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Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis

  • Rubio Moscardó, Fanny
  • Bosch Morató, Mònica, 1986-
  • Plata, Cristina
  • Gené, Gemma
  • Muñoz López, Francisco José, 1964-
  • Valverde, M. A. (Miguel Ángel), 1963-
  • Clarimón Echevarría, Jordi
Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade., This study was supported by grants from Instituto de Salud Carlos III (PI12/01311, PI10/000587, Red HERACLES RD12/0042/0014), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain), Spanish Ministry of Economy and Competiveness (SAF2012-38140), FEDER Funds, and Generalitat de Catalunya (SGR05-266). Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, the Strategic Funding of the University on Eastern Finland (UEF-Brain) (to M.H and H.S). M.A.V. is the recipient of an ICREA Academia Award
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Vitamin E dietary supplementation improves neurological symptoms and decreases c-Abl/p73 activation in niemann-pick C mice

  • Marín, Tamara
  • Contreras, Pablo
  • Castro, Juan Francisco
  • Chamorro, David
  • Balboa, Elisa
  • Bosch Morató, Mònica, 1986-
  • Muñoz López, Francisco José, 1964-
  • Álvarez, Alejandra R.
  • Zanlungo, Silvana
Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. We have previously reported that oxidative stress is the main upstream stimulus activating the proapoptotic c-Abl/p73 pathway in NPC neurons. We have also observed accumulation of vitamin E in NPC lysosomes, which could lead to a potential decrease of its bioavailability. Our aim was to determine if dietary vitamin E supplementation could improve NPC disease in mice. NPC mice received an alpha-tocopherol (α-TOH) supplemented diet and neurological symptoms, survival, Purkinje cell loss, α-TOH and nitrotyrosine levels, astrogliosis, and the c-Abl/p73 pathway functions were evaluated. In addition, the effect of α-TOH on the c-Abl/p73 pathway was evaluated in an in vitro NPC neuron model. The α-TOH rich diet delayed loss of weight, improved coordination and locomotor function and increased the survival of NPC mice. We found increased Purkinje neurons and α-TOH levels and reduced astrogliosis, nitrotyrosine and phosphorylated p73 in cerebellum. A decrease of c-Abl/p73 activation was also observed in the in vitro NPC neurons treated with α-TOH. In conclusion, our results show that vitamin E can delay neurodegeneration in NPC mice and suggest that its supplementation in the diet could be useful for the treatment of NPC patients., This study was supported by grants from the Fondo Nacional de Desarrollo Científico y/nTecnológico (FONDECYT) (grant numbers 1120512 to A.R.A, and 1110310 to S.Z); Fondo de/nFomento al Desarrollo Científico y Tecnológico FONDEF D10I1077 (to A.R.A and S.Z.);/nFondo Nacional de Desarrollo de Areas Prioritarias, FONDAP, Project no. 15090007, Center for/nGenome Regulation (CGR) to S.Z.; Generalitat de Catalunya (SGR2009-1369) and La Marató de TV3/n(No. 100310)
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Molecular dating of caprines using ancient DNA sequences of Myotragus balearicus, an extinct endemic Balearic mammal

  • Lalueza Fox, Carles, 1965-
  • Castresana Ruiz-Carrillo, José Ignacio
  • Sampietro Bergua, Mª Lourdes
  • Marquès i Bonet, Tomàs, 1975-
  • Alcover, Josep Antoni
  • Bertranpetit, Jaume, 1952-
Background: Myotragus balearicus was an endemic bovid from the Balearic Islands (Western Mediterranean) that became extinct around 6,000-4,000 years ago. The Myotragus evolutionary lineage became isolated in the islands most probably at the end of the Messinian crisis, when the desiccation of the Mediterranean ended, in a geological date established at 5.35 Mya. Thus, the sequences of Myotragus could be very valuable for calibrating the mammalian mitochondrial DNA clock and, in particular, the tree of the Caprinae subfamily, to which Myotragus belongs. Results: We have retrieved the complete mitochondrial cytochrome b gene (1,143 base pairs), plus fragments of the mitochondrial 12S gene and the nuclear 28S rDNA multi-copy gene from a well preserved Myotragus subfossil bone. The best resolved phylogenetic trees, obtained with the cytochrome b gene, placed Myotragus in a position basal to the Ovis group. Using the calibration provided by the isolation of Balearic Islands, we calculated that the initial radiation of caprines can be dated at 6.2 ± 0.4 Mya. In addition, alpine and southern chamois, considered until recently the same species, split around 1.6 ± 0.3 Mya, indicating that the two chamois species have been separated much longer than previously thought. Conclusion: Since there are almost no extant endemic mammals in Mediterranean islands, the sequence of the extinct Balearic endemic Myotragus has been crucial for allowing us to use the Messinian crisis calibration point for dating the caprines phylogenetic tree., This research was supported by the Dirección General de Investigación, Ministerio de Ciencia y Tecnología of Spain (grants BFU2004-02002 and BOS2003-08070), by Departament d'Universitats, Recerca i Societat de la Informació, Generalitat de Catalunya (grant 2001SGR00285) and a fellowship to LS.
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Bilingualism at the core of the brain: structural differences between bilinguals and monolinguals revealed by subcortical shape analysis

  • Burgaleta Díaz, Miguel, 1981-
  • Sanjuán, Ana
  • Ventura Campos, Noelia
  • Ávila, César
  • Sebastián Gallés, Núria
Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control — two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N = 88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes., This work was supported by grants from the Spanish Ministerio de Ciencia e Innovación (JCI-2009-04492, PSI2010-20168), the Spanish Ministerio de Economía y Competitividad (MINECO-PSI2012-34071), the European Community's Seventh Framework Programme (FP7/2007–2013) / ERC grant agreement n°323961, and Grup de Recerca en Neurociència Cognitiva (GRNC), AGAUR (2014 SGR 1210 N). M.B. was funded by the Spanish Ministerio de Economía y Competitividad (MINECO-FPDI-2013-17528).
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Neuroanatomical markers of social hierarchy recognition in humans: a combined ERP/MRI study

  • Santamaría-García, Hernando, 1981-
  • Burgaleta Díaz, Miguel, 1981-
  • Sebastián Gallés, Núria
Social hierarchy is an ubiquitous principle of social organization across animal species. Although some progress has been made in our understanding of how humans infer hierarchical identity, the neuroanatomical basis for perceiving key social dimensions of others remains unexplored. Here, we combined event-related potentials and structural MRI to reveal the neuroanatomical substrates of early status recognition. We designed a covertly simulated hierarchical setting in which participants performed a task either with a superior or with an inferior player. Participants showed higher amplitude in the N170 component when presented with a picture of a superior player compared with an inferior player. Crucially, the magnitude of this effect correlated with brain morphology of the posterior cingulate cortex, superior temporal gyrus, insula, fusiform gyrus, and caudate nucleus. We conclude that early recognition of social hierarchies relies on the structural properties of a network involved in the automatic recognition of social identity., This work was supported by the Spanish Ministerio de Economía y Competitividad Grant MINECO-PSI2012-34071), the European Community's Seventh Framework Programme (Grant FP7/2007-2013)/European Research Council (Grant 323961), and Grup de Recerca en Neurociència Cognitiva, AGAUR (Grant 2014 SGR 1210N). M.B. was funded by a postdoctoral fellowship from the Spanish Ministerio de Economía y Competitividad (MINECO-FPDI-2013-17528). N.S.-G. received the prize ICREA Acadèmia for Excellence in Research, funded by the Generalitat de Catalunya.
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Irreversible electroporation of the liver: is there a safe limit to the ablation volume?

  • Sánchez-Velázquez, Joan
  • Castellví Fernández, Quim
  • Villanueva, Alberto
  • Quesada Diez, Rita
  • Pañella-Vilamú, Clara
  • Cáceres Aguilar, Mario
  • Dorcaratto, Dimitri
  • Andaluz, Anna
  • Moll, Xavier
  • Trujillo Guillén, Macarena
  • Burdío, José Miguel
  • Berjano, Enrique J.
  • Grande Posa, Luís
  • Ivorra Cano, Antoni, 1974-
  • Burdío Pinilla, Fernando
Irreversible electroporation is a fast-growing liver ablation technique. Although safety has been well documented in small ablations, our aim is to assess its safety and feasibility when a large portion of liver is ablated. Eighty-seven mice were subjected to high voltage pulses directly delivered across parallel plate electrodes comprising around 40% of mouse liver. One group consisted in 55 athymic-nude, in which a tumor from the KM12C cell line was grown and the other thirty-two C57-Bl6 non-tumoral mice. Both groups were subsequently divided into subsets according to the delivered field /nstrength (1000V/cm, 2000V/cm) and whether or not they received anti-hyperkalemia therapy. Early mortality (less than 24hours post-IRE) in the 2000V/cm group was observed and revealed considerably higher mean potassium levels. In contrast, the animals subjected to a 2000V/cm field treated with the anti-hyperkalemia therapy had higher survival rates (OR=0.1, 95%CI=0.02–0.32, p<0.001). Early mortality also depended on the electric field magnitude of the IRE protocol, as mice given 1000V/cm survived longer than those given 2000V/cm (OR=4.7, 95%CI=1.8–11.8, p=0.001). Our findings suggest that ionic disturbances, mainly due to potassium alterations, should be warned and envisioned when large volume ablations are performed by IRE., This research was supported by the Spanish “Plan Estatal de Investigación, Desarrollo e Innovación Orientada/na los Retos de la Sociedad” under Grant TEC2014–52383-C3 (TEC2014-52383-C3-1-R, TEC2014-52383-C3-/n2-R, and TEC2014-52383-C3-3-R), and by the Spanish “Plan Nacional de I + D + i del Ministerio de Ciencia e/nInnovación” under Grants TEC2011-27133-C02 and TEC2010-17285.
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A versatile multilevel converter platform for cancer treatment using irreversible electroporation

  • Sarnago, Héctor
  • Lucía, Óscar
  • Naval, Alejandro
  • Burdío, José Miguel
  • Castellví Fernández, Quim
  • Ivorra Cano, Antoni, 1974-
Electroporation is an effective technique based on applying an electric field to cells, commonly used to increase the effectivity of drug and gene delivery. When the applied electric field is strong enough, it can be used for selective cell death with promising results in cancer treatment. This paper proposes the development of a modular multilevel topology in order to provide a high-performance tool for research in electroporation. The proposed converter based on a scalable multicell approach is detailed and analyzed in this paper, and an experimental prototype has been designed and built. The experimental results prove the feasibility of this proposal to enable advanced electroporation techniques., This work was supported in part by Diputación General de Aragón-Fondo Social Europeo, in part by the University of Zaragoza/nunder Grant JIUZ-2014-TEC-08, and in part by the Spanish Ministerio de Economía y Competitividad under Grant CSD2009-00046, Grant TEC2013-42937-R, and Grant Project RTC-2014-1847-6.
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Tumor growth delay by adjuvant alternating electric fields which appears non-thermally mediated

  • Castellví Fernández, Quim
  • Ginestà, Mireia M.
  • Capellá, Gabriel
  • Ivorra Cano, Antoni, 1974-
Delivery of the so-called Tumor Treatment Fields (TTFields) has been proposed as a cancer/ntherapy. These are low magnitude alternating electric fields at frequencies from 100 to 300 kHz/nwhich are applied continuously in a non-invasive manner. Electric field delivery may produce an/nincrease in temperature which cannot be neglected. We hypothesized that the reported results/nobtained by applying TTFields in vivo could be due to heat rather than to electrical forces as/npreviously suggested. Here it is presented an in vivo study in which pancreatic tumors/nsubcutaneously implanted in nude mice were treated for a week either with mild hyperthermia/n(41°C) or with TTFields (6 V/cm, 150 kHz) and tumor growth was assessed. Although the TTFields/napplied singly did not produce any significant effect, the combination with chemotherapy did show/na delay in tumor growth in comparison to animals treated only with chemotherapy (median relative/nreduction = 47%). We conclude that concomitant chemotherapy and TTFields delivery show a/nbeneficial impact on pancreatic tumor growth. Contrary to our hypothesis, this impact is nonrelated/nwith the induced temperature increase., This research was supported by project grants (AR00311 - MICINN-TEC2010-11182-E, SAF2012-/n33636, RTICCC RD12/0036/0031) from the Spanish government and in part by a Marie Curie grant/n(IRG 256376) from the European Commission and by the Generalitat de Catalunya (2009 SGR/n1356).
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Can electroporation previous to radiofrequency hepatic ablation enlarge thermal lesion size? A feasibility study based on theoretical modelling and in vivo experiments

  • Trujillo Guillén, Macarena
  • Castellví Fernández, Quim
  • Burdío Pinilla, Fernando
  • Ivorra Cano, Antoni, 1974-
  • Andaluz, Anna
  • Sanchez Velazquez Patricia
  • Berjano, Enrique J.
Purpose: To assess the feasibility of a hybrid ablative technique based on applying electroporation (EP) pulses just before conducting radiofrequency ablation (RFA). The rationale was that the EP-induced reduction in blood perfusion could be sufficient to reduce the thermal sink effect and hence to increase the coagulation volume in comparison to that created exclusively by RFA./nMaterials and methods: Modeling study and in vivo experimental study. A Cool-tip RF applicator was used both for EP and RFA./nResults: Overall, the results did not show any synergy effect from using the hybrid technique. Applying EP pulses prior to RFA did not increase the coagulation zone obtained and the lesions were almost identical. Additional computer simulations provided an explanation for this; the effect of reducing blood perfusion by thermal damage during RFA completely masks the effect of reducing blood perfusion by EP. This is because both thermal damage and EP affect the same zone, i.e. the tissue around the electrode./nConclusions: Our computer modeling and in vivo experimental findings suggest that the combination of EP and RFA with monopolar applicators does not provide an additional benefit over the use of RFA alone., This work received financial support from the Spanish “Plan Nacional de I+D+I del Ministerio de Ciencia e Innovación” Grants No. TEC2011-27133-C02-01,02 and TEC2010-17285, from the European Commission through the Marie Curie IRG grant TAMIVIVE (256376) and from the Universitat Politècnica de València (INNOVA11-01-5502; and PAID-06-11 Ref. 1988). The linguistic revision of this paper was funded by the Universitat Politècnica de València, Spain.
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In vivo demonstration of injectable microstimulators based on charge-balanced rectification of epidermically applied currents

  • Ivorra Cano, Antoni, 1974-
  • Becerra-Fajardo, Laura
  • Castellví Fernández, Quim
Objective. It is possible to develop implantable microstimulators whose actuation principle is based on rectification of high frequency (HF) current bursts supplied through skin electrodes. This has been demonstrated previously by means of devices consisting of a single diode. However, previous single diode devices caused DC currents which made them impractical for clinical applications. Here flexible thread-like stimulation implants which perform charge balance are demonstrated in vivo. Approach. The implants weight 40.5 mg and they consist of a 3 cm long tubular silicone body with a diameter of 1 mm, two electrodes at opposite ends and, within the central section of the body, an electronic circuit made up of a diode, two capacitors and a resistor. In the present study, each implant was percutaneously introduced through a 14G catheter into either the gastrocnemius muscle or the cranial tibial muscle of a rabbit hind limb. Then stimulation was performed by delivering HF bursts (amplitude < 60 V, frequency 1 MHz, burst repetition frequency from 10 Hz to 200 Hz, duration = 200 μs) through a pair of textile electrodes strapped around the hind limb and either isometric plantarflexion or dorsiflexion forces were recorded. Stimulation was also assayed 1, 2 and 4 weeks after implantation. Main results. The implants produced bursts of rectified current whose mean value was of a few mA and were capable of causing local neuromuscular stimulation. The implants were well tolerated during the 4 weeks. Significance. Existing power supply methods, and in particular inductive links, comprise stiff and bulky parts. This hinders the development of minimally invasive implantable devices for neuroprostheses based on electrical stimulation. The proposed methodology is intended for relieving such bottleneck. In terms of mass, thinness and flexibility, the demonstrated implants appear to be unprecedented among the intramuscular stimulation implants ever assayed in vertebrates., AI’s research was supported by a Ramón y Cajal fellowship from the Spanish government and a Marie Curie grant (IRG 256376) from the European Commission. LB’s research is supported by a scholarship from the UPF. QC’s research is supported by a scholarship from the Spanish Ministry of Education.
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