Institut de Microelectrònica de Barcelona, IMB-CNM (CSIC). C/dels Til·lers, Campus Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain. [Puntes V] Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. Instiut Català de Nanociència I Nanotecnologia (ICN2), CSIC and The Barcelona Institute of Science and Technology (BIST). Campus UAB, Barcelona, Spain. Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Chemical Phenomena::Oxidation-Reduction [PHENOMENA AND PROCESSES], Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], Nanopartícules, Farmacocinètica, Reacció d'oxidació-reducció, Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacokinetics [PHENOMENA AND PROCESSES], fenómenos químicos::oxidación-reducción [FENÓMENOS Y PROCESOS], fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::farmacocinética [FENÓMENOS Y PROCESOS], tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], General Materials Science
Abstract: This manuscript proves the reproducibility and robustness of cerium oxide nanoparticles, nanoceria, employed as a chemical reagent with oxidizing capacity (as an electron sink) at acidic pH. Unlike nanoceria multi-enzyme-mimetic capabilities at neutral or high pH, nanoceria can behave as a stoichiometric reagent at low pH where insoluble Ce4+ ions transform into soluble Ce3+ in the nanocrystal that finally dissolves. This behaviour can be interpreted as enzyme-like when nanoceria is in excess with respect to the substrate. Under these conditions, the Ce3+/Ce4+ ratio in the NPs can easily be estimated by titration with ferrocyanide. This procedure could become a rapid assessment tool for evaluating nanoceria capacity in liquid environments., N. Sabaté would like to acknowledge the financial support received from ERC Consolidator Grant (SUPERCELL – GA.648518). N. G. B and V. P. acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER,UE) proyectos de I + D + i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya. Dmitry Galyamin thanks the doctoral program “Electroquímica. Ciència i Tecnologia” of the Universitat Autònoma de Barcelona (UAB).
Published: 2022

7. Clinical development of therapies targeting TGFβ: current knowledge and future perspectives

Author: Joan Seoane, Elena Elez, Davide Ciardiello, Josep Tabernero, Institut Català de la Salut, [Ciardiello D] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. Department of Medicina di Precisione, Università degli studi della Campania, Luigi Vanvitelli, Naples, Italy. [Elez E] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Tabernero J] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Seoane J] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBERONC, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Angiogenesis, medicine.medical_treatment, Immunoteràpia, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Context (language use), Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Transforming Growth Factor beta [CHEMICALS AND DRUGS], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Factors de creixement, neoplasias [ENFERMEDADES], 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, Neoplasms, Tumor Microenvironment, Medicine, Humans, aminoácidos, péptidos y proteínas::péptidos::péptidos y proteínas de señalización intercelular::citocinas::factor de crecimiento transformador beta [COMPUESTOS QUÍMICOS Y DROGAS], Tumor microenvironment, biology, business.industry, Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Càncer - Tractament, terapéutica::terapia biológica::inmunomodulación::inmunoterapia [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Cancer, Hematology, Immunotherapy, Transforming growth factor beta, Oncogenes, medicine.disease, Clinical trial, Neoplasms [DISEASES], 030104 developmental biology, Oncology, Tumor progression, 030220 oncology & carcinogenesis, biology.protein, Cancer research, business
Abstract: Biomarcadors; Immunoteràpia; Microambient tumoral Biomarcadores; Inmunoterapia; Microambiente tumoral Biomarkers; Immunotherapy; Tumor microenvironment Transforming growth factor beta (TGFβ) is a pleiotropic cytokine that plays a key role in both physiologic and pathologic conditions, including cancer. Importantly, TGFβ can exhibit both tumor-suppressive and oncogenic functions. In normal epithelial cells TGFβ acts as an antiproliferative and differentiating factor, whereas in advanced tumors TGFβ can act as an oncogenic factor by creating an immune-suppressive tumor microenvironment, and inducing cancer cell proliferation, angiogenesis, invasion, tumor progression, and metastatic spread. A wealth of preclinical findings have demonstrated that targeting TGFβ is a promising means of exerting antitumor activity. Based on this rationale, several classes of TGFβ inhibitors have been developed and tested in clinical trials, namely, monoclonal, neutralizing, and bifunctional antibodies; antisense oligonucleotides; TGFβ-related vaccines; and receptor kinase inhibitors. It is now >15 years since the first clinical trial testing an anti-TGFβ agent was engaged. Despite the promising preclinical studies, translation of the basic understanding of the TGFβ oncogenic response into the clinical setting has been slow and challenging. Here, we review the conclusions and status of all the completed and ongoing clinical trials that test compounds that inhibit the TGFβ pathway, and discuss the challenges that have arisen during their clinical development. With none of the TGFβ inhibitors evaluated in clinical trials approved for cancer therapy, clinical development for TGFβ blockade therapy is primarily oriented toward TGFβ inhibitor combinations. Immune checkpoint inhibitors are considered candidates, albeit with efficacy anticipated to be restricted to specific populations. In this context, we describe current efforts in the search for biomarkers for selecting the appropriate cancer patients who are likely to benefit from anti-TGFβ therapies. The knowledge accumulated during the last 15 years of clinical research in the context of the TGFβ pathway is crucial to design better, innovative, and more successful trials. The authors acknowledge Asociación Española contra el Cáncer (AECC), Fondo de Investigación Sanitaria (FIS) Instituto de Salud Carlos III grant [grant number PI19/00318], Fundación Areces, Fundación BBVA, Fundación Catalunya La Pedrera, and Cellex support.
Published: 2020

8. Challenging local realism with human choices

Author: The BIG Bell Test Collaboration, Abellán, C., Acín, A., Alarcón, A., Alibart, O., Andersen, C. K., Andreoli, F., Beckert, A., Beduini, F. A., Bendersky, A., Bentivegna, M., Bierhorst, P., Burchardt, D., Cabello, A., Cariñe, J., Carrasco, S., Carvacho, G., Cavalcanti, D., Chaves, R., Cortés-Vega, J., Cuevas, A., Delgado, A., de Riedmatten, H., Eichler, C., Farrera, P., Fuenzalida, J., García-Matos, M., Garthoff, R., Gasparinetti, S., Gerrits, T., Jouneghani, F. Ghafari, Glancy, S., Gómez, E. S., González, P., Guan, J. -Y., Handsteiner, J., Heinsoo, J., Heinze, G., Hirschmann, A., Jiménez, O., Kaiser, F., Knill, E., Knoll, L. T., Krinner, S., Kurpiers, P., Larotonda, M. A., Larsson, J. -Å., Lenhard, A., Li, H., Li, M. -H., Lima, G., Liu, B., Liu, Y., Grande, I. H. López, Lunghi, T., Ma, X., Magaña-Loaiza, O. S., Magnard, P., Magnoni, A., Martí-Prieto, M., Martínez, D., Mataloni, P., Mattar, A., Mazzera, M., Mirin, R. P., Mitchell, M. W., Nam, S., Oppliger, M., Pan, J. -W., Patel, R. B., Pryde, G. J., Rauch, D., Redeker, K., Rieländer, D., Ringbauer, M., Roberson, T., Rosenfeld, W., Salathé, Y., Santodonato, L., Sauder, G., Scheidl, T., Schmiegelow, C. T., Sciarrino, F., Seri, A., Shalm, L. K., Shi, S. -C., Slussarenko, S., Stevens, M. J., Tanzilli, S., Toledo, F., Tura, J., Ursin, R., Vergyris, P., Verma, V. B., Walter, T., Wallraff, A., Wang, Z., Weinfurter, H., Weston, M. M., White, A. G., Wu, C., Xavier, G. B., You, L., Yuan, X., Zeilinger, A., Zhang, Q., Zhang, W., Zhong, J., Institut de Ciencies Fotoniques [Castelldefels] ( ICFO ), Institució Catalana de Recerca i Estudis Avançats ( ICREA ), Universidad de Concepción [Chile], Institut de Physique de Nice ( INPHYNI ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Swiss Federal Institute of Technology in Zürich ( ETH Zürich ), Università degli Studi di Roma 'La Sapienza' [Rome], Universidad de Buenos Aires [Buenos Aires], National Institute of Standards and Technologies ( NIST ), Ludwig-Maximilians-Universität München, Universidad de Sevilla, Federal University of Rio Grande do Norte, Institut fur Quantenoptik und Quanteninformation ( IQOQI ), Osterreichische Akademie der Wissenschaften ( ÖAW ), University of Vienna [Vienna], Griffith University [Brisbane], University of Science and Technology of China, Linköping University ( LIU ), Chinese Academy of Sciences, Tsinghua University [Beijing], University of Queensland [Brisbane], Max-Planck-Institut für Quantenoptik ( MPQ ), Max-Planck-Institut, Institut de Ciencies Fotoniques [Castelldefels] (ICFO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Institut de Physique de Nice (INPHYNI), Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Universidad de Buenos Aires [Buenos Aires] (UBA), National Institute of Standards and Technology [Gaithersburg] (NIST), Ludwig-Maximilians-Universität München (LMU), Institut fur Quantenoptik und Quanteninformation (IQOQI), Osterreichische Akademie der Wissenschaften (ÖAW), Linköping University (LIU), Tsinghua University [Beijing] (THU), Max-Planck-Institut für Quantenoptik (MPQ), Max-Planck-Gesellschaft, and Patel, R
Subjects: Freedom, [ PHYS.QPHY ] Physics [physics]/Quantum Physics [quant-ph], FOS: Physical sciences, Geographic Mapping, Quantum entanglement, Choice Behavior, 01 natural sciences, 010305 fluids & plasmas, Quantum nonlocality, [PHYS.QPHY]Physics [physics]/Quantum Physics [quant-ph], Human–computer interaction, Teknik och teknologier, Naturvetenskap, 0103 physical sciences, Humans, Bell test experiments, 010306 general physics, Set (psychology), ComputingMilieux_MISCELLANEOUS, Randomness, Quantum Mechanics, Quantum Physics, Multidisciplinary, Quantum Information, Single Photons and Qauntum Effects, Data flow diagram, Video Games, Hidden variable theory, Scalability, Engineering and Technology, Quantum Physics (quant-ph), Natural Sciences
Abstract: A Bell test is a randomized trial that compares experimental observations against the philosophical worldview of local realism. A Bell test requires spatially distributed entanglement, fast and high-efficiency detection and unpredictable measurement settings. Although technology can satisfy the first two of these requirements, the use of physical devices to choose settings in a Bell test involves making assumptions about the physics that one aims to test. Bell himself noted this weakness in using physical setting choices and argued that human `free will' could be used rigorously to ensure unpredictability in Bell tests. Here we report a set of local-realism tests using human choices, which avoids assumptions about predictability in physics. We recruited about 100,000 human participants to play an online video game that incentivizes fast, sustained input of unpredictable selections and illustrates Bell-test methodology. The participants generated 97,347,490 binary choices, which were directed via a scalable web platform to 12 laboratories on five continents, where 13 experiments tested local realism using photons, single atoms, atomic ensembles, and superconducting devices. Over a 12-hour period on 30 November 2016, participants worldwide provided a sustained data flow of over 1,000 bits per second to the experiments, which used different human-generated data to choose each measurement setting. The observed correlations strongly contradict local realism and other realistic positions in bipartite and tripartite scenarios. Project outcomes include closing the `freedom-of-choice loophole' (the possibility that the setting choices are influenced by `hidden variables' to correlate with the particle properties), the utilization of video-game methods for rapid collection of human generated randomness, and the use of networking techniques for global participation in experimental science., This version includes minor changes resulting from reviewer and editorial input. Abstract shortened to fit within arXiv limits
Published: 2018

9. Molecular memory near room temperature in an iron polyanionic complex

Author: Andrea Moneo-Corcuera, David Nieto-Castro, Jordi Cirera, Verónica Gómez, Jesús Sanjosé-Orduna, Carla Casadevall, Gábor Molnár, Azzedine Bousseksou, Teodor Parella, José María Martínez-Agudo, Julio Lloret-Fillol, Mónica Helvia Pérez-Temprano, Eliseo Ruiz, José Ramón Galán-Mascarós, Institute of Chemical Research of Catalonia (ICIQ), Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona (UB), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Servei de Ressonància Magnètica Nuclear, Facultat de Ciències, Universitat Autònoma de Barcelona, Universitat Autònoma de Barcelona (UAB), Universitat de València (UV), Institució Catalana de Recerca i Estudis Avançats (ICREA), Spanish Ministerio de Ciencia e Innovación, Generalitat de Catalunya, European Project: 279313,EC:FP7:ERC,ERC-2011-StG_20101014,CHEMCOMP(2012), and European Project: 648304,H2020,ERC-2014-CoG,GREENLIGHT_REDCAT(2015)
Subjects: History, Polymers and Plastics, Iron, General Chemical Engineering, Biochemistry (medical), General Chemistry, Spin crossover, DFT calculations, Biochemistry, Industrial and Manufacturing Engineering, Molecular memory, Materials Chemistry, Thermal hysteresis, Polyanion, Environmental Chemistry, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Bistability, Triazole, Business and International Management
Abstract: International audience; Bistable molecules represent a potential miniaturization limit for high-density information technologies. However, molecules exhibit memory effect typically at very low temperatures. This is the case of spin-crossover (SCO) complexes, where the concept of a molecular memory has not been considered due to the fast spin-state interconversion of all previous systems. Breaking this principle, here we report a slow relaxation process found in an SCO iron-triazole polyanionic complex. Multiple experimental evidences confirm the opening of a thermal hysteresis upon solid dilution and even in liquid solution. Density functional theory (DFT) calculations reveal the origin of this unexpected phenomenon to the appearance of an energy barrier that slows down the spin-state relaxation processes at the molecular level. These results show how SCO molecules may store information at room temperature, opening unique opportunities for molecular data storage.
Published: 2023

10. Decadal Climate Prediction: An Update from the Trenches

Author: Meehl, G., Goddard, L., Kirtman, B., Branstator, G., Danabasoglu, G., Hawkins, E., Kumar, A., Rosati, T., Smith, D., Sutton, R., Boer, G., Burgman, R., Carson, C., Corti, S., Karspeck, A., Keenlyside, N., Kimoto, M., Matei, D., https://orcid.org/0000-0002-3735-8802, Mignot, J., Msadek, R., Navarra, A., Pohlmann, H., Rienecker, M., Schneider, E., Tebaldi, C., Teng, H., van Oldenborgh, G., Vecchi, G., Yeager, S., National Center for Atmospheric Research [Boulder] ( NCAR ), International Research Institute for Climate and Society ( IRI ), Earth Institute at Columbia University, Columbia University [New York]-Columbia University [New York], CERFACS [Toulouse], Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Neurological Sciences, University of Milan, Institut Català de Ciències del Clima, Institució Catalana de Recerca i Estudis Avançats ( ICREA ), Department of Meteorology [Reading], University of Reading ( UOR ), Laboratoire Interdisciplinaire Carnot de Bourgogne ( LICB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Max Planck Institute for Meteorology ( MPI-M ), Processus de la variabilité climatique tropicale et impacts ( PARVATI ), Laboratoire d'Océanographie et du Climat : Expérimentations et Approches Numériques ( LOCEAN ), Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), NOAA Geophysical Fluid Dynamics Laboratory ( GFDL ), National Oceanic and Atmospheric Administration ( NOAA ), Dipartimento di Matematica e Informatica [Perugia] ( DMI ), Università degli Studi di Perugia ( UNIPG ), NASA Goddard Space Flight Center ( GSFC ), Espaces et Sociétés ( ESO ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Le Mans Université ( UM ) -Université d'Angers ( UA ) -AGROCAMPUS OUEST-Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut de Géographie et d'Aménagement ( IGARUN ), Université de Nantes ( UN ) -Université de Nantes ( UN ) -Centre National de la Recherche Scientifique ( CNRS ), Royal Netherlands Meteorological Institute ( KNMI ), National Center for Atmospheric Research [Boulder] (NCAR), International Research Institute for Climate and Society (IRI), Canadian Centre for Climate Modelling and Analysis (CCCma), Environment and Climate Change Canada, Florida International University [Miami] (FIU), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Institució Catalana de Recerca i Estudis Avançats (ICREA), University of Reading (UOR), The University of Tokyo (UTokyo), Laboratoire Interdisciplinaire Carnot de Bourgogne (LICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Meteorology (MPI-M), Max-Planck-Gesellschaft, Processus de la variabilité climatique tropicale et impacts (PARVATI), Laboratoire d'Océanographie et du Climat : Expérimentations et Approches Numériques (LOCEAN), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Muséum national d'Histoire naturelle (MNHN)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Muséum national d'Histoire naturelle (MNHN)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), NOAA Geophysical Fluid Dynamics Laboratory (GFDL), National Oceanic and Atmospheric Administration (NOAA), Dipartimento di Matematica e Informatica [Perugia] (DMI), Università degli Studi di Perugia (UNIPG), NASA Goddard Space Flight Center (GSFC), Espaces et Sociétés (ESO), Institut de Géographie et d'Aménagement Régional de l'Université de Nantes (IGARUN), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université d'Angers (UA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Le Mans Université (UM), Met Office Hadley Centre for Climate Change (MOHC), United Kingdom Met Office [Exeter], National Centre for Atmospheric Science, University of Reading, Reading, United Kingdom, Royal Netherlands Meteorological Institute (KNMI), Meehl GA, Goddard L, Boer G, Burgman R, Branstator G, Cassou C, Corti S, Danabasoglu G, Doblas-Reyes F, Hawkins E, Karspeck A, Kimoto M, Kumar A, Matei D, Mignot J, Msadek R, Navarra A, Pohlmann H, Rienecker M, Rosati T, Schneider E, Smith D, Sutton R, Teng HY, van Oldenborgh GJ, Vecchi G, and Yeager S
Subjects: Atmospheric Science, 010504 meteorology & atmospheric sciences, Atmosphere, Climate system, Initialization, [PHYS.PHYS.PHYS-GEO-PH]Physics [physics]/Physics [physics]/Geophysics [physics.geo-ph], Forcing (mathematics), Hiatus, 010502 geochemistry & geophysics, 01 natural sciences, [ PHYS.PHYS.PHYS-GEO-PH ] Physics [physics]/Physics [physics]/Geophysics [physics.geo-ph], Climatic changes--Simulation methods, Climatic changes--Forecasting, 13. Climate action, Climatology, Environmental science, decadal predictions, climate, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences
Abstract: This paper provides an update on research in the relatively new and fast-moving field of decadal climate prediction, and addresses the use of decadal climate predictions not only for potential users of such information but also for improving our understanding of processes in the climate system. External forcing influences the predictions throughout, but their contributions to predictive skill become dominant after most of the improved skill from initialization with observations vanishes after about 6–9 years. Recent multimodel results suggest that there is relatively more decadal predictive skill in the North Atlantic, western Pacific, and Indian Oceans than in other regions of the world oceans. Aspects of decadal variability of SSTs, like the mid-1970s shift in the Pacific, the mid-1990s shift in the northern North Atlantic and western Pacific, and the early-2000s hiatus, are better represented in initialized hindcasts compared to uninitialized simulations. There is evidence of higher skill in initialized multimodel ensemble decadal hindcasts than in single model results, with multimodel initialized predictions for near-term climate showing somewhat less global warming than uninitialized simulations. Some decadal hindcasts have shown statistically reliable predictions of surface temperature over various land and ocean regions for lead times of up to 6–9 years, but this needs to be investigated in a wider set of models. As in the early days of El Niño–Southern Oscillation (ENSO) prediction, improvements to models will reduce the need for bias adjustment, and increase the reliability, and thus usefulness, of decadal climate predictions in the future.
Published: 2014

11. Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis

Author: Ángel Edo, Laura Calvo-Barreiro, Herena Eixarch, Assumpció Bosch, Miguel Chillón, Carmen Espejo, Institut Català de la Salut, [Edo A] Institut de Neurociències (INc), Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Calvo-Barreiro L, Eixarch H, Espejo C] Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Bosch A] Institut de Neurociències (INc), Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Chillón M] Institut de Neurociències (INc), Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain. Vector Production Unit (UPV), Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Nervous System Autoimmune Disease, Experimental::Encephalomyelitis, Autoimmune, Experimental [DISEASES], Multiple sclerosis, Mice, IL-21, Animals, Therapeutics::Biological Therapy::Genetic Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Pharmacology (medical), enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes experimentales del sistema nervioso::encefalomielitis autoinmune experimental [ENFERMEDADES], Receptors, Cytokine, Otros calificadores::/terapia [Otros calificadores], Pharmacology, EAE, Soluble receptor, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [DISEASES], AAV, Genetic Therapy, Other subheadings::/therapy [Other subheadings], Encefalomielitis - Tractament, Mice, Inbred C57BL, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple [ENFERMEDADES], Cytokines, Teràpia genètica, Neurology (clinical), terapéutica::terapia biológica::terapia genética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Esclerosi múltiple - Tractament
Abstract: Soluble receptor; Multiple sclerosis Receptor soluble; Esclerosis múltiple Receptor soluble; Esclerosi múltiple The pathogenic role of the interleukin 21 (IL-21) in different autoimmune diseases, such as multiple sclerosis (MS), has been extensively studied. However, its pleiotropic nature makes it a cytokine that may exhibit different activity depending on the immunological stage of the disease. In this study, we developed a gene therapy strategy to block the interaction between IL-21 and its receptor (IL-21R) by using adeno-associated vectors (AAV) encoding a new soluble cytokine receptor (sIL21R) protein. We tested this strategy in a murine model of experimental autoimmune encephalomyelitis (EAE), obtaining different clinical effects depending on the time at which the treatment was applied. Although the administration of the treatment during the development of the immune response was counterproductive, the preventive administration of the therapeutic vectors showed a protective effect by reducing the number of animals that developed the disease, as well as an improvement at the histopathological level and a modification of the immunological profile of the animals treated with the AAV8.sIL21R. The beneficial effect of the treatment was also observed when inducing the expression of the therapeutic molecule once the first neurological signs were established in a therapeutic approach with a doxycyline (Dox)-inducible expression system. All these clinical results highlight the pleiotropicity of this cytokine in the different clinical stages and its key role in the EAE immunopathogenesis. Open Access Funding provided by Universitat Autonoma de Barcelona. This project was supported by the Ministerio Ciencia Innovación, retos Sociedad (PI15/0271). A.E was a recipient of a VHIR fellowship.
Published: 2022

12. Exploiting endocytosis for transfection of mRNA for cytoplasmatic delivery using cationic gold nanoparticles

Author: Muriel F. Gustà, Michael J. Edel, Vivian A. Salazar, Belén Alvarez-Palomo, Manel Juan, Massimo Broggini, Giovanna Damia, Paolo Bigini, Alessandro Corbelli, Fabio Fiordaliso, Alexander Barbul, Rafi Korenstein, Neus G. Bastús, Víctor Puntes, Institut Català de la Salut, [Gustà MF] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. [Edel MJ] Hospital Clínic de Barcelona, Servei Immunologia-IDIBAPS, Barcelona, Spain. Unit of Anatomy and Embryology, Universitat Autònoma de Barcelona, Faculty of Medicine, Barcelona, Spain. University of Western Australia, Faculty of Medicine, Discipline of Medical Sciences and Genetics, School of Biomedical Sciences, Perth, WA, Australia. [Salazar VA] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [Alvarez-Palomo B] Banc de Sang i Teixits, Cell Therapy Service, Barcelona, Spain. [Juan M] Hospital Clínic de Barcelona, Servei Immunologia-IDIBAPS, Barcelona, Spain. [Broggini M] IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. [Puntes V] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Nanopartícules, Immunology, Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles::Metal Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ARN::ARN mensajero [COMPUESTOS QUÍMICOS Y DROGAS], técnicas de investigación::técnicas genéticas::técnicas de transferencia génica::transfección [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas::nanopartículas metálicas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Endocitosi, Transfecció, Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [CHEMICALS AND DRUGS], fenómenos fisiológicos celulares::endocitosis [FENÓMENOS Y PROCESOS], RNA, Immunology and Allergy, Cell Physiological Phenomena::Endocytosis [PHENOMENA AND PROCESSES], Investigative Techniques::Genetic Techniques::Gene Transfer Techniques::Transfection [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
Abstract: Gene therapeutics; Gold nanoparticles; Safety Terapia génica; Nanopartículas de oro; Seguridad Teràpia gènica; Nanopartícules d'or; Seguretat Introduction: Gene therapy holds promise to cure various diseases at the fundamental level. For that, efficient carriers are needed for successful gene delivery. Synthetic ‘non-viral’ vectors, as cationic polymers, are quickly gaining popularity as efficient vectors for transmitting genes. However, they suffer from high toxicity associated with the permeation and poration of the cell membrane. This toxic aspect can be eliminated by nanoconjugation. Still, results suggest that optimising the oligonucleotide complexation, ultimately determined by the size and charge of the nanovector, is not the only barrier to efficient gene delivery. Methods: We herein develop a comprehensive nanovector catalogue comprising different sizes of Au NPs functionalized with two different cationic molecules and further loaded with mRNA for its delivery inside the cell. Results and Discussion: Tested nanovectors showed safe and sustained transfection efficiencies over 7 days, where 50 nm Au NPs displayed the highest transfection rates. Remarkably, protein expression was increased when nanovector transfection was performed combined with chloroquine. Cytotoxicity and risk assessment demonstrated that nanovectors are safe, ascribed to lesser cellular damage due to their internalization and delivery via endocytosis. Obtained results may pave the way to design advanced and efficient gene therapies for safely transferring oligonucleotides. We acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER,UE) proyectos de I+D+i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya.
Published: 2023

13. Algorithm to improve the diagnosis of paraneoplastic neurological syndromes associated with SOX1 antibodies

Author: Cristina Arnaldos-Pérez, Andreu Vilaseca, Laura Naranjo, Lidia Sabater, Josep Dalmau, Raquel Ruiz-García, Francesc Graus, Institut Català de la Salut, [Arnaldos-Pérez C, Naranjo L] Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain. [Vilaseca A] Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Sabater L] Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. [Dalmau J] Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States. [Ruiz-García R] Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain. Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Neoplasms::Paraneoplastic Syndromes [DISEASES], Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [DISEASES], neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares [ENFERMEDADES], Immunology, Pulmons - Càncer - Diagnòstic, Other subheadings::/diagnosis [Other subheadings], Otros calificadores::/diagnóstico [Otros calificadores], Immunology and Allergy, Algorismes, Mathematical Concepts::Algorithms [PHENOMENA AND PROCESSES], Símptomes, conceptos matemáticos::algoritmos [FENÓMENOS Y PROCESOS], neoplasias::síndromes paraneoplásicos [ENFERMEDADES]
Abstract: Cell-based assay; Paraneoplastic neurological syndromes; Small-cell lung cancer Assaig basat en cèl·lules; Síndromes neurològiques paraneoplàstiques; Càncer de pulmó de cèl·lules petites Ensayo basado en células; Síndromes neurológicos paraneoplásicos; Cáncer de pulmón de células pequeñas SOX1 antibodies (SOX1-abs) are associated with paraneoplastic neurological syndromes (PNS) and small cell lung cancer (SCLC). In many clinical laboratories SOX1-abs are determined by commercial line blots without confirmation by cell-based assay (CBA) with HEK293 cells expressing SOX1. However, the diagnostic yield of commercial line blots is low and the accessibility to the CBA, that is not commercially available, limited. Here, we evaluated if the addition of the band intensity data of the line blot and the immunoreactivity in a tissue-based assay (TBA) improve the diagnostic performance of the line blot. We examined serum of 34 consecutive patients with adequate clinical information that tested positive for SOX1-abs in a commercial line blot. Samples were also assessed by TBA and CBA. SOX1-abs were confirmed by CBA in 17 (50%) patients, all (100%) had lung cancer (SCLC in 16) and 15/17 (88%) had a PNS. In the remaining 17 patients the CBA was negative and none had PNS associated with lung cancer. TBA was assessable in 30/34 patients and SOX1-abs reactivity was detected in 15/17 (88%) with positive and in 0/13 (0%) with negative CBA. Only 2 (13%) of the 15 TBA-negative patients were CBA-positive. The frequency of TBA-negative but CBA-positive increased from 10% (1/10) when the band intensity of the line blot was weak to 20% (1/5) in patients with a moderate or strong intensity band. Confirmation by CBA should be mandatory for samples (56% in this series) not assessable (4/34; 12%) or negative in the TBA (15/34; 44%). This study was funded by Instituto de Salud Carlos III - Subdirección General de Evaluación y Formento de la Investigación Sanitaria and co-funded by European Union, FIS (PI21/00255, RR-G).
Published: 2023

14. Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer

Author: Alessio Fiascarelli, Giuseppe Merlino, Stefania Capano, Simone Talucci, Diego Bisignano, Alessandro Bressan, Daniela Bellarosa, Corrado Carrisi, Alessandro Paoli, Mario Bigioni, Patrizia Tunici, Clelia Irrissuto, Massimiliano Salerno, Joaquin Arribas, Elisa de Stanchina, Maurizio Scaltriti, Monica Binaschi, Institut Català de la Salut, [Fiascarelli A, Merlino G, Capano S, Talucci S, Bisignano D, Bressan A] Menarini Group, Preclinical and Translational Sciences, Menarini Ricerche SpA, Pomezia, Rome, Italy. [Arribas J] Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Oncology, acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::/uso terapéutico [Otros calificadores], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Mama - Càncer - Tractament, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::/therapeutic use [Other subheadings], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS], Proteïnes quinases - Inhibidors - Ús terapèutic
Abstract: Purpose Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors. Methods Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models. Results Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment. Conclusions The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).
Published: 2023

15. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer

Author: Anna Adam-Artigues, Enrique J. Arenas, Alex Martínez-Sabadell, Fara Brasó-Maristany, Raimundo Cervera, Eduardo Tormo, Cristina Hernando, María Teresa Martínez, Juan Carbonell-Asins, Soraya Simón, Jesús Poveda, Santiago Moragón, Sandra Zazo, Débora Martínez, Ana Rovira, Octavio Burgués, Federico Rojo, Joan Albanell, Begoña Bermejo, Ana Lluch, Aleix Prat, Joaquín Arribas, Pilar Eroles, Juan Miguel Cejalvo, Institut Català de la Salut, [Adam-Artigues A, Cervera R] INCLIVA Biomedical Research Institute, Valencia, Spain. [Arenas EJ] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain. [Martínez-Sabadell A] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Brasó-Maristany F] August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. [Tormo E] INCLIVA Biomedical Research Institute, Valencia, Spain. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain. [Arribas J] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain. Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES], Multidisciplinary, Receptor, ErbB-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Breast Neoplasms, Trastuzumab, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Càncer de mama, Càncer--Tractament, Phosphatidylinositol 3-Kinases, Breast cancer, Drug Resistance, Neoplasm, Cell Line, Tumor, Drug resistance, Mama - Càncer - Tractament, Mama--Càncer, Humans, Female, Tumors, Resistència als medicaments
Abstract: Breast cancer; Heterodimerization Cáncer de mama; Heterodimerización Càncer de mama; Heterodimerització Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer. A.A.-A., E.J.A., and F.B.-M. were supported by Asociación Española contra el Cáncer AECC (PRDVA18013LLUC to A.A.-A., POSTD211413AREN to E.J.A., and AECC_Postdoctoral17-1062 to F.B.-M.). A.M.-S. was funded by the Spanish Government (PFIS FI20/00188). J.Ar. is supported by Breast Cancer Research Foundation (BCRF-20-08), Instituto de Salud Carlos III Project reference number AC15/00062, and the EC under the framework of the ERA-NET TRANSCAN-2 initiative cofinanced by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181), and Asociación Española Contra el Cáncer (AECC). A.P. was supported by Instituto de Salud Carlos III—PI19/01846, Breast Cancer Now—2018NOVPCC1294. P.E. and A.L. were funded by Instituto de Salud Carlos III and cofinanced by FEDER (PI18/01219 to P.E. and CB16/12/00481 to A.L.). J.M.C. was funded by Sociedad Española de Oncología Médica (Rio Hortega-SEOM) and Compromiso ADAMED.
Published: 2023

16. p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor–positive breast cancer

Author: Silvana Mouron, Maria J Bueno, Manuel Muñoz, Raul Torres, Sandra Rodríguez, Juan V Apala, Jorge Silva, Rodrigo Sánchez-Bayona, Luis Manso, Juan Guerra, Laura Rodriguez-Lajusticia, Diego Malon, Marcos Malumbres, Miguel Quintela-Fandino, Institut Català de la Salut, [Mouron S, Bueno MJ, Muñoz M, Apala JV] Breast Cancer Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas—CNIO, Madrid, Spain. [Torres R, Rodríguez S] Molecular Cytogenetics Unit, Centro Nacional de Investigaciones Oncologicas—CNIO, Madrid, Spain. [Malumbres M] Cell Division & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Cancer Cell Cycle group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Oncology, acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::/uso terapéutico [Otros calificadores], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Mama - Càncer - Tractament, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::/therapeutic use [Other subheadings], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS], Proteïnes quinases - Inhibidors - Ús terapèutic
Abstract: Biomarker; Hormone receptor-positive; Breast cancer Biomarcador; Cáncer de mama; Receptor hormonal positivo Biomarcador; Càncer de mama; Receptor hormonal positiu CDK4/6 inhibitors benefit a minority of patients who receive them in the breast cancer adjuvant setting. p27Kip1 is a protein that inhibits CDK/Cyclin complexes. We hypothesized that single-nucleotide polymorphisms that impaired p27Kip1 function could render patients refractory to endocrine therapy but responsive to CDK4/6 inhibitors, narrowing the patient subpopulation that requires CDK4/6 inhibitors. We found that the p27Kip1 V109G single-nucleotide polymorphism is homozygous in approximately 15% of hormone-positive breast cancer patients. Polymorphic patients experience rapid failure in response to endocrine monotherapy compared with wild-type or heterozygous patients in the first-line metastatic setting (progression-free survival: 92 vs 485 days, P
Published: 2023

17. Defensive‐lipid droplets: Cellular organelles designed for antimicrobial immunity

Author: Rémi Safi, Miguel Sánchez‐Álvarez, Marta Bosch, Caroline Demangel, Robert G. Parton, Albert Pol, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Josep Carreras Leukaemia Research Institute (IJC), Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain] (CNIC), Instituto de Salud Carlos III [Madrid] (ISC), Instituto de Investigaciones Biomédicas Alberto Sols [Madrid, Spain] (IIBM), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Immunobiologie et Thérapie - Immunobiology and Therapy, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institute for Molecular Bioscience, University of Queensland [Brisbane], Institució Catalana de Recerca i Estudis Avançats (ICREA), and RS is recipient of the Lady Tata Memorial Trust grant for leukemia research and the Marie Skłodowska-Curie Actions Postdoctoral Fellowship (MSCA-PF) granted by the European commission. MS-A is recipient of a Ramón y Cajal researcher contract and a research grant from the Spanish Ministerio de Innovación y Ciencia (RYC2020-029690 and PID2021-128106NA-I00). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). AP and MB are supported by I+D+i RETOS INVESTIGACIÓN from the Ministerio de Ciencia e Investigación (MICINN, PID2021-127043OB-I00) and the CERCA Programme/Generalitat de Catalunya. AP is supported by the H2020-MSCA-ITN-2018, 953489 (ENDOCONNECT). RGP is a Laureate Fellow of the Australian Research Council. AP, RGP, and CD are supported by the ERC Synergy Grant ERC-2022-SYG, 101071784 (DRIMMS).
Subjects: lipid droplets, [SDV]Life Sciences [q-bio], Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, interferon, virus, parasites, bacteria, innate immunity
Abstract: International audience; Microbes have developed many strategies to subvert host organisms, which, in turn, evolved several innate immune responses. As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders. Intracellular viruses, bacteria, and protozoan parasites induce and physically interact with LDs, and the current view is that they "hijack" LDs to draw on substrates for host colonization. This dogma has been challenged by the recent demonstration that LDs are endowed with a protein-mediated antibiotic activity, which is upregulated in response to danger signals and sepsis. Dependence on host nutrients could be a generic "Achilles' heel" of intracellular pathogens and LDs a suitable chokepoint harnessed by innate immunity to organize a front-line defense. Here, we will provide a brief overview of the state of the conflict and discuss potential mechanisms driving the formation of the 'defensive-LDs' functioning as hubs of innate immunity.
Published: 2023

18. Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity

Author: Lise Mangiante, Nicolas Alcala, Alexandra Sexton-Oates, Alex Di Genova, Abel Gonzalez-Perez, Azhar Khandekar, Erik N. Bergstrom, Jaehee Kim, Xiran Liu, Ricardo Blazquez-Encinas, Colin Giacobi, Nolwenn Le Stang, Sandrine Boyault, Cyrille Cuenin, Severine Tabone-Eglinger, Francesca Damiola, Catherine Voegele, Maude Ardin, Marie-Cecile Michallet, Lorraine Soudade, Tiffany M. Delhomme, Arnaud Poret, Marie Brevet, Marie-Christine Copin, Sophie Giusiano-Courcambeck, Diane Damotte, Cecile Girard, Veronique Hofman, Paul Hofman, Jérôme Mouroux, Charlotte Cohen, Stephanie Lacomme, Julien Mazieres, Vincent Thomas de Montpreville, Corinne Perrin, Gaetane Planchard, Nathalie Rousseau, Isabelle Rouquette, Christine Sagan, Arnaud Scherpereel, Francoise Thivolet, Jean-Michel Vignaud, Didier Jean, Anabelle Gilg Soit Ilg, Robert Olaso, Vincent Meyer, Anne Boland-Auge, Jean-Francois Deleuze, Janine Altmuller, Peter Nuernberg, Alejandro Ibáñez-Costa, Justo P. Castaño, Sylvie Lantuejoul, Akram Ghantous, Charles Maussion, Pierre Courtiol, Hector Hernandez-Vargas, Christophe Caux, Nicolas Girard, Nuria Lopez-Bigas, Ludmil B. Alexandrov, Françoise Galateau-Salle, Matthieu Foll, Lynnette Fernandez-Cuesta, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Stanford University, Universidad de O'Higgins (UOH), Centre de modélisation mathématique (CMM), Universitad de Chile-Centre National de la Recherche Scientifique (CNRS), Barcelona Institute of Science and Technology (BIST), Instituto de Salud Carlos III [Madrid] (ISC), University of California [San Diego] (UC San Diego), University of California (UC), Cornell University [New York], Maimonides Institute of Biomedical Research of Cordoba, Partenaires INRAE, Universidad de Córdoba = University of Córdoba [Córdoba], Hospital Universitario Reina Sofia [Cordoue, Espagne], CIBER Fisiopatología de la Obesidad y Nutrición [Cordoue, Espagne] (CIBEROBN), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Cypath and Cypath-rb [Villeurbanne] (2C), Tumorothèque du Centre de Référence Régional en Cancérologie [CHRU Lille] (T-C2RC), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut de Pathologie de Lille (IPL), Hôpital Nord [CHU - APHM], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Tumorothèque - Centre de Ressources Biologiques Cancer Cochin [Hôpital Cochin AP-HP] (T-CRB Cancer Cochin), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupes hospitalo-universitaires Paris Centre AP-HP [Paris] (GHU Paris Centre), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Pasteur [Nice] (CHU), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Marie-Lannelongue, Tissu-Tumorothèque Est - Centre de Ressources Biologiques [HCL, Lyon] (2TE - CRB HCL), Hospices Civils de Lyon (HCL), Réseau d'expertise anatomopathologique et de recherche sur les tumeurs de la plèvre [CHU Caen] (MESOPATH), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Ressources Biologiques - Cancer - IUCT Oncopole [Toulouse] (CRB - Cancer Toulouse), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cologne Centre for Genomics [Cologne, Germany] (2CG), Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Université Grenoble Alpes (UGA), Owkin [New York, NY, USA] (O), Institut Curie [Paris], Institut Mutualiste de Montsouris (IMM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Saclay, and Institució Catalana de Recerca i Estudis Avançats (ICREA)
Subjects: [SDV]Life Sciences [q-bio], Genetics, Technology Platforms
Abstract: Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that—in the case of the interdependent tumor cell morphology and adapted immune response—reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.
Published: 2023

19. The development of highly dense highly protected surfactant ionizable lipid RNA loaded nanoparticles

Author: González-Rioja, Ramon, Bastús, Neus G, Franco Puntes, Victor, Salazar, Vivian Angélica, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Generalitat de Catalunya, Institut Català de la Salut, [González-Rioja R, Salazar VA] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona, Bellaterra, Spain. [Bastús NG] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) en Bioingeniería, Biomateriales y Nanomedicina, Centro de Investigación Biomédica en Red en Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain. [Puntes V] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) en Bioingeniería, Biomateriales y Nanomedicina, Centro de Investigación Biomédica en Red en Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain. Grup de Recerca de Nanopartícules Farmacocinètiques, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Grup de Recerca de Malalties Infeccioses, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], Drug delivery carriers, Biodistribution and clearance, Ionizable lipid nanoparticles, Nanopartícules, Pharmaceutical Preparations::Dosage Forms::Drug Carriers [CHEMICALS AND DRUGS], RNA-loading, Immunology, Medicaments - Modes d'administració, Immunology and Allergy, tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Pharmacokinetics, preparados farmacéuticos::formas farmacéuticas::portadores de fármacos [COMPUESTOS QUÍMICOS Y DROGAS]
Abstract: The long quest for efficient drug administration has been looking for a universal carrier that can precisely transport traditional drugs, new genomic and proteic therapeutic agents. Today, researchers have found conditions to overcome the two main drug delivery dilemmas. On the one side, the versatility of the vehicle to efficiently load, protect and transport the drug and then release it at the target place. On the other hand, the questions related to the degree of PEGylation which are needed to avoid nanoparticle (NP) aggregation and opsonization while preventing cellular uptake. The development of different kinds of lipidic drug delivery vehicles and particles has resulted in the development of ionizable lipid nanoparticles (iLNPs), which can overcome most of the typical drug delivery problems. Proof of their success is the late approval and massive administration as the prophylactic vaccine for SARS-CoV-2. These ILNPs are built by electrostatic aggregation of surfactants, the therapeutic agent, and lipids that self-segregate from an aqueous solution, forming nanoparticles stabilized with lipid polymers, such as PEG. These vehicles overcome previous limitations such as low loading and high toxicity, likely thanks to low charge at the working pH and reduced size, and their entry into the cells via endocytosis rather than membrane perforation or fusion, always associated with higher toxicity. We herein revise their primary features, synthetic methods to prepare and characterize them, pharmacokinetic (administration, distribution, metabolization and excretion) aspects, and biodistribution and fate. Owing to their advantages, iLNPs are potential drug delivery systems to improve the management of various diseases and widely available for clinical use., We acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965- B-I00, AEI/FEDER,UE) proyectos de I+D+i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019- 103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya.
Published: 2023

20. Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer

Author: Brittiny Dhital, Sandra Santasusagna, Perumalraja Kirthika, Michael Xu, Peiyao Li, Marc Carceles-Cordon, Rajesh K. Soni, Zhuoning Li, Ronald C. Hendrickson, Matthew J. Schiewer, William K. Kelly, Cora N. Sternberg, Jun Luo, Amaia Lujambio, Carlos Cordon-Cardo, Monica Alvarez-Fernandez, Marcos Malumbres, Haojie Huang, Adam Ertel, Josep Domingo-Domenech, Veronica Rodriguez-Bravo, Institut Català de la Salut, [Dhital B] Biochemistry and Molecular Biology Department, Mayo Clinic, Rochester, USA. Urology Department, Mayo Clinic, Rochester, USA. Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, USA. [Santasusagna S, Kirthika P] Biochemistry and Molecular Biology Department, Mayo Clinic, Rochester, USA. Urology Department, Mayo Clinic, Rochester, USA. [Xu M, Li P] Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, USA. [Carceles-Cordon M] Urology Department, Mayo Clinic, Rochester, USA. [Malumbres M] Cell Division & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. Cancer Cell Cycle group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: afecciones patológicas, signos y síntomas::procesos patológicos::aberraciones cromosómicas::inestabilidad cromosómica [ENFERMEDADES], Anomalies cromosòmiques, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración [ENFERMEDADES], Pathological Conditions, Signs and Symptoms::Pathologic Processes::Chromosome Aberrations::Chromosomal Instability [DISEASES], Pròstata - Càncer - Aspectes genètics, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant [DISEASES], General Biochemistry, Genetics and Molecular Biology
Abstract: Chromosomal instability; Lethal prostate cancer; Therapy resistance Inestabilidad cromosómica; Cáncer de próstata letal; Resistencia a la terapia Inestabilitat cromosòmica; Càncer de pròstata letal; Resistència a la teràpia Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa. Research was supported by NIH/NCI grants P30CA08748 (to R.C.H.); R01CA207311 and R01CA261925 (to J.D.-D.); K22CA207458 and R01CA237398 (to V.R.-B.); and funding to V.R.-B. from the Mayo Clinic Foundation, The Margaret Q. Landenberger Research Foundation, The W.W. Smith Charitable Trust, The AACR, and The Prostate Cancer Foundation (PCF).
Published: 2023

21. Association of central obesity with unique cardiac remodelling in young adults born small for gestational age

Author: Gabriel Bernardino, Álvaro Sepúlveda-Martínez, Mérida Rodríguez-López, Susanna Prat-González, Carolina Pajuelo, Rosario J Perea, Maria T Caralt, Francesca Crovetto, Miguel A González Ballester, Marta Sitges, Bart Bijnens, Fàtima Crispi, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinic Barcelona Hospital Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Universitat Pompeu Fabra [Barcelona] (UPF), Institució Catalana de Recerca i Estudis Avançats (ICREA), ANR-11-LABX-0063,PRIMES,Physique, Radiobiologie, Imagerie Médicale et Simulation(2011), ANR-19-CE45-0005,MIC-MAC,Modélisation de la hiérarchie entre descripteurs cardiaques par apprentissage automatique(2019), and European Project: 642676,H2020,H2020-MSCA-ITN-2014,CardioFunXion(2015)
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Radiology, Nuclear Medicine and imaging, General Medicine, Cardiology and Cardiovascular Medicine
Abstract: Aims Being born small for gestational age (SGA, 10% of all births) is associated with increased risk of cardiovascular mortality in adulthood together with lower exercise tolerance, but mechanistic pathways are unclear. Central obesity is known to worsen cardiovascular outcomes, but it is uncertain how it affects the heart in adults born SGA. We aimed to assess whether central obesity makes young adults born SGA more susceptible to cardiac remodelling and dysfunction. Methods and results A perinatal cohort from a tertiary university hospital in Spain of young adults (30–40 years) randomly selected, 80 born SGA (birth weight below 10th centile) and 75 with normal birth weight (controls) was recruited. We studied the associations between SGA and central obesity (measured via the hip-to-waist ratio and used as a continuous variable) and cardiac regional structure and function, assessed by cardiac magnetic resonance using statistical shape analysis. Both SGA and waist-to-hip were highly associated to cardiac shape (F = 3.94, P < 0.001; F = 5.18, P < 0.001 respectively) with a statistically significant interaction (F = 2.29, P = 0.02). While controls tend to increase left ventricular end-diastolic volumes, mass and stroke volume with increasing waist-to-hip ratio, young adults born SGA showed a unique response with inability to increase cardiac dimensions or mass resulting in reduced stroke volume and exercise capacity. Conclusion SGA young adults show a unique cardiac adaptation to central obesity. These results support considering SGA as a risk factor that may benefit from preventive strategies to reduce cardiometabolic risk.
Published: 2023

22. Les sinus frontaux au cours de l’évolution humaine

Author: Balzeau, Antoine, Albessard-Ball, Lou, Kubicka, Anna Maria, Filippo, Andréa, Beaudet, Amélie, Santos, Elena, Bienvenu, Thibault, Arsuaga, Juan-Luis, Bartsiokas, Antonis, Berger, Lee, Bermúdez de Castro, José María, Brunet, Michel, Carlson, Kristian J., Daura, Joan, Gorgoulis, Vassilis G., Grine, Frederick E., Harvati, Katerina, Hawks, John, Herries, Andy, Hublin, Jean-Jacques, Martin, Jesse, Martinón-Torres, Maria, May, Hila, Mounier, Aurélien, Du Plessis, Anton, Rae, Todd, Röding, Carolin, Sanz, Montserrat, Semal, Patrick, Stratford, Dominic, Stringer, Chris, Tawane, Mirriam, Temming, Heiko, Tsoukala, Evangelia, Zilhão, João, Zipfel, Bernhard, Buck, Laura T., Histoire naturelle de l'Homme préhistorique (HNHP), Muséum national d'Histoire naturelle (MNHN)-Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Poznan University of Life Sciences (Uniwersytet Przyrodniczy w Poznaniu) (PULS), University of Cambridge [UK] (CAM), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Departamento de Ciencias de la Vida, Universidad de Alcalá - University of Alcalá (UAH), Universität Zürich [Zürich] = University of Zurich (UZH), Democritus University of Thrace (DUTH), James Cook University (JCU), Centro Nacional de Investigación sobre la Evolución Humana (CENIEH), Department of Anthropology [University College of London], University College of London [London] (UCL), Laboratoire de paléontologie, évolution, paléoécosystèmes, paléoprimatologie (PALEVOPRIM ), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), University of the Witwatersrand [Johannesburg] (WITS), Universitat de Barcelona (UB), University of Athens Medical School [Athens], Biomedical Research Foundation of the Academy of Athens (BRFAA), Ninewells Hospital and Medical School [Dundee], Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Senckenberg Centre for Human Evolution and Palaeoenvironment (HEP), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, University of Wisconsin-Madison, Department of Earth Ocean and Ecological Sciences [Liverpool], University of Liverpool, Collège de France - Chaire Paléoanthropologie, Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Tel Aviv University (TAU), Turkana Basin Institute, University of Roehampton, United Kingdom, UNIARQ, Universidade de Lisboa = University of Lisbon (ULISBOA), Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Archaeology, School of Geography, Archaeology and Environmental Studies, University of the Witwatersrand, (GAES), The Natural History Museum [London] (NHM), Ditsong National Museum of Natural History, Department of Human Evolution [Leipzig], Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, School of Geology, Thessaloniki, Aristotle University of Thessaloniki, Institució Catalana de Recerca i Estudis Avançats (ICREA), and Centro de Arqueologia da Universidade de Lisboa (UNIARQ)
Subjects: [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, [SHS]Humanities and Social Sciences
Abstract: International audience
Published: 2023

23. An epigenetic switch controls an alternative NR2F2 isoform 2 that unleashes a metastatic program in melanoma

Author: Davalos, Verónica, Lovell, Claudia, von Itter, Richard, Dolgalev, Igor, Agrawal, Praveen, Baptiste, Gillian, Kahler, David, Sokolova, Elena, Moran, Sebastian, Piqué, Laia, Vega-Saenz de Miera, Eleazar, Fontanals-Cirera, Barbara, Karz, Alcida, Tsirigos, Aristotelis, Yun, Chi, Darvishian, Farbod, Etchevers, Heather, Osman, Iman, Esteller, Manel, Schober, Markus, Hernando, Eva, Department of Pathology, New York University Grossman School of Medicine, NY 10016, USA, Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, NY 10016, USA, Bellvitge Biomedical Research Institute, Partenaires INRAE, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain, New York University School of Medicine (NYU Grossman School of Medicine), National Tsing Hua University [Hsinchu] (NTHU), City University of Hong Kong [Hong Kong] (CUHK), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, NY 10016, USA (NYUSM), Institució Catalana de Recerca i Estudis Avançats (ICREA), Josep Carreras Leukaemia Research Institute (IJC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universitat de Barcelona (UB), New York University [New York] (NYU), NYU System (NYU), and We thank the NYU Experimental Pathology Core, the NYU Genome Technology Center, the NYUCenter for Biospecimen Research and Development, and the Small Animal Imaging core, all partially supported by the Laura and Isaac Perlmutter Cancer Center Support Grant (CCSG) NIH/NCI P30CA016087 (NIH/NCI), and National Institute of Health S10 Grants NIH/ORIP S10OD01058 and S10OD018338. We thank the High Throughput Biology Core partially funded by P30CA16087 and NYSTEM Contract C026719. V.D. was supported by the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7-PEOPLE30 2013-IOF) under REA grant agreement n° PIOF-GA-2013-623443. This work was funded by NCI/NIH R01CA202027, R01CA274100, P01CA206980 and NYU Melanoma SPOREP50CA225450 (PI: I.O).
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-tomesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-bindingdomain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanomaprogression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
Published: 2023

24. Immunotherapies against HER2-Positive Breast Cancer

Author: Macarena Roman Alonso, Joaquin Arribas, Santiago Duro Sánchez, Institut Català de la Salut, [Duro-Sánchez S, Alonso MR] Preclinical & Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. [Arribas J] Preclinical & Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, Mama - Càncer - Prognosi, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Vaccines, Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], CAR-Ts, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], terapéutica::terapia biológica::inmunomodulación::inmunoterapia [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Resistance, Other subheadings::/therapy [Other subheadings], afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::progresión de la enfermedad [ENFERMEDADES], TCBs, Oncology, HER2, Mama - Càncer - Immunoteràpia, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Progression [DISEASES], Immunotherapy, Otros calificadores::/terapia [Otros calificadores]
Abstract: A wide range of treatments are available for HER2-positive breast cancer, which have greatly improved the prognosis and quality of life of these patients. However, resistance to HER2-targeted or untargeted therapies is common in clinical practice and is associated with metastasis, recurrence, and cancer-related death. To address this clinical need, researchers are exploring immunotherapeutic approaches to completely eradicate tumor cells and prevent tumor relapse and progression. In this review, we focus on how these emerging strategies can overcome current resistance and improve the prognosis of patients who do not respond to standard therapies. Breast cancer is the leading cause of cancer-related deaths among women worldwide. HER2-positive breast cancer, which represents 15–20% of all cases, is characterized by the overexpression of the HER2 receptor. Despite the variety of treatments available for HER2-positive breast cancer, both targeted and untargeted, many patients do not respond to therapy and relapse and eventually metastasize, with a poor prognosis. Immunotherapeutic approaches aim to enhance the antitumor immune response to prevent tumor relapse and metastasis. Several immunotherapies have been approved for solid tumors, but their utility for HER2-positive breast cancer has yet to be confirmed. In this review, we examine the different immunotherapeutic strategies being tested in HER2-positive breast cancer, from long-studied cancer vaccines to immune checkpoint blockade, which targets immune checkpoints in both T cells and tumor cells, as well as the promising adoptive cell therapy in various forms. We discuss how some of these new approaches may contribute to the prevention of tumor progression and be used after standard-of-care therapies for resistant HER2-positive breast tumors, highlighting the benefits and drawbacks of each. We conclude that immunotherapy holds great promise for the treatment of HER2-positive tumors, with the potential to completely eradicate tumor cells and prevent the progression of the disease.
Published: 2023

