1,108 research outputs found
Estudio del movimiento de madera de consumo en el departamento del Magdalena
En el siguiente trabajo se expresa la necesidad de las investigaciones en el campo de la tecnología de la madera y productos forestales, porque conocemos que el desarrollo económico del País requiere una utilización racional de todos sus recursos renovables más abundantes, ocupando actualmente una extensión aproximada de 50 millones de Há., que equivalen al 45% del total de la superficie de Colombia. Su utilización racional es, sin embargo, en extremo deficiente en los bosques tropicales accesibles y actualmente en explotación se extraen selectivamente algunas pocas especies, quedando bosques pobres en especies comerciales y con fuertes disturbios ecológicos. Esta utilización deficiente, que es realmente el despilfarro de un capital necesario al desarrollo del País, solo puede corregirse mediante la ejecución de investigaciones planificadas con un enfoque global del problema, en cuya realización se coordinen los recursos humanos y económicos que se dispone actualmente
Genetic inhibition of flowering differs between juvenile and adult Citrus trees
[EN] Background and Aims In woody species, the juvenile period maintains the axillary meristems in a vegetative stage, unable to flower, for several years. However, in adult trees, some 1-year-old meristems flower whereas others remain vegetative to ensure a polycarpic growth habit. Both types of trees, therefore, have non-flowering meristems, and we hypothesize that the molecular mechanism regulating flower inhibition in juvenile trees is different from that in adult trees.
Methods In adult Citrus trees, the main endogenous factor inhibiting flower induction is the growing fruit. Thus, we studied the expression of the main flowering time, identity and patterning genes of trees with heavy fruit load (not-flowering adult trees) compared to that of 6-month-old trees (not-flowering juvenile trees). Adult trees without fruits (flowering trees) were used as a control. Second, we studied the expression of the same genes in the meristems of 6-month, and 1-, 3-, 5-and 7-year-old juvenile trees compared to 10-year-old flowering trees.
Key Results The axillary meristems of juvenile trees are unable to transcribe flowering time and patterning genes during the period of induction, although they are able to transcribe the FLOWERING LOCUS T citrus orthologue (CiFT2) in leaves. By contrast, meristems of not-flowering adult trees are able to transcribe the flowering network genes but fail to achieve the transcription threshold required to flower, due to CiFT2 repression by the fruit. Juvenile meristems progressively achieve gene expression, with age-dependent differences from 6 months to 7 years, FD-like and CsLFY being the last genes to be expressed.
Conclusions During the juvenile period the mechanism inhibiting flowering is determined in the immature bud, so that it progressively acquires flowering ability at the gene expression level of the flowering time programme, whereas in the adult tree it is determined in the leaf, where repression of CiFT2 gene expression occurs.We thank Cristina Ferrandiz (IBMCP-UPV, Spain) and Fernando Andres (UMR AGAP, France) for useful comments on the manuscript. We thank D. Westall for her help in editing the manuscript. This work was supported by a grant from the Ministerio de Economia y Competitividad, Spain (RTA2013-0024-C02-02)Muñoz Fambuena, N.; Nicolas-Almansa, M.; Martinez Fuentes, A.; Reig Valor, C.; Iglesias, DJ.; Primo-Millo, E.; Mesejo Conejos, C.... (2019). Genetic inhibition of flowering differs between juvenile and adult Citrus trees. Annals of Botany. 123(3):483-490. https://doi.org/10.1093/aob/mcy179S4834901233Abe, M. (2005). FD, a bZIP Protein Mediating Signals from the Floral Pathway Integrator FT at the Shoot Apex. Science, 309(5737), 1052-1056. doi:10.1126/science.1115983Albani, M. C., & Coupland, G. (2010). Comparative Analysis of Flowering in Annual and Perennial Plants. Plant Development, 323-348. doi:10.1016/s0070-2153(10)91011-9Andrés, F., & Coupland, G. (2012). The genetic basis of flowering responses to seasonal cues. Nature Reviews Genetics, 13(9), 627-639. doi:10.1038/nrg3291Balanzà, V., Martínez-Fernández, I., Sato, S., Yanofsky, M. F., Kaufmann, K., Angenent, G. C., … Ferrándiz, C. (2018). Genetic control of meristem arrest and life span in Arabidopsis by a FRUITFULL-APETALA2 pathway. Nature Communications, 9(1). doi:10.1038/s41467-018-03067-5Bäurle, I., & Dean, C. (2006). The Timing of Developmental Transitions in Plants. Cell, 125(4), 655-664. doi:10.1016/j.cell.2006.05.005Betancourt, M., Sistachs, V., Martínez-Fuentes, A., Mesejo, C., Reig, C., & Agustí, M. (2014). Influence of harvest date on fruit yield and return bloom in ‘Marsh’ grapefruit trees (Citrus paradisiMacf.) grown under a tropical climate. The Journal of Horticultural Science and Biotechnology, 89(4), 435-440. doi:10.1080/14620316.2014.11513103Blázquez, M. A., Ferrándiz, C., Madueño, F., & Parcy, F. (2006). How Floral Meristems are Built. Plant Molecular Biology, 60(6), 855-870. doi:10.1007/s11103-006-0013-zBlümel, M., Dally, N., & Jung, C. (2015). Flowering time regulation in crops — what did we learn from Arabidopsis? Current Opinion in Biotechnology, 32, 121-129. doi:10.1016/j.copbio.2014.11.023Castillo, M.-C., Forment, J., Gadea, J., Carrasco, J. L., Juarez, J., Navarro, L., & Ancillo, G. (2013). Identification of transcription factors potentially involved in the juvenile to adult phase transition in Citrus. Annals of Botany, 112(7), 1371-1381. doi:10.1093/aob/mct211Chica, E. J., & Albrigo, L. G. (2013). Expression of Flower Promoting Genes in Sweet Orange during Floral Inductive Water Deficits. Journal of the American Society for Horticultural Science, 138(2), 88-94. doi:10.21273/jashs.138.2.88Endo, T., Shimada, T., Fujii, H., Kobayashi, Y., Araki, T., & Omura, M. (2005). Ectopic Expression of an FT Homolog from Citrus Confers an Early Flowering Phenotype on Trifoliate Orange (Poncirus trifoliata L. Raf.). Transgenic Research, 14(5), 703-712. doi:10.1007/s11248-005-6632-3Haberman, A., Ackerman, M., Crane, O., Kelner, J.-J., Costes, E., & Samach, A. (2016). Different flowering response to various fruit loads in apple cultivars correlates with degree of transcript reaccumulation of a TFL1-encoding gene. The Plant Journal, 87(2), 161-173. doi:10.1111/tpj.13190Hanano, S., & Goto, K. (2011). Arabidopsis TERMINAL FLOWER1 Is Involved in the Regulation of Flowering Time and Inflorescence Development through Transcriptional Repression. The Plant Cell, 23(9), 3172-3184. doi:10.1105/tpc.111.088641Mafra, V., Kubo, K. S., Alves-Ferreira, M., Ribeiro-Alves, M., Stuart, R. M., Boava, L. P., … Machado, M. A. (2012). Reference Genes for Accurate Transcript Normalization in Citrus Genotypes under Different Experimental Conditions. PLoS ONE, 7(2), e31263. doi:10.1371/journal.pone.0031263Martínez-Fuentes, A., Mesejo, C., Reig, C., & Agustí, M. (2010). Timing of the inhibitory effect of fruit on return bloom of ‘Valencia’ sweet orange (Citrus sinensis
(L.) Osbeck). Journal of the Science of Food and Agriculture, 90(11), 1936-1943. doi:10.1002/jsfa.4038Michaels, S. D., & Amasino, R. M. (1999). FLOWERING LOCUS C Encodes a Novel MADS Domain Protein That Acts as a Repressor of Flowering. The Plant Cell, 11(5), 949-956. doi:10.1105/tpc.11.5.949Muñoz-Fambuena, N., Mesejo, C., Carmen González-Mas, M., Primo-Millo, E., Agustí, M., & Iglesias, D. J. (2011). Fruit regulates seasonal expression of flowering genes in alternate-bearing ‘Moncada’ mandarin. Annals of Botany, 108(3), 511-519. doi:10.1093/aob/mcr164Muñoz-Fambuena, N., Mesejo, C., González-Mas, M. C., Primo-Millo, E., Agustí, M., & Iglesias, D. J. (2012). Fruit load modulates flowering-related gene expression