Developmental regulation of apical endocytosis controls epithelial patterning in vertebrate tubular organs

© 2015 Macmillan Publishers Limited. Epithelial organs develop through tightly coordinated events of cell proliferation and differentiation in which endocytosis plays a major role. Despite recent advances, how endocytosis regulates the development of vertebrate organs is still unknown. Here we describe a mechanism that facilitates the apical availability of endosomal SNARE receptors for epithelial morphogenesis through the developmental upregulation of plasmolipin (pllp) in a highly endocytic segment of the zebrafish posterior midgut. The protein PLLP (Pllp in fish) recruits the clathrin adaptor EpsinR to sort the SNARE machinery of the endolysosomal pathway into the subapical compartment, which is a switch for polarized endocytosis. Furthermore, PLLP expression induces apical Crumbs internalization and the activation of the Notch signalling pathway, both crucial steps in the acquisition of cell polarity and differentiation of epithelial cells. We thus postulate that differential apical endosomal SNARE sorting is a mechanism that regulates epithelial patterning.MINECO (BFU2011-22622) and CONSOLIDER (CSD2009-00016); Fundación Obra Social `La Caixa' PhD fellowship. G.A. was supported by the Amarouto Program for senior researchers from the Comunidad Autónoma de Madrid.Peer Reviewe

SILEX: a fast and inexpensive high-quality DNA extraction method suitable for multiple sequencing platforms and recalcitrant plant species

