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Funder: Hong Kong PhD Fellowship Scheme ; Funder: Hong Kong Special Administrative Region Government ; G-quadruplexes are non-helical secondary structures that can fold in vivo in both DNA and RNA. In human cells, they can influence replication, transcription and telomere maintenance in DNA, or translation, transcript processing and stability of RNA. We have previously showed that G-quadruplexes are detectable in the DNA of the malaria parasite Plasmodium falciparum, despite a very highly A/T-biased genome with unusually few guanine-rich sequences. Here, we show that RNA G-quadruplexes can also form in P. falciparum RNA, using rG4-seq for transcriptome-wide structure-specific RNA probing. Many of the motifs, detected here via the rG4seeker pipeline, have non-canonical forms and would not be predicted by standard in silico algorithms. However, in vitro biophysical assays verified formation of non-canonical motifs. The G-quadruplexes in the P. falciparum transcriptome are frequently clustered in certain genes and associated with regions encoding low-complexity peptide repeats. They are overrepresented in particular classes of genes, notably those that encode PfEMP1 virulence factors, stress response genes and DNA binding proteins. In vitro translation experiments and in vivo measures of translation efficiency showed that G-quadruplexes can influence the translation of P. falciparum mRNAs. Thus, the G-quadruplex is a novel player in post-transcriptional regulation of gene expression in this major human pathogen. ; UK Medical Research Council [grants MR/K000535/1 and MR/L008823/1] to CJM. Shenzhen Basic Research Project [JCYJ20180507181642811], Research Grants Council of the Hong Kong SAR, China Projects [CityU 11100421, CityU 11101519, CityU 11100218, N_CityU110/17, CityU 21302317], Croucher Foundation [Project No. 9500030, 9509003], State Key Laboratory of Marine Pollution Director Discretionary Fund, City University of Hong Kong [projects 6000711, 7005503, 9667222, 9680261] to CKK. A generous donation from Mr. and Mrs. Sunny Yang, the University Grants Committee Area of Excellence Scheme (AoE/M-403/16), and the Innovation and Technology Commission, Hong Kong Special Administrative Region Government to the State Key Laboratory of Agrobiotechnology (CUHK) to TFC. EYCC was supported by the Hong Kong PhD Fellowship Scheme.

Long non-coding RNAs (lncRNAs) can perform a variety of key cellular functions by interacting with proteins and other RNAs. Recent studies have shown that the functions of lncRNAS are largely mediated by their structures. However, our structural knowledge for most lncRNAS is limited to sequence-based computational predictions. Non-coding RNA activated by DNA damage (NORAD) is an atypical lncRNA due to its abundant expression and high sequence conservation. NORAD regulates genomic stability by interacting with proteins and microRNAs. Previous sequence-based characterization has identified a modular organization of NORAD composed of several NORAD repeat units (NRUs). These units comprise the protein-binding elements and are separated by regular spacers. Here, we experimentally determine for the first time the secondary structure of NORAD using the nextPARS approach. Our results suggest that the spacer regions provide structural stability to NRUs. Furthermore, we uncover two previously unreported NRUs, and determine the core structural motifs conserved across NRUs. Overall, these findings will help to elucidate the function and evolution of NORAD. ; UC was funded in part through H2020 Marie Skłodowska-Curie Actions (H2020-MSCA-IF-2017-793699) and MICINN (IJC2019-039402-I). TG group acknowledges support from the Spanish Ministry of Science and Innovation for grant PGC2018-099921-B-I00, cofounded by European Regional Development Fund (ERDF); from the Catalan Research Agency (AGAUR) SGR423; from the European Union's Horizon 2020 research and innovation programme (ERC-2016-724173); from the Gordon and Betty Moore Foundation (Grant GBMF9742) and from the Instituto de Salud Carlos III (INB Grant PT17/0009/0023 - ISCIII-SGEFI/ERDF). ; Peer Reviewed ; Postprint (published version)