25. The molecular evolution of spermatogenesis across mammals

Author: Svante Pääbo, Henrik Kaessmann, Thoomke Brüning, Frank Grützner, Philipp Khaitovich, Francesco Lamanna, Mari Sepp, Meritxell Riera Belles, Julia Schmidt, Katharina Mößinger, Christian Conrad, Rüdiger Behr, Celine Schneider, Ronald E. Bontrop, Sofia B. Winge, Kristian Almstrup, Timo Trefzer, Florent Murat, Ivanela Kondova, Margarida Cardoso-Moreira, Evgeny Leushkin, Noe Mbengue, Mikkel H. Schierup, Tomas Marques-Bonet, Theoretical Biology and Bioinformatics, Sub Theoretical Biology, Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH), Universität Heidelberg [Heidelberg], Aarhus University [Aarhus], University of Copenhagen = Københavns Universitet (KU), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], The Francis Crick Institute [London], Biomedical Primate Research Centre [Rijswijk] (BPRC), German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne] (GPC - DPZ), German Center for Cardiovascular Research (DZHK), Skolkovo Institute of Science and Technology [Moscow] (Skoltech), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Institut de Biologia Evolutiva [Barcelona] (IBE / UPF - CSIC), Universitat Pompeu Fabra [Barcelona] (UPF), Institució Catalana de Recerca i Estudis Avançats (ICREA), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona (UAB), Robinson Research Institute, and University of Adelaide
Subjects: Male, [SDV]Life Sciences [q-bio], Gene Expression, Cell-adhesion, 0302 clinical medicine, Ecology,Evolution & Ethology, Origins, Sex-chromosomes, Features, X chromosome, X-chromosome, 0303 health sciences, Spermatogenic Cell, Human Biology & Physiology, Multidisciplinary, Chromatin/genetics, Sertoli cell, Gene expression profiling, Dynamics, Chromatin, medicine.anatomical_structure, Sexual selection, Genetics & Genomics, Macaque, Model organisms, Evolution, Mammals/genetics, Biology, Chromosomes, Evolutionary genetics, Evolution, Molecular, 03 medical and health sciences, Meiosis, Molecular evolution, medicine, Animals, mammals, General, 030304 developmental biology, Computational & Systems Biology, Spermatogenesis/genetics, Molecular, Chromosome, Evolutionary pressure, spermatogenesis, Genes, Meiosis/genetics, Evolutionary biology, Testis/metabolism, 030217 neurology & neurosurgery, Developmental Biology
Abstract: The testis produces gametes through spermatogenesis and evolves rapidly at both the morphological and molecular level in mammals1-6, probably owing to the evolutionary pressure on males to be reproductively successful7. However, the molecular evolution of individual spermatogenic cell types across mammals remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from 11 species that cover the three main mammalian lineages (eutherians, marsupials and monotremes) and birds (the evolutionary outgroup), and include seven primates. We find that the rapid evolution of the testis was driven by accelerated fixation rates of gene expression changes, amino acid substitutions and new genes in late spermatogenic stages, probably facilitated by reduced pleiotropic constraints, haploid selection and transcriptionally permissive chromatin. We identify temporal expression changes of individual genes across species and conserved expression programs controlling ancestral spermatogenic processes. Genes predominantly expressed in spermatogonia (germ cells fuelling spermatogenesis) and Sertoli (somatic support) cells accumulated on X chromosomes during evolution, presumably owing to male-beneficial selective forces. Further work identified transcriptomal differences between X- and Y-bearing spermatids and uncovered that meiotic sex-chromosome inactivation (MSCI) also occurs in monotremes and hence is common to mammalian sex-chromosome systems. Thus, the mechanism of meiotic silencing of unsynapsed chromatin, which underlies MSCI, is an ancestral mammalian feature. Our study illuminates the molecular evolution of spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals. We thank all members of the Kaessmann group, S. Tirier for discussions and N. Trost for the administration of the Kaessmann laboratory server. Computations were performed on the Kaessmann laboratory server and the bwForCluster from the Heidelberg University Computational Center (supported by the state of Baden-Württemberg through bwHPC and the German Research Foundation grant no. INST 35/1134-1 FUGG). This research was supported by grants from the ERC (grant no. 615253, OntoTransEvol) and German Research Council (DFG, grant nos. SFB 873 and KA 1710/4-1) to H.K., by the CellNetworks Postdoc Fellowship and EMBO Long-Term Fellowship to F.M. (grant no. ALTF 591-2017), and by the Australian Research Council (grant no. FT160100267) to F.G. and by the Novo Nordisk Foundation (grant no. NNF21OC0069913) to K.A. and (grant no. NNF18OC0031004) to M.H.S. The use of all other mammalian samples for the type of work described in this study was approved by ERC ethics screening panels (ERC starting grant no. 242597, SexGenTransEvolution and ERC consolidator grant no. 615253, OntoTransEvol).
Published: 2023
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26. Challenges and opportunities in the use of ponds and pondscapes as Nature-based Solutions

Author: M. Cuenca-Cambronero, M. Blicharska, J.-A. Perrin, T. A. Davidson, B. Oertli, M. Lago, M. Beklioglu, M. Meerhoff, M. Arim, J. Teixeira, L. De Meester, J. Biggs, J. Robin, B. Martin, H. M. Greaves, C. D. Sayer, P. Lemmens, D. Boix, T. Mehner, M. Bartrons, S. Brucet, CENTRAL UNIVERSITY OF CATALONIA AQUATIC ECOLOGY GROUP VIC ESP, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Uppsala University, Agroécologie et Environnement (AGE), Isara, Laboratoire d'Études Rurales (LER), Université Lumière - Lyon 2 (UL2), Department of Ecoscience - Aarhus University [Denmark], Aarhus University [Aarhus], Haute Ecole du Paysage, d'Ingénierie et d'Architecture de Genève (HEPIA), ECOLOGIC INSTITUTE BERLIN DEU, Middle East Technical University [Ankara] (METU), Universidad de la República del Uruguay, Interdisciplinary Centre of Marine and Environmental Research [Matosinhos, Portugal] (CIIMAR), Universidade do Porto = University of Porto, Laboratory of Aquatic Ecology, Evolution and Conservation, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Leibniz Institute of Freshwater Ecology and Inland Fisheries (IGB), University College of London [London] (UCL), Universitat de Girona (UdG), Institució Catalana de Recerca i Estudis Avançats (ICREA), Horizon Europe - Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature., and European Project: 27632,CRUE
Subjects: [SDE]Environmental Sciences, Nature contributions to people, Climate change, Nature-based Solutions, 500 Naturwissenschaften und Mathematik::570 Biowissenschaften, Biologie::570 Biowissenschaften, Biologie, Aquatic Science, Freshwater biodiversity, Nature- based Solutions, Ponds and pondscapes, Societal challenges
Abstract: Ponds and “pondscapes” (networks of ponds) are crucial habitats for biodiversity and for delivering multiple benefits to humans, so-called “Nature’s Contribution to People”, such as climate mitigation and adaptation to climate change, creation, and maintenance of habitat for biodiversity, water purification, flood mitigation and cultural benefits (e.g., recreational possibilities). However, ponds are not often considered as Nature-based Solutions to provide all these benefits. In addition, there is insufficient knowledge on how to manage and restore ponds to maximise their role to increase the resilience of ecosystems and society to climate change. To facilitate improved implementation of ponds as Nature-based Solutions for the delivery of a wide range of Nature Contributions to People, it is important to generate and integrate biodiversity, ecosystems, societal, economic and policy knowledge. Hence, there is a need for evidence-based guidance to support the broader use of ponds. Here, we review the role of ponds and pondscapes in delivering Nature’s Contributions to People and provide an overview of the challenges and opportunities for their broader implementation as Nature-based Solutions. Finally, we propose a conceptual framework that can help the implementation of pond Nature-based Solutions, and that outlines future research needs.
Published: 2023

27. Variability and predictability of West African droughts : a review on the role of sea surface temperature anomalies

Author: Bernard Fontaine, Edward K. Vizy, Marco Gaetani, Fred Kucharski, Andrew Colman, Michael Vellinga, Serge Janicot, Aurore Voldoire, Michela Biasutti, Francisco J. Doblas-Reyes, Elsa Mohino, Carlos R. Mechoso, Cyril Caminade, David P. Rowell, Irene Polo, William K. M. Lau, Lisa Goddard, Javier García-Serrano, Teresa Losada, Juergen Bader, Alberto Arribas, Leonard M. Druyan, Yongkang Xue, Belén Rodríguez-Fonseca, Kerry H. Cook, Departamento Fisica de la Tierra, Astronomía y Astrofísica [Madrid], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Instituto de Geociencias, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Atmospheric and Oceanic Sciences [Los Angeles] (AOS), University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), School of Environmental Sciences, University of Liverpool, Lamont-Doherty Earth Observatory (LDEO), Columbia University [New York], Istituto di Biometeorologia [Roma] (IBIMET), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Institut Català de Ciències del Clima, Department of Geological Sciences [Austin], Jackson School of Geosciences (JSG), University of Texas at Austin [Austin]-University of Texas at Austin [Austin], NCAS-Climate [Reading], Department of Meteorology [Reading], University of Reading (UOR)-University of Reading (UOR), Instituto de Ciencias Ambientales [Toledo] (ICAM), Universidad de Castilla-La Mancha = University of Castilla-La Mancha (UCLM), Center for Climate Systems Research [New York] (CCSR), Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Meteorology (MPI-M), Max-Planck-Gesellschaft, Institució Catalana de Recerca i Estudis Avançats (ICREA), International Research Institute for Climate and Society (IRI), Earth Institute at Columbia University, Columbia University [New York]-Columbia University [New York], Processus de la variabilité climatique tropicale et impacts (PARVATI), Laboratoire d'Océanographie et du Climat : Expérimentations et Approches Numériques (LOCEAN), Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Met Office Hadley Centre for Climate Change (MOHC), United Kingdom Met Office [Exeter], GSFC Laboratory for Atmospheres, NASA Goddard Space Flight Center (GSFC), Abdus Salam International Centre for Theoretical Physics [Trieste] (ICTP), Centre national de recherches météorologiques (CNRM), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), This work was supported by Spanish projectsMINECO CGL2011-13564-E and GL2012-38923-C02-01. Support from the U.S. National Science Foundation(Awards SES-1048946, ATM-1036604, AGS-1041477,and AGS-1115506) is gratefully acknowledged. Alsogratefully acknowledged are theGCMmodeling groups,the Program for Climate Model Diagnosis and Intercomparison(PCMDI), and the World Climate ResearchProgramme’s Working Group on CoupledModeling (WGCM) for their roles in making availablethe WCRP CMIP5 multimodel dataset. Support of thisdataset is provided by the Office of Science, U.S. Departmentof Energy (DOE). We acknowledge the EUQWECI, PREFACE, and SPECS projects both fundedby the European Commission’s Seventh FrameworkResearch Programme under Grant Agreements 243964,603521, and 308378 respectively. Based on a Frenchinitiative, AMMA was built by an international scientificgroup and is currently funded by a large numberof agencies, especially from France, the United Kingdom,the United States, and Africa. It has been thebeneficiary of a major financial contribution from theEuropean Community’s Sixth Framework ResearchProgramme., Universidad Complutense de Madrid [Madrid] ( UCM ), Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ) -Universidade Complutense Madrid, Department of Atmospheric and Oceanic Sciences [Los Angeles] ( AOS ), University of California at Los Angeles [Los Angeles] ( UCLA ), Lamont-Doherty Earth Observatory ( LDEO ), Istituto di Biometeorologia [Roma] ( IBIMET ), Consiglio Nazionale delle Ricerche ( CNR ), Department of Geological Sciences, University of Texas at Austin [Austin], University of Reading ( UOR ) -University of Reading ( UOR ), Instituto de Ciencias Ambientales [Toledo] ( ICAM ), Universidad de Castilla-La Mancha ( UCLM ), Center for Climate Systems Research [New York] ( CCSR ), Biogéosciences [Dijon] ( BGS ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Max Planck Institute for Meteorology ( MPI-M ), Institució Catalana de Recerca i Estudis Avançats ( ICREA ), International Research Institute for Climate and Society ( IRI ), Processus de la variabilité climatique tropicale et impacts ( PARVATI ), Laboratoire d'Océanographie et du Climat : Expérimentations et Approches Numériques ( LOCEAN ), Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Met Office Hadley Centre ( MOHC ), NASA Goddard Space Flight Center ( GSFC ), International Center for Theoretical Physics [Trieste] ( ICTP ), Groupe d'étude de l'atmosphère météorologique ( CNRM-GAME ), Institut national des sciences de l'Univers ( INSU - CNRS ) -Météo France-Centre National de la Recherche Scientifique ( CNRS ), University of California-University of California, Consiglio Nazionale delle Ricerche (CNR), Universidad de Castilla-La Mancha (UCLM), Biogéosciences [UMR 6282] [Dijon] (BGS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Muséum national d'Histoire naturelle (MNHN)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Muséum national d'Histoire naturelle (MNHN)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), Groupe d'étude de l'atmosphère météorologique (CNRM-GAME), and Institut national des sciences de l'Univers (INSU - CNRS)-Météo France-Centre National de la Recherche Scientifique (CNRS)
Subjects: Atmospheric Science, Monsoons, Monsoon, Oceanography, Climate prediction, Atmospheric Sciences, Mediterranean sea, Meteorology & Atmospheric Sciences, 14. Life underwater, Predictability, Climate variability, geography, geography.geographical_feature_category, Meteorología, Tropics, Tropical variability, Geofísica, Climate Action, Sea surface temperature, Geomatic Engineering, 13. Climate action, [SDU.STU.CL]Sciences of the Universe [physics]/Earth Sciences/Climatology, Climatology, Teleconnections, Africa, Period (geology), Environmental science, [ SDU.STU.CL ] Sciences of the Universe [physics]/Earth Sciences/Climatology, Oceanic basin, Teleconnection
Abstract: The Sahel experienced a severe drought during the 1970s and 1980s after wet periods in the 1950s and 1960s. Although rainfall partially recovered since the 1990s, the drought had devastating impacts on society. Most studies agree that this dry period resulted primarily from remote effects of sea surface temperature (SST) anomalies amplified by local land surface–atmosphere interactions. This paper reviews advances made during the last decade to better understand the impact of global SST variability on West African rainfall at interannual to decadal time scales. At interannual time scales, a warming of the equatorial Atlantic and Pacific/Indian Oceans results in rainfall reduction over the Sahel, and positive SST anomalies over the Mediterranean Sea tend to be associated with increased rainfall. At decadal time scales, warming over the tropics leads to drought over the Sahel, whereas warming over the North Atlantic promotes increased rainfall. Prediction systems have evolved from seasonal to decadal forecasting. The agreement among future projections has improved from CMIP3 to CMIP5, with a general tendency for slightly wetter conditions over the central part of the Sahel, drier conditions over the western part, and a delay in the monsoon onset. The role of the Indian Ocean, the stationarity of teleconnections, the determination of the leader ocean basin in driving decadal variability, the anthropogenic role, the reduction of the model rainfall spread, and the improvement of some model components are among the most important remaining questions that continue to be the focus of current international projects., This work was supported by Spanish projects MINECO CGL2011-13564-E and GL2012-38923-C02-01. Support from the U.S. National Science Foundation (awards ATM-1036604 and AGS-1041477) is gratefully acknowledged.
Published: 2015

28. Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

Author: Duro-Sánchez, Santiago, Nadal-Serrano, Mercedes, Lalinde-Gutiérrez, Marta., Arenas, Enrique J, Bernadó Morales, Cristina, Morancho, Beatriz, Escorihuela, Marta, Pérez-Ramos, Sandra, Escrivá-de-Romaní, Santiago, Gandullo-Sánchez, Lucía, Pandiella, Atanasio, Esteve-Codina, Anna, Rodilla, Verónica, Dijcks, Fred .A., Dokter, Wim .H.A., Cortés, Javier, Saura, Cristina, Arribas, Joaquín V, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Duro-Sánchez S, Lalinde-Gutiérrez M] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigacion Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. [Nadal-Serrano M, Arenas EJ, Bernadó Morales C, Morancho B] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigacion Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. [Escorihuela M, Pérez-Ramos S, Rodilla V, Cortés J] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Escrivá-de-Romaní S] Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Gandullo-Sánchez L] Centro de Investigacion Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Saura C] Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. [Arribas J] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigacion Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, American Breast Cancer Foundation, Instituto de Salud Carlos III, Fundación Mutua Madrileña, and Asociación Española Contra el Cáncer
Subjects: Cancer Research, Immunoconjugates, Receptor, ErbB-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Mama--Càncer--Aspectes genètics, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Antineoplastic Agents, Breast Neoplasms, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Cathepsin B, Medicaments antineoplàstics, Mama--Tumors, Cell Line, Tumor, Humans, Animals, Other subheadings::/therapeutic use [Other subheadings], Mama--Càncer--Tractament, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Anticossos monoclonals - Ús terapèutic, Otros calificadores::/uso terapéutico [Otros calificadores], Chemical Actions and Uses::Toxic Actions::Noxae::Immunoconjugates [CHEMICALS AND DRUGS], acciones y usos químicos::acciones tóxicas::noxas::inmunoconjugados [COMPUESTOS QUÍMICOS Y DROGAS], Trastuzumab, Xenograft Model Antitumor Assays, Oncology, Mama - Càncer - Tractament, Female
Abstract: Antibody–drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression., This work was supported by Breast Cancer Research Foundation (BCRF-20-008), Instituto de Salud Carlos III (project reference numbers AC15/00062, CB16/12/00449 and PI19/01181), the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Fundacion Mutua Madrilena and Asociación ~ Española Contra el Cáncer. S. Duro-Sanchez is supported by the Spanish Ministerio de Universidades by the grant Formacion de Profesorado Universitario (FPU20/05388). A. Esteve-Codina is funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER.
Published: 2022