[EN] Background The use of sequencing and genotyping platforms has undergone dramatic improvements, enabling the generation of a wealth of genomic information. Despite this progress, the availability of high-quality genomic DNA (gDNA) in sufficient concentrations is often a main limitation, especially for third-generation sequencing platforms. A variety of DNA extraction methods and commercial kits are available. However, many of these are costly and frequently give either low yield or low-quality DNA, inappropriate for next generation sequencing (NGS) platforms. Here, we describe a fast and inexpensive DNA extraction method (SILEX) applicable to a wide range of plant species and tissues. Results SILEX is a high-throughput DNA extraction protocol, based on the standard CTAB method with a DNA silica matrix recovery, which allows obtaining NGS-quality high molecular weight genomic plant DNA free of inhibitory compounds. SILEX was compared with a standard CTAB extraction protocol and a common commercial extraction kit in a variety of species, including recalcitrant ones, from different families. In comparison with the other methods, SILEX yielded DNA in higher concentrations and of higher quality. Manual extraction of 48 samples can be done in 96 min by one person at a cost of 0.12 euro/sample of reagents and consumables. Hundreds of tomato gDNA samples obtained with either SILEX or the commercial kit were successfully genotyped with Single Primer Enrichment Technology (SPET) with the Illumina HiSeq 2500 platform. Furthermore, DNA extracted fromSolanum elaeagnifoliumusing this protocol was assessed by Pulsed-field gel electrophoresis (PFGE), obtaining a suitable size ranges for most sequencing platforms that required high-molecular-weight DNA such as Nanopore or PacBio. Conclusions A high-throughput, fast and inexpensive DNA extraction protocol was developed and validated for a wide variety of plants and tissues. SILEX offers an easy, scalable, efficient and inexpensive way to extract DNA for various next-generation sequencing applications including SPET and Nanopore among others.This research has been funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No 677379 (Linking genetic resources, genomes and phenotypes of Solanaceous crops; G2P-SOL). David Alonso is grateful to Universitat Politecnica de Valencia for a predoctoral (PAID-01-16) contract under the Programa de Ayudas de Investigacion y Desarrollo initiative. Mariola Plazas is grateful to Generalitat Valenciana and Fondo Social Europeo for a postdoctoral grant (APOSTD/2018/014). Pietro Gramazio is grateful to Japan Society for the Promotion of Science for a Postdoctoral Grant (P19105, FY2019 JSPS Postdoctoral Fellowship for Research in Japan (Standard)). The Spanish Ministerio de Educacion, Cultura y Deporte funded a predoctoral fellowship granted to Edgar Garcia-Fortea (FPU17/02389).Vilanova Navarro, S.; Alonso-Martín, D.; Gramazio, P.; Plazas Ávila, MDLO.; García-Fortea, E.; Ferrante, P.; Schmidt, M.... (2020). SILEX: a fast and inexpensive high-quality DNA extraction method suitable for multiple sequencing platforms and recalcitrant plant species. Plant Methods. 16(1):1-11. https://doi.org/10.1186/s13007-020-00652-yS111161Scheben A, Batley J, Edwards D. Genotyping-by-sequencing approaches to characterize crop genomes: choosing the right tool for the right application. Plant Biotechnol J. 2017;15:149–61.Jung H, Winefield C, Bombarely A, Prentis P, Waterhouse P. Tools and strategies for long-read sequencing and de novo assembly of plant genomes. 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Anal Chim Acta. 2018;1020:30–40.Branton D, Deamer D, Quick J, Loman NJ. DNA extraction strategies for nanopore sequencing. Nanopore Seq. World Sci. 2019;1:91–105.Cheng H, Zhang K, Libera J, De La Cruz M, Bedzyk M. Polynucleotide adsorption to negatively charged surfaces in divalent salt solutions. Biophys J. 2016;90:1164–74.Shi B, Shin Y, Hassanali A, Singer S. DNA Binding to the Silica Surface. J Phys Chem B. 2015;119:11030–40.Katevatis C, Fan A, Klapperich CM. Low concentration DNA extraction and recovery using a silica solid phase. PLoS ONE. 2017;12:e0176848.Green MR, Sambrook J. Isolation and quantification of DNA. Cold Spring Harb Protoc. 2018;2018:403–14.Toole K, Roffey P, Young E, Cho K, Shaw T, Smith M, Blagojevic N. Evaluation of commercial forensic DNA extraction kits for decontamination and extraction of DNA from biological samples contaminated with radionuclides. Forensic Sci Int. 2019;302:109867.Piskata Z, Servusova E, Babak V, Nesvadbova M, Borilova G. The quality of DNA isolated from processed food and feed via different extraction procedures. Molecules. 2019;24:1188.Xia Y, Chen F, Du Y, Liu C, Bu G, Xin Y, Boye L. A modified SDS-based DNA extraction method from raw soybean. Biosci Rep. 2019;39:2.Akkurt M. Comparison between modified DNA extraction protocols and commercial isolation kits in grapevine (Vitis vinifera L.). Genet Mol Res. 2012;11:2343–51.Marsal G, Baiges I, Canals JM, Zamora F, Fort F. A Fast, efficient method for extracting DNA from leaves, stems, and seeds of Vitis vinifera L. Am J Enol Vitic. 2011;62:376–81.Abdel-Latif A, Osman G. Comparison of three genomic DNA extraction methods to obtain high DNA quality from maize. Plant Methods. 2017;13:1.Huang J, Ge X, Sun M. Modified CTAB protocol using a silica matrix for isolation of plant genomic DNA. Biotechniques. 2000;28:432–4.Rogstad SH. Plant DNA extraction using silica. Plant Mol Biol Report. 2012;21:463.Li J-F, Li L, Sheen J. Protocol: a rapid and economical procedure for purification of plasmid or plant DNA with diverse applications in plant biology. Plant Methods. 2010;6:1.Li J-F, Sheen J. DNA purification from multiple sources in plant research with homemade silica resins. Humana Press. 2012;862:53–9.Vandeventer PE, Lin JS, Zwang TJ, Nadim A, Johal MS, Niemz A. Multiphasic DNA adsorption to silica surfaces under varying buffer, pH, and ionic strength conditions. J Phys Chem B. 2012;116:5661–70.Boesenberg-Smith KA, Pessarakli MM, Wolk DM. Assessment of DNA yield and purity: an overlooked detail of PCR troubleshooting. Clin Microbiol Newsl. 2012;34:1–6.Emaus MN, Clark KD, Hinners P, Anderson JL. Preconcentration of DNA using magnetic ionic liquids that are compatible with real-time PCR for rapid nucleic acid quantification. Anal Bioanal Chem. 2018;410:4135–44.Dumschott K, Schmidt MHW, Chawla HS, Snowdon R, Usadel B. Oxford Nanopore sequencing: new opportunities for plant genomics? 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La cueva de El Sidrón (Borines, Piloña, Asturias): primeros resultados