RNA structure plays a fundamental role in internal initiation of translation. Picornavirus internal ribosome entry site (IRES) are long, efficient cis-acting elements that recruit the ribosome to internal mRNA sites. However, little is known about long-range constraints determining the IRES RNA structure. Here, we sought to investigate the functional and structural relevance of the invariant apical stem of a picornavirus IRES. Mutation of this apical stem revealed better performance of G:C compared with C:G base pairs, demonstrating that the secondary structure solely is not sufficient for IRES function. In turn, mutations designed to disrupt the stem abolished IRES activity. Lack of tolerance to accept genetic variability in the apical stem was supported by the presence of coupled covariations within the adjacent stem-loops. SHAPE structural analysis, gel mobility-shift and microarrays-based RNA accessibility revealed that the apical stem contributes to maintain IRES RNA structure through the generation of distant interactions between two adjacent stem-loops. Our results demonstrate that a highly interactive structure constrained by distant interactions involving invariant G:C base pairs plays a key role in maintaining the RNA conformation necessary for IRES-mediated translation. © The Author(s) 2011. Published by Oxford University Press. ; Ministerio de Ciencia e Innovación (BFU2008-02159, CSD2009-00080 to E.M.S.); Institutional grant from Fundació n Ramón Areces. Work at Universitat Pompeu Fabra was supported by grant BIO2008-01091. Work at Centro de Astrobiología was supported by grants BIO2007-67523, BIO2010-20696, EUI2008-00158; CSIC (grant 200920I040); European Union and Comunidad de Madrid. CIBERehd is funded by the Instituto de Salud Carlos III. Funding for open access charge: CSD-2009-0080, BFU2008-0 ; Peer Reviewed

Salvador Ventura is supported by SOE4/P1/E831 grant from SUDOE. INTERREG IV B. EUROPEAN UNION. SV is supported by ICREA Academia 2009 ; Background: rhe formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states. - Results: here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic. - Conclusions: our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation.

Newly synthesized mitochondrial RNA is concentrated in structures juxtaposed to nucleoids, called RNA granules, that have been implicated in mitochondrial RNA processing and ribosome biogenesis. Here we show that two classical mtDNA replication factors, the mtDNA helicase Twinkle and single-stranded DNA-binding protein mtSSB, contribute to RNA metabolism in mitochondria and to RNA granule biology. Twinkle colocalizes with both mitochondrial RNA granules and nucleoids, and it can serve as bait to greatly enrich established RNA granule proteins, such as G-rich sequence factor 1, GRSF1. Likewise, mtSSB also is not restricted to the nucleoids, and repression of either mtSSB or Twinkle alters mtRNA metabolism. Short-term Twinkle depletion greatly diminishes RNA granules but does not inhibit RNA synthesis or processing. Either mtSSB or GRSF1 depletion results in RNA processing defects, accumulation of mtRNA breakdown products as well as increased levels of dsRNA and RNA:DNA hybrids. In particular, the processing and degradation defects become more pronounced with both proteins depleted. These findings suggest that Twinkle is essential for RNA organization in granules, and that mtSSB is involved in the recently proposed GRSF1-mtRNA degradosome pathway, a route suggested to be particularly aimed at degradation of G-quadruplex prone long non-coding mtRNAs. ; Prinses Beatrix Spierfonds and the Stichting Spieren voor Spieren [W.OR15–05 to J.N.S.]; European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement [721757 to A.P.]; PhD fellowship from the Radboud Institute for Molecular Life Sciences; Radboudumc [R0002792 to S.LvE.]; Spanish Ministry of Economy and Competitiveness (MINECO) [BFU2015-70645-R to M.S.]; Ministry of Education, Culture and Sports [FPU14-06021 to A.T.-S.]; Generalitat de Catalunya [2017-SGR-1192 to M.S.]; European Union [FP7-HEALTH-2012-306029-2 to M.S.]; ITN Fellowship FP7-PEOPLE-2011-290246 to A.C.]; The Structural Biology Unit at IBMB-CSIC is a 'Maria de Maeztu' Unit of Excellence awarded by MINECO [MDM-2014-0435].

mRNA metabolism is tightly orchestrated by highly-regulated RNA Binding Proteins (RBPs) that determine mRNA fate, thereby influencing multiple cellular functions across biological contexts. Here, we review the interplay between six well-known RBPs (TTP, AUF-1, KSRP, HuR, TIA-1, and TIAR) that recognize AU-rich elements (AREs) at the 3' untranslated regions of mRNAs, namely ARE-RBPs. Examples of the links between their cross-regulations and modulation of their targets are analyzed during mRNA processing, turnover, localization, and translational control. Furthermore, ARE recognition can be self-regulated by several factors that lead to the prevalence of one RBP over another. Consequently, we examine the factors that modulate the dynamics of those protein-RNA transient interactions to better understand the final consequences of the regulation mediated by ARE-RBPs. For instance, factors controlling the RBP isoforms, their conformational state or their post-translational modifications (PTMs) can strongly determine the fate of the protein-RNA complexes. Moreover, mRNA specific sequence and secondary structure or subtle environmental changes are also key determinants to take into account. To sum up, the whole understanding of such a fine tuned regulation is a challenge for future research and requires the integration of all the available structural and functional data by in vivo, in vitro and in silico approaches. ; Financial support was provided by the Andalusian Government (P11-CVI-7216, BIO198); the Spanish Ministry of Economy, Industry and Competitiveness (BFU2015-71017-P); the Spanish Ministry of Education, Culture and Sports (FPU013/04373, FPU016/01513) and the Ramón Areces Foundation. ; Peer reviewed

Isolates of citrus tristeza virus (CTV) differ widely in their biological properties. These properties may depend on the structure of viral RNA populations comprising the different isolates. As a first approach to study the molecular basis of the biological variability, we have compared the sequences of multiple cDNA clones of the two terminal regions of the RNA from different CTV isolates. The polymorphism of the 5' untranslated region (UTR) allowed the classification of the sequences into three groups, with intragroup sequence identity higher than 88% and intergroup sequence identity as low as 44%. The variability of an open reading frame (ORF) 1a segment adjacent to the 5' UTR supports the same grouping. Some CTV isolates contained sequences of more than one group. Most sequences from Spanish isolates belonged to group III, whereas a Japanese isolate was composed mostly of sequences of groups I and II. The mildest isolates contained only sequences of group III, whereas the most severe isolates also contained sequences of groups I, II, or both. The most stable secondary structure predicted for the 5' UTR was composed of two stem-loops and remained essentially unchanged as a result of compensatory mutations in the stems and accommodation of most of the variability in the loops. In contrast to the 5'-terminal region, the variability of the 3'-terminal region of CTV RNA was very much restricted, with nucleotide identity values higher than 90%. The presence of a conserved putative 'zinc-finger' domain adjacent to a basic region in p23, the predicted product of ORF II, suggests that this protein might act as a regulatory factor during virus replication. ; This work was partially supported by grants from the Conselleria de Agricultura y Medio Ambiente, Conselleria de Cultura, Educación y Ciencia (GV-3116/95), INIA (project SC-93111), as well as by contract ERBIC18CT960044 from the European Union ; Peer Reviewed

Multiple biological processes involve the stretching of nucleic acids (NAs). Stretching forces induce local changes in the molecule structure, inhibiting or promoting the binding of proteins, which ultimately affects their functionality. Understanding how a force induces changes in the structure of NAs at the atomic level is a challenge. Here, we use all-atom, microsecond-long molecular dynamics to simulate the structure of dsDNA and dsRNA subjected to stretching forces up to 20 pN. We determine all of the elastic constants of dsDNA and dsRNA and provide an explanation for three striking differences in the mechanical response of these two molecules: the threefold softer stretching constant obtained for dsRNA, the opposite twist-stretch coupling, and its nontrivial force dependence. The lower dsRNA stretching resistance is linked to its more open structure, whereas the opposite twist-stretch coupling of both molecules is due to the very different evolution of molecules' interstrand distance with the stretching force. A reduction of this distance leads to overwinding in dsDNA. In contrast, dsRNA is not able to reduce its interstrand distance and can only elongate by unwinding. Interstrand distance is directly correlated with the slide base-pair parameter and its different behavior in dsDNA and dsRNA traced down to changes in the sugar pucker angle of these NAs. ; We thank the Spanish Ministry of Economy and Competitiveness (Projects CSD2010-00024, MAT2014-54484-P, and FIS2014-58328-P) for financial support. F.M.-H. received support from the European Research Council under the European Union's Horizon 2020 Framework Programme for Research and Innovation (Grant 681299). ; Peer reviewed