29. Evidence for increasing global wheat yield potential

Author: Jose Rafael Guarin, Pierre Martre, Frank Ewert, Heidi Webber, Sibylle Dueri, Daniel Calderini, Matthew Reynolds, Gemma Molero, Daniel Miralles, Guillermo Garcia, Gustavo Slafer, Francesco Giunta, Diego N L Pequeno, Tommaso Stella, Mukhtar Ahmed, Phillip D Alderman, Bruno Basso, Andres G Berger, Marco Bindi, Gennady Bracho-Mujica, Davide Cammarano, Yi Chen, Benjamin Dumont, Ehsan Eyshi Rezaei, Elias Fereres, Roberto Ferrise, Thomas Gaiser, Yujing Gao, Margarita Garcia-Vila, Sebastian Gayler, Zvi Hochman, Gerrit Hoogenboom, Leslie A Hunt, Kurt C Kersebaum, Claas Nendel, Jørgen E Olesen, Taru Palosuo, Eckart Priesack, Johannes W M Pullens, Alfredo Rodríguez, Reimund P Rötter, Margarita Ruiz Ramos, Mikhail A Semenov, Nimai Senapati, Stefan Siebert, Amit Kumar Srivastava, Claudio Stöckle, Iwan Supit, Fulu Tao, Peter Thorburn, Enli Wang, Tobias Karl David Weber, Liujun Xiao, Zhao Zhang, Chuang Zhao, Jin Zhao, Zhigan Zhao, Yan Zhu, Senthold Asseng, University of Florida [Gainesville] (UF), Center for Climate Systems Research [New York] (CCSR), Columbia University [New York], Écophysiologie des Plantes sous Stress environnementaux (LEPSE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Leibniz-Zentrum für Agrarlandschaftsforschung = Leibniz Centre for Agricultural Landscape Research (ZALF), Institute of Crop Science and Resource Conservation [Bonn] (INRES), Rheinische Friedrich-Wilhelms-Universität Bonn, Universidad Austral de Chile, International Maize and Wheat Improvement Center (CIMMYT), Consultative Group on International Agricultural Research [CGIAR] (CGIAR), KWS Momont SAS, Universitad de Buenos Aires = University of Buenos Aires [Argentina], Instituto de Investigaciones Fisiologicas y Ecologicas Vinculadas a la Agricultura (IFEVA), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Agronomía [Buenos Aires], Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA), Universitat de Lleida, Institució Catalana de Recerca i Estudis Avançats (ICREA), Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Pir Mehr Ali Shah Arid Agriculture University = PMAS-Arid Agriculture University Rawalpindi (AAUR), Swedish University of Agricultural Sciences (SLU), Oklahoma State University [Stillwater] (OSU), Michigan State University [East Lansing], Michigan State University System, Instituto Nacional de Investigación Agropecuaria (INIA), Department of Agriculture, Food, Environment and Forestry (DAGRI), Università degli Studi di Firenze = University of Florence (UniFI), Georg-August-University = Georg-August-Universität Göttingen, Purdue University [West Lafayette], Institute of geographical sciences and natural resources research [CAS] (IGSNRR), Chinese Academy of Sciences [Beijing] (CAS), Gembloux Agro-Bio Tech [Gembloux], Université de Liège, Instituto de Agricultura Sostenible - Institute for Sustainable Agriculture (IAS CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Universidad de Córdoba = University of Córdoba [Córdoba], University of Hohenheim, Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), University of Guelph, Global Change Research Centre (CzechGlobe), University of Potsdam = Universität Potsdam, Aarhus University [Aarhus], Natural Resources Institute Finland (LUKE), Helmholtz Zentrum München = German Research Center for Environmental Health, Universidad de Castilla-La Mancha = University of Castilla-La Mancha (UCLM), Centro de Estudios e Investigación para la Gestión de Riesgos Agrarios y Medioambientales (CEIGRAM), Universidad Politécnica de Madrid (UPM), Centre for Biodiversity and Sustainable Land-use [University of Göttingen] (CBL), Rothamsted Research, Biotechnology and Biological Sciences Research Council (BBSRC), Washington State University (WSU), Wageningen University and Research [Wageningen] (WUR), Universität Kassel [Kassel], Zhejiang University, Nanjing Agricultural University (NAU), Building artificial Intelligence between trust, Responsibility and Decision (BIRD), Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Beijing Normal University (BNU), China Agricultural University (CAU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), International Wheat Yield Partnership (IWYP, Grant IWYP115) and the International Maize and Wheat Improvement Center (CIMMYT)., IWYP, CIMMYT (Mexico), and the Chilean Technical and Scientific Research Council (CONICYT) by FONDECYT Project 1141048, National Natural Science Foundation of China (Project Nos. 31761143006 and 41571493), Ministry of Education, Youth and Sports of Czech Republic through SustEs (CZ.02.1.01/0.0/0.0/16_019/000797), Biotechnology and Biological Sciences Research Council (BBSRC) through Designing Future Wheat (BB/P016855/1) and Achieving Sustainable Agricultural Systems (NE/N018125/1)., International Wheat Yield Partnership, International Maize and Wheat Improvement Center, Comisión Nacional de Investigación Científica y Tecnológica (Chile), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), National Natural Science Foundation of China, Ministry of Education, Youth and Sports (Czech Republic), and Biotechnology and Biological Sciences Research Council (UK)
Subjects: Crop Population, Crop Model Ensemble, Global Food Security Supplementary Material For This Article Is Available Online, Radiation Use Efficiency, Wheat Potential Yield, Yield Increase, Climate, Global Food Security, crop model ensemble, Grain Number, global food security Supplementary material for this article is available online, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Photosynthesis, yield increase, General Environmental Science, WIMEK, radiation use efficiency, Renewable Energy, Sustainability and the Environment, Spring Wheat, Public Health, Environmental and Occupational Health, Letter, wheat potential yield, global food security, Food Demand, ddc, Solar-Radiation, Water Systems and Global Change, Biomass Accumulation
Abstract: Wheat is the most widely grown food crop, with 761 Mt produced globally in 2020. To meet the expected grain demand by mid-century, wheat breeding strategies must continue to improve upon yield-advancing physiological traits, regardless of climate change impacts. Here, the best performing doubled haploid (DH) crosses with an increased canopy photosynthesis from wheat field experiments in the literature were extrapolated to the global scale with a multi-model ensemble of process-based wheat crop models to estimate global wheat production. The DH field experiments were also used to determine a quantitative relationship between wheat production and solar radiation to estimate genetic yield potential. The multi-model ensemble projected a global annual wheat production of 1050 ± 145 Mt due to the improved canopy photosynthesis, a 37% increase, without expanding cropping area. Achieving this genetic yield potential would meet the lower estimate of the projected grain demand in 2050, albeit with considerable challenges., This study was a part of the Agricultural Model Intercomparison and Improvement Project (AgMIP) Wheat Phase 4. The study was supported by the International Wheat Yield Partnership (IWYP, Grant IWYP115) and the International Maize and Wheat Improvement Center (CIMMYT). Experiments carried out in Valdivia (Chile) were funded by IWYP, CIMMYT (Mexico), and the Chilean Technical and Scientific Research Council (CONICYT) by FONDECYT Project 1141048. The experimental work conducted at Valdivia by Dr Jaime Herrera (UACh) is appreciated. F T was supported by the National Natural Science Foundation of China (Project Nos. 31761143006 and 41571493). K C K was supported by the Ministry of Education, Youth and Sports of Czech Republic through SustEs (CZ.02.1.01/0.0/0.0/16_019/000797). Rothamsted Research receives support from the Biotechnology and Biological Sciences Research Council (BBSRC) through Designing Future Wheat (BB/P016855/1) and Achieving Sustainable Agricultural Systems (NE/N018125/1).
Published: 2022

30. Considering waning immunity to better explain dengue dynamics

Author: Leonardo López, Richard E. Paul, Van-Mai Cao-Lormeau, Xavier Rodó, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Écologie et Émergence des Pathogènes Transmis par les Arthropodes / Ecology and Emergence of Arthropod-borne Pathogens, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD), Institució Catalana de Recerca i Estudis Avançats (ICREA), XR and LL acknowledge support from the Spanish Ministry of Science and Innovation through the ‘Centro de Excelencia Severo Ochoa 2019 2023’ Program (CEX2018 000806S), and support from the Generalitat de Catalunya, Spain through the CERCA Program. The research leading to these results has received funding from the European Commission Seventh Framework Program for the DENFREE project under Grant Agreement n282378 to RP, XR, VMCL., and European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012)
Subjects: DENV, French, Epidemiology, [SDV]Life Sciences [q-bio], Public Health, Environmental and Occupational Health, Monotypic, Immunity, Microbiology, Polynesia, Dengue, Infectious Diseases, Virology, Parasitology, Epidemics, Vaccine, Model
Abstract: International audience; Lifelong serotype-specific immunity following dengue virus infection may not always occur, but the true extent of this effect is unknown. Analysis of more than 20 years of monotypic epidemics in the isolated French Polynesian islands revealed that whilst the risk of symptomatic dengue infection did conform to the classical paradigms of homotypic immunity and increased disease risk in heterotypic secondary infections, incorporation of waning immunity improved the ability of epidemiological models to capture the observed epidemic dynamics. Not only does this show how inclusion of waning immunity into classical models can reveal important facets of the immune response to natural dengue virus infection, it also has significant ramifications for vaccine development and implementation in dengue endemic areas.
Published: 2022

31. Human metastatic cholangiocarcinoma patient-derived xenografts and tumoroids for preclinical drug evaluation

Author: Queralt Serra-Camprubí, Helena Verdaguer, Winona Oliveros, Núria Lupión-Garcia, Alba Llop-Guevara, Cristina Molina, Maria Vila-Casadesús, Anthony Turpin, Cindy Neuzillet, Joan Frigola, Jessica Querol, Mariana Yáñez-Bartolomé, Florian Castet, Carles Fabregat-Franco, Carmen Escudero-Iriarte, Marta Escorihuela, Enrique J. Arenas, Cristina Bernadó-Morales, Noemí Haro, Francis J. Giles, Óscar J. Pozo, Josep M. Miquel, Paolo G. Nuciforo, Ana Vivancos, Marta Melé, Violeta Serra, Joaquín Arribas, Josep Tabernero, Sandra Peiró, Teresa Macarulla, Tian V. Tian, Institut Català de la Salut, [Serra-Camprubí Q, Lupión-Garcia N, Llop-Guevara A, Molina C, Querol J, Yáñez-Bartolomé M, Escudero-Iriarte C, Escorihuela M, Arenas EJ, Bernadó-Morales C, Miquel JM, Nuciforo PG, Serra V, Peiró S, Tian TV] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Verdaguer H, Castet F, Fabregat-Franco C, Tabernero J, Macarulla T] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Gastrointestinal and Endocrine Tumor Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Oliveros W] Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain. [Vila-Casadesús M, Vivancos A] Cancer Genomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Frigola J] Clinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Arribas J] Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigacion Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain. Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, and Barcelona Supercomputing Center
Subjects: Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], neoplasias::neoplasias por tipo histológico::neoplasias glandulares y epiteliales::carcinoma::adenocarcinoma::colangiocarcinoma [ENFERMEDADES], Cancer Research, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Adenocarcinoma::Cholangiocarcinoma [DISEASES], Metastatic Cholangiocarcinoma, Conductes biliars - Càncer - Tractament, Conductes biliars -- Tumors, Drug response, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias del tracto biliar::neoplasias de los conductos biliares [ENFERMEDADES], Investigative Techniques::Drug Development::Drug Evaluation, Preclinical [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], técnicas de investigación::desarrollo de medicamentos::evaluación preclínica de medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Biliary Tract Neoplasms::Bile Duct Neoplasms [DISEASES], Oncology, Statistical analysis, Simulació per ordinador, Medicaments - Assaigs clínics, Pathogenic mutations, Càncer, Genètica, Cancer
Abstract: Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30\\%–50\\% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA\_PDX). The CCA\_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA\_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA\_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.This collection of CCA\_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA\_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA\_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA\_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials. The authors would like to thank the patients and their families for their support. This work was supported by grants from the Fundaci o Marat o TV3 awarded to T. Macarulla, M. Mel e, and S. Peir o; BeiGene research grant awarded toT. Macarulla and S. Peir o; AECC (INVES20036TIAN), Ram on y Cajal investigator program (RYC2020-029098-I), Proyecto de IþDþi (PID2019-108008RJ-I00), and FERO Foundation grant awarded to T.V. Tian; Proyecto de Investigaci on en Salud from the Instituto de Salud Carlos III (ISCIII) (PI20/00898) awarded to T. Macarulla; FIS/FEDER from the Instituto de Salud Carlos III (ISCIII) (PI12/01250; CP08/00223; PI16/00253 and CB16/12/00449) awarded to S. Peir o; and Ram on y Cajal investigator program (RYC-2017-22249) awarded to M. Mel e. Q. Serra-Camprubí is a recipient of the Ph.D. fellowship from La Caixa Foundation (LCF/PR/PR12/51070001). A. LlopGuevara was supported by the AECC (INVES20095LLOP) and V. Serra by the ISCIII (CPII19/00033). E.J. Arenas was funded by the AECC (POSTD211413AREN).J. Arribas is funded by the Instituto de Salud Carlos III (AC15/00062, CB16/12/00449, and PI22/00001). This publication is based upon the work of COST Action CA18122, European Cholangiocarcinoma Network, supported by the COST (European Cooperation in Science and Technology, www.cost.eu), a funding agency for research and innovation networks. The authors would like to thank Dr. V.A. Raker for manuscript editing and Drs. N. Herranz and J. Mateo for scientific discussions. The authors acknowledge the infrastructure and support of the FERO Foundation, La Caixa Foundation, and the Cellex Foundation. Peer Reviewed "Article signat per 31 autors/es: Queralt Serra-Camprubí; Helena Verdaguer; Winona Oliveros; Núria Lupión-Garcia; Núria Lupión-Garcia;Alba Llop-Guevara; Cristina Molina; Maria Vila-Casadesús; Anthony Turpin; Cindy Neuzillet; Joan Frigola; Jessica Querol; Mariana Yáñez-Bartolomé; Florian Castet; Carles Fabregat-Franco; Carmen Escudero-Iriarte; Marta Escorihuela; Enrique J. Arenas; Cristina Bernadó-Morales; Noemí Haro; Francis J. Giles; Óscar J. Pozo; Josep M. Miquel ; Paolo G. Nuciforo; Ana Vivancos; Marta Melé; Violeta Serra ; Joaquín Arribas; Josep Tabernero; Sandra Peiró; Teresa Macarulla; Tian V. Tian"
Published: 2022

32. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Author: Stefan Michiels, Cristina Saura, Cristina Viaplana, Marta Palafox, Abel Gonzalez-Perez, Alejandra Bruna, Paolo Nuciforo, Marta Guzman, Arribas Joaquín, Meritxell Bellet, Alicia García-Sanz, Violeta Serra, Faye Su, Olga Rodriguez, Nuria Lopez-Bigas, Analia Azaro, Monica Arnedos, Javier Hernández-Losa, Maurizio Scaltriti, Mafalda Oliveira, Laia Monserrat, Marta Capelán, Maria Teresa Herrera-Abreu, Carlos Caldas, Guillermo Villacampa, Leonardo Mina, Judit Grueso, Chandra S. Verma, Srinivasaraghavan Kannan, Robert Clarke, Nusaibah Ibrahimi, R. Dienstmann, Andreu Ódena, Nicholas C. Turner, Fara Brasó-Maristany, Aleix Prat, Mònica Sánchez-Guixé, Kui Lin, Gonzalez-Perez, Abel [0000-0002-8582-4660], Oliveira, Mafalda [0000-0001-9152-8799], Ibrahimi, Nusaibah [0000-0003-4537-0323], Kannan, Srinivasaraghavan [0000-0002-9539-5249], Sánchez-Guixé, Mònica [0000-0002-9430-4413], Hernández, Javier [0000-0003-1526-3201], Clarke, Robert B [0000-0001-5407-3123], Caldas, Carlos [0000-0003-3547-1489], Arribas, Joaquín [0000-0002-0504-0664], Michiels, Stefan [0000-0002-6963-2968], Turner, Nicholas C [0000-0001-8937-0873], Prat, Aleix [0000-0003-2377-540X], Nuciforo, Paolo [0000-0003-1380-0990], Lopez-Bigas, Nuria [0000-0003-4925-8988], Scaltriti, Maurizio [0000-0002-5522-1447], Saura, Cristina [0000-0001-8296-5065], Serra, Violeta [0000-0001-6620-1065], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Palafox M, Monserrat L, Òdena A, Sánchez-Guixé M, Rodríguez O, Guzmán M, Grueso J] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Bellet M, Bellet M, Capelán M, Azaro A, Saura C] Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Villacampa G, Viaplana C, Dienstmann R] Oncology Data Science Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Gonzalez-Perez A] Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain. Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain. [Hernández J] Grup de Recerca de Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Arribas J] CIBERONC, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Growth Factors Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: endocrine system, Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES], endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Ubiquitin-Protein Ligases, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], General Physics and Astronomy, Antineoplastic Agents, Breast Neoplasms, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Predictive markers, Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS], General Biochemistry, Genetics and Molecular Biology, Càncer de mama, Phosphatidylinositol 3-Kinases, Text mining, Breast cancer, Er breast cancer, Medicine, Humans, Cancer models, neoplasms, Protein Kinase Inhibitors, Resistència als medicaments, fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Multidisciplinary, Manchester Cancer Research Centre, acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS], business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Inhibitor resistance, Cyclin-Dependent Kinase 4, General Chemistry, Cyclin-Dependent Kinase 6, Proteïnes quinases - Inhibidors, Retinoblastoma Binding Proteins, Receptors, Estrogen, Drug Resistance, Neoplasm, Drug resistance, Mama - Càncer - Tractament, Cancer research, Female, business, Biomarkers
Abstract: CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies. This study has been supported by the Susan G. Komen Foundation (CCR15330331) and by the Catalan Agency AGAUR (2017 SGR 540) [to V.S.]. V.S. received funds from the Instituto de Salud Carlos III: grants PI13/01714, CP14/00228, MV15/00041, CPII19/00033 and PI20/00892. M.P. received a Juan de la Cierva Grant from the Ministerio de Economía y Competitividad (FJCI-2015-25412), L.Mo. a grant from FI-AGAUR (2019 FI_B 01199), F.B-M. a grant from the Fundación Científica Asociación Española Contra el Cáncer (AECC_Postdoctoral17-1062) and M.S-G, a Marie Slodowska-Curie Innovative Training Networks PhD fellowship (H2020-MSCA-ITN-2015_675392). This work was supported by Breast Cancer Research Foundation (BCRF-19-08), Instituto de Salud Carlos III Project Reference number AC15/00062 and the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181) and Asociación Española Contra el Cáncer (to J.A.). R.B.C. laboratory is supported by Breast Cancer Now (grant numbers: MAN-Q1 and MAN-Q2), NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007) and EdiREX Horizon 2020 grant No.731105. The xenograft program in the C.C. laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). This work has been supported by NIH grants P30 CA008748 and RO1CA190642-01, the CDMRP grant BC171535P1, and the Breast Cancer Research Foundation [to M.S.]. A.P. received funds from Instituto de Salud Carlos III—PI16/00904 and PI19/01846, Breast Cancer Now—2018NOVPCC1294, Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-PRAT, Fundació La Marató TV3 201935-30, the European Union’s Horizon 2020 research and innovation program H2020-SC1-BHC-2018-2020. IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). C. S. Verma reports grants from MSD International and grants from Ipsen outside the submitted work.
Published: 2022
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33. From Binary to Ternary Transition-Metal Nitrides: A Boost toward Nitrogen Magneto-Ionics

Author: Zhengwei Tan, Sofia Martins, Michael Escobar, Julius de Rojas, Fatima Ibrahim, Mairbek Chshiev, Alberto Quintana, Aitor Lopeandia, José L. Costa-Krämer, Enric Menéndez, Jordi Sort, Département de physique [Departament de Física, Universitat Autònoma de Barcelona], Universitat Autònoma de Barcelona (UAB), Department of Physics [Durham University], Durham University, SPINtronique et TEchnologie des Composants (SPINTEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut de Ciència de Materials de Barcelona (ICMAB), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), ICN2 - Institut Catala de Nanociencia i Nanotecnologia (ICN2), IMN-Instituto de Micro y Nanotecnología (CNM-CSIC), Isaac Newton 8, PTM, 28760 Tres Cantos, Madrid, Spain, Institució Catalana de Recerca i Estudis Avançats (ICREA), European Research Council, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Generalitat de Catalunya, KU Leuven, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Rojas, Julius de, Chshiev, Mairbek, Quintana, Alberto, Menéndez, Enric, Sort, Jordi, Rojas, Julius de [0000-0002-1206-4744], Chshiev, Mairbek [0000-0001-9232-7622], Quintana, Alberto [0000-0002-9813-735X], Menéndez, Enric [0000-0003-3809-2863], and Sort, Jordi [0000-0003-1213-3639]
Subjects: Magnetoelectricity, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], Ion diffusion, General Materials Science, Voltage control of magnetism (VCM), Magneto-ionics, Transition metal nitride
Abstract: Magneto-ionics is an emerging actuation mechanism to control the magnetic properties of materials via voltage-driven ion motion. This effect largely relies on the strength and penetration of the induced electric field into the target material, the amount of generated ion transport pathways, and the ionic mobility inside the magnetic media. Optimizing all these factors in a simple way is a huge challenge, although highly desirable for technological applications. Here, we demonstrate that the introduction of suitable transition-metal elements to binary nitride compounds can drastically boost magneto-ionics. More specifically, we show that the attained magneto-ionic effects in CoN films (i.e., saturation magnetization, toggling speeds, and cyclability) can be drastically enhanced through 10% substitution of Co by Mn in the thin-film composition. Incorporation of Mn leads to transformation from nanocrystalline into amorphous-like structures, as well as from metallic to semiconducting behaviors, resulting in an increase of N-ion transport channels. Ab initio calculations reveal a lower energy barrier for CoMn-N compared to Co-N that provides a fundamental understanding of the crucial role of Mn addition in the voltage-driven magnetic effects. These results constitute an important step forward toward enhanced voltage control of magnetism via electric field-driven ion motion., Financial support by the European Research Council (MAGIC-SWITCH 2019-Proof of Concept Grant, agreement no 875018; REMINDS 2021-ERC-Advanced Grant, agreement no 101054687), the European Union’s Horizon 2020 research and innovation program (European Training Network, ETN/ITN Marie Skłodowska-Curie grant no 861145; and Integrated Infrastructure, RADIATE, grant no 824096), the Spanish Government (PID2020-116844RB-C21 and PDC2021-121276-C31), the Generalitat de Catalunya (2017-SGR-292), and the KU Leuven (BOF program) is acknowledged. We acknowledge the technical support from the MiNa Laboratory at IMN in Madrid, who received funding from the CM (project S2018/NMT-4291 TEC2SPACE), MINECO (project CSIC13-4E-1794), and EU (FEDER, FSE). A.Q. acknowledges financial support from the Spanish Ministry of Science, Innovation and Universities through the “Severo Ochoa” Programme for Centers of Excellence in R&D (FUNFUTURE CEX2019-000917-S) and the “Juan de la Cierva─Formación” contract (FJC2019-039780-I). J.S. thanks the Spanish “Fábrica Nacional de Moneda y Timbre” (FNMT) for fruitful discussions. E.M. is a Serra Húnter Fellow., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).
Published: 2022

34. The Colour Lexicon Is Shaped by Environment and Biology: Comparing Himba and French Colour Perception

Author: Josserand, Mathilde, Caparos, Serge, Pellegrino, François, Dediu, Dan, Dynamique Du Langage (DDL), Université Lumière - Lyon 2 (UL2)-Centre National de la Recherche Scientifique (CNRS), Fonctionnement et Dysfonctionnement Cognitifs : Les âges de la vie (DysCo), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat de Barcelona (UB), Andrea Ravignani, Rie Asano, Olga Vasileva, Sławomir Wacewicz, Daria Valente, Francesco Ferretti, Stefan Hartmann, Misato Hayashi, Yannick Jadoul, Mauricio Martins, Yohei Oseki, Evelina Daniela Rodrigues, ANR-10-LABX-0081,ASLAN,Advanced Studies on Language Complexity(2010), Pellegrino, François, and Advanced Studies on Language Complexity - - ASLAN2010 - ANR-10-LABX-0081 - LABX - VALID
Subjects: [SCCO.LING] Cognitive science/Linguistics, [SCCO.LING]Cognitive science/Linguistics
Abstract: International audience
Published: 2022

35. Loss of seryl-tRNA synthetase ( SARS1 ) causes complex spastic paraplegia and cellular senescence

Author: Edgard Verdura, Bruno Senger, Miquel Raspall-Chaure, Agatha Schlüter, Nathalie Launay, Montserrat Ruiz, Carlos Casasnovas, Agustí Rodriguez-Palmero, Alfons Macaya, Hubert Dominique Becker, Aurora Pujol, Génétique et Physiopathologie des Maladies Cérébro-Vasculaires (U1161 / UMR_S 1161), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitat Autònoma de Barcelona (UAB), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Pediatrics Department, Hospital Universitari Germans Trias I Pujol, Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Neurometabolic Diseases Laboratory [Barcelona, Spain], Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Institut Català de la Salut, [Verdura E, Schlüter A, Launay N, Ruiz M] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. [Senger B] Université de Strasbourg 1, Strasbourg, France. [Raspall-Chaure M] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Macaya A] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: nervous system diseases, Paraplegia - Aspectes genètics, Sequence analysis, RNA, pediatrics, sequence analysis, Otros calificadores::Otros calificadores::/genética [Otros calificadores], neurology, [SDV]Life Sciences [q-bio], Cell Physiological Phenomena::Cellular Senescence [PHENOMENA AND PROCESSES], genetic research, Nervous system diseases, Pediatrics, Nervous System Diseases::Neurologic Manifestations::Paralysis::Paraplegia [DISEASES], enfermedades del sistema nervioso::manifestaciones neurológicas::parálisis::paraplejía [ENFERMEDADES], Neurology, Other subheadings::Other subheadings::/genetics [Other subheadings], Genetics, RNA, fenómenos fisiológicos celulares::senescencia celular [FENÓMENOS Y PROCESOS], Cèl·lules - Envelliment, Genetic research, Genetics (clinical)
Abstract: Genetic research; Nervous system diseases; Pediatrics Investigación genética; Enfermedades del sistema nervioso; Pediatría Recerca genètica; Malalties del sistema nerviós; Pediatria Background Aminoacyl-tRNA synthetases (ARS) are key enzymes catalysing the first reactions in protein synthesis, with increasingly recognised pleiotropic roles in tumourgenesis, angiogenesis, immune response and lifespan. Germline mutations in several ARS genes have been associated with both recessive and dominant neurological diseases. Recently, patients affected with microcephaly, intellectual disability and ataxia harbouring biallelic variants in the seryl-tRNA synthetase encoded by seryl-tRNA synthetase 1 (SARS1) were reported. Methods We used exome sequencing to identify the causal variant in a patient affected by complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Complementation and serylation assays using patient’s fibroblasts and an Saccharomyces cerevisiae model were performed to examine this variant’s pathogenicity. Results A de novo splice site deletion in SARS1 was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in S. cerevisiae and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect. Fibroblasts showed an abnormal cell shape, arrested division and increased beta-galactosidase staining along with a senescence-associated secretory phenotype (raised interleukin-6, p21, p16 and p53 levels). Conclusion We refine the phenotypic spectrum and modes of inheritance of a newly described, ultrarare neurodevelopmental disorder, while unveiling the role of SARS1 as a regulator of cell growth, division and senescence. This study was supported by grants from the Undiagnosed Rare Disease programme URD-Cat (SLT002/16/00174) from the Generalitat de Catalunya, the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759), the ASL-HSP France and the Hesperia Foundation to AP. This study was also funded by the Instituto de Salud Carlos III and ‘Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, una manera de hacer Europa’ (FIS PI20/00758) to CC and ‘La Marató de TV3’ Foundation (202006-30) to CC and AP. This study was also funded by Instituto de Salud Carlos III (Sara Borrell programme, CD19/00221) to EV, the Spanish Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811) to EV, and the Center for Biomedical Research on Rare Diseases (CIBERER) to MR and NL. This study was supported by the French National Programme Investissement d’Avenir administered by the ‘Agence National de la Recherche’ (ANR), ‘MitoCross’ Laboratory of Excellence (Labex), funded as ANR-10-IDEX-0002-02, the University of Strasbourg and CNRS (to HB, BS). The CERCA Programme/Generalitat de Catalunya provided institutional support. AP is member of the Undiagnosed Disease Network International (UDNI).
Published: 2022

36. Nucleation and growth of gold nanoparticles in the presence of different surfactants. A dissipative particle dynamics study

Author: Rosa Suárez-López, Víctor F. Puntes, Neus G. Bastús, Carmen Hervés, Carlos Jaime, Universidad Autónoma de Barcelona, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Institut Català de la Salut, [Suárez-López R, Jaime C] Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Puntes VF] Institut Català de Nanociència i Nanotecnologia (ICN2), CSIC and BIST, Campus UAB, Bellaterra, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Bastús NG, Hervés C] Institut Català de Nanociència i Nanotecnologia (ICN2), CSIC and BIST, Campus UAB, Bellaterra, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Computational chemistry, Multidisciplinary, Nanopartícules, Nanotecnologia, Lipid Bilayers, Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles::Metal Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], Metal Nanoparticles, Pulmonary Surfactants, disciplinas de las ciencias naturales::nanotecnología [DISCIPLINAS Y OCUPACIONES], Chemical Actions and Uses::Specialty Uses of Chemicals::Surface-Active Agents [CHEMICALS AND DRUGS], tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas::nanopartículas metálicas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Coarse-grained models, Surface-Active Agents, Medicina - Investigació, Natural Science Disciplines::Nanotechnology [DISCIPLINES AND OCCUPATIONS], Nanoparticles, Gold, Colloids, acciones y usos químicos::usos especializados de productos químicos::tensoactivos [COMPUESTOS QUÍMICOS Y DROGAS]
Abstract: Nanoparticles (NPs) show promising applications in biomedicine, catalysis, and energy harvesting. This applicability relies on controlling the material’s features at the nanometer scale. Surfactants, a unique class of surface-active molecules, have a remarkable ability to tune NPs activity; provide specific functions, avoid their aggregation, and create stable colloidal solutions. Surfactants also control nanoparticles’ nucleation and growth processes by modifying nuclei solubility and surface energy. While nucleation seems independent from the surfactant, NP’s growth depends on it. NP`s size is influenced by the type of functional group (C, O, S or N), length of its C chain and NP to surfactant ratio. In this paper, gold nanoparticles (Au NPs) are taken as model systems to study how nucleation and growth processes are affected by the choice of surfactants by Dissipative Particle Dynamics (DPD) simulations. DPD has been mainly used for studying biochemical structures, like lipid bilayer models. However, the study of solid NPs, and their conjugates, needs the introduction of a new metallic component. To represent the collective phenomena of these large systems, their degrees of freedom are reduced by Coarse-Grained (CG) models. DPD behaved as a powerful tool for studying complex systems and shedding some light on some experimental observations, otherwise difficult to explain., Authors are gratefully acknowledged for a fellowship to R.S-L provided by Universitat Autònoma de Barcelona, and for the financial support obtained through grant number RTI2018-099965-B-I00 from Ministerio de Ciencia, Innovación y Universidades, Spain. NGB and VP acknowledge financial support from R&D&I projects for international joint programming from MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and from Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya.
Published: 2022

37. Pathways Related to NLRP3 Inflammasome Activation Induced by Gold Nanorods

Author: Rob J. Vandebriel, Sylvie Remy, Jolanda P. Vermeulen, Evelien G. E. Hurkmans, Kirsten Kevenaar, Neus G. Bastús, Beatriz Pelaz, Mahmoud G. Soliman, Victor F. Puntes, Wolfgang J. Parak, Jeroen L. A. Pennings, Inge Nelissen, Institut Català de la Salut, [Vandebriel RJ, Vermeulen JP, Hurkmans EGE, Kevenaar K] Centre for Health Protection, National Institute for Public Health & the Environment, Bilthoven, The Netherlands. [Remy S] Health Unit, VITO NV, Mol, Belgium. [Bastús NG] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona, Bellaterra, Spain. [Puntes VF] Institut Català de Nanociència i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas (CSIC), The Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, and European Commission
Subjects: Macromolecular Substances::Multiprotein Complexes::Inflammasomes [CHEMICALS AND DRUGS], Inflammasomes, Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles::Metal Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], oxidative phosphorylation, Metal Nanoparticles, Or, Nanorod, purinergic receptor, tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanotubos [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Catalysis, tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas::nanopartículas metálicas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], Inorganic Chemistry, NLRP3, NLR Family, Pyrin Domain-Containing 3 Protein, Humans, Oxidative phosphorylation, Physical and Theoretical Chemistry, paraoxonase-2, Molecular Biology, Nanosphere, Paraoxonase-2, Spectroscopy, Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanotubes [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], Inflammation, Nanotubes, sustancias macromoleculares::complejos multiproteicos::inflamasomas [COMPUESTOS QUÍMICOS Y DROGAS], Nanopartícules, integumentary system, Organic Chemistry, cholesterol, General Medicine, gold, nanorod, Computer Science Applications, nanosphere, Cholesterol, inflammation, nanostar, Gold, Nanotubs, Purinergic receptor, Nanostar
Abstract: The widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to ENM through inflammatory reactions. The NLRP3 inflammasome responds to a wide range of ENM, and its activation is associated with various inflammatory diseases. Recently, anisotropic ENM have become of increasing interest, but knowledge of their effects on the immune system is still limited. The objective of the study was to compare the effects of gold ENM of different shapes on NLRP3 inflammasome activation and related signalling pathways. Differentiated THP-1 cells (wildtype, ASC-or NLRP3-deficient), were exposed to PEGylated gold nanorods, nanostars, and nanospheres, and, thus, also different surface chemistries, to assess NLRP3 inflammasome activation. Next, the exposed cells were subjected to gene expression analysis. Nanorods, but not nanostars or nanospheres, showed NLRP3 inflammasome activation. ASC-or NLRP3-deficient cells did not show this effect. Gene Set Enrichment Analysis revealed that gold nanorod-induced NLRP3 inflammasome activation was accompanied by downregulated sterol/cholesterol biosynthesis, oxidative phosphorylation, and purinergic receptor signalling. At the level of individual genes, downregulation of Paraoxonase-2, a protein that controls oxidative stress, was most notable. In conclusion, the shape and surface chemistry of gold nanoparticles determine NLRP3 inflammasome activation. Future studies should include particle uptake and intracellular localization., This research was funded by the EU FP7 project FutureNanoNeeds (GA N° 604602), RIVM, and VITO.
Published: 2022

38. Representation and Annual to Decadal Predictability of Euro‐Atlantic Weather Regimes in the CMIP6 Version of the EC‐Earth Coupled Climate Model

Author: C. Delgado‐Torres, D. Verfaillie, E. Mohino, M. G. Donat, Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Department of Physics of the Earth and Astrophysics, Universidad Complutense de Madrid, Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institució Catalana de Recerca i Estudis Avançats (ICREA), and Barcelona Supercomputing Center
Subjects: Atmospheric circulation, Atmospheric Science, Enginyeria agroalimentària::Ciències de la terra i de la vida::Climatologia i meteorologia [Àrees temàtiques de la UPC], Geophysics, Space and Planetary Science, North Atlantic oscillation, Simulació per ordinador, [SDE]Environmental Sciences, Física atmosférica, Earth and Planetary Sciences (miscellaneous), Decadal predictability, Climate model, Euro-Atlantic weather regimes
Abstract: Weather regimes are large-scale atmospheric circulation states that frequently occur in the climate system with persistence and recurrence, and are associated with the occurrence of specific local weather conditions. This study evaluates the representation of the four Euro-Atlantic weather regimes in uninitialized historical forcing simulations and initialized decadal predictions performed with the EC-Earth3 coupled climate model. The four weather regimes are the positive and negative phases of the North Atlantic Oscillation (NAO+ and NAO−, respectively), Blocking, and Atlantic Ridge in winter; and the NAO−, Blocking, Atlantic Ridge, and Atlantic Low in summer. We also analyze the impact that the model initialization toward the observed state of the climate system has on the ability to predict the variability of the weather regimes' seasonal frequency of occurrence. We find that the EC-Earth3 model correctly reproduces the spatial patterns and climatological occurrence frequencies of the four weather regimes. By contrast, the skill in predicting the inter-annual to decadal variations of the weather regimes' seasonal frequencies is generally low, and the initialization does not significantly improve such skill. The observed teleconnections between the weather regimes and the North Atlantic sea surface temperatures are generally not reproduced by the model, which could be a reason for the low skill in predicting the temporal variations of the weather regime frequencies. This research has received support by the AXA Research Fund, the CLINSA project (CGL2017-85791-R), and the EUCP project (Horizon 2020 Grant 776613). CDT acknowledges financial support from the Spanish Ministry for Science and Innovation (FPI PRE2019-08864 financed by MCIN/ AEI/10.13039/501100011033 and by FSE invierte en tu futuro). EH was supported by the Spanish Project PRE4CAST (grant CGL2017-86415-R). MGD has also beensupported by the Spanish Ministry for the Economy, Industry and Competitiveness (grant RYC-2017-22964).
Published: 2022

39. Nanoindenting the Chelyabinsk Meteorite to Learn about Impact Deflection Effects in asteroids

Author: Sort, Jordi [Institució Catalana de Recerca i Estudis Avançats (ICREA) and Departament de Física, Universitat Autónoma de Barcelona, E-08193 Bellaterra (Spain)]
Published: 2017
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40. A Single Hydrogen Bond Controls the Selectivity of Transglycosylation vs Hydrolysis in Family 13 Glycoside Hydrolases

Author: Zhiyong Guo, Lei Wang, Lingqia Su, Sheng Chen, Wei Xia, Isabelle André, Carme Rovira, Binju Wang, Jing Wu, Yangzhou University, Shanghai Jiao Tong University School of Medicine, Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universitat de Barcelona and the Intitut de Recerca en Química Teòrica i Computacional (IQTCUB), Institució Catalana de Recerca i Estudis Avançats (ICREA), Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Jiangnan University, Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona (UB), Xiamen University, National Natural Science Foundation of China (NSFC, Grants 31730067 and 21933009), National Science Fund for Distinguished Young Scholars (Grant 31425020), NSFC (Grants 22073077, 32001637, and 31972032), Spanish Ministry of Science and Innovation (Grants PID2020-118893GB-I00 and MDM-2017-0767), European Research Council (Grant ERC-2020-SyG-95123), National First-Class Discipline Program of Light Industry Technology and Engineering (Grant LITE2018-03), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant KYCX19_1839).
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Glycosylation, Glycoside Hydrolases, Hydrolysis, General Materials Science, Hydrogen Bonding, [CHIM.CATA]Chemical Sciences/Catalysis, Physical and Theoretical Chemistry, Hydrogen
Abstract: International audience; Converting glycoside hydrolases (GHs) from hydrolytic to synthetic enzymes via transglycosylation is a long-standing goal for the biosynthesis of complex carbohydrates. However, the molecular determinants for the selectivity of transglycosylation (T) vs hydrolysis (H) are still not fully unraveled. Herein, we show experimentally that mutation of one active site residue can switch the enzyme activity between hydrolysis and transglycosylation in two highly homologous GHs. Further QM/MM simulations reveal that the mutation modulates the T vs H reaction barriers via the presence/absence of a single H-bond with the nucleophile Asp. Such a H-bond controls the product selectivity via a dual effect: on one hand, it facilitates the breaking of the glycosyl-enzyme intermediate. On the other, it displaces the sugar acceptor, resulting in a reduced affinity and significant steric repulsion for transglycosylation. These findings expand our understanding of the molecular mechanisms that modulate the T/H balance in GHs.
Published: 2022

41. Two-dimensional materials prospects for non-volatile spintronic memories

Author: Hyunsoo Yang, Sergio O. Valenzuela, Mairbek Chshiev, Sébastien Couet, Bernard Dieny, Bruno Dlubak, Albert Fert, Kevin Garello, Matthieu Jamet, Dae-Eun Jeong, Kangho Lee, Taeyoung Lee, Marie-Blandine Martin, Gouri Sankar Kar, Pierre Sénéor, Hyeon-Jin Shin, Stephan Roche, Department of Electrical and Computer Engineering, National University of Singapore (NUS), ICN2 - Institut Catala de Nanociencia i Nanotecnologia (ICN2), Universitat Autònoma de Barcelona (UAB), Institució Catalana de Recerca i Estudis Avançats (ICREA), SPINtronique et TEchnologie des Composants (SPINTEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), IMEC (IMEC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité mixte de physique CNRS/Thales (UMPhy CNRS/THALES), THALES [France]-Centre National de la Recherche Scientifique (CNRS), Samsung Electronics [Korea], GLOBALFOUNDRIES Singapore Pte Ltd., Thales Research and Technology [Palaiseau], THALES [France], Samsung Advanced Institute of Technology (SAIT), Samsung, ANR-18-CE24-0007,MAGICVALLEY,Polarisation de vallée induite par couplage d'échange magnétique dans les matériaux 2D à grande échelle(2018), European Project: 881603,H2020,H2020-SGA-FET-GRAPHENE-2019, GrapheneCore3(2020), European Project: 306652,EC:FP7:ERC,ERC-2012-StG_20111012,SPINBOUND(2013), European Project: 669204,H2020,ERC-2014-ADG,MAGICAL(2015), European Commission, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), National Research Foundation Singapore, and Agence Nationale de la Recherche (France)
Subjects: Multidisciplinary, Magnetic devices, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], Electrical and electronic engineering, [SPI.MAT]Engineering Sciences [physics]/Materials, [SPI.TRON]Engineering Sciences [physics]/Electronics
Abstract: Non-volatile magnetic random-access memories (MRAMs), such as spin-transfer torque MRAM and next-generation spin–orbit torque MRAM, are emerging as key to enabling low-power technologies, which are expected to spread over large markets from embedded memories to the Internet of Things. Concurrently, the development and performances of devices based on two-dimensional van der Waals heterostructures bring ultracompact multilayer compounds with unprecedented material-engineering capabilities. Here we provide an overview of the current developments and challenges in regard to MRAM, and then outline the opportunities that can arise by incorporating two-dimensional material technologies. We highlight the fundamental properties of atomically smooth interfaces, the reduced material intermixing, the crystal symmetries and the proximity effects as the key drivers for possible disruptive improvements for MRAM at advanced technology nodes., M.C., S.C., B.D., A.F., K.G., M.-B. M., P.S., S.O.V. and S.R. acknowledge the European Union Horizon 2020 research and innovation programme for grant number 881603 (Graphene Flagship). The Catalan Institute of Nanoscience and Nanotechnology is supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant number SEV-2017-0706). S.O.V. thanks the European Research Council (ERC) under grant agreements 306652 SPINBOUND and 899896 SOTMEM, and the Spanish Research Agency (AEI), Ministry of Science and Innovation (PID2019-111773RB-I00/AEI/10.13039/501100011033). H.Y. is supported by SpOT-LITE programme (A*STAR grant, A18A6b0057) through RIE2020 funds, Singapore Ministry of Education (MOE) Tier 2 (R-263-000-E29-112), National Research Foundation (NRF) Singapore Investigatorship (NRFI06-2020-0015) and Samsung Electronics’ University R&D programme. S.C. and G.S.K. acknowledge IMEC’s Industrial Affiliation Program on MRAM devices. M.C. and M.J. acknowledge the French National Research Agency through the MAGICVALLEY project (ANR-18-CE24-0007). B. Dieny acknowledges ERC MAGICAL 669204. M.C. acknowledges H. X. Yang, A. Hallal and F. Ibrahim. P.S. and B. Dlubak acknowledge the French National Research Agency through the SoGraphMem project (ANR-18-CE24-0007).
Published: 2022

42. Metal transfer to sediments, invertebrates and fish following waterborne exposure to silver nitrate or silver sulfide nanoparticles in an indoor stream mesocosm

Author: Nathaniel Clark, Joanne Vassallo, Patrícia V. Silva, Ana Rita R. Silva, Marta Baccaro, Neja Medvešček, Magdalena Grgić, Abel Ferreira, Martí Busquets-Fité, Kerstin Jurkschat, Anastasios G. Papadiamantis, Victor Puntes, Iseult Lynch, Claus Svendsen, Nico W. van den Brink, Cornelis A.M. van Gestel, Susana Loureiro, Richard D. Handy, Institut Català de la Salut, [Clark N, Vassallo J] School of Biological and Marine Sciences, University of Plymouth, Plymouth, UK. [Silva PV, Silva ARR] Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal. [Baccaro M] Department of Toxicology, Wageningen University, Wageningen, the Netherlands. [Medvešček N] Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia. [Puntes V] Institut Català de Nanociència i Nanotecnologia (ICN2), CSIC, The Barcelona Institute of Science and Technology (BIST), Campus UAB, Bellaterra, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, European Commission, Fundação para a Ciência e a Tecnologia (Portugal), Ministério da Ciência, Tecnologia e Ensino Superior (Portugal), and Animal Ecology
Subjects: Environmental Engineering, Engineered nanomaterials, Trout, Ecosistemes, Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles::Metal Nanoparticles [TECHNOLOGY, INDUSTRY, AND AGRICULTURE], Metal Nanoparticles, fenómenos biológicos::fenómenos ecológicos y ambientales::ambiente::ecosistema [FENÓMENOS Y PROCESOS], Sulfides, Toxicology, Silver uptake, Ecology and Environment, tecnología, industria y agricultura::productos manufacturados::nanoestructuras::nanopartículas::nanopartículas metálicas [TECNOLOGÍA, INDUSTRIA Y AGRICULTURA], acciones y usos químicos::acciones tóxicas::contaminantes ambientales::contaminantes del agua::contaminantes químicos del agua [COMPUESTOS QUÍMICOS Y DROGAS], Rivers, Contaminants, Metal partitioning, Environmental Chemistry, Animals, SDG 14 - Life Below Water, Coloring Agents, Waste Management and Disposal, Toxicologie, Ecosystem, Nanopartícules, Biological Phenomena::Ecological and Environmental Phenomena::Environment::Ecosystem [PHENOMENA AND PROCESSES], Silver Compounds, Freshwater sediments, Benthic and planktonic invertebrates, TroutSilver uptake, Pollution, Chemical Actions and Uses::Toxic Actions::Environmental Pollutants::Water Pollutants::Water Pollutants, Chemical [CHEMICALS AND DRUGS], Daphnia, Metals, Oncorhynchus mykiss, Silver Nitrate, SDG 6 - Clean Water and Sanitation, Water Pollutants, Chemical
Abstract: The fate of engineered nanomaterials in ecosystems is unclear. An aquatic stream mesocosm explored the fate and bioaccumulation of silver sulfide nanoparticles (AgS NPs) compared to silver nitrate (AgNO). The aims were to determine the total Ag in water, sediment and biota, and to evaluate the bioavailable fractions of silver in the sediment using a serial extraction method. The total Ag in the water column from a nominal daily dose of 10 μg L of Ag for the AgNO or AgS NP treatments reached a plateau of around 13 and 12 μg L, respectively, by the end of the study. Similarly, the sediment of both Ag-treatments reached ~380 μg Ag kg, and with most of it being acid-extractable/labile. The biota accumulated 4–59 μg Ag g dw, depending on the type of Ag-treatment and organism. The oligochaete worm, Lumbriculus variegatus, accumulated Ag from the AgS exposure over time, which was similar to the AgNO treatment by the end of the experiment. The planarian, Girardia tigrina, and the chironomid larva, Chironomus riparius, showed much higher Ag concentrations than the oligochaete worms; and with a clearer time-dependent statistically significant Ag accumulation relative to the untreated controls. For the pulmonate snail, Physa acuta, bioaccumulation of Ag from AgNO and AgS NP exposures was observed, but was lower from the nano treatment. The AgNO exposure caused appreciable Ag accumulation in the water flea, Daphnia magna, but accumulation was higher in the AgS NP treatment (reaching 59 μg g dw). In the rainbow trout, Oncorhynchus mykiss, AgNO, but not AgS NPs, caused total Ag concentrations to increase in the tissues. Overall, the study showed transfer of total Ag from the water column to the sediment, and Ag bioaccumulation in the biota, with Ag from AgS NP exposure generally being less bioavailable than that from AgNO., This work was supported by the project NanoFASE (Nanomaterial Fate and Speciation in the Environment), financed by the European Union's Horizon 2020 research and innovation programme under grant agreement no 646002. RDH was partly supported by NanoHarmony under grant agreement 885931 in Horizon 2020 while redrafting the main text. PVS was awarded with a PhD grant (SFRH/BD/51571/2014) by FCT – Fundação para a Ciência e a Tecnologia. SL and PVS received additional financial support from FCT/MCTES, through national funds, to CESAM (UIDP/50017/2020+UIDB/50017/2020+ LA/P/0094/2020).
Published: 2022

43. GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells

Author: Chiara Bellio, Marta Emperador, Pol Castellano, Albert Gris-Oliver, Francesc Canals, Alex Sánchez-Pla, Esther Zamora, Joaquín Arribas, Cristina Saura, Violeta Serra, Josep Tabernero, Bruce A. Littlefield, Josep Villanueva, Institut Català de la Salut, [Bellio C, Emperador M, Castellano P, Gris-Oliver A, Canals F] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Sánchez-Pla A] Genetics Microbiology and Statistics Department, Universitat de Barcelona, Barcelona, Spain. Unitat d'Estadística i Bioinformàtica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Zamora E, Saura C] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Grup de Càncer de Mama, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Arribas J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Serra V, Tabernero J, Villanueva J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Cancer Research, Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES], Breast cancer (BC), Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Drug tolerant persister (DTP), Biological Factors::Biomarkers [CHEMICALS AND DRUGS], factores biológicos::biomarcadores [COMPUESTOS QUÍMICOS Y DROGAS], drug tolerance, drug tolerant persister (DTP), eribulin, growth differentiation factor 15 (GDF15), breast cancer (BC), secretome, Càncer de mama, Growth differentiation factor 15 (GDF15), Breast cancer, Oncology, Marcadors bioquímics, Mama - Càncer - Tractament, Extracellular space, Eribulin, Drug tolerance, Espai extracel·lular, Resistència als medicaments, Secretome
Abstract: Breast cancer; Drug tolerance; Secretome Cáncer de mama; Tolerancia a los fármacos; Secretoma Càncer de mama; Tolerància als fàrmacs; Secretoma Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after drug treatment. We performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. We showed that the growth differentiation factor 15 (GDF15) is a protein significantly over-secreted upon eribulin treatment. The biomarker potential of GDF15 was confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. We also found that GDF15 is required for survival of DTP cells. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function assays. Finally, we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired resistance. This research was funded by Eisai Inc.
Published: 2022

44. How Reliable Are Decadal Climate Predictions of Near-Surface Air Temperature?

Author: Francisco J. Doblas-Reyes, Verónica Torralba, Deborah Verfaillie, Núria Pérez-Zanón, Balakrishnan Solaraju-Murali, Markus G. Donat, Simon Wild, Universitat Politècnica de Catalunya. Doctorat en Enginyeria Ambiental, Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Institut des Géosciences de l’Environnement (IGE), Institut de Recherche pour le Développement (IRD)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Earth and Life Institute [Louvain-La-Neuve] (ELI), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institució Catalana de Recerca i Estudis Avançats (ICREA), and Barcelona Supercomputing Center
Subjects: Atmospheric Science, 010504 meteorology & atmospheric sciences, media_common.quotation_subject, Library science, Decadal variability, 010502 geochemistry & geophysics, Climate prediction, 01 natural sciences, Climate models, Surface air temperature, Simulació per ordinador, Political science, Gratitude, media_common.cataloged_instance, European union, Weatther forecasting -- Mathematical models, Physics::Atmospheric and Oceanic Physics, 0105 earth and related environmental sciences, media_common, Enginyeria agroalimentària::Ciències de la terra i de la vida::Climatologia i meteorologia [Àrees temàtiques de la UPC], Computer simulation, Desenvolupament humà i sostenible::Enginyeria ambiental [Àrees temàtiques de la UPC], Climatology, Previsió del temps -- Models matemàtics, 13. Climate action, [SDE]Environmental Sciences, Christian ministry, Forecast verification/skill, Forecasting
Abstract: Decadal climate predictions are being increasingly used by stakeholders interested in the evolution of climate over the coming decade. However, investigating the added value of those initialized decadal predictions over other sources of information typically used by stakeholders generally relies on forecast accuracy, while probabilistic aspects, although crucial to users, are often overlooked. In this study, the quality of the near-surface air temperature from initialized predictions has been assessed in terms of reliability, an essential characteristic of climate simulation ensembles, and compared to the reliability of noninitialized simulations performed with the same model ensembles. Here, reliability is defined as the capability to obtain a true estimate of the forecast uncertainty from the ensemble spread. We show the limited added value of initialization in terms of reliability, the initialized predictions being significantly more reliable than their noninitialized counterparts only for specific regions and the first forecast year. By analyzing reliability for different forecast system ensembles, we further highlight the fact that the combination of models seems to play a more important role than the ensemble size of each individual forecast system. This is due to sampling different model errors related to model physics, numerics, and initialization approaches involved in the multimodel, allowing for a certain level of error compensation. Finally, this study demonstrates that all forecast system ensembles are affected by systematic biases and dispersion errors that affect the reliability. This set of errors makes bias correction and calibration necessary to obtain reliable estimates of forecast probabilities that can be useful to stakeholders. The EUCP project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement 776613. The research leading to these results has also received funding from the Spanish Ministerio de Ciencia, Innovación y Universidades as part of the CLINSA project with funding reference CGL2017-85791-R. MGD is also supported by the Spanish Ministry of Science, Innovation and Universities Grant RYC-2017-22964. BSM acknowledges financial support from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement 713673 and from a fellowship of “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/IN17/11620038. SW has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement H2020-MSCA-COFUND-2016-754433. We acknowledge the use of the s2dverification (Manubens et al. 2018), startR (BSC/CNS and Manubens 2020), SpecsVerification (Siegert 2017), CSTools (Perez-Zanon et al. 2019), ClimProjDiags (BSC/CNS et al. 2020), and boot (Davison and Hinkley 1997; Canty and Ripley 2020) R (R Core Team 2013) software packages. We also thank Nicolau Manubens, An-Chi Ho, Pablo Ortega, Rashed Mahmood, Yohan Ruprich-Robert, and Roberto Bilbao from the BSC for their technical and scientific support. We further express our gratitude to Charles Pelletier from ELI for his careful reading of the manuscript. Finally, we would like to thank Antje Weisheimer (University of Oxford) and two anonymous reviewers for constructive comments that helped us greatly improve this article.
Published: 2021