Se exponen los resultados preliminares de las excavaciones arqueológicas llevadas a cabo en la Cueva de El Sidrón entre 2000 y 2002, de acuerdo con los tres objetivos principales que conciernen al registro fósil humano: las características antropológicas, cómo y cuándo llegaron allí y la relación entre fósiles y cultura. Las primeras conclusiones obtenidas son que los restos humanos pertenecen al Neandertal, que el registro arqueológico corresponde a un tecno-complejo del Paleolítico Medio y que están en posición secundaria.We expose the preliminary results of the archaeological excavations developed between 2000-2002 in Sidrón's Cave, according to the three main objectives that concern the human fossil record: the anthropological characteristics, how and when they arrived there and the relation between fossils and culture. We conclude preliminarily that the record belongs to Horno Neanderthalensis, archeological remains to the Middle Paleolithic techno-complex, and they are in a secondary position.Este trabajo se ha realizado en el marco del Convenio Consejería de Cultura del Principado de Asturias/Universidad de Oviedo (CN-00-184-D3 y CN-01-132, 133, 134-B1) y del Plan I+D+I Concertada (Ficyt/Consejería de Cultura: FC-02-PC-SPV01-27)

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVE: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 +/- 19.2 years) recruited from 29 international centers. RESULTS At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% +/- 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of <= 35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Altres ajuts: European Alzheimer DNA BioBank, EADB; EU Joint Programme, Neurodegenerative Disease Research (JPND); Neurodegeneration research program of Amsterdam Neuroscience; Stichting Alzheimer Nederland; Stichting VUmc fonds; Stichting Dioraphte; JPco-fuND FP-829-029 (ZonMW projectnumber 733051061); Dutch Federation of University Medical Centers; Dutch Government (from 2007-2011); JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A); German Research Foundation (DFG RA 1971/6-1, RA1971/7-1, RA 1971/8-1); Grifols SA; Fundación bancaria 'La Caixa'; Fundació ACE; CIBERNED; Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'); NIH (P30AG066444, P01AG003991); Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund; Siemens Healthineers; Valdecilla Biobank (PT17/0015/0019); Academy of Finland (338182); German Center for Neurodegenerative Diseases (DZNE); German Federal Ministry of Education and Research (BMBF 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711); ZonMW (#73305095007); Health~Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106); Hersenstichting; Edwin Bouw Fonds; Gieskes-Strijbisfonds; NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012); Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361); Dementia Foundation (2020-04-13, 2021-04-17); Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALF 716681); Swedish Research Council (11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096); Swedish Research Council for Health, Working Life and Welfare (2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496); Swedish Brain Power, Hjärnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163); Alzheimer's Association Zenith Award (ZEN-01-3151); Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimer's Association (IIRG-03-6168, IIRG-09-131338); Bank of Sweden Tercentenary Foundation; Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALFGBG-771071); Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825); Swedish Research Council (2019-02075); Swedish Research Council (2016-01590); BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012); Swedish Research Council (2018-02532); Swedish State Support for Clinical Research (ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862); UK Dementia Research Institute at UCL; Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); National Institute of Health (NIH), USA, (#1R01AG068398-01); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614); Chuck Zuckerberg Initiative (CZI).Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele