201 research outputs found

    Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

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    Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early Dual SMAD and WNT inhibition course is necessary and sufficient to establish robust and lasting cortical organoid NSC identity, efficiently suppressing non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC-specification capacity. Accordingly, this method selectively enriches for outer radial glia NSCs, which cyto-architecturally demarcate well-defined outer sub-ventricular-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD and WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring of fundamental molecular and cyto-architectural features of cortical development and meaningful disease modelling

    Education and Training of Future Nuclear Engineers at DIN: From Advanced Computer Codes to an Interactive Plant Simulator

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    ABSTRACT This paper summarizes the work being performed at the Department of Nuclear Engineering (www.din.upm.es) of the Universidad Politécnica de Madrid to improve the education and training of future Spanish nuclear engineers according to the Bologna rules. We present two main efforts introduced in our programme: i) the understanding of the current computational methodologies/codes starting from the nuclear data processing, then the lattice and core calculations codes, and finally the power plant simulators, ii) the development of practical teaching-learning experiences with an Interactive Graphical Simulator of a real nuclear power plant

    Role of Mitochondrial Complex IV in Age-Dependent Obesity

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    Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion

    A mutation in the melon Vacuolar Protein Sorting 41prevents systemic infection of Cucumber mosaic virus

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    [EN] In the melon exotic accession PI 161375, the gene cmv1, confers recessive resistance to Cucumber mosaic virus (CMV) strains of subgroup II. cmv1 prevents the systemic infection by restricting the virus to the bundle sheath cells and impeding viral loading to the phloem. Here we report the fine mapping and cloning of cmv1. Screening of an F2 population reduced the cmv1 region to a 132 Kb interval that includes a Vacuolar Protein Sorting 41 gene. CmVPS41 is conserved among plants, animals and yeast and is required for post-Golgi vesicle trafficking towards the vacuole. We have validated CmVPS41 as the gene responsible for the resistance, both by generating CMV susceptible transgenic melon plants, expressing the susceptible allele in the resistant cultivar and by characterizing CmVPS41 TILLING mutants with reduced susceptibility to CMV. Finally, a core collection of 52 melon accessions allowed us to identify a single amino acid substitution (L348R) as the only polymorphism associated with the resistant phenotype. CmVPS41 is the first natural recessive resistance gene found to be involved in viral transport and its cellular function suggests that CMV might use CmVPS41 for its own transport towards the phloem.The TILLING platform is supported by the Program Saclay Plant Sciences (SPS, ANR-10-LABX-40) and the European Research Council (ERC-SEXYPARTH). This work was supported by grants AGL2009-12698-C02-01 and AGL2012-40130-C02-01 from the Spanish Ministry of Science and Innovation, the Spanish Ministry of Econom and Competitiveness, through the "Severo Ochoa Programme for Centres of Excellence in R&D" 2016-2019 (SEV-2015-0533)" and the CERCA Programme/Generalitat de Catalunya.Giner, A.; Pascual, L.; Bourgeois, M.; Gyetvai, G.; Rios, P.; Picó Sirvent, MB.; Troadec, C.... (2017). 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Molecular Plant Pathology 16, 675–684, doi: 10.1111/mpp.12225 (2015).Guiu-Aragonés, C. et al. The complex resistance to Cucumber mosaic cucumovirus (CMV) in the melon accession PI 161375 is governed by one gene and at least two quantitative trait loci. Molecular Breeding 34, 351–362, doi: 10.1007/s11032-014-0038-y (2014).Guiu-Aragonés, C. et al. cmv1 is a gate for Cucumber mosaic virus transport from bundle sheath cells to phloem in melon. Mol. Plant Pathology 17, 973–984 (2016).Sanseverino, W. et al. Transposon Insertions, Structural Variations, and SNPs Contribute to the Evolution of the Melon Genome. Molecular Biology and Evolution 32, 2760–2774, doi: 10.1093/molbev/msv152 (2015).Pols, M. S., ten Brink, C., Gosavi, P., Oorschot, V. & Klumperman, J. The HOPS Proteins hVps41 and hVps39 Are Required for Homotypic and Heterotypic Late Endosome Fusion. Traffic 14, 219–232, doi: 10.1111/tra.12027 (2013).Asensio, C. S. et al. Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway. Developmental cell 27, 425–437, doi: 10.1016/j.devcel.2013.10.007 (2013).Kolesnikova, L. et al. Vacuolar protein sorting pathway contributes to the release of Marburg virus. Journal of Virology8 3, 2327–2337, doi: 10.1128/JVI.02184-08 (2009).Nuñez-Palenius, H. G. et al. Melon Fruits: Genetic Diversity, Physiology, and Biotechnology Features. Critical Reviews in Biotechnology 28, 13–55, doi: 10.1080/07388550801891111 (2008).Castelblanque, L. et al. Improving the genetic transformation efficiency of Cucumis melo subsp. melo “Piel de Sapo” via Agrobacterium. Procedings of the IXth UECARPIA Meeting on Genetics and Breeding of Cucurbitaceae, 21-24th May, Avignon,, 627–631 (2008).Dahmani-Mardas, F. et al. Engineering melon plants with improved fruit shelf life using the TILLING approach. PLoS ONE 5, doi: 10.1371/journal.pone.0015776 (2010).Esteras, C. et al. SNP genotyping in melons: genetic variation, population structure, and linkage disequilibrium. Theoretical and Applied Genetics 126, 1285–1303, doi: 10.1007/s00122-013-2053-5 (2013).Leida, C. et al. Variability of candidate genes, genetic structure and association with sugar accumulation and climacteric behavior in a broad germplasm collection of melon (Cucumis melo L.). BMC Genetics 16, 28, doi: 10.1186/s12863-015-0183-2 (2015).Balderhaar, H. Jk & Ungermann, C. CORVET and HOPS tethering complexes – coordinators of endosome and lysosome fusion. Journal of Cell Science 126, 1307–1316, doi: 10.1242/jcs.107805 (2013).Darsow, T., Katzmann, D. J., Cowles, C. R. & Emr, S. D. Vps41p Function in the Alkaline Phosphatase Pathway Requires Homo-oligomerization and Interaction with AP-3 through Two Distinct Domains. Molecular Biology of the Cell 12, 37–51 (2001).Ostrowicz, C. W. et al. Defined subunit arrangement and Rab interactions are required for functionality of the HOPS tethering complex. 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The Plant Journal 32, 1067–1075, doi: 10.1046/j.1365-313X.2002.01499.x (2002).Morosky, S., Lennemann, N. J. & Coyne, C. B. BPIFB6 regulatessecretory pathway trafficking and Enterovirus replication. Journal of Virology 90, 5098–5107, doi: 10.1128/jvi.00170-16 (2016).Serra-Soriano, M., Pallás, V. & Navarro, J. A. A model for transport of a viral membrane protein through the early secretory pathway: minimal sequence and endoplasmic reticulum lateral mobility requirements. The Plant Journal 77, 863–879, doi: 10.1111/tpj.12435 (2014).Vale-Costa, S. & Amorim, M. J. Recycling Endosomes and Viral Infection. Viruses 8, 64, doi: 10.3390/v8030064 (2016).Carette, J. E. et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477, 340–343, doi: 10.1038/nature10348 (2011).Barajas, D., Martín, I. Fd. C., Pogany, J., Risco, C. & Nagy, P. D. Noncanonical role for the host Vps4 AAA + ATPase ESCRT protein in the formation of Tomato bushy stunt virus replicase. 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    Determinants of the current and future distribution of the West Nile virus mosquito vector Culex pipiens in Spain

