dataesr/scientific-paragraphs-categorization huggingface dataset:
Conclusions Taken together, our findings confirm the strong genetic association of the complement genes CR1 and CLU with LOAD and that there is no statistically significant association signal for other complement genes apparent in the dataset used for the analysis. CR1 and clusterin are important regulators of the complement pathway, suggesting that its dysregulation is important in LOAD. The recent GWAS association of C1S with LOAD demonstrates the potential for missing associations in this complex gene-set and raises the possibility that other loci may be missed by current large-scale genotyping and shortread sequencing technologies. Application of long read sequencing technologies could significantly alter the current landscape of complement system genetics in relation to LOAD risk.
Acknowledgments: Data used in the preparation of this article were obtained from the  Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium. Cardiff University  was supported by the  Wellcome Trust, Medical Research Council (MRC) ,  Alzheimer's Research U. K. (ARUK)  and the  Welsh Assembly Government. Cambridge University and Kings College London acknowledge support from the  MRC. ARUK supported sample collections at the  South West Dementia Bank  and the  Universities of Nottingham, Manchester , and Belfast. The Belfast group acknowledges support from the  Alzheimer's Society ,  Ulster Garden Villages ,  Northern Ireland R&D Office , and the  Royal College of Physicians/Dunhill Medical Trust. The  MRC and Mercer's Institute for Research on Ageing  supported the  Trinity College group.
The South West Dementia Brain Bank acknowledges support from  Bristol Research into Alzheimer's and Care of the Elderly. The  Charles Wolfson Charitable Trust  supported the OPTIMA group. Washington University was funded by  NIH  grants,  Barnes Jewish Foundation  and the  Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the  MRC Prion Unit/UCL Department of Neurodegenerative Disease collection  was supported by the  UCLH/UCL Biomedical Centre  and  NIHR Queen Square Dementia Biomedical Research Unit. LASER-AD was funded by  Lundbeck SA. The Bonn group was supported by the  German Federal Ministry of Education and Research (BMBF) ,  Competence Network Dementia and Competence Network Degenerative Dementia , and by the  Alfried Krupp von Bohlen und Halbach-Stiftung.
The  GERAD1  Consortium also used samples ascertained by the  NIMH AD Genetics Initiative. The GERAD data used in this paper included 5770 additional population controls; including the 1958  British Birth Cohort  ( 1958BC ), the  KORA F4 Study, Heinz Nixdorf Recall Study  and controls from the  National Blood Service  genotyped as part of the  Wellcome Trust Case Control Consortium. The KORA F4 studies were financed by  Helmholtz Zentrum München ;  German Research Center for Environmental Health ; BMBF;  German National Genome Research Network  and the  Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the  Heinz Nixdorf Foundation  (jur. G. Schmidt, Chairman) and  BMBF. Coriell Cell Repositories is supported by  NINDS  and the  Intramural Research Program  of the  National Institute on Aging.
IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips were funded by the  French National Foundation on Alzheimer 's disease and related disorders. EADI was supported by the  LABEX (laboratory of excellence program  investment for the future) DISTALZ grant,  Inserm ,  Institut Pasteur de Lille, Université de Lille 2 , and the  Lille University Hospital. GERAD/PERADES was supported by the  Medical Research Council  (grant no. 503480 ),  Alzheimer's Research U. K. (grant no. 503176 ), the  Wellcome Trust  (grant no. 082604/2/07/Z ) and the  German Federal Ministry of Education and Research (BMBF) :  Competence Network Dementia (CND)  grant no. 01GI0102 ,  01GI0711 ,  01GI0420.
Significance A key link to understand human history in Island Southeast Asia is the Philippine archipelago and its poorly investigated genetic diversity. We analyzed the most comprehensive set of population-genomic data for the Philippines: 1,028 individuals covering 115 indigenous communities. We demonstrate that the Philippines were populated by at least five waves of human migration. The Cordillerans migrated into the Philippines prior to the arrival of rice agriculture, where some remain as the least admixed East Asians carrying an ancestry shared by all Austronesian-speaking populations, thereby challenging an exclusive out-of-Taiwan model of joint farming-languagepeople dispersal. Altogether, our findings portray the Philippines as a crucial gateway, with a multilayered history, that ultimately changed the genetic landscape of the Asia-Pacific region.
Materials and Methods Sampling and Ethical Considerations (SI Appendix, Sections 1. 1 and 1. 2). This research project, with the aim of establishing baseline scientific data for the genetic diversity, interrelatedness, and migration history of Philippine indigenous cultural communities, is recognized by, and implemented in partnership with, the National Commission for Culture and the Arts (NCCA) of the Philippines, in accordance with the provisions of Philippine Republic Act 7356, or the Law Creating the NCCA. Saliva samples were collected with the use of the Oragene Saliva Collection Kit (DNA Genotek Inc. , Ottawa, ON, Canada). Consent was secured from each individual and, whenever necessary, from each respective Indigenous Cultural Community Council. The consent process, sampling, and/or subsequent validation were performed in coordination with the NCCA and, in some regional areas, with local partners or agencies, including nongovernmental and cultural organizations, local educational institutions, Indigenous Cultural