in buds of alternate-bearing ‘Moncada’ mandarin. Annals of Botany, 110(6), 1109-1118. doi:10.1093/aob/mcs190Nishikawa, F., Endo, T., Shimada, T., Fujii, H., Shimizu, T., Omura, M., & Ikoma, Y. (2007). Increased CiFT abundance in the stem correlates with floral induction by low temperature in Satsuma mandarin (Citrus unshiu Marc.). Journal of Experimental Botany, 58(14), 3915-3927. doi:10.1093/jxb/erm246Peña, L., Martín-Trillo, M., Juárez, J., Pina, J. A., Navarro, L., & Martínez-Zapater, J. M. (2001). Constitutive expression of Arabidopsis LEAFY or APETALA1 genes in citrus reduces their generation time. Nature Biotechnology, 19(3), 263-267. doi:10.1038/85719Pillitteri, L. J., Lovatt, C. J., & Walling, L. L. (2004). Isolation and Characterization of a TERMINAL FLOWER Homolog and Its Correlation with Juvenility in Citrus. Plant Physiology, 135(3), 1540-1551. doi:10.1104/pp.103.036178Seo, E., Lee, H., Jeon, J., Park, H., Kim, J., Noh, Y.-S., & Lee, I. (2009). Crosstalk between Cold Response and Flowering in Arabidopsis Is Mediated through the Flowering-Time Gene SOC1 and Its Upstream Negative Regulator FLC. The Plant Cell, 21(10), 3185-3197. doi:10.1105/tpc.108.063883Sgamma, T., Jackson, A., Muleo, R., Thomas, B., & Massiah, A. (2014). TEMPRANILLO is a regulator of juvenility in plants. Scientific Reports, 4(1). doi:10.1038/srep03704Shalom, L., Samuels, S., Zur, N., Shlizerman, L., Zemach, H., Weissberg, M., … Sadka, A. (2012). Alternate Bearing in Citrus: Changes in the Expression of Flowering Control Genes and in Global Gene Expression in ON- versus OFF-Crop Trees. PLoS ONE, 7(10), e46930. doi:10.1371/journal.pone.0046930Shalom, L., Samuels, S., Zur, N., Shlizerman, L., Doron-Faigenboim, A., Blumwald, E., & Sadka, A. (2014). Fruit load induces changes in global gene expression and in abscisic acid (ABA) and indole acetic acid (IAA) homeostasis in citrus buds. Journal of Experimental Botany, 65(12), 3029-3044. doi:10.1093/jxb/eru148Sohn, E. J., Rojas-Pierce, M., Pan, S., Carter, C., Serrano-Mislata, A., Madueno, F., … Raikhel, N. V. (2007). The shoot meristem identity gene TFL1 is involved in flower development and trafficking to the protein storage vacuole. Proceedings of the National Academy of Sciences, 104(47), 18801-18806. doi:10.1073/pnas.0708236104Spiegel-Roy, P., & Goldschmidt, E. E. (1996). The Biology of Citrus. doi:10.1017/cbo9780511600548Sussmilch, F. C., Berbel, A., Hecht, V., Vander Schoor, J. K., Ferrándiz, C., Madueño, F., & Weller, J. L. (2015). Pea VEGETATIVE2 Is an FD Homolog That Is Essential for Flowering and Compound Inflorescence Development. The Plant Cell, 27(4), 1046-1060. doi:10.1105/tpc.115.136150Tan, F.-C., & Swain, S. M. (2007). Functional characterization of AP3, SOC1 and WUS homologues from citrus (Citrus sinensis). Physiologia Plantarum, 131(3), 481-495. doi:10.1111/j.1399-3054.2007.00971.xLeal Valentim, F., Mourik, S. van, Posé, D., Kim, M. C., Schmid, M., van Ham, R. C. H. J., … van Dijk, A. D. J. (2015). A Quantitative and Dynamic Model of the Arabidopsis Flowering Time Gene Regulatory Network. PLOS ONE, 10(2), e0116973. doi:10.1371/journal.pone.0116973Wang, J.-W., Czech, B., & Weigel, D. (2009). miR156-Regulated SPL Transcription Factors Define an Endogenous Flowering Pathway in Arabidopsis thaliana. Cell, 138(4), 738-749. doi:10.1016/j.cell.2009.06.014Weigel, D. (1995). The Genetics of Flower Development: From Floral Induction to Ovule Morphogenesis. Annual Review of Genetics, 29(1), 19-39. doi:10.1146/annurev.ge.29.120195.00031
Comparative Analysis of Primary and Secondary Metabolites in the Peel of Eight Blood Orange Varieties
The global cultivation of blood oranges is experiencing an increase due to their remarkable nutritional properties. Blood orange by-products, especially the peel, have a high concentration of bioactive compounds with exceptional antioxidant potential, making them an ideal choice for incorporation into various food products. This study aimed to determine the morphological parameters and primary and secondary metabolite content of peel of eight blood orange varieties using 1H NMR and HPLC-ESI-DAD-MSn. “Tarocco Meli” had the highest weight (367.83 g), caliber (94.13 mm and 88.87 mm), peel thickness (6.73 mm), and peel weight (155.0 g). “Tarocco Rosso”, “Sanguinelli”, and “Tarocco Gallo” had the highest levels of total amino acids (25.57 g kg−1 DW), total organic acids (29.99 g kg−1 DW), and total sugars (68.56 g 100 g−1 DW), respectively. The peel of “Moro” had significantly higher concentrations of total anthocyanins, hydroxycinnamic acids, and flavones (650.67, 263.33, and 449.85 mg kg−1, respectively) compared to the other varieties. In conclusion, “Tarocco Meli” had the most interesting values for morphological parameters, “Tarocco Rosso”, “Sanguinelli”, and “Tarocco Gallo” for primary metabolites, and “Moro” for secondary metabolites. With the increasing interest in utilizing co-products, these findings could be useful in developing functional food products that meet consumer demands for healthier and more sustainable food choice
Autophagy-inducing peptides from mammalian VSV and fish VHSV rhabdoviral G glycoproteins (G) as models for the development of new therapeutic molecules
It has not been elucidated whether or not autophagy is induced by rhabdoviral G glycoproteins (G) in vertebrate organisms for which rhabdovirus infection is lethal. Our work provides the first evidence that both mammalian (vesicular stomatitis virus, VSV) and fish (viral hemorrhagic septicemia virus, VHSV, and spring viremia carp virus, SVCV) rhabdoviral Gs induce an autophagic antiviral program in vertebrate cell lines. The transcriptomic profiles obtained from zebrafish genetically immunized with either Gsvcv or Gvhsv suggest that autophagy is induced shortly after immunization and therefore, it may be an important component of the strong antiviral immune responses elicited by these viral proteins. Pepscan mapping of autophagy-inducing linear determinants of Gvhsv and Gvsv showed that peptides located in their fusion domains induce autophagy. Altogether these results suggest that strategies aimed at modulating autophagy could be used for the prevention and treatment of rhabdoviral infections such as rabies, which causes thousands of human deaths every year
Herbicidal Activity of Thymbra capitata (L.) Cav. Essential Oil
[EN] The bioherbicidal potential ofThymbra capitata(L.) Cav. essential oil (EO) and its main compound carvacrol was investigated. In in vitro assays, the EO blocked the germination and seedling growth ofErigeron canadensisL.,Sonchus oleraceus(L.) L., andChenopodium albumL. at 0.125 mu L/mL, ofSetaria verticillata(L.) P.Beauv.,Avena fatuaL., andSolanum nigrumL. at 0.5 mu L/mL, ofAmaranthus retroflexusL. at 1 mu L/mL and ofPortulaca oleraceaL., andEchinochloa crus-galli(L.) P.Beauv. at 2 mu L/mL. Under greenhouse conditions,T. capitataEO was tested towards the emergent weeds from a soil seedbank in pre and post emergence, showing strong herbicidal potential in both assays at 4 mu L/mL. In addition,T. capitataEO, applied by spraying, was tested againstP. oleracea,A. fatuaandE. crus-galli. The species showed different sensibility to the EO, beingE. crus-gallithe most resistant. Experiments were performed againstA. fatuatestingT. capitataEO and carvacrol applied by spraying or by irrigation. It was verified that the EO was more active at the same doses in monocotyledons applied by irrigation and in dicotyledons applied by spraying. Carvacrol effects onArabidopsisroot morphology were also studied.This research was supported by the Universitat Politècnica de València [project number: SP20120543],
by Generalitat Valenciana [project number GV/2014/039], and by the Spanish Ministry of Science, Innovation
and Universities [project number: RTI2018¿094716¿B¿I00].
Thanks to Jovano Erris Nugroho and Muhamad Iqbal who collaborate to carry out in vivo experiment 4 during their internship in the Plant Health in Sustainable Cropping Systems Erasmus+ Programme. This research work has been developed as a result of a mobility stay funded by the Erasmus+-KA1 Erasmus Mundus Joint Master Degrees Programme of the European Commission under the PLANT HEALTH Project. Thanks to Xeda Italia S.r.l. for providing us Fitoil always when we need it. Thanks to Vicente Estornell Campos and the Library staff from Polytechnic University of Valencia that assisted us to get some helpful references.Verdeguer Sancho, MM.; Torres-Pagan, N.; Muñoz, M.; Jouini, A.; García-Plasencia, S.; Chinchilla, P.; Berbegal Martinez, M.... (2020). Herbicidal Activity of Thymbra capitata (L.) Cav. Essential Oil. Molecules. 25(12):1-31. https://doi.org/10.3390/molecules25122832S1312512Barros, L., Heleno, S. A., Carvalho, A. M., & Ferreira, I. C. F. R. (2010). 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Diversity, identity and influence of other breeds in the development of Creole populations of domestic animals
Creole breeds of the various livestock species mainly derive from animals imported to America from the Iberian Peninsula, starting in the early years of discovery and colonization. Creoles have undergone a long period of selective adaptation to a very diverse set of environmental conditions in the American continent, and over the last two centuries some Creole populations have been admixed with breeds originating from other European countries and India. In spite of the various threats undergone, some Creole populations are still maintained nowadays, especially in marginal regions, but they need to be better known, in order to recognize their identity and establish conservation programs. In this paper, we review the results published over the last five years by various Consortia established under the framework of the CONBIAND network, with the goal of studying the genetic diversity, structure and breed relationships in Creole breeds. In all species, Creole breeds reveal high levels of genetic diversity and clear signatures of their Iberian origin, even though many breeds also show signs of genetic erosion, due to either accumulated inbreeding or admixture with exotic breeds. The research conducted until now demonstrates that the vast majority of Creoles still maintain their own identity, even though they are seldom recognized and protected. These results can be used as a basis for recognition, conservation and genetic improvement of Creoles, which are the result of more than 500 years of selective adaptation
Axillary lymph node dissection versus radiotherapy in breast cancer with positive sentinelnodes after neoadjuvant therapy (ADARNAT trial)
Introduction: Breast cancer surgery currently focuses on de-escalating treatment without compromising patient survival. Axillary radiotherapy (ART) now replaces axillary lymph node dissection (ALND) in patients with limited sentinel lymph node (SLN) involvement during the primary surgery, and this has significantly reduced the incidence of lymphedema without worsening the prognosis. However, patients treated with neoadjuvant systemic treatment (NST) cannot benefit from this option despite the low incidence of residual disease in the armpit in most cases. Data regarding the use of radiotherapy instead of ALND in this population are lacking. This study will assess whether ART is non-inferior to ALND in terms of recurrence and overall survival in patients with positive SLN after NST, including whether it reduces surgery-related adverse effects. Methods and analyses: This multicenter, randomized, open-label, phase 3 trial will enroll 1660 patients with breast cancer and positive SLNs following NST in approximately 50 Spanish centers over 3 years. Patients will be stratified by NST regimen and nodal involvement (isolated tumoral cells or micrometastasis versus macrometastasis) and randomly assigned 1:1 to ART without ALND (study arm) or ALND alone (control arm). Level 3 and supraclavicular radiotherapy will be added in both arms. The primary outcome is the 5-year axillary recurrence determined by clinical and radiological examination. The secondary outcomes include lymphedema or arm dysfunction, quality of life based (EORTC QLQ-C30 and QLQ-BR23 questionnaires), disease-free survival, and overall survival. Discussion: This study aims to provide data to confirm the efficacy and safety of ART over ALND in patients with a positive SLN after NST, together with the impact on morbidity. Ethics and dissemination: The Research Ethics Committee of Bellvitge University Hospital approved this trial (Protocol Record PR148/21, version 3, 1/2/2022) and all patients must provide written informed consent. The involvement of around 50 centers across Spain will facilitate the dissemination of our results
Using surveillance data to estimate pandemic vaccine effectiveness against laboratory confirmed influenza A(H1N1)2009 infection : two case-control studies, Spain, season 2009-2010
Background: Physicians of the Spanish Influenza Sentinel Surveillance System report and systematically swab patients attended to their practices for influenza-like illness (ILI). Within the surveillance system, some Spanish regions also participated in an observational study aiming at estimating influenza vaccine effectiveness (cycEVA study). During the season 2009-2010, we estimated pandemic influenza vaccine effectiveness using both the influenza surveillance data and the cycEVA study. Methods: We conducted two case-control studies using the test-negative design, between weeks 48/2009 and 8/2010 of the pandemic season. The surveillance-based study included all swabbed patients in the sentinel surveillance system. The cycEVA study included swabbed patients from seven Spanish regions. Cases were laboratory-confirmed pandemic influenza A(H1N1)2009. Controls were ILI patients testing negative for any type of influenza. Variables collected in both studies included demographic data, vaccination status, laboratory results, chronic conditions, and pregnancy. Additionally, cycEVA questionnaire collected data on previous influenza vaccination, smoking, functional status, hospitalisations, visits to the general practitioners, and obesity. We used logistic regression to calculate adjusted odds ratios (OR), computing pandemic influenza vaccine effectiveness as (1-OR *100. Results: We included 331 cases and 995 controls in the surveillance-based study and 85 cases and 351 controls in the cycEVA study. We detected nine (2.7%) and two (2.4%) vaccine failures in the surveillance-based and cycEVA studies, respectively. Adjusting for variables collected in surveillance database and swabbing month, pandemic influenza vaccine effectiveness was 62% (95% confidence interval (CI): -5; 87). The cycEVA vaccine effectiveness was 64% (95%CI: -225; 96) when adjusting for common variables with the surveillance system and 75% (95%CI: -293; 98) adjusting for all variables collected. Conclusion: Point estimates of the pandemic influenza vaccine effectiveness suggested a protective effect of the pandemic vaccine against laboratory-confirmed influenza A(H1N1)2009 in the season 2009-2010. Both studies were limited by the low vaccine coverage and the late start of the vaccination campaign. Routine influenza surveillance provides reliable estimates and could be used for influenza vaccine effectiveness studies in future seasons taken into account the surveillance system limitations
Abacavir increases purinergic P2X7 receptor activation by ATP: does a pro-inflammatory synergism underlie its cardiovascular toxicity?
16 p.-9 fig.-1 tab.The cardiovascular toxicity of Abacavir is related to its purinergic structure. Purinergic P2X7-receptors (P2X7R), characterized by activation by high concentrations of ATP and with high plasticity, seem implicated. We appraise the nature of the interplay between Abacavir and P2X7R in generating vascular inflammation. The effects of Abacavir on leukocyte-endothelium interactions were compared with those of its metabolite carbovir triphosphate (CBV-TP) or ATP in the presence of apyrase (ATP-ase) or A804598 (P2X7R-antagonist). CBV-TP and ATP levels were evaluated by HPLC, while binding of Abacavir, CBV-TP and ATP to P2X7R was assessed by radioligand and docking studies. Hypersensitivity studies explored a potential allosteric action of Abacavir. Clinical concentrations of Abacavir (20 µmol/L) induced leukocyte-endothelial cell interactions by specifically activating P2X7R, but the drug did not show affinity for the P2X7R ATP-binding site (site 1). CBV-TP levels were undetectable in Abacavir-treated cells, while those of ATP were unaltered. The effects of Abacavir were Apyrase-dependent, implying dependence on endogenous ATP. Exogenous ATP induced a profile of proinflammatory actions similar to Abacavir, but was not entirely P2X7R-dependent. Docking calculations suggested ATP-binding to sites 1 and 2, and Abacavir-binding only to allosteric site 2. A combination of concentrations of Abacavir (1 µmol/L) and ATP (0.1 µmol/L) that had no effect when administered separately induced leukocyte-endothelium interactions mediated by P2X7R and involving Connexin43 channels. Therefore, Abacavir acts as a positive allosteric modulator of P2X7R, turning low concentrations of endogenous ATP themselves incapable of stimulating P2X7R into a functional proinflammatory agonist of the receptor.This work was supported by Ministerio de Economía y Competitividad and the European Regional Development fund of the European Union (FEDER) (SAF2015–67678-R, RTI2018-094436-B-I00 and CTQ2017-88353-R), Ministerio de Sanidad y Consumo (CB06/04/0071, CIBERehd) and Generalitat Valenciana (PROMETEOII/2014/035 and PROMETEO 2018/141), along with an unrestricted grant from GILEAD S.L. VCD and ASL were funded by VALI + D program from Generalitat Valenciana (grants number ACIF/2015/316 and ACIF/2016/119, respectively) and PGM by FPU program from Ministerio de Educación, Cultura y Deporte (grant number FPU16/06064) and MABR by FPU program from Ministerio de Ciencia, Innovación y Universidades (grant number FPU17/04249).Peer reviewe
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