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Resumen del póster presentado al VIII International Congress on Analytical Nanoscience and Nanotechnology, celebrado en Barcelona (España) del 3 al 5 de julio de 2017., Simple, inexpensive and rapid sensing systems are very demanded for a myriad of uses. Intrinsic properties of emerging paper-based analytical devices have demonstrated considerable potential to fulfill such demand. This work reports an easy-to-use, low cost, and disposable paper-based sensing device for rapid chemical screening with a smartphone readout. The device comprises luminescent graphene quantum dots (GQDs) sensing probes embedded into a nitrocellulose matrix where the resonance energy transfer phenomenon seems to be the sensing mechanism. The GQDs probes were synthesized from citric acid by a pyrolysis procedure, further physisorbed and confined into small wax-traced spots on the nitrocellulose substrate. The GQDs were excited by an UV LED, this, is powered by a smartphone used as both; energy source and imaging capture. The LED was contained within a 3D-printed dark chamber that isolates the paper platform from external light fluctuations leading to highly reproducible data. The cellulose-based device was proven as a promising screening tool for phenols and polyphenols in environmental and food samples, respectively. It opens up new opportunities for simple and fast screening of organic compounds and offers numerous possibilities for versatile applications. It can be especially useful in remote settings where sophisticated instrumentation is not always available.

A self-powered skin patch for the measurement of sweat conductivity is presented. The key component of the patch consists of a paper battery that is activated upon absorption of sweat. This body fluid acts as the battery electrolyte, the conductivity of which has a direct impact on the battery-generated output power and voltage. This particular behaviour enables the operation of a very simple and robust conductivity sensor in direct current mode without needing an external power source. The device presented in this paper takes advantage of this new measurement method to develop a sweat patch for screening cystic fibrosis that operates with an extremely simple electronic circuit that minimizes its cost and environmental impact. The patch provides an unambiguous digital result that can be read in an electrochromic display and yields 95% sensitivity and 100% specificity when tested with artificial eccrine perspiration samples.

Polyethylene furandicarboxylate (PEF) is considered as a renewable-based solution to its fossil-based counterpart polyethylene terephthalate (PET). However, due to its lengthy and energy-intensive production process, PEF has not been established at a commercial scale. Here we present a new study on PEF produced from industrial carbon dioxide (CO2) emissions and non-food-derived biomass to provide an alternative for PET. We assess PEF production from an energy consumption, environmental impacts and production cost point of view at an industrial scale using mass and energy balance, life-cycle assessment and payback period. The results show that emissions and energy consumption can be reduced up to 40.5% compared with PET. Abiotic depletion (fossil) (6.90 × 104 MJ), global-warming potential (3.75 × 103 kg CO2-equivalent) and human toxicity potential (2.18 × 103 kg 1,4-dichlorobenzene equivalent) are the three most substantial impacts in producing one tonne of PEF. By applying optimal design and mature technology, PEF produced from industrial CO2 and biowastes could be a feasible and competitive substitute for PET and other materials. The renewable polyethylene furandicarboxylate (PEF) has potential to replace the fossil-based polyethylene terephthalate, but the energy-intensive production hinders wider adoption. This study shows that PEF from industrial CO2 emissions and non-food biomass can save 40.5% emissions and energy use.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34 + cells, EPC-mobilizing cytokines-vascular endothelial growth factor and stromal cell-derived factor-1α-and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines neovascularization, brain repair and neurological recovery after ICH. This study is the first in which the Pro allele of Tp53 is linked to vascular repair and ability to functionally recover from stroke., This work was funded by The Instituto de Salud Carlos III Grants PI12/00685, PI15/00473 and RD12/0014/0007 (to AA), RD12/0014/0001 (to JC), PI14/01879 and CP12/03121 (to TS), RD12/0043/0021 (to JPB), CD11/00348 (to CR), CD12/00685 (to JA), CM11/00140 (to JJD), CM14/00096 (to MER-A), The Ministerio de Economía y Competitividad Grant SAF2013-41177-R (JPB), The Junta de Castilla y León (GRS843/A/13 and GRS1004/A/14; to JCG-S), The Xunta de Galicia (GRC2014/027; to JC) and the European Regional Development Fund (ERDF).

__Abstract__ Aims: To investigate the association of the GOLD ABCD groups classification with costs and health-related quality of life (HR-QoL) and to compare this with the GOLD 1234 grades classification that was primarily based on lung function only. Methods: In a cross-sectional study, we selected patients diagnosed with chronic obstructive pulmonary disease (COPD) from electronic medical records of general practices. Multi-level analysis was used with costs (medication, primary care, healthcare, societal), diseasespecific and generic HR-QoL as independent variables. Either the new or the old GOLD stages were included in the analysis together with several covariates (age, gender, living situation, co-morbidity, self-efficacy, smoking, education, employment). Results: 611 patients from 28 general practices were categorised as GOLD-A (n=333), GOLD-B (n=110), GOLD-C (n=80) and GOLD-D (n=88). Patients in the GOLD-B and GOLD-D groups had the highest prevalence of co-morbidities and the lowest level of physical activity, self-efficacy, and employment. The models with GOLD ABCD groups were more strongly related to and explained more variance in costs and in disease-specific and generic HR-QoL than the models with GOLD 1234 grades. The mean Clinical COPD Questionnaire score worsened significantly, with scores 1.04 (GOLD-B), 0.4 (GOLD-C) and 1.21 (GOLD-D) worse than for patients in GOLD-A. Healthcare costs per patient were significantly higher in GOLD-B (72%), GOLD-C (74%) and GOLD-D (131%) patients than in GOLD-A patients. Conclusions: The GOLD ABCD groups classification is more closely associated with costs and HR-QoL than the GOLD 1234 grades classification. Furthermore, patients with GOLD-C had a better HR-QoL than those with GOLD-B but the costs of the two groups did not differ.

Rodríguez-Vargas, José Manuel et al., AMPK is a central energy sensor linking extracellular milieu fluctuations with the autophagic machinery. In the current study we uncover that Poly(ADP-ribosyl)ation (PARylation), a post-translational modification (PTM) of proteins, accounts for the spatial and temporal regulation of autophagy by modulating AMPK subcellular localisation and activation. More particularly, we show that the minority AMPK pool needs to be exported to the cytosol in a PARylation-dependent manner for optimal induction of autophagy, including ULK1 phosphorylation and mTORC1 inactivation. PARP-1 forms a molecular complex with AMPK in the nucleus in non-starved cells. In response to nutrient deprivation, PARP-1 catalysed PARylation, induced the dissociation of the PARP-1/AMPK complex and the export of free PARylated nuclear AMPK to the cytoplasm to activate autophagy. PARP inhibition, its silencing or the expression of PARylation-deficient AMPK mutants prevented not only the AMPK nuclear-cytosolic export but also affected the activation of the cytosolic AMPK pool and autophagosome formation. These results demonstrate that PARylation of AMPK is a key early signal to efficiently convey extracellular nutrient perturbations with downstream events needed for the cell to optimize autophagic commitment before autophagosome formation., ES was supported by Newcastle University's Institute of Neuroscience and MS performed this work as part of her degree in Newcastle University's MRes Programme in Medical and Molecular Biosciences.

Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-d-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca 2+ influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca 2+ and protein kinase Cδ activation. Active protein kinase Cδ promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr395, Ser433 and Thr439 that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival., DJ-B is the recipient of a FIS Fellowship. PS-C was granted a fellowship from Gobierno de Extremadura (PD10058; Consejería de Empleo, Empresa e Innovación) and European Social Fund. This work was funded by the Spanish Ministerio de Economia y Competitividad (to JPB, grant number SAF2013-41177-R), the Instituto de Salud Carlos III (to JPB, grant number RD12/0043/0021; to AA, grant numbers PI12/00685 and RD12/0014/0007), Junta de Castilla y Leon (to JPB, SA003U13), the SP3-People-MC-ITN program of the European Commission (to JPB, 608381 TINTIN), the National Institutes of Drug Abuse/National Institutes of Health (NIH/NIDA) (to JPB, 1R21DA037678-01) and the European Regional Development Fund.

et al., Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumor-suppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis., This work was supported by grants from Spanish Ministry of Economy and Competitiveness (MINECO) and Fondo Europeo de Desarrollo Regional (FEDER) (PS09/01401; PI12/02248, FR2009-0052 and IT2009-0053 to GV), Comunidad de Madrid (S2011/BMD-2308 to MG), Fundación Mutua Madrileña (AP101042012 to GV) and Breast Cancer Campaign (2012NovSP033 to EKT and GV). Purchase of the TRIB3-deficient mice (LEXKO-1947) line was funded by the Wellcome Trust. MS was recipient of a fellowship from Spanish Ministry of Education and Science (MEC), a research formation contract from Comunidad de Madrid and a Postdoctoral Research Contract from Fundación Científica Asociación Española Contra el Cáncer (AECC); ML was sequentially the recipient of a ‘Juan de la Cierva’ contract, a postdoctoral contract from Spanish Ministry of Education and Science (MEC) and a postdoctoral contract from Comunidad de Madrid. AC is supported by an ERC StG (336343), the Ramón y Cajal award (Spanish Ministry of Education), the Basque Department of Industry, Tourism and Trade (Etortek), Marie Curie Reintegration grant (277043), Movember Global Action Plan, ISCIII (PI10/01484) and the Basque Government of health (2012111086) and education (PI2012-03). EPG was the recipient of a Postdoctoral Research Contract from AECC.

Crumpled graphene films are broadly used, for instance in electronics1, energy storage2, 3, composites4, 5, and biomedicine6. Although it is known that the degree of crumpling affects graphene's properties and the performance of graphene-based devices and materials3, 5, 7, the controlled folding and unfolding of crumpled graphene films has not been demonstrated. Here we report an approach to reversibly control the crumpling and unfolding of large-area graphene sheets. We show with experiments, atomistic simulations and theory that, by harnessing the mechanical instabilities of graphene adhered on a biaxially pre-stretched polymer substrate and by controlling the relaxation of the pre-strains in a particular order, graphene films can be crumpled into tailored self-organized hierarchical structures that mimic superhydrophobic leaves. The approach enables us to fabricate large-area conductive coatings and electrodes showing superhydrophobicity, high transparency, and tunable wettability and transmittance. We also demonstrate that crumpled graphene-polymer laminates can be used as artificial-muscle actuators.

Background and Purpose PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti-inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. Experimental Approach Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well-known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti-inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro. Key Results TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL-10 and IL-27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL-17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker Foxp3. Conclusions and Implications These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS. © 2013 The British Pharmacological Society.

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License., 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a master regulator of glycolysis by its ability to synthesize fructose-2,6-bisphosphate, a potent allosteric activator of 6-phosphofructo-1-kinase. Being a substrate of the E3 ubiquitin ligase anaphase-promoting complex-Cdh1 (APC(Cdh1)), PFKFB3 is targeted to proteasomal degradation in neurons. Here, we show that activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) stabilized PFKFB3 protein in cortical neurons. Expressed PFKFB3 was found to be mainly localized in the nucleus, where it is subjected to degradation; however, expression of PFKFB3 lacking the APC(Cdh1)-targeting KEN motif, or following NMDAR stimulation, promoted accumulation of PFKFB3 and its release from the nucleus to the cytosol through an excess Cdh1-inhibitable process. NMDAR-mediated increase in PFKFB3 yielded neurons having a higher glycolysis and lower pentose-phosphate pathway (PPP); this led to oxidative stress and apoptotic neuronal death that was counteracted by overexpressing glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Furthermore, expression of the mutant form of PFKFB3 lacking the KEN motif was sufficient to trigger oxidative stress and apoptotic death of neurons. These results reveal that, by inhibition of APC(Cdh1), glutamate receptors activation stabilizes PFKFB3 thus switching neuronal metabolism leading to oxidative damage and neurodegeneration. Cell Death and Differentiation (2012) 19, 1582-1589; doi:10.1038/cdd.2012.33; published online 16 March 2012, J.P.B. is funded by Spanish Ministerio de Economia y Competitividad (SAF2010-20008; Consolider-Ingenio CSD2007-00020), FEDER (European regional development fund), ISCIII (RETICEF, RD12/0043/0021) and Junta de Castilla y León (SA112A12-2). A.A. is funded by Instituto de Salud Carlos III (PS09/0366; RD06/0026/1008). P.R.-R. is a recipient of a predoctoral FPU fellowship from the Ministerio de Ciencia e Innovación.

Background and Purpose The perception of pain and its inhibition varies considerably between individuals, and this variability is still unexplained. The aim of the present study is to determine whether functional interactions between opioid receptors are involved in the inter-individual variability in the sensitivity to μ-opioid receptor agonists. Experimental Approach Anti-nociceptive tests, radioligand binding, stimulation of [ 35S]GTP-γ-S binding, inhibition of cAMP production and co-immunoprecipitation experiments were performed in two strains of rat (Sprague-Dawley bred at our university - SDU - and Wistar) that differ in their sensitivity to opioids. Key Results The increased anti-nociceptive potency of μ-opioid receptor agonists in SDU rats was reversed by the δ-opioid receptor antagonist, naltrindole. Inhibition of the binding of [ 3H] naltrindole by μ-opioid receptor agonists was different in brain membranes from SDU and Wistar rats. Differences were also evident in the effect of δ-opioid receptor ligands on the binding of [ 35S]GTP-γ-S stimulated by μ-opioid receptors agonists. No strain-related differences were detected in spinal cord membranes. The potency of morphine to inhibit cAMP production in brain membranes varied between the strains, in the presence of deltorphin II and naltrindole. Co-immunoprecipitation experiments demonstrated that δ-opioid receptors were associated with μ-opioid receptors to a higher extent in brain synaptosomal fractions from SDU than in those from Wistar rats. Conclusions and Implications There was increased supraspinal cross-talk between μ and δ-opioid receptors in SDU, as compared with Wistar rats. This was related to an enhanced sensitivity to anti-nociception induced by μ-opioid receptor agonists. © 2011 The British Pharmacological Society., This work was supported by grants from the Spanish MCyT (SAF 2000-0120-C02-02 to CCF and SAF 2003-08140-C02-02 to JJB), FIS (FIS05/PI050590 to CCF) and Instituto de Salud Carlos III (PS09/00332 to JG). JC was a recipient of predoctoral fellowships from the Instituto Upsa de Dolor and Generalitat Valenciana-Fondo Social Europeo.

Producción Científica, Cyclosporin A (CsA) is a widely used compound because ofits potent immunosupressive properties, derived mainly from the inhibition of calcineurin, and also because of its ability to block the mitochondrial permeability transition pore (PTP). This second effect has been involved in the protection against apoptosis mediated by release ofmitochondrial factors. We show here that CsA (1– 10mM) has an additional effect on Ca2+ homeostasis in mitochondria that cannot be attributed to inhibition ofPTP. By measuring specifically mitochondrial [Ca2+] with targeted aequorin, we show that CsA inhibited Ca2+ entry into mitochondria both in intact and in permeabilized cells, and this effect was stronger when Ca2+ entry was triggered by low cytosolic [Ca2+], below 5 mM. Inhibition ofmitochondrial Ca2+ uptake required micromolar concentrations ofCsA and was not mimicked by other inhibitors of calcineurin such as FK-506 or cypermethrin, nor by a different inhibitor ofthe PTP, bongkrekic acid. CsA blocked the increase in mitochondrial Ca2+ uptake rate induced by the mitochondrial Ca2+ uniporter activator SB202190. 5 Our results suggest that CsA inhibits Ca2+ entry through the Ca2+ uniporter by a mechanism independent ofthe inhibition ofPTP or calcineurin. This effect may contribute to reduce depolarization and Ca2+ overloading in mitochondria after cell stimulation, and thus cooperate with the direct inhibition ofPTP to prevent apoptosis., 2015-09-15

1. The effects of two new synthetic compounds showing in vitro catechol-O-methyl transferase (COMT) inhibitor properties were studied in vivo and compared with the effects of nitecapone and Ro-41-0960. 2. QO IA (3-(3-hydroxy-4-methoxy-5-nitrobenzylidene)-2,4-pentanedione), QO IIR ([2-(3,4-dihydroxy-2-nitrophenyl)vinyl]phenyl ketone), nitecapone and Ro-41-0960 (30 mg kg-1, i.p.) were given to reserpinized rats 1 h before the administration of L-DOPA/carbidopa (LD/CD, 50:50 mg kg-1, i.p.). Locomotor activity was assessed 1 h later. All the COMT inhibitors (COMTI), with the exception of QO IA, markedly potentiated LD/CD reversal of reserpine-induced akinesia. Similar results were obtained when the COMTI were coadministered with LD/CD. The effect of compound QO IIR was dose-dependent (7.5-30 mg kg-1, i.p.). 3. The COMTI (30 mg kg-1, i.p.) potentiated LD/CD reversal of both catalepsy and hypothermia of reserpinized mice. 4. QO IIR, nitecapone and Ro-41-0960 (30 mg kg-1, i.p.) reduced striatal 3-methyl-DOPA (3-OMD) levels and increased dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels. Compound QO IA was devoid of any effect on striatal amine levels. In contrast to the other inhibitors, Ro-41-0961 reduced HVA levels as well. The effect of QO IIR on striatal amine levels was dose-dependent (7.5-60 mg kg-1, i.p.) 5. These results suggest that the new compound QO IIR is an effective peripherally acting COMT inhibitor in vivo.

Oily extracts of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-alpha-sanshool (alpha-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations.The structure-activity relationships of these molecules on TRPA1 and TRPV1 was measured by testing natural and synthetic analogues using calcium and voltage imaging on dissociated dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addition, using Trpv1 knockout mice, the compounds' aversive responses were measured in a taste brief-access test.For TRPA1 activation, the cis C6 double bond in the polyenic chain of alpha-SOH was critical, whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compounds activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to alpha-SOH.The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compounds.

RESP-5451

15 páginas, 7 figuras. The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-24808-z. The data that support this study are available from the corresponding authors upon reasonable request. ChIP-seq data generated in the course of this work have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE145966. Encode data for RAD21 (ENCFF361FUX) and MNase (ENCFF000VLK), GEO data for CTCF (GSM733672) and DNase (GSM816655), and Enhancer Atlas database for enhancer information (http://www.enhanceratlas.org/) were used for Fig. 5 and Supplementary Fig. 7. GEO data for CTCF (GSM935404) and the high-resolution Hi-C data for IMR90 cell lines (GSE63525) were used for the intra-TAD prediction tool for Fig. 7 and Supplementary Fig. 8. Other data supporting the findings of this study are available within the paper, its supplementary information files, and the source data file. Source data are provided with this paper. The custom scripts generated during the current study are available from https:// bitbucket.org/qgenomics/smc1a-nipbl., Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF., This work was funded by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), which is part of the State Agency, through the projects BFU2013-43132-P and BFU2016-77975-R to E.Q., and BFU2016-79841 to A.L. (co-funded by the European Regional Development Fund, ERDF, a way to build Europe) and the MaratóTV3 (101030 FMTV3) to E.Q. A.L.-P., B.P., F.R., and J.P. are funded by the Spanish Ministry of Health ISCIIIFIS (Ref. PI19/01860) and by the Gobierno de Aragon (Ref. B32_17R) and belong to the GCV02 of CIBERER. J.L.M. is a recipient of a grant from the Instituto Carlos III, which is part of the State Agency, grant number CA18/00045 (co-funded by the European Regional Development Fund, ERDF, a way to build Europe) and M.M. is a recipient of the fellowship “Personal Técnico de Apoyo” number PTA2018-016371-I funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), which is part of the State Agency.

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The increasing demand for efficient sensing devices with facile low-cost fabrication has attracted a lot of scientific research effort in the recent years. In particular, the scientific community aims to develop new candidate materials suitable for energy-related devices, such as sensors and photovoltaics or clean energy applications such as hydrogen production. One of the most prominent methods to improve materials functionality and performance is doping key device component(s). This paper aims to examine in detail, both from a theoretical and an experimental point of view, the effect of halogen doping on the properties of tin dioxide (SnO2) and provide a deeper understanding on the atomic scale mechanisms with respect to their potential applications in sensors. Density Functional Theory (DFT) calculations are used to examine the defect processes, the electronic structure and the thermodynamical properties of halogen-doped SnO2. Calculations show that halogen doping reduces the oxide bandgap by creating gap states which agree well with our experimental data. The crystallinity and morphology of the samples is also altered. The synergy of these effects results in a significant improvement of the gas-sensing response. This work demonstrates for the first time a complete theoretical and experimental characterization of halogen-doped SnO2 and investigates the possible responsible mechanisms. Our results illustrate that halogen doping is a low-cost method that significantly enhances the room temperature response of SnO2.

Explainable artificial intelligence (XAI) has emerged as a promising solution for addressing the implementation challenges of AI/ML in healthcare. However, little is known about how developers and clinicians interpret XAI and what conflicting goals and requirements they may have. This paper presents the findings of a longitudinal multi-method study involving 112 developers and clinicians co-designing an XAI solution for a clinical decision support system. Our study identifies three key differences between developer and clinician mental models of XAI, including opposing goals (model interpretability vs. clinical plausibility), different sources of truth (data vs. patient), and the role of exploring new vs. exploiting old knowledge. Based on our findings, we propose design solutions that can help address the XAI conundrum in healthcare, including the use of causal inference models, personalized explanations, and ambidexterity between exploration and exploitation mindsets. Our study highlights the importance of considering the perspectives of both developers and clinicians in the design of XAI systems and provides practical recommendations for improving the effectiveness and usability of XAI in healthcare., npj Digital Medicine, 6 (1), ISSN:2398-6352

The material characterization of nineteenth-century artifacts is of great interest, due both to the breakthrough technological advances and to the unprecedented spread of forgeries of antiquities which took place in that period. However, this type of artifacts has been largely overlooked in the past. In this paper we present the compositional analysis of gold jewels by the Castellani, one of the most important families of goldsmiths in nineteenth-century Europe. The use of a portable micro-XRF spectrometer, specifically developed for jewellery analysis at the Centro Nacional de Aceleradores (Seville), allowed us to analyse, in a completely non-invasive way, the alloys, joining techniques and surface treatments of the jewels of the Castellani collection at the National Etruscan Museum of Villa Giulia in Rome. The addition to the spectrometer of a second X-rays detector with a zinc filter allowed us to check the possible presence of low amounts of cadmium, a metal added to gold soldering only from the nineteenth century and often used in authenticity studies. Moreover, the relative intensities of the Au X-ray lines were studied in order to check non-invasively the presence of surface enrichments in gold., RM’s PhD was funded with a “Regione Toscana Pegaso PhD Scholarship 2017”. IOF wishes to acknowledge the “V Plan Propio de Investigación“ of the University of Seville.

R.A. Fisher was one of the greatest scientists of the 20th century, whose scientific contributions ranged over a very wide area of science. He was, however, from an early age a supporter of eugenic ideas, and for this reason has been accused of being a racist and an advocate of forced sterilisation of certain kinds of people. Concerns are now increasingly being raised about historical figures such as Fisher, stimulated by recent abhorrent racially motivated events. A primary aim of this paper is to conduct a careful analysis of Fisher’s writings on eugenics and related areas, in the context of these adverse views. We first review his scientific achievements and then describe his early development of interests in genetics and eugenic ideas. We outline his concerns about the inverse relationship between intellectual ability and fertility, his views on how this might adversely affect the development of human societies, his eugenic proposals for differential family allowances, and his support for voluntary sterilisation for the “feebleminded”. We follow this with an account of Fisher’s interaction with the Nazi-supporting German human geneticist Verschuer, and Fisher’s response to the 1952 UNESCO statement on “The Race Concept”. We finally discuss attitudes to Fisher’s eugenics related activities in a modern context. Our conclusion is that, however much people now reasonably disagree with his stated ideas on eugenics and racial issues, there is no case for dishonouring him and allowing these concerns to outweigh the appreciation of his enormous scientific and humanitarian contributions.

Background The presence of women in decision-making positions, such as on editorial committees of biomedical journals, is not the same as that of men. This paper analyzes the gender composition of editorial committees (EBMs) and editors-in-chief (ECs) positions of pediatric journals. Methods The gender of EBMs and ECs of 125 journals classified in the pediatrics area of the Journal Citation Report (JCR) was analyzed. The following indicators were calculated: gender distribution of ECs and EBMs by journal, publisher, subject speciality, country, quartile of the journal in JCR and country of affiliation of the members. Results The total number of EBMs was 4242. The distribution by sex of the ECs was 19.44% women and 80.56% men, while that of the EBMs were 33.05% women and 66.95% men. Twenty journals exhibited a greater representation of women than of men, and in four there was parity. Journals with greater participation of women specialized in nursing and physical therapy and were related to nutrition (lactation and breastfeeding). Conclusions Only one-fifth of ECs and one-third of EBMs are females. Women's participation is higher in journals related to nursing, physical and occupational therapy, and nutrition. The United States has the highest number of EBMs, followed by the European Union. Impact Only one-fifth of Editors-in-chief in pediatrics journals are female. Only one-third of Editorial Board Members in pediatrics journals are female. Women's participation is higher in editorials committees in pediatrics journals related to nursing, physical and occupational therapy, and nutrition. Medical and pediatric associations and societies must work together to eliminate the disparities that exist between women and men. Achieving gender equity and empowering all women is one of the World Health Organization's Sustainable Development Goals.

2 pages.-- Reply to: Ecological variables for deep-ocean monitoring must include microbiota and meiofauna for effective conservation, J. Ingels et al. Nature Ecology & Evolution 5: 27-29 (2021), doi: 10.1038/s41559-020-01335-6, Meiofauna and microbes are key components of deep-sea ecosystem assessments and were included among the list of essential variables in our recent comprehensive assessment and prioritization of a global deep-ocean monitoring and conservation strategy1. Meiofauna ranked in the top three variables, whereas microbes (bacteria, and archaea) were reported as key variables for some aspects of monitoring the deep sea. However, larger components of the deep-sea fauna (such as macro- and megafauna) received the highest priority. In their Matters Arising, Ingels and co-workers2 criticized the ranking because, in their opinion, macro- and megafaunal components cannot be considered higher-priority variables than microbes and meiofauna. They concluded that this result reflects an unequal distribution of the competence of the authors and of the respondents to the elicitation survey. However, their criticisms are unjustified for conceptual, methodological and operational reasons. On semantic and theoretical grounds, Ingels et al. confused the concept of priority with that of relevance/importance. Ingels et al. seem also to confound the concept of monitoring and protecting with the importance of research for advancing scientific knowledge; these are two partly related, but distinct, objectives. Indeed, recognizing the ecological importance of one biological component is one thing, but identifying the monitoring variables where capacity to deliver for conservation management globally is well established, is quite another. We cannot apply the same monitoring and conservation approach to all biological components because small organisms, such as prokaryotes, protists and meiofauna encompass massive numbers of undescribed species with largely unknown ecologies3,4 and shorter turnover times, which may make them more resilient to disturbance than larger biota. Even an ocean completely depleted of large fauna, for example, sharks and all predators, would remain flush with meiofauna and microbes. Yet, a deep-sea system with abundant meiofauna and prokaryotes would almost certainly function poorly without higher trophic levels. This well-known ecological principle is certainly one of the reasons there was a wide consensus among the 112 experts (including the microbiologists and meiofauna experts who participated in the expert elicitation) on censusing larger species to protect vulnerable habitats they inhabit or create. The much more limited evidence for microbial and meiofaunal endemicity, the great proportion of unidentified species and the lack of life-history information, greatly compromise any proposal to use these components as proxies for monitoring and mapping conservation areas. Thus, the results of the expert elicitation, on the one hand, reflect the maturity of the disciplines and the capability to deliver indicator information and, on the other hand, recognize the role of larger organisms in current conservation priorities, while acknowledging fundamental roles of all groups., Another important aspect overlooked by Ingels et al. is that deep-sea biodiversity was only one of the five main research areas addressed by the study. In the second research area we considered, which was dedicated to ecosystem functions, benthic faunal biomass and benthic faunal production were ranked as top variables (see table 1 in Danovaro et al.1). Because meiofauna and microbes typically dominate benthic faunal biomass at abyssal depths5,6, we took care to emphasize the functional role of microbial components: “microbes (primarily bacteria followed by archaea) largely dominate overall biomass and production. These microscopic components, essential for deep-sea ecosystem functions … we stress microbial heterotrophic and chemoautotrophic C production as two essential ecological variables needed for understanding the key processes sustaining the functioning of deep-sea food webs and biogeochemical cycles”. We also strongly disagree with the methodological criticisms of Ingels et al. As scientists, we endeavour to remove all potential sources of bias in the framework of standard good practices for data evaluation. Our study is based on expert elicitation, which is a procedure to find consensus on priorities, not an experiment with treatments and controls; thus, standard deviations cannot be treated as in ecological experimental designs. Our Perspective describes how we endeavoured to achieve an objective methodology (that is, coverage of different research fields and knowledge for each of the five main themes, scientists covered a broad range of geographic regions, different taxonomic expertise, academic qualifications and years of experience). These aspects, including statistical treatment, were discussed in detail using multiple rounds of enquiries, following rigorous procedures7, and were presented transparently in the supplementary information of our paper1. To our knowledge, the 112 scientists participating in this elicitation make this study the widest deep-sea community ever to participate in defining priorities based on standardized questions. Ingels et al. assumed that microbial and meiofaunal components were not prioritized because most of the respondents were macrofaunal or megafaunal experts. However, this is not evident in our data, because a large fraction of respondents covered multiple fields of expertise (note that the supplementary information1 reported only one main topic per scientist). Their criticism suggests that deep-sea scientists are divided into two groups: micro- meiofaunal experts competing against macro- megafaunal experts, fighting to prioritize their own work, rather than a community working together towards a common objective. Obtaining expert opinions for comprehensive deep-sea management, as we did, requires the involvement of scientists working in different sectors (such as deep-sea technologies, conservation biology, biological oceanography, biogeochemistry, policy and management), thus participants cannot simply be classified as experts by faunal size category. The fact that many scientists, in responding to the questionnaire, did not automatically prioritize their own research specialty for deep-ocean monitoring, conservation and impact assessment suggests that this is a false and non-productive dichotomy. Accordingly, we reaffirm that the expert elicitation reported in Danovaro et al.1 is robust, accurate and balanced, and simply reflects the prioritization of the groups of organisms/habitats and associated variables to monitor in light of anthropogenic impacts, conservation needs and currently available technology, feasibility and knowledge. In operational terms, environmental monitoring, especially in the deep sea, requires ready-to-use technologies and methods that are employable, which greatly influences the choice of monitoring priorities and rankings of the consulted experts. Our paper innovatively coupled this need with the readiness levels of the described technologies. We agree that the scientific community should do more to document the importance of small organisms, to establish and disseminate the best standardized practices for collecting such observations and to increase our knowledge of undescribed species and their ecological roles to use them more effectively in future monitoring plans, particularly in light of the ongoing effects of global change8,9,10. At the same time, no marine protected area (in both shallow waters and in the open ocean) or other conservation initiative anywhere targets the loss of meiofaunal or microbial diversity. The reference to the Marine Strategy Framework Directive (MSFD 2008/56/EC), designed to address the Good Environmental Status of marine ecosystems (including the deep sea), does not support the position of Ingels et al.2 as the analysis of deep-sea biodiversity in the MSFD is, at present, limited to species of commercial interest and deep-water corals. None of the European directives prioritize meiofauna or microbes. Moreover, to the best of our knowledge, there is no single ongoing, nor planned, monitoring strategy of a national agency based on or prioritizing microbial or meiofaunal diversity in their standard protocols. Given the current limitation in the use of high-throughput sequencing (for example, for the identification of meiofauna3), further efforts are thus necessary to better integrate microbes and meiofauna in future monitoring and conservation programmes. To do this, the global deep-sea community must encourage joint efforts, share common goals and use standardized tools, This work was supported by the H2020 projects MERCES (Grant agreement no. 689518), and IDEM (Grant agreement no. 11.0661/2017/750680/SUB/EN V.C2.), by the Norwegian Institute for Water Research, by the NSERC Canadian Healthy Oceans Network and CFREF Ocean Frontier Institute, by JPI Oceans2 and ONC, by ARIM (MartTERA ERA-Net Cofound), by NSF grant OCE 1634172, by DOOS from the Consortium for Ocean Leadership, by the EMSO-Link EU project (Grant agreement ID: 731036) and by the Faculty of Science RAE Improvement Fund of The University of Hong Kong, With the funding support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S), of the Spanish Research Agency (AEI)

A Correction to this paper has been published: .

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21566-w

13 pages, 4 figures, 3 tables, supplementary Information https://doi.org/10.1038/s41598-021-85240-3, Underwater Television (UWTV) surveys provide fishery-independent stock size estimations of the Norway lobster (Nephrops norvegicus), based directly on burrow counting using the survey assumption of “one animal = one burrow”. However, stock size may be uncertain depending on true rates of burrow occupation. For the first time, 3055 video transects carried out in several Functional Units (FUs) around Ireland were used to investigate this uncertainty. This paper deals with the discrimination of burrow emergence and door-keeping diel behaviour in Nephrops norvegicus, which is one of the most commercially important fisheries in Europe. Comparisons of burrow densities with densities of visible animals engaged in door-keeping (i.e. animals waiting at the tunnel entrance) behaviour and animals in full emergence, were analysed at time windows of expected maximum population emergence. Timing of maximum emergence was determined using wave-form analysis and GAM modelling. The results showed an average level of 1 visible Nephrops individual per 10 burrow systems, depending on sampling time and depth. This calls into question the current burrow occupancy assumption which may not hold true in all FUs. This is discussed in relation to limitations of sampling methodologies and new autonomous robotic technological solutions for monitoring, This work received financial support from the Spanish Ministerio de Economía y Competitividad (Contract TEC2017-87861-R Project RESBIO, RTI2018-095112-B-I00 Project SASES and CTM2017-82991-C2-1-R Project RESNEP), from the Generalitat de Catalunya “Sistemas de Adquisición Remota de datos. This work acknowledges the ‘Severo Ochoa Centre of Excellence’ accreditation (CE

The inner ear, or cochlea, is a fluid-filled organ housing the mechanosensitive hair cells. Sound stimulation is relayed to the hair cells through waves that propagate on the elastic basilar membrane. Sensorineural hearing loss occurs from damage to the hair cells and cannot currently be cured. Although drugs have been proposed to prevent damage or restore functionality to hair cells, a difficulty with such treatments is ensuring adequate drug delivery to the cells. Because the cochlea is encased in the temporal bone, it can only be accessed from its basal end. However, the hair cells that are responsible for detecting speech-frequency sounds reside at the opposite, apical end. In this paper we show that steady streaming can be used to transport drugs along the cochlea. Steady streaming is a nonlinear process that accompanies many fluctuating fluid motions, including the sound-evoked waves in the inner ear. We combine an analytical approximation for the waves in the cochlea with computational fluid dynamic simulations to demonstrate that the combined steady streaming effects of several different frequencies can transport drugs from the base of the cochlea further towards the apex. Our results therefore show that multi-frequency sound stimulation can serve as a non-invasive method to transport drugs efficiently along the cochlea.

Objective To elucidate whether women at risk of gestational diabetes mellitus (GDM) have a unique fatty acid profile compared to women considered normal healthy controls (NHC). Methods Three hundred pregnant women were randomized to a control group (NHC) (n = 50) and to one of three high risk groups (n = 250), one of which was GDM (n = 50). At recruitment participants’ booking bloods were taken and analyzed for lipid profiles. The GDM group’s fatty acid profile is reported here. Results GDM women compared to NHC had elevated levels of omega 6 (n-6) fatty acids compared to omega 3 (n-3) fatty acids (p = 0.01), of linoleic acid (LA) to docosahexaenoic acid (DHA) p = 0.001, sequentially distorted levels of n-6 fatty acids LA and arachidonic acid (ArA) p = 0.035, as well as significantly depressed levels of n-3 DHA (p = 0.01). Conclusion This paper shows that GDM women have a unique fatty acid profile with elevated levels of n-6 fats, depressed levels of n-3 fats and an abnormal pattern of sequential n-6 metabolism. This profile probably results from a combination of factors including underexpression and or poor utilization of desaturase enzymes, suboptimal dietary fatty acids intake, poor micronutrient status or dysbiosis of the microbiome. These results help inform development of a clinical predictive tool.

Competition for limiting natural resources generates complex networks of relationships between individuals, both at the intra- and interspecifc levels, establishing hierarchical scenarios among diferent population groups. Within obligate scavengers, and especially in vultures, the coevolutionary mechanisms operating during carrion exploitation are highly specialized and determined in part by agonistic behavior resulting in intra-guild hierarchies. This paper revisits the behavioral and hierarchical organization within the guild of European vultures, on the basis of their agonistic activities during carrion exploitation. We used a dataset distilled from high-quality videorecordings of competitive interactions among the four European vulture species during feeding events. We found a despotic dominance gradient from the larger species to smaller ones, and from the adults to subadults and juveniles, following an age and body size-based linear pattern. The four studied species, and to some extent age classes, show despotic dominance and organization of their guild exerting diferential selection to diferent parts of the carrion. The abundance of these parts could ultimately condition the level of agonistic interactions. We discuss the behavioral organization and the relationship of hierarchies according to the feeding behavior and prey selection, by comparing with other scavenger guilds.

This paper presents a dataset of high-density surface EMG signals (HD-sEMG) designed to study patterns of sEMG spatial distribution over upper limb muscles during voluntary isometric contractions. Twelve healthy subjects performed four different isometric tasks at different effort levels associated with movements of the forearm. Three 2-D electrode arrays were used for recording the myoelectric activity from five upper limb muscles: biceps brachii, triceps brachii, anconeus, brachioradialis, and pronator teres. Technical validation comprised a signals quality assessment from outlier detection algorithms based on supervised and non-supervised classification methods. About 6% of the total number of signals were identified as "bad" channels demonstrating the high quality of the recordings. In addition, spatial and intensity features of HD-sEMG maps for identification of effort type and level, have been formulated in the framework of this database, demonstrating better performance than the traditional time-domain features. The presented database can be used for pattern recognition and MUAP identification among other uses.

In this paper, the first study on NHCN polymerization induced by microwave radiation is described, where a singular kinetic behaviour, especially when this reaction is conducted in the absence of air, is found. As a result, a complex conjugated N-heterocyclic polymer system is obtained, whose properties are very different, and even improved according to morphological features, characterized by their X-ray diffraction patterns and scanning electron microscopy analysis, with respect to those produced under conventional thermal treatment. In addition, a wide variety of relevant bioorganics have been identified, such as amino acids, nucleobases, co-factors, etc., from the synthetized NHCN polymers. These particular families of polymers are of high interest in the fields of astrobiology and prebiotic chemistry and, more recently, in the development of smart multifunctional materials. From an astrobiological perspective, microwave-driven syntheses may simulate hydrothermal environments, which are considered ideal niches for increasing organic molecular complexity, and eventually as scenarios for an origin of life. From an industrial point of view and for potential applications, a microwave irradiation process leads to a notable decrease in the reaction times, and tune the properties of these new series macromolecular systems. The characteristics found for these materials encourage the development of further systematic research on this alternative HCN polymerization., With funding from the Spanish government through the "María de Maeztu Unit of Excellence" accreditation (MDM-2017-0737)

Members of the H-NS protein family play a role both in the chromosome architecture and in the regulation of gene expression in bacteria. The genomes of the enterobacteria encode an H-NS paralogue, the StpA protein. StpA displays specific regulatory properties and provides a molecular backup for H-NS. Some enterobacteria also encode third H-NS paralogues. This is the case of the enteroaggregative E. coli (EAEC) strain 042, which encodes the hns, stpA and hns2 genes. We provide in this paper novel information about the role of the H-NS2 protein in strain 042. A C > T transition in the hns2 promoter leading to increased H-NS2 expression is readily selected in hns mutants. Increased H-NS2 expression partially compensates for H-NS loss. H-NS2 levels are critical for the strain 042 fitness. Under some circumstances, high H-NS2 expression levels dictated by the mutant hns2 promoter can be deleterious. The selection of T > C revertants or of clones harboring insertional inactivations of the hns2 gene can then occur. Temperature also plays a relevant role in the H-NS2 regulatory activity. At 37 °C, H-NS2 targets a subset of the H-NS repressed genes contributing to their silencing. When temperature drops to 25 °C, the repressory ability of H-NS2 is significantly reduced. At low temperature, H-NS plays the main repressory role.