Pollution from human activities is a major threat to the ecological integrity of fluvial ecosystems. Microbial communities are the most abundant organisms in biofilms, and are key indicators of various pollutants. We investigated the effects some human stressors (nutrients and heavy metals) have on the structure and activity of microbial communities in seven sampling sites located in the Ter River basin (NE Spain). Water and biofilm samples were collected in order to characterize physicochemical and biofilm parameters. The 16S rRNA gene was analysed out from DNA and RNA extracts to obtain α and β diversity. Principal coordinates analyses (PCoA) of the operational taxonomic units (OTUs) in the resident microbial community revealed that nutrients and conductivity were the main driving forces behind the diversity and composition. The effects of mining have had mainly seen on the taxonomic composition of the active microbial community, but also at the OTUs level. Remarkably, metal-impacted communities were very active, which would indicate a close link with the stress faced, that is probably related to the stimulation of detoxification ; Authors acknowledge the Spanish Ministry of Economy and Competitiveness for its financial support through the STREAMFISH Project ref: CGL2013-43822-R and the STRESSFISH Project ref: CGL2016-80820-R. This research work was also funded by the program of grants for the improvement of the scientific productivity of the research groups of the University of Girona 2016-2018 (MPCUdG2016/120) with the Project: "Fluvial microbial microfilms under conditions of stress" and María Argudo was supported by FI-DGR pre-doctoral scholarship 2016 FI-B 00284 from the Agency for Management of University and Research Grants (AGAUR) of Government of Catalonia. In addition, we are grateful to the Technical Research Services of the University of Girona

Non-canonical, four-stranded nucleic acids secondary structures are present within regulatory regions in the human genome and transcriptome. To date, these quadruplex structures include both DNA and RNA G-quadruplexes, formed in guanine-rich sequences, and i-Motifs, found in cytosine-rich sequences, as their counterparts. Quadruplexes have been extensively associated with cancer, playing an important role in telomere maintenance and control of genetic expression of several oncogenes and tumor suppressors. Therefore, quadruplex structures are considered attractive molecular targets for cancer therapeutics with novel mechanisms of action. In this review, we provide a general overview about recent research on the implications of quadruplex structures in cancer, firstly gathering together DNA G-quadruplexes, RNA G-quadruplexes as well as DNA i-Motifs. ; This study was supported by 3TR, IMI2 (H2020-JTI538 IMI2-2018) and by Instituto de Salud Carlos III under the frame of EuroNanoMed III (AC18/00008) to J.A.G.S. The Government of Spain granted with PhD fellowship FPU16/05822 to V.S.M. ; Yes

Cells are subjected to dramatic changes of gene expression upon environmental changes. Stress/ncauses a general down-regulation of gene expression together with the induction of a set of stress-responsive/ngenes. The p38-related stress-activated protein kinase Hog1 is an important regulator of transcription upon/nosmostress in yeast. Genome-wide localization studies of RNA polymerase II (RNA Pol II) and Hog1 showed that stress induced major changes in RNA Pol II localization, with a shift toward stress-responsive genes relative to housekeeping genes. RNA Pol II relocalization required Hog1, which was also localized to stress-responsive loci. In addition to RNA Pol II-bound genes, Hog1 also localized to RNA polymerase III-bound genes, pointing to a wider role for Hog1 in transcriptional control than initially expected. Interestingly, an increasing association of Hog1 with stressresponsive genes was strongly correlated with chromatin remodeling and increased gene expression. Remarkably, MNase-Seq analysis showed that although chromatin structure was not significantly altered at a genome-wide level in response to stress, there was pronounced chromatin remodeling for those genes that displayed Hog1 association. Hog1 serves to bypass the general down-regulation of gene expression that occurs in response to osmostress, and does so both by targeting RNA Pol II machinery and by inducing chromatin remodeling at stressresponsive loci. ; MN is a recipient of an FIS fellowship. This work was supported by grants from the Spanish Government (BIO2011-23920 to EE, BIO2009-07762 and BFU2012-33503 to FP, BFU2011-26722 to EN), the Consolider Ingenio 2010/nprogramme CSD2007-0015 to FP and FP7 UNICELLSYS grant 201142, the Fundación Marcelino Botín (FMB) to FP. EN and FP are recipients of an ICREA Acadèmia (Generalitat de Catalunya).

Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed during the cell-intrinsic immune response to viral infection. IFIT1 inhibits translation by binding directly to the 5' end of foreign RNAs, particularly those with non-self cap structures, precluding the recruitment of the cap-binding eukaryotic translation initiation factor 4F and ribosome recruitment. The presence of IFIT1 imposes a requirement on viruses that replicate in the cytoplasm to maintain mechanisms to avoid its restrictive effects. Interaction of different IFIT family members is well described, but little is known of the molecular basis of IFIT association or its impact on function. Here, we reconstituted different complexes of IFIT1, IFIT2 and IFIT3 in vitro, which enabled us to reveal critical aspects of IFIT complex assembly. IFIT1 and IFIT3 interact via a YxxxL motif present in the C-terminus of each protein. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that also associates with IFIT1. We show for the first time that IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to a cap0 Zika virus reporter mRNA and enhances IFIT1 translation inhibition. This work reveals molecular aspects of IFIT interaction and provides an important missing link between IFIT assembly and function. ; This work was supported by a joint Royal Society/Wellcome Trust Sir Henry Dale Fellowship (202471/Z/16/Z) and a Royal Society Research Grant (RG140708) to TRS. HVM is supported by a University of Cambridge, Department of Pathology PhD studentship. XYL is supported by a King's Scholarship from the Malaysian government. TJS is supported by a Wellcome Trust PhD studentship (105389/Z/14/Z). RCF and DSM are supported by CAPES Computational Biology (23038.010048/2013-27). DSM is also supported by the Academy of Medical Sciences/UK (NAF004/1005). SCG is a Sir Henry Dale Fellow (098406/Z/12/Z) co-funded by the Wellcome Trust and Royal Society.

Unlike their counterparts in bacterial and higher eukaryotic hosts, most fungal viruses are transmitted intracellularly and lack an extracellular phase. Here we determined the cryo-EM structure at 3.7 Å resolution of Rosellinia necatrix quadrivirus 1 (RnQV1), a fungal double-stranded (ds)RNA virus. RnQV1, the type species of the family Quadriviridae, has a multipartite genome consisting of four monocistronic segments. Whereas most dsRNA virus capsids are based on dimers of a single protein, the ~450-Å-diameter, T = 1 RnQV1 capsid is built of P2 and P4 protein heterodimers, each with more than 1000 residues. Despite a lack of sequence similarity between the two proteins, they have a similar α-helical domain, the structural signature shared with the lineage of the dsRNA bluetongue virus-like viruses. Domain insertions in P2 and P4 preferential sites provide additional functions at the capsid outer surface, probably related to enzyme activity. The P2 insertion has a fold similar to that of gelsolin and profilin, two actin-binding proteins with a function in cytoskeleton metabolism, whereas the P4 insertion suggests protease activity involved in cleavage of the P2 383-residue C-terminal region, absent in the mature viral particle. Our results indicate that the intimate virus-fungus partnership has altered the capsid genome-protective and/or receptor-binding functions. Fungal virus evolution has tended to allocate enzyme activities to the virus capsid outer surface. ; This work was supported by grants from the Spanish Ministry of Economy and Competitivity (BFU2013-43149-R to DL and JMR, BFU2014-54181 to JLC and BFU2014-55475-R to JRC), the Madrid regional government (S2013/MIT-2850 to JLC and S2013/MIT-2807 to JRC), the Japanese Ministry of Education, Culture, Sports, Science, and Technology (KAKENHI 25252011 and 16H06436, 16H06429, and 16K21723 to NS), and the NIH Intramural Research Program, Center for Information Technology (to BLT). The CNB-CSIC Proteomics Facility, which belongs to ProteoRed, PRB2-ISCIII, was ...

