dataesr/scientific-paragraphs-categorization huggingface dataset:
Alternatively, PCR analysis was performed on customized molecular MSI panels including markers from the following list: NR-21, NR-22, NR-24, NR-27, BAT-25, BAT-26, BAT-40, D2S123, D5S346, D10S197, D13S153, D17S250, D18S58, D18S69, CAT25, HSP110, TGFbetaRII, and MYCL1. For the molecular reference methods, criteria for defining MSI-H and MSS were according to the manufacturer's assay instructions and each laboratory procedure. For the IHC reference methods, variability has been detected, as some centers defined the loss of one protein marker as being sufficient to call it deficient MMR, whereas other centers defined the loss of a paired protein marker. In this the study, the site-specific standard laboratory procedure was followed to present a reallife data cohort.
Acknowledgments The Idylla™ MSI assay cartridges used in the current study were kindly provided by  Biocartis (Mechelen, Belgium) , and Biocartis has seen the manuscript prior to submission. The authors thank  Luc Geeraert  ( Bench to Pen -Scientific Writing ) for his editorial and writing support,  Prof. Umit Ince  and  Prof. Sibel Erdamar  (both from the  Dept. of Pathology Acıbadem Mehmet Ali Aydınlar University, Istanbul, Turkey ),  Prof. M. Cengiz Yakıcıer  (Dept. of  Molecular Bıology and Genetics Acıbadem Mehmet Ali Aydınlar University, Istanbul, Turkey ),  Dr. Matthew J. Smith  ( Molecular Pathology Diagnostic Service, University Hospitals Birmingham Foundation Trust, UK ),  Prof. Dr. Med. Thomas Rüdiger  ( Städtisches Klinikum Karlsruhe gGmbH, Institut für Pathologie, Karlsruhe, Germany ) for his support,  Stephen Rodgers  ( Barking, Havering and Redbridge University Hospitals NHS Trust, Queen's Hospital ),  Dr.
GWAS analysis. The European Alzheimer's Disease BioBank (EADB) consortium brings together the various European GWAS consortia already working on AD and a new dataset of 20,464 AD cases and 22,244 controls collated from 15 European countries. The EADB GWAS results were meta-analysed with a proxy-ADD GWAS performed in the UK Biobank (UKBB; the UKBB proxy-ADD designation is based on questionnaire data asking if parents had AD which is less specific than clinically or pathological diagnosed AD). The EADB Stage I (GWAS metaanalysis) was based on 39,106 clinically diagnosed AD cases, 46,828 proxy-ADD cases (as defined in the Supplementary Information) and 401,577 controls (Supplementary Tables  1  and 2 ) and on 21,101,114 variants that passed quality control measures (Fig. 1  and see Supplementary Fig.
A similar result was also observed using the mouse single cell dataset (Supplementary Table  17 ). We finally tested whether the relationship between microglial expression and association with ADD risk was specific to particular areas of biology (Supplementary Table  18 ). The most significant interaction was detected between GO:1902991 (regulation of amyloid precursor protein catabolic process) and gene expression level in microglia (q=1. 2x10 -1  and 8. 3x10 -8 for % Cell Exp. and Av. Exp. respectively). Thus, genes in the amyloid-beta pathways with highest microglial expression show the strongest association with ADD, suggesting a functional relationship between microglia and APP/A pathways (Supplementary Table  19 ).
METHODS Online Samples. All discovery meta-analysis samples are from the following consortia/datasets: EADB, GR@ACE, EADI, GERAD/PERADES, DemGene, Bonn, the Rotterdam study, the CCHS study, NxC and the UK Biobank. Of note, in the UK Biobank, individual who did not report dementia or any family history of dementia were used as controls: analysis included 2,447 diagnosed cases, 46,828 proxy cases of dementia and 338,440 controls. Summary demographics of these case-control studies are described in Supplementary Table  1  and more detailed descriptions are available in the Supplementary Information. Replication samples are from the ADGC, CHARGE and FinnGen consortia (Supplementary Table  1  and Supplementary Information) and fully described elsewhere  5, 6, 9, 10, [29] [30] [31]. Written informed consent was obtained from study participants or, for those with substantial cognitive impairment, from a caregiver, legal guardian, or other proxy.
Study protocols for all cohorts were reviewed and approved by the appropriate institutional review boards. Quality control and imputation. Standard quality control was performed on variants and samples on all datasets individually. The samples were then imputed with the Trans-Omics for Precision Medicine (TOPMed) reference panel  32, 33. The Haplotype Reference Consortium (HRC) panel  34  was also used for some datasets (Supplementary Table  2 ). For the UK Biobank, we used the provided imputed data, generated from a combination of the 1000 Genomes (1000G), HRC and UK10K reference panels. See Supplementary Information for details.
Stage I analyses. Association tests between ADD clinical or proxy status and autosomal genetic variant were conducted separately in each dataset using logistic regression assuming an additive genetic model as implemented in SNPTEST  35  or in PLINK  3  , except in the UK Biobank where a logistic mixed model as implemented in SAIGE  36  was considered. Analyses were performed on the genotype probabilities in SNPTEST (newml method) and on dosages in PLINK and SAIGE. Analyses were adjusted for principal components and genotyping centers when necessary (Supplementary Table  2 ). For the UK Biobank dataset, effect sizes and standard errors were corrected by a factor of two to take into account that proxy cases were analysed  7. We filtered out duplicated variants and variants with (i) missing effect size, standard error or P value, (ii) absolute value of effect size above 5, (iii) imputation quality less than 0.
3, (iv) the product of the minor allele count (MAC) and the imputation quality (mac-info score) less than 20. In the UK Biobank dataset, only variants with minor allele frequency (MAF) above 0. 01% and MAC above 3 were analyzed. For datasets not imputed with the TOPMed reference panel, we also excluded (i) variants for which conversion of position or alleles from the GRCh37 assembly to the GRCh38 assembly was not possible or problematic, or (ii) variants with very large difference of frequency between the TOPMed reference panel and the reference panels used to perform imputation. Results were then combined across studies with a fixed-effect meta-analysis using the inverse variance weighted approach as implemented in the METAL software  37. We filtered (i) variants with heterogeneity P value below 5x10 -8 , (ii) variants analyzed in less than 20% of the total number of cases and (iii) variants with frequency amplitude above 0.
4 (defined as the difference between the maximum and minimum frequency across studies). We further excluded variants analyzed in the UK Biobank only or variants not analyzed in the EADB-TOPMed dataset. Genomic inflation factor lambda was computed with the R package GenABEL 38 using the median approach after exclusion of the APOE region (44 Mb to 46 Mb on chromosome 19 in GRCh38). The linkage disequilibrium (LD) score (LDSC) regression intercept was computed with the LDSC software using the "baselineLD" LD scores built from 1000 Genomes Phase 3.
Definition of associated loci. A region of +/-500kb was defined around each variant with a Stage I P value below 1x10 -5. Those regions were then merged with the bedtools software to define non-overlapping regions. The region corresponding to the APOE locus was excluded. We then applied the PLINK clumping procedure to define independent hits in each of those regions. The clumping procedure was applied on all variants with a Stage I P value below 1x10 -5. It is an iterative process beginning with the variant with the lowest P value, named index variant. Variants with a Stage I P value below 1x10 -5 , located within 500 kb of this index variant, and in LD with the index variant (r 2 above 0. 001) are assigned to the clump of this index variant. The clumping procedure is then applied on all the remaining variants, until no variant is left.
LD was computed in the EADB-TOPMed dataset using high quality (probability ≥ 0. 8) imputed genotypes. Stage II analyses. Variants with a Stage I P value below 1x10 -5 were followed up (see Supplementary Information). A fixed-effect meta-analysis was performed with METAL (inverse variance weighted approach) to combine the results across Stages I and II. In each clump, we then reported the replicated variant (same direction of effects between Stage I and Stage II, with a Stage II P value below 0. 05) with the lowest P value in the meta-analysis. Those variants were considered associated at the genome-wide significance level if they had a P value below 5x10 -8 in the Stages I + II meta-analysis. Among them, we excluded the variant chr6:32657066:G:A because its frequency amplitude was large. Pathway analysis.