45. An anatomy of Arctic sea ice forecast biases in the seasonal prediction system with EC-Earth

Author: Pablo Ortega, Juan C. Acosta Navarro, François Massonnet, Virginie Guemas, Rubén Cruz-García, Francisco J. Doblas-Reyes, Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Centre national de recherches météorologiques (CNRM), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institució Catalana de Recerca i Estudis Avançats (ICREA), Météo France-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), and Barcelona Supercomputing Center
Subjects: Atmospheric Science, Dynamic climatology, Artic, 010504 meteorology & atmospheric sciences, Sea ice, Initialization, Context (language use), Prediction system, 010502 geochemistry & geophysics, 01 natural sciences, Arctic, Bias, Sea ice concentration, 0105 earth and related environmental sciences, [SDU.OCEAN]Sciences of the Universe [physics]/Ocean, Atmosphere, geography, geography.geographical_feature_category, Sea ice--Arctic regions, Shock, Arctic ice pack, 13. Climate action, General Circulation Model, Climatology, Enginyeria agroalimentària::Ciències de la terra i de la vida [Àrees temàtiques de la UPC], Environmental science, Forecast, Simulacio per ordinador
Abstract: The quality of initial conditions (ICs) in climate predictions controls the level of skill. Both the use of the latest high-quality observations and of the most efficient assimilation method are of paramount importance. Technical challenges make it frequent to assimilate observational information independently in the various model components. Inconsistencies between the ICs obtained for the different model components can cause initialization shocks. In this study, we identify and quantify the contribution of the ICs inconsistency relative to the model inherent bias (in which the Arctic is generally too warm) to the development of sea ice concentration forecast biases in a seasonal prediction system with the EC-Earth general circulation model. We estimate that the ICs inconsistency dominates the development of forecast biases for as long as the first 24 (19) days of the forecasts initialized in May (November), while the development of model inherent bias dominates afterwards. The effect of ICs inconsistency is stronger in the Greenland Sea, in particular in November, and mostly associated to a mismatch between the sea ice and ocean ICs. In both May and November, the ICs inconsistency between the ocean and sea ice leads to sea ice melting, but it happens in November (May) in a context of sea ice expansion (shrinking). The ICs inconsistency tend to postpone (accelerate) the November (May) sea ice freezing (melting). Our findings suggest that the ICs inconsistency might have a larger impact than previously suspected. Detecting and filtering out this signal requires the use of high frequency data. We thank Magdalena Balmaseda for providing sea ice data used to produce ORAS4. Also to Javier Vegas-Regidor, Nicolau Manubens and Pierre-Antoine Bretonniere for the technical support. The R-package s2dverification was used for processing the data and calculating different scores (Manubens et al. 2018). We thank three anonymous reviewers for their constructive and helpful comments for improving the manuscript. This study was funded by the projects APPLICATE (H2020 GA 727862) and the Spanish national grant Formación de Profesorado Universitario (FPU15/01511; Ministerio de Ciencia, Innovación y Universidades). JCAN received financial support from the Ministerio de Ciencia, Innovación y Universidades through a Juan de la Cierva personal grant (FJCI-2017-34027).
Published: 2021

46. Constraints on the magnitude and patterns of ocean cooling at the Last Glacial Maximum

Author: Waelbroeck, C., Paul, A., Kucera, Michal, Rosell-Melé, Antoni, Weinelt, Mara, Schneider, Ralph, Mix, Alan C., Abelmann, Andrea, Armand, Leanne, Bard, Edouard, Barker, Stephen, Barrows, Timothy T., Benway, H., Cacho, Isabel, Chen, Min-Te, Cortijo, Elsa, Crosta, X., de Vernal, Anne, Dokken, Trond, Duprat, Josette, Elderfield, Harry, Eynaud, Frédérique, Gersonde, Rainer, Hayes, Angela, Henry, M., Hillaire-Marcel, Claude, Huang, C.-C., Jansen, Eystein, Juggins, Stephen, Kallel, N., Kiefer, Thorsten, Kienast, M., Labeyrie, Laurent, Leclaire, H., Londeix, L., Mangin, S., Matthiessen, Jens, Marret, F., Meland, M., Morey, Ann E., Mulitza, Stefan, Pflaumann, Uwe, Pisias, N. G., Radi, T., Rochon, A., Rohling, Eelco J., Sbaffi, Laura, Schaefer-Neth, C., Solignac, Sandrine, Spero, Howard J., Kazuyo, Tachikawa, Turon, J.-L., Members, Margo Project, Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Paléocéanographie (PALEOCEAN), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Department of Geosciences, Institute of Geosciences, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institute of Environmental Science and Technology [Barcelona] (ICTA), Universitat Autònoma de Barcelona (UAB), Institució Catalana de Recerca i Estudis Avançats (ICREA), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Evolution du climat et de l'océan, Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Stratigraphy Paleontology and Marine Geosciences, University of Barcelona, Environnements et Paléoenvironnements OCéaniques (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Bjerknes Centre for Climate Research (BCCR), Department of Biological Sciences [Bergen] (BIO / UiB), University of Bergen (UiB)-University of Bergen (UiB), Centre de Spectrométrie Nucléaire et de Spectrométrie de Masse (CSNSM), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Department of Bentho-pelagic processes, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Division of Geological and Planetary Sciences [Pasadena], California Institute of Technology (CALTECH), Centre de recherche sur la dynamique du système Terre (GEOTOP), École Polytechnique de Montréal (EPM)-McGill University = Université McGill [Montréal, Canada]-Université de Montréal (UdeM)-Université du Québec en Abitibi-Témiscamingue (UQAT)-Université du Québec à Rimouski (UQAR)-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Unité GEOGLOB, Faculté des Sciences de Sfax, Université de Sfax - University of Sfax-Université de Sfax - University of Sfax, Past Global Changes International Project Office (PAGES), Past Global Changes International Project Office, Centre d'Études Biologiques de Chizé (CEBC), Centre National de la Recherche Scientifique (CNRS), School of Environmental Sciences, University of Liverpool, Center for Marine Environmental Sciences [Bremen] (MARUM), Universität Bremen, National Oceanography Centre [Southampton] (NOC), University of Southampton, Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Chaire Evolution du climat et de l'océan, Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Université de Montréal (UdeM)-McGill University = Université McGill [Montréal, Canada]-École Polytechnique de Montréal (EPM)-Concordia University [Montreal]-Université du Québec à Rimouski (UQAR)-Université du Québec à Montréal = University of Québec in Montréal (UQAM)-Université du Québec en Abitibi-Témiscamingue (UQAT), Centre d'études biologiques de Chizé (CEBC), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre-Simon-Laplace (IPSL), École normale supérieure - Paris (ENS Paris)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National d'Études Spatiales [Toulouse] (CNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Eberhard Karls Universität Tübingen, Universitat Autònoma de Barcelona [Barcelona] (UAB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Collège de France (CdF)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), École Polytechnique de Montréal (EPM)-Université McGill -Université de Montréal (UdeM)-Université du Québec en Abitibi-Témiscamingue (UQAT)-Université du Québec à Rimouski (UQAR)-Concordia University [Montreal]-Université du Québec à Montréal (UQAM), PAGES International Project Office, Zähringerstrasse 25, 3122 Bern, Switzerland, Univsersity of Liverpool, Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] ( LSCE ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut Pierre-Simon-Laplace ( IPSL ), École normale supérieure - Paris ( ENS Paris ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National d'Etudes Spatiales ( CNES ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Inst. of Environmental Science and Technology (ICTA), Institució Catalana de Recerca i Estudis Avançats, Institució Catalana de Recerca i Estudis Avançats ( ICREA ), Service de Chimie Inorganique et Biologique ( SCIB - UMR E3 ), Institut Nanosciences et Cryogénie ( INAC ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes ( UGA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre européen de recherche et d'enseignement de géosciences de l'environnement ( CEREGE ), Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Collège de France ( CdF ) -Institut National de la Recherche Agronomique ( INRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ), Environnements et Paléoenvironnements OCéaniques ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Bjerknes Centre for Climate Research ( BCCR ), University of Bergen ( UIB ), Centre de Spectrométrie Nucléaire et de Spectrométrie de Masse ( CSNSM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research ( AWI ), California Institute of Technology ( CALTECH ), GEOTOP-UQAM-McGill, Faculté des sciences de Sfax, Centre d'études biologiques de Chizé ( CEBC ), Centre National de la Recherche Scientifique ( CNRS ), MARUM &ndash, Center For Marine Environmental Sciences, National Oceanography Centre [Southampton] ( NOC ), and University of Southampton [Southampton]
Subjects: [SDU.OCEAN]Sciences of the Universe [physics]/Ocean, Atmosphere, geography, geography.geographical_feature_category, 010504 meteorology & atmospheric sciences, [SDU.ASTR]Sciences of the Universe [physics]/Astrophysics [astro-ph], Climate change, Last Glacial Maximum, 010502 geochemistry & geophysics, 01 natural sciences, Sea surface temperature, [SDU.STU.CL]Sciences of the Universe [physics]/Earth Sciences/Climatology, 13. Climate action, Climatology, Paleoclimate Modelling Intercomparison Project, Deglaciation, General Earth and Planetary Sciences, Climate sensitivity, 14. Life underwater, Glacial period, Oceanic basin, [ SDU.ASTR ] Sciences of the Universe [physics]/Astrophysics [astro-ph], [SDU.STU.OC]Sciences of the Universe [physics]/Earth Sciences/Oceanography, Geology, 0105 earth and related environmental sciences
Abstract: International audience; Observation-based reconstructions of sea surface temperature from relatively stable periods in the past, such as the Last Glacial Maximum, represent an important means of constraining climate sensitivity and evaluating model simulations 1. The first quantitative global reconstruction of sea surface temperatures during the Last Glacial Maximum was developed by the Climate Long-Range Investigation, Mapping and Prediction (CLIMAP) project in the 1970s and 1980s (refs 2,3). Since that time, several shortcomings of that earlier effort have become apparent 4. Here we present an updated synthesis of sea surface temperatures during the Last Glacial Maximum, rigorously defined as the period between 23 and 19 thousand years before present, from the Multiproxy Approach for the Reconstruction of the Glacial Ocean Surface (MARGO) project 5. We integrate microfossil and geochemical reconstructions of surface temperatures and include assessments of the reliability of individual records. Our reconstruction reveals the presence of large longitudinal gradients in sea surface temperature in all of the ocean basins, in contrast to the simulations of the Last Glacial Maximum climate available at present 6,7. Studies following the Climate Long-Range Investigation, Mapping and Prediction (CLIMAP) project mainly reanalysed old primary data, applied single new proxies or concentrated on specific ocean basins 8-11. The Multiproxy Approach for the Reconstruction of the Glacial Ocean Surface (MARGO) project's objective has been to compile and analyse available estimates of Last Glacial Maximum (LGM) sea surface temperatures (SSTs) based on all prevalent microfossil-based (transfer functions based on planktonic foraminifera, diatom, dinoflagellate cyst and radiolarian abundances) and geochemical (alkenones and planktonic foraminifera Mg/Ca) palaeothermometers. The MARGO project approach is to argue that no current proxy method is objectively better than another to provide an accurate picture of past SST, and that consequently the multiproxy approach yields the least biased representation of past reality. By using a rigorous definition of the LGM time interval (19-23 cal kyr bp; ref. 4), many records used previously had to be discarded. Other key features are the use of a common data set of ambient temperatures for the calibration of all proxies and the assessment of the reliability of individual SST estimates 5. The MARGO compilation combines 696 individual SST reconstructions (Fig.
Published: 2009

47. TFIIIC as a Potential Epigenetic Modulator of Histone Acetylation in Human Stem Cells

Author: Marco Vezzoli, Lara Isabel de Llobet Cucalon, Chiara Di Vona, Marco Morselli, Barbara Montanini, Susana de la Luna, Martin Teichmann, Giorgio Dieci, Roberto Ferrari, Institut Català de la Salut, [Vezzoli M, Morselli M, Montanini B] Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy. [de Llobet Cucalon LI] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Di Vona C] Genome Biology Program, Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST) and Universitat Pompeu Fabra (UPF), Barcelona, Spain. CIBER of Rare Diseases (CIBERER), Barcelona, Spain. [de la Luna S] Genome Biology Program, Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST) and Universitat Pompeu Fabra (UPF), Barcelona, Spain. CIBER of Rare Diseases (CIBERER), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: fenómenos genéticos::regulación de la expresión génica::epigénesis genética [FENÓMENOS Y PROCESOS], células::células madre::células madre pluripotentes::células madre embrionarias::células madre embrionarias humanas [ANATOMÍA], Neurogenesis, Cells::Stem Cells::Pluripotent Stem Cells::Embryonic Stem Cells::Human Embryonic Stem Cells [ANATOMY], p300, Catalysis, Epigènesi, neoplasias [ENFERMEDADES], Inorganic Chemistry, Physical and Theoretical Chemistry, Molecular Biology, TFIIIC, Otros calificadores::/terapia [Otros calificadores], Spectroscopy, Cèl·lules mare embrionàries, Càncer - Tractament, Organic Chemistry, Acetylation, Other subheadings::/therapy [Other subheadings], General Medicine, H3K27ac, Computer Science Applications, Neoplasms [DISEASES], H3K18ac, Genetic Phenomena::Gene Expression Regulation::Epigenesis, Genetic [PHENOMENA AND PROCESSES], hESCs
Abstract: Acetylation; Neurogenesis Acetilación; Neurogénesis Acetilació; Neurogènesi Regulation of histone acetylation dictates patterns of gene expression and hence cell identity. Due to their clinical relevance in cancer biology, understanding how human embryonic stem cells (hESCs) regulate their genomic patterns of histone acetylation is critical, but it remains largely to be investigated. Here, we provide evidence that acetylation of histone H3 lysine-18 (H3K18ac) and lysine-27 (H3K27ac) is only partially established by p300 in stem cells, while it represents the main histone acetyltransferase (HAT) for these marks in somatic cells. Our analysis reveals that whereas p300 marginally associated with H3K18ac and H3K27ac in hESCs, it largely overlapped with these histone marks upon differentiation. Interestingly, we show that H3K18ac is found at “stemness” genes enriched in RNA polymerase III transcription factor C (TFIIIC) in hESCs, whilst lacking p300. Moreover, TFIIIC was also found in the vicinity of genes involved in neuronal biology, although devoid of H3K18ac. Our data suggest a more complex pattern of HATs responsible for histone acetylations in hESCs than previously considered, suggesting a putative role for H3K18ac and TFIIIC in regulating “stemness” genes as well as genes associated with neuronal differentiation of hESCs. The results break ground for possible new paradigms for genome acetylation in hESCs that could lead to new avenues for therapeutic intervention in cancer and developmental diseases. This work was supported by Bando Galileo 2022 (G22-142) to R.F. and M.T. The research is also supported by the AIRC IG Grant 27712-A to R.F. This work was also supported by the Spanish Ministry of Science and Innovation (PID2019-107185GB-I00) to S.d.l.L. The CRG acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the support of the CERCA Programme/Generalitat de Catalunya. This work was also supported by the Ligue Contre le Cancer, committees des Landes et de la Dordogne to M.T.
Published: 2023

48. Constraints on deviations from ΛCDM within Horndeski gravity

Author: Verde, Licia [Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona (Spain)]
Published: 2016
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49. Probing quantum entanglement from magnetic-sublevels populations: beyond spin squeezing inequalities

Author: Guillem Müller-Rigat, Maciej Lewenstein, Irénée Frérot, Institut de Ciencies Fotoniques [Castelldefels] (ICFO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Nanophysique et Semiconducteurs (NEEL - NPSC), Institut Néel (NEEL), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), and European Project: 101031549,QuoMoDys
Subjects: Condensed Matter::Quantum Gases, Quantum Physics, Physics and Astronomy (miscellaneous), [PHYS.COND.GAS]Physics [physics]/Condensed Matter [cond-mat]/Quantum Gases [cond-mat.quant-gas], [PHYS.QPHY]Physics [physics]/Quantum Physics [quant-ph], Quantum Gases (cond-mat.quant-gas), FOS: Physical sciences, Physics::Atomic Physics, Quantum Physics (quant-ph), Condensed Matter - Quantum Gases, Atomic and Molecular Physics, and Optics
Abstract: Spin squeezing inequalities (SSI) represent a major tool to probe quantum entanglement among a collection of few-level atoms, and are based on collective spin measurements and their fluctuations. Yet, for atomic ensembles of spin-$j$ atoms and ultracold spinor gases, many experiments can image the populations in all Zeeman sublevels $s=-j, -j+1, \dots, j$, potentially revealing finer features of quantum entanglement not captured by SSI. Here we present a systematic approach which exploits Zeeman-sublevel population measurements in order to construct novel entanglement criteria, and illustrate our approach on ground states of spin-1 and spin-2 Bose-Einstein condensates. Beyond these specific examples, our approach allows one to infer, in a systematic manner, the optimal permutationally-invariant entanglement witness for any given set of collective measurements in an ensemble of $d$-level quantum systems., 6 + 9 pages, 2 figures. Final version accepted in Quantum Journal
Published: 2022

50. Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Author: Kalthoum Tizaoui, Seo Kyoung Chung, Jo Won Jung, Ai Koyanagi, Salvatore Terrazzino, Joe-Elie Salem, Ramy Abou Ghayda, Andreas Kronbichler, Keum Hwa Lee, Jae Young Choi, Louis Jacob, Seung Won Lee, Seong Woo Choi, Marco Solmi, Yun Young Go, Jae Il Shin, Karel Kostev, Jin Soo Shin, Sung-Hwan Moon, Ah Young Kim, Lee Smith, Sung Hwi Hong, Dong Keon Yon, Nam Kyun Kim, Kiwon Ban, Han Li, Min Seo Kim, Elena Dragioti, Sarah Cargnin, Soon-Jung Park, Se Yong Jung, Yonsei University, Korea University [Seoul], Sungkyunkwan University [Suwon] (SKKU), University of Florida [Gainesville] (UF), Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), University of Ottawa [Ottawa], Innsbruck Medical University [Austria] (IMU), Linköping University (LIU), Université de Tunis El Manar (UTM), Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Case Western Reserve University [Cleveland], Emory University School of Medicine, Emory University [Atlanta, GA], EWHA Womans University (EWHA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche Clinique de l’Est Parisien [CHU Saint-Antoine] (URC-EST), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Rothschild [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de REcherche en Cardio Oncologie [CHU Saint-Antoine] (GRC 27 GRECO), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Seoul National University [Seoul] (SNU), College of Convergence Software (Myongji University), Philipps Universität Marburg, Korea Research Institute of Bioscience & Biotechnology (KRIBB), City University of Hong Kong [Hong Kong] (CUHK), and Anglia Ruskin University (ARU)
Subjects: Drug, Databases, Factual, media_common.quotation_subject, MEDLINE, RM1-950, 030204 cardiovascular system & hematology, computer.software_genre, World Health Organization, Antiviral Agents, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Annan medicinsk grundvetenskap, Medicine, Humans, Myocytes, Cardiac, 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Medical prescription, Other Basic Medicine, media_common, Retrospective Studies, Cardiotoxicity, Alanine, Database, business.industry, SARS-CoV-2, General Neuroscience, Confounding, General Medicine, Odds ratio, Confidence interval, Adenosine Monophosphate, 3. Good health, COVID-19 Drug Treatment, Cardiovascular Diseases, Therapeutics. Pharmacology, Public aspects of medicine, RA1-1270, business, computer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin. Funding Agencies|Yonsei University College of Medicine for 2021 [2021-32-0049] Funding Source: Medline
Published: 2022

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