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    Changes in environmental conditions, whether related or not to human activities, are continuously modifying the geographic distribution of vectors, which in turn affects the dynamics and distribution of vector-borne infectious diseases. Determining the main ecological drivers of vector distribution and how predicted changes in these drivers may alter their future distributions is therefore of major importance. However, the drivers of vector populations are largely specific to each vector species and region. Here, we identify the most important human-activity-related and bioclimatic predictors affecting the current distribution and habitat suitability of the mosquito Culex pipiens and potential future changes in its distribution in Spain. We determined the niche of occurrence (NOO) of the species, which considers only those areas lying within the range of suitable environmental conditions using presence data. Although almost ubiquitous, the distribution of Cx. pipiens is mostly explained by elevation and the degree of urbanization but also, to a lesser extent, by mean temperatures during the wettest season and temperature seasonality. The combination of these predictors highlights the existence of a heterogeneous pattern of habitat suitability, with most suitable areas located in the southern and northeastern coastal areas of Spain, and unsuitable areas located at higher altitude and in colder regions. Future climatic predictions indicate a net decrease in distribution of up to 29.55%, probably due to warming and greater temperature oscillations. Despite these predicted changes in vector distribution, their effects on the incidence of infectious diseases are, however, difficult to forecast since different processes such as local adaptation to temperature, vector-pathogen interactions, and human-derived changes in landscape may play important roles in shaping the future dynamics of pathogen transmission.info:eu-repo/semantics/acceptedVersio

    Identifying the Profile of Helicobacter pylori-Negative Gastric Cancers: A Case-Only Analysis within the Stomach Cancer Pooling (StoP) Project

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    Background: The prevalence of Helicobacter pylori-negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors. Methods: Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serologic test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (OR). Results: Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n = 166/853) and decreased to 7.0% (n = 55) when considering CagA status; estimates for all criteria were 21.8% (n = 276/1, 325) and 6.6% (n = 97), respectively. HpNGC had a family history of gastric cancer more often [OR = 2.18; 95% confidence interval (CI), 1.03-4.61] and were current smokers (OR = 2.16; 95% CI, 0.52-9.02). Conclusion: This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives. Impact: Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.S. Morais, B. Peleteiro, N. Araújo, and N. Lunet received national funding from the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education), under the Unidade de Investigação em Epidemiologia – Instituto de Saúde Pública da Universidade do Porto (EPIUnit; UIDB/04750/2020). S. Morais received funding under the scope of the project “NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline” (POCI-01-0145-FEDER-032358; ref. PTDC/SAU-EPI/32358/2017) funded by FEDER through the Operational Program Competitiveness and Internationalization, and national funding from FCT, and the EPIunit – Junior Research – Prog Financing (UIDP/04750/2020). N. Araújo received an individual grant (SFRH/BD/119390/2016) funded by FCT and the ‘Programa Operacional Capital Humano’ (POCH/FSE). C. La Vecchia received funding from the Italian Association for Cancer Research (AIRC, investigator grant no. 21378). All authors received support from the European Cancer Prevention (ECP) Organization for project meetings. All authors thank all MCC-Spain study collaborators (CIBERESP, ISCIII, ISGlobal, ICO, University of Huelva, University of Oviedo, University of Cantabria, University of León, ibs. Granada, Instituto Salud Pública de Navarra, FISABIO, Murcia Regional Health Authority and cols). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact

    Mercury, cadmium, and lead levels in human placenta: a systematic review

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    BACKGROUND: Placental tissue may furnish information on the exposure of both mother and fetus. Mercury (Hg), cadmium (Cd), and lead (Pb) are toxicants of interest in pregnancy because they are associated with alterations in child development. OBJECTIVES: The aim of this study was to summarize the available information regarding total Hg, Cd, and Pb levels in human placenta and possible related factors. METHODS: We performed a systematic search of PubMed/MEDLINE, EMBASE, Lilacs, OSH, and Web of Science for original papers on total Hg, Cd, or Pb levels in human placenta that were published in English or Spanish (1976-2011). Data on study design, population characteristics, collection and analysis of placenta specimens, and main results were extracted using a standardized form. RESULTS: We found a total of 79 papers (73 different studies). Hg, Cd, and Pb levels were reported in 24, 46, and 46 studies, respectively. Most studies included small convenience samples of healthy pregnant women. Studies were heterogeneous regarding populations selected, processing of specimens, and presentation of results. Hg concentrations > 50 ng/g were found in China (Shanghai), Japan, and the Faroe Islands. Cd levels ranged from 1.2 ng/g to 53 ng/g and were highest in the United States, Japan, and Eastern Europe. Pb showed the greatest variability, with levels ranging from 1.18 ng/g in China (Shanghai) to 500 ng/g in a polluted area of Poland. CONCLUSION: The use of the placenta as a biomarker to assess heavy metals exposure is not properly developed because of heterogeneity among the studies. International standardized protocols are needed to enhance comparability and increase the usefulness of this promising tissue in biomonitoring studies.We thank the librarians of the Móstoles Hospital and of the National Health Sciences Library (ISCIII).S

    On decoding and rewriting genomes: a psychoanalytical reading of a scientific revolution

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    In various documents the view emerges that contemporary biotechnosciences are currently experiencing a scientific revolution: a massive increase of pace, scale and scope. A significant part of the research endeavours involved in this scientific upheaval is devoted to understanding and, if possible, ameliorating humankind: from our genomes up to our bodies and brains. New developments in contemporary technosciences, such as synthetic biology and other genomics and “post-genomics” fields, tend to blur the distinctions between prevention, therapy and enhancement. An important dimension of this development is “biomimesis”: i.e. the tendency of novel technologies and materials to mimic or plagiarize nature on a molecular and microscopic level in order to optimise prospects for the embedding of technological artefacts in natural systems such as human bodies and brains. In this paper, these developments are read and assessed from a psychoanalytical perspective. Three key concepts from psychoanalysis are used to come to terms with what is happening in research laboratories today. After assessing the general profile of the current revolution in this manner, I will focus on a particular case study, a line of research that may serve as exemplification of the vicissitudes of contemporary technosciences, namely viral biomaterials. Viral life forms can be genetically modified (their genomes can be rewritten) in such a manner that they may be inserted in human bodies in order to produce substances at specific sites such as hormones (testosterone), neurotransmitters (dopamine), enzymes (insulin) or bone and muscle tissue. Notably, certain target groups such as top athletes, soldiers or patients suffering from degenerative diseases may become the pioneers serving as research subjects for novel applications. The same technologies can be used for various purposes ranging from therapy up to prevention and enhancement

    Municipal distribution of ovarian cancer mortality in Spain

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    <p>Abstract</p> <p>Background</p> <p>Spain was the country that registered the greatest increases in ovarian cancer mortality in Europe. This study describes the municipal distribution of ovarian cancer mortality in Spain using spatial models for small-area analysis.</p> <p>Methods</p> <p>Smoothed relative risks of ovarian cancer mortality were obtained, using the Besag, York and Molliè autoregressive spatial model. Standardised mortality ratios, smoothed relative risks, and distribution of the posterior probability of relative risks being greater than 1 were depicted on municipal maps.</p> <p>Results</p> <p>During the study period (1989–1998), 13,869 ovarian cancer deaths were registered in 2,718 Spanish towns, accounting for 4% of all cancer-related deaths among women. The highest relative risks were mainly concentrated in three areas, i.e., the interior of Barcelona and Gerona (north-east Spain), the north of Lugo and Asturias (north-west Spain) and along the Seville-Huelva boundary (in the south-west). Eivissa (Balearic Islands) and El Hierro (Canary Islands) also registered increased risks.</p> <p>Conclusion</p> <p>Well established ovarian cancer risk factors might not contribute significantly to the municipal distribution of ovarian cancer mortality. Environmental and occupational exposures possibly linked to this pattern and prevalent in specific regions, are discussed in this paper. Small-area geographical studies are effective instruments for detecting risk areas that may otherwise remain concealed on a more reduced scale.</p
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