The assignment of Gene Ontology (GO) terms to human genes was obtained from the "gene2go" file, downloaded from NCBI on March 11 th 2020. "Parent" GO terms were assigned to genes using the ontology file also downloaded on the same date. GO terms were assigned to genes based on experimental or curated evidence of a specific type, so evidence codes IEA (electronic annotation), NAS (non-traceable author statement), RCA (inferred from reviewed computational analysis) were excluded. Pathways were downloaded from the Reactome website on April 26 th 2020. Biocarta, KEGG and Pathway Interaction Database (PID) pathways were downloaded from v7. 1 (March 2020) of the Molecular Signatures Database. Analysis was restricted to GO terms containing between 10 and 2000 genes. No size restrictions were placed on the other gene sets, since there were fewer of them.
This resulted in a total of 10,271 gene sets for analysis. Gene set enrichment analyses were performed in MAGMA  40  , correcting for the number of variants in each gene, linkage disequilibrium (LD) between variants and LD between genes. LD was computed in the EADB-TOPMed dataset using high quality (probability ≥ 0. 9) imputed genotypes. The measure of pathway enrichment is the MAGMA "competitive" test (where the association statistic for genes in the pathway is compared to those of all other protein-coding genes), as recommended by De Leeuw et al. 41. We used the "mean" test statistic, which uses the sum of -log(variant P value) across all genes. The primary analysis assigned variants to genes if they lie within the gene boundaries, but a secondary analysis used a window of 35kb upstream and 10kb downstream to assign variants to genes, as in Kunkle et al  5.
In the 3C study, analysis was adjusted on age, sex, the two first PCs and center. Analyses were additionally controlled for the number of APOE-e4 and APOE-e2 alleles (assuming an additive effect) to assess the independence of the PRS from APOE. The interaction between the PRS and the number of APOE-e4 alleles was tested. Analyses were repeated stratified by the presence or absence of at least one APOE-e4 allele. Results from individual cohorts were meta-analyzed using fixed effects meta-analysis. Imputations in Rotterdam were performed using the HRC imputation panel and 6 variants were missing. This study was therefore not included in the meta-analysis. Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.
bancoadn. org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain). EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Nord Pas de Calais. This work was supported by INSERM, the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Recherche en Génomique Humaine, CEA, the JPND PERADES, the Laboratory of Excellence GENMED (Medical Genomics) grant no.
ANR-10-LABX-0013 managed by the National Research Agency (ANR) part of the Investment for the Future program, and the FP7 AgedBrainSysBio. The Three-City Study was performed as part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM "Cohortes et collections de données biologiques" programme.
Bedtools: https://bedtools. readthedocs. io/en/latest/ BCFtools: http://samtools. github. io/bcftools/bcftools. html Samtools: http:/www. htslib. org/doc/samtools. html gene2go: ftp://ftp. ncbi. nlm. nih. gov/gene/DATA/ Gene Ontology: http://geneontology. org/docs/download-ontology/ project PTDC/DTP_PIC/5587/2014 at the University of Aveiro, Portugal. Lausanne study: Investigación Biomédica en Red Enfermedades Neurodegenerativas (Program 1, Alzheimer Disease to MB and AR)). A. R. and M. B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M. B. and A. R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474 and PI19/01240. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud.
Acknowledgments EADB. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. We thank the high performance computing service of the  University of Lille. We thank all the  CEA-CNRGH  staff who contributed to sample preparation and genotyping for their excellent technical assistance. This research has been conducted using the UK Biobank Resource under Application Number  61054. This work was supported by a grant ( European Alzheimer DNA BioBank, EADB)  from the  EU Joint Programme -Neurodegenerative Disease Research (JPND). Inserm   UMR1167  is also funded by  Inserm ,  Institut Pasteur de Lille , the  Lille Métropole Communauté Urbaine , the  French government 's  LABEX DISTALZ program  (development of innovative strategies for a transdisciplinary approach to Alzheimer's disease).
Additional support for EADB cohorts was provided by: The work for this manuscript was further supported by the  CoSTREAM  project (www. costream. eu)and funding from the  European Union 's  Horizon 2020 research and innovation programme  under grant agreement No  667375. Italian Ministry of Health (Ricerca Corrente); Ministero dell'Istruzione, dell'Università e della Ricerca-MIUR  project " Dipartimenti di Eccellenza 2018-2022 " to  Department of Neuroscience "Rita Levi Montalcini", University of Torino (IR) , and  AIRAlzh Onlus-ANCC-COOP (SB) ; Partly supported by  "Ministero della Salute", I. R. C. C. S. Research Program ,  Ricerca Corrente   2018-2020 , Linea n. 2 " Meccanismi genetici, predizione e terapie innovative delle malattie complesse " and by the "5 x 1000" voluntary contribution to the  Fondazione I.
VITA study: The support of the  Ludwig Boltzmann Society  and the  AFI Germany have  supported the VITA study. The former VITA study group should be acknowledged:  W. Danielczyk ,  G. Gatterer ,  K Jellinger ,  S Jugwirth ,  KH Tragl ,  S Zehetmayer. Vogel Study: This work was financed by a research grant of the '' Vogelstiftung Dr. Eckernkamp''. HELIAD  study: This study was supported by the grants:  IIRG-09-133014  from the  Alzheimer's Association ,  189 10276/8/9/2011  from the  ESPA-EU program Excellence Grant (ARISTEIA)  and the ∆Υ2β/οικ. 51657/14. 4. 2009 of the  Ministry for Health and Social Solidarity (Greece). Biobank Department of Psychiatry ,  UMG :  Prof. Jens Wiltfang  is supported by an  Ilídio Pinho professorship and iBiMED  ( UID/BIM/04501/2013 ), and FCT This work was supported by grants from the  Swiss National Research Foundation  ( SNF 320030_141179 ).
PAGES study:  Harald Hampel  is an employee of  Eisai Inc. During part of this work he was supported by the  AXA Research Fund , the  "Fondation partenariale Sorbonne Université" and the "Fondation pour la Recherche sur Alzheimer", Paris ,  France. Mannheim ,  Germany Biobank :  Department of geriatric Psychiatry, Central Institute for Mental Health, Mannheim, University of Heidelberg, Germany. Genotyping  for the  Swedish Twin Studies of Aging  was supported by  NIH/NIA  grant  R01 AG037985. Genotyping in TwinGene was supported by  NIH/NIDDK   U01 DK066134. WvdF is recipient of  Joint Programming for Neurodegenerative Diseases (JPND)  grants  PERADES  ( ANR-13-JPRF-0001 ) and EADB (733051061). Gothenburg Birth Cohort (GBC) Studies: We would like to thank  UCL Genomics  for performing the genotyping analyses.
This work was supported by  InnoMed (Innovative Medicines in Europe) , an integrated project funded by the  European Union  of the  Sixth Framework program  priority ( FP6-2004-LIFESCIHEALTH-5 ). Oviedo: This work was partly supported by Grant from  Fondo de Investigaciones Sanitarias-Fondos FEDER EuropeanUnion  to  Victoria Alvarez   PI15/00878. Pascual Sánchez-Juan is supported by  CIBERNED  and  Carlos III Institute of Health, Spain  ( PI08/0139 ,  PI12/02288 , and  PI16/01652 ), jointly funded by  Fondo Europeo de Desarrollo Regional (FEDER) ,  Unión Europea , " Una manera de hacer Europa ". Project MinE: The ProjectMinE study was supported by the  ALS Foundation Netherlands  and the  MND association (UK)  (Project  MinE , www. projectmine. com). The SPIN cohort: We are indebted to patients and their families for their participation in the " Sant Pau Initiative on Neurodegeneration cohort ", at the  Sant Pau Hospital (Barcelona).
114/17 ). Gra@ce. The  Genome Research @ Fundació ACE  project ( GR@ACE ) is supported by  Grifols SA, Fundación bancaria 'La Caixa', Fundació ACE , and  CIBERNED (Centro de   R01 AG042437 ;  University of Wisconsin ,  P50 AG033514 ;  Vanderbilt University ,  R01 AG019085 ; and  Washington University ,  P50 AG005681 ,  P01 AG03991 ,  P01 AG026276. HP was supported by  AG025711. ER was supported by  CCNA. The  Kathleen Price Bryan Brain Bank at Duke University Medical Center  is funded by  NINDS  grant #  NS39764 ,  NIMH MH60451  and by  Glaxo Smith Kline. Support was also from the  Alzheimer's Association (LAF ,  IIRG-08-89720 ;  MP-V, IIRG-05-14147 ), the  US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program , and  BrightFocus Foundation  ( MP-V, A2111048 ).