The importance of soil age as an ecosystem driver across biomes remains largely unresolved. By combining a cross-biome global field survey, including data for 32 soil, plant, and microbial properties in 16 soil chronosequences, with a global meta-analysis, we show that soil age is a significant ecosystem driver, but only accounts for a relatively small proportion of the cross-biome variation in multiple ecosystem properties. Parent material, climate, vegetation and topography predict, collectively, 24 times more variation in ecosystem properties than soil age alone. Soil age is an important local-scale ecosystem driver; however, environmental context, rather than soil age, determines the rates and trajectories of ecosystem development in structure and function across biomes. Our work provides insights into the natural history of terrestrial ecosystems. We propose that, regardless of soil age, changes in the environmental context, such as those associated with global climatic and land-use changes, will have important long-term impacts on the structure and function of terrestrial ecosystems across biomes., This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 702057 (CLIMIFUN). M.D.-B. is supported by a Ramón y Cajal grant from the Spanish Ministry of Science and Innovation (RYC2018-025483-I), and by the BES Grant Agreement No. LRB17\1019 (MUSGONET). F.B. is grateful to the Spanish Ministry and FEDER funds for the project AGL2017–85755-R, the i-LINK+2018 (LINKA20069) from CSIC, and received funds from “Fundación Séneca” from Murcia Province (19896/GERM/15). S.R. was supported by the US Geological Survey Ecosystems Mission Area. C.P. acknowledges support from the Spanish State Plan for Scientific and Technical Research and Innovation (2013–2016), award ref. AGL201675762-R (AEI/FEDER, UE). A.G. acknowledges support from the Spanish Ministry of Science (CGL2017-88124-R). F.A. is supported by FONDECYT 11180538 and S.A. by FONDECYT 1170995. We would like to thank Peter Vitousek for his comments on a previous draft of this paper. Moreover, we thank Matt Gebert, Jessica Henley, Fernando T. Maestre, Victoria Ochoa, and Beatriz Gozalo for their help with lab analyses, and Emilio Guirado for his advice with topographic analyses. We also want to thank Osvaldo Sala, Matthew A. Bowker, Peter Vitousek, Courtney Currier, Martin Kirchmair, Victor M. Peña-Ramírez, Lynn Riedel, Julie Larson, Katy Waechter, David Buckner, and Brian Anacker for their help with soil sampling, and to the City of Boulder Open Space and Mountain Parks for allowing us to conduct these samplings. We are also grateful to the Division of Forestry and Wildlife of the State of Hawai’i and Koke’e State Park for their logistical assistance and for allowing us access to the HA sites. The Arizona research sites were established with the support of an EPA‐STAR Graduate Fellowship (U‐916251), a Merriam‐Powell Center for Environmental Research Graduate Fellowship, an Achievement Rewards for College Scientists (ARCS) Foundation of Arizona Scholarship, and McIntire‐Stennis appropriations to Northern Arizona University and the State of Arizona. Any use of trade, product, or firm names is for descriptive purposes only and does not imply endorsement by the U.S. Government.

Upregulation of fatty acid synthase (FASN) is a common event in cancer, although its mechanistic and potential therapeutic roles are not completely understood. In this study, we establish a key role of FASN during transformation. FASN is required for eliciting the anaplerotic shift of the Krebs cycle observed in cancer cells. However, its main role is to consume acetyl-CoA, which unlocks isocitrate dehydrogenase (IDH)-dependent reductive carboxylation, producing the reductive power necessary to quench reactive oxygen species (ROS) originated during the switch from two-dimensional (2D) to three-dimensional (3D) growth (a necessary hallmark of cancer). Upregulation of FASN elicits the 2D-to-3D switch; however, FASN's synthetic product palmitate is dispensable for this process since cells satisfy their fatty acid requirements from the media. In vivo, genetic deletion or pharmacologic inhibition of FASN before oncogenic activation prevents tumor development and invasive growth. These results render FASN as a potential target for cancer prevention studies., M.Q.F. is a recipient of the following grants: FIS PI13/00430 and FIS PI16/00354 funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund (ERDF) and AECC Scientific Foundation (Beca de Retorno 2010). R.C. is a recipient of the following grants: FIS PI11/00832 and FIS PI14/00726 funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund (ERDF), II14/00009 and PIE15/00068 from the Ministerio de Sanidad, Spain. N.S.C. is a recipient of an NIH grant (5R35CA197532). O.Y.T. is a recipient of the grants BFU2014-57466 from the Ministerio de Economía y Competitividad (MINECO). J.P.B. is funded by MINECO (SAF2016-78114-R), Instituto de Salud Carlos III (RD12/0043/0021), Junta de Castilla y León (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA, and Fundación Ramón Areces. This study was partially supported by the generous donations from Fundación CRIS Contra el Cáncer and AVON Spain. We thank Drs. Erwin Wagner and Nabil Djouder for their critical review of the paper.

15 páginas.- 4 figuras.- 3 tablas.- 165 referencias.- Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-45702-1, Droughts associated with climate change alter ecosystem functions, especially in systems characterized by low biodiversity, such as agricultural fields. Management strategies aimed at buffering climate change effects include the enhancement of intraspecific crop diversity as well as the diversity of beneficial interactions with soil biota, such as arbuscular mycorrhizal fungi (AMF). However, little is known about reciprocal relations of crop and AMF diversity under drought conditions. To explore the interactive effects of plant genotype richness and AMF richness on plant yield under ambient and drought conditions, we established fully crossed diversity gradients in experimental microcosms. We expected highest crop yield and drought tolerance at both high barley and AMF diversity. While barley richness and AMF richness altered the performance of both barley and AMF, they did not mitigate detrimental drought effects on the plant and AMF. Root biomass increased with mycorrhiza colonization rate at high AMF richness and low barley richness. AMF performance increased under higher richness of both barley and AMF. Our findings indicate that antagonistic interactions between barley and AMF may occur under drought conditions, particularly so at higher AMF richness. These results suggest that unexpected alterations of plant-soil biotic interactions could occur under climate change. © 2019, The Author(s)., This project was supported by the German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, funded by the German Research Foundation (DFG; FZT 118). We acknowledge support from the German ResearchFoundation (DFG) and Leipzig University within the program of Open Access Publishing.

Cardiovascular diseases (CVDs) affect the myocardium and vasculature, inducing remodelling of the heart from cellular to whole organ level. To assess their impact at micro and macroscopic level, multi-resolution imaging techniques that provide high quality images without sample alteration and in 3D are necessary: requirements not fulfilled by most of current methods. In this paper, we take advantage of the non-destructive time-efficient 3D multiscale capabilities of synchrotron Propagation-based X-Ray Phase Contrast Imaging (PB-X-PCI) to study a wide range of cardiac tissue characteristics in one healthy and three different diseased rat models. With a dedicated image processing pipeline, PB-X-PCI images are analysed in order to show its capability to assess different cardiac tissue components at both macroscopic and microscopic levels. The presented technique evaluates in detail the overall cardiac morphology, myocyte aggregate orientation, vasculature changes, fibrosis formation and nearly single cell arrangement. Our results agree with conventional histology and literature. This study demonstrates that synchrotron PB-X-PCI, combined with image processing tools, is a powerful technique for multi-resolution structural investigation of the heart ex-vivo. Therefore, the proposed approach can improve the understanding of the multiscale remodelling processes occurring in CVDs, and the comprehensive and fast assessment of future interventional approaches.

The incorporation into clinical practice of immune-checkpoint inhibitors (ICIs), such as those targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) and its ligand (PD-L1), has represented a major breakthrough in non-small cell lung cancer (NSCLC) treatment, especially in cases where the cancer has no druggable genetic alterations. Despite becoming the standard of care in certain clinical settings, either alone or in combination with chemotherapy, a proportion of patients do not respond while others actually progress during treatment. Therefore, there is a clinical need to identify accurate predictive biomarkers and to develop novel therapeutic strategies based on ICIs. Although they have limitations, the current markers evaluated to select which patients will undergo ICI treatment are the levels of PD-Ll and the tumor mutational burden. In this paper we describe what is currently known about the dynamic interaction between the cancer cell and the immune system during carcinogenesis, with a particular focus on the description of the functions and gene alterations that preclude the host immunoresponse in NSCLC. We emphasize the deleterious gene alterations in components of the major histocompatibility complex (HLA-I or B2M) and of the response to IFN gamma (such as JAK2) which are mutually exclusive and can affect up to one fifth of the NSCLCs. The participation of other gene alterations, such as those of common oncogenes and tumor suppressors, and of the epigenetic alterations will also be discussed, in detail. Finally, we discuss the potential use of the tumor's genetic profile to predict sensitivity to ICIs.

Syndromic monogenic obesity is a rare and severe early-onset form of obesity. It is characterized by intellectual disability, congenital malformations, and/or dysmorphic facies. The diagnosis of patients is challenging due to the genetic heterogenicity of this condition. However, the use of microarray technology in combination with public databases has been successful on genotype-phenotype correlations, especially for body mass index (BMI) alteration. In this study, the relationship between copy number variations (CNVs) detected by microarray mapping on 16p region and BMI alterations in syndromic patients were assessed. In order to achieve this goal, 680 unrelated Spanish children with intellectual disability were included. 16p region was characterized by using microarray platforms. All detected variants were classified as: (I) one previously non-described 10-Mb duplication in 16p13.2p12.3 region considered causal of intellectual disability and severe overweight, and (II) eleven 16p11.2 CNVs of low prevalence but with recurrence in syndromic patients with severe BMI alteration (nine proximal and two distal). Proximal 16p11.2 CNVs have a dose-dependent effect: underweight in carriers of duplication and obesity in carriers of deletion. KCTD13 was identified as a possible candidate gene for BMI alteration on proximal syndromes, whereas SH2B1 gene was identified as candidate for distal syndromes. The results shown in this paper suggest that syndromic patients could constitute a reliable model to evaluate hypothalamic satiety and obesity disorders as well as generate a wide expectation for primary prevention of comorbidities. Furthermore, 16p13.2p12.3 showed to be an important region on the regulation of body fatness.

Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials.

Work in Dr. Manzanera’s laboratory was funded by the Spanish Ministry for Economy and Competitiveness, within the context of the research projects CTM2017-84332-R, and CGL2017-91737-EXP. Dr. Krell’s laboratory was supported by FEDER funds and Fondo Social Europeo through grants from the Junta de Andalucía (grant CVI-7335) and the Spanish Ministry for Economy and Competitiveness (grants BIO2013-42297 and BIO2016-76779-P). We thank Prof. Caroline Harwood (University of Washington) for providing a P. aeruginosa PAO1 wt strain and the mcpB mutant, that were used for initial experiments not reported here., Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-49697-7., Pseudomonas aeruginosa is an opportunistic human pathogen causing infections in a variety of plant and animal hosts. The gene mcpB, part of the chemosensory gene cluster II, encodes a soluble chemoreceptor whose function remains unknown. Previous studies show that the cheB2 gene, also located in the chemosensory cluster II, is involved in a specific response during infection and it is required for full pathogenicity of P. aeruginosa. To determine whether the McpB (or Aer2) chemoreceptor is involved in virulence processes, we generated a mcpB mutant and tested its phenotype using a virulence-measuring system. This system was developed by our group and is based on different bioassays using organisms living at different soil trophic levels, including microbial, nematode, arthropod, annelid, and plant model systems. The deletion of mcpB resulted in an attenuation of bacterial virulence in different infection models, and wild-type virulence was restored following genetic complementation of the mutant strain. Our study indicates that the McpB chemoreceptor is linked to virulence processes and may constitute the basis for the development of alternative strategies against this pathogen., CTM2017-84332-R, CGL2017-91737-EXP, FEDER funds and Fondo Social Europeo through grants from the Junta de Andalucía (grant CVI-7335), Spanish Ministry for Economy and Competitiveness (grants BIO2013-42297 and BIO2016-76779-P)

This paper details an investigation into the characteristic ‘plink’ sound produced by water droplets impacting a liquid surface, such as those falling from a dripping tap. Modern high-speed video and audio capture techniques have been applied to this problem for the first time. Previous literature investigating the underwater sound produced has been validated, with the key sound producing feature both above and below the water confirmed to be the entrainment of a small underwater air bubble. Recorded sound frequencies have been shown to align with the theoretical natural oscillation frequency of the entrained bubble, confirming this to be the driver of the characteristic ‘plink’ sound. For the first time these oscillations of the entrained bubble have been directly observed on video footage. An investigation into the effect of underwater reverberation showed that the airborne sound field is not simply the underwater field propagating through the water-air interface, as had previously been assumed. An alternative hypothesis is that the oscillating bubble induces oscillations of the water surface itself, giving a more efficient mechanism by which the underwater bubble drives the airborne sound field. A model for this new hypothesis produces good agreement with experimental data.

The extremely low decay factor on the trapped magnetic field by stacks of second-generation high-temperature superconducting tapes reported in Appl. Phys. Lett. 104, 232602 (2014), is in apparent contradiction with the classical results for the demagnetization of superconducting bulks and thin films, where the samples undergo a severe and progressive decay under crossed magnetic field conditions. Nevertheless, in this paper, we demonstrate how the theoretical approaches and experimental measurements on superconducting bulks, thin films, and stacks of superconducting tapes can be reconciled, not only under the crossed field configuration but also under rotating magnetic field conditions, by showing that the stacks of commercial tapes behave as a system of electrically unconnected layers preventing the deformation of profiles of current along its external contour. This study extends up to the consideration of using novel superconducting/ferromagnetic metastructures, where soft ferromagnetic films are interlayered, reporting a further reduction on the magnetization decay of about 50% in the crossed field configuration. Remarkably, after applying the same number of cycles either of rotating or crossed magnetic field to these metastructures, the difference between the magnetization decay is found to be negligible, what demonstrates their highly superior performance when compared to conventional stacks of superconducting tapes.