Mammalian genomes encode tens of thousands of noncoding RNAs. Most noncoding transcripts exhibit nuclear localization and several have been shown to play a role in the regulation of gene expression and chromatin remodeling. To investigate the function of such RNAs, methods to massively map the genomic interacting sites of multiple transcripts have been developed; however, these methods have some limitations. Here, we introduce RNA And DNA Interacting Complexes Ligated and sequenced (RADICL-seq), a technology that maps genome-wide RNA–chromatin interactions in intact nuclei. RADICL-seq is a proximity ligation-based methodology that reduces the bias for nascent transcription, while increasing genomic coverage and unique mapping rate efficiency compared with existing methods. RADICL-seq identifies distinct patterns of genome occupancy for different classes of transcripts as well as cell type–specific RNA-chromatin interactions, and highlights the role of transcription in the establishment of chromatin structure. ; This work was funded by a Research Grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, to the RIKEN Center for Life Science Technologies (http://www.mext.go.jp/en/). This work was also supported by the Francis Crick Institute, UK, which receives its core funding from Cancer Research UK (FC010110), the UK Medical Research Council (FC010110), and the Wellcome Trust (FC010110). N.M.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of the Francis Crick Institute. N.M.L. isadditionally funded by a Wellcome Trust Joint Investigator Award (103760/Z/14/Z) and the MRC eMedLab Medical Bioinformatics Infrastructure Award (MR/L016311/1). Work in G.C.-B.'s laboratory was supported by the European Union (Horizon 2020 European Research Council Consolidator Grant EPIScOPE), Swedish Research Council (no. 2015-03558), Swedish Brain Foundation (no. FO2017-0075), and Ming Wai Lau Centre for Reparative Medicine, Hong Kong. E.A. was supported by European Union, Horizon 2020, Marie-Skłodowska Curie Actions, grant SOLO no. 794689. Y.A.M. was partially supported by RSF grant 18-14-00240 and the Russian Ministry for Science and Higher Education. Work in V.O.'s laboratory (J.G. and V.O.) was supported by grants from the European Union FP7 (InteGeR Marie Curie Initial Training Network and MODHEP), the Italian Ministry of Education, University and Research MIUR and the National Research Center CNR (Epigen), and grant from KAUST BAS01-01-37. Open access funding provided by Karolinska Institute.

Thiosemicarbazones and their metal derivatives have long been screened as antitumor agents, and their interactions with DNA have been analysed. Herein, we describe the synthesis and characterization of compounds containing [CuL]+ entities (HL = pyridine-2-carbaldehyde thiosemicarbazone) and adenine, cytosine or 9-methylguanine, and some of their corresponding nucleotides. For the first time, crystal structures of adenine- and 9-methylguanine-containing thiosemicarbazone complexes are reported. To the best of our knowledge, the first study on the affinity thiosemicarbazone–RNA is also provided here. Experimental and computational studies have shown that [CuL(OH2)]+ entities at low concentration intercalate into dsRNA poly(rA)·poly(rU) through strong hydrogen bonds involving uracil residues and π–π stacking interactions. In fact, noncovalent interactions are present both in the solid state and in solution. This behaviour diverges from that observed with DNA duplexes and creates an optimistic outlook in achieving selective binding to RNA for subsequent possible medical applications. ; Obra Social "la Caixa" (OSLC-2012-007), Ministerio de Economía y Competitividad and FEDER funds (CTQ2013-48937-C2-1-P, CTQ2015-70371- REDT, MAT2012-34740 and CTQ2014-58812-C2-2-R), Junta de Castilla y León (BU237U13), the Basque Government (IT-779- 13), Gerencia Regional de Salud, Consejería de Sanidad, Junta de Castilla y León (GRS 1023/A/14 and GR172).