P. S. G. -H. is supported by  Wellcome Trust ,  Howard Hughes Medical Institute , and the  Canadian Institute of Health Research. Genotyping of the TGEN2 cohort was supported by  Kronos Science. The TGen series was also funded by  NIA  grant  AG041232  to AJM and MJH, The  Banner Alzheimer's Foundation ,  The Johnnie B. Byrd Sr. Alzheimer's Institute , the  Medical Research Council , and the state of  Arizona  and also includes samples from the following sites:  Newcastle Brain Tissue Resource  (funding via the  Medical Research Council , local NHS trusts and  Newcastle University) ,  MRC London Brain Bank for Neurodegenerative Diseases  (funding via the  Medical Research Council) , South West Dementia Brain Bank  (funding via numerous sources including the  Higher Education Funding Council for England (HEFCE) ,  Alzheimer's Research Trust (ART) ,  BRACE  as well as  North Bristol NHS Trust Research and Innovation department and DeNDRoN) ,  The Netherlands Brain Bank  (funding via numerous sources including Stichting  MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek ),  Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona.
: Bedtools: https://bedtools. readthedocs. io/en/latest/ BCFtools: http://samtools. github. io/bcftools/bcftools. html Samtools: http:/www. htslib. org/doc/samtools. html gene2go: ftp://ftp. ncbi. nlm. nih. gov/gene/DATA/ Gene Ontology: http://geneontology. org/docs/download-ontology/ project PTDC/DTP_PIC/5587/2014 at the University of Aveiro, Portugal. Lausanne study: Investigación Biomédica en Red Enfermedades Neurodegenerativas (Program 1, Alzheimer Disease to MB and AR)). A. R. and M. B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M. B. and A. R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474 and PI19/01240. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud.
In fact, the closed and open zebrafish P2X4 crystal structures (PDB: 4DW0 and 4DW1, respectively) have previously been used to build other P2X structural models, namely P2X2, highlighting the conserved shape of P2Xs  [3]. While ATP is released by neurons (as well as by glial cells in the CNS), direct evidence supporting the function of P2X in synaptic transmission is limited. ATP can be coreleased with GABA or glutamate at the central synapse  [4, 5] , suggesting a modulatory role in synaptic activity or plasticity in the brain. For example, studies on P2X4 knockout (P2X4 KO) mice suggested that calcium entry via P2X4 played a role in the induction of long-term potentiation (LTP) via modulation NMDARs  [6]. Additional studies on P2X4 KO mice support the notion that P2X4 modulates NMDARs, although results indicated that calcium influx from P2X4 alone was not sufficient to explain changes in synaptic plasticity  [7].
ATP solutions were prepared fresh daily using stocks of 10 mM, which were dissolved in perfusion solution and stored at -20 • C. In the presence of calcium, Glutamate and/or ATP were applied for 10 s (to reach a peak current response). In the absence of calcium, (i. e. , Calcium-free Ringer's solution or CfRS) Glutamate and/or ATP were applied for 25 s. A wait time of at least 5 min of perfusion buffer occurred between any agonist applications to ensure complete washout of agonist. The resulting currents were filtered at 5 kHz and recorded using an analog chart recorder (P2X4 studies) or digitized using a Digidata 1320 (P2X2 studies). The voltage-clamp was continuously monitored for errors (i. e. , failure to maintain -70 mV), in which case data were not used. All current values obtained were normalized to the most recent stable responses obtained immediately before agonist coapplications began, unless stated otherwise.
Acknowledgments: We would like to thank  Albert Lam , and  Audrey Martinez  for their technical assistance during this project, as well as  Jesse Chen ,  Tahmina Hasan ,  Ed Jeong ,  Michael Bloomfield ,  Alan Guan ,  Istiak Aziz , and  Nirali Patel  for their assistance in collecting data. We would also like to thank  John Woodward  for his kind gift of plasmids containing the GluN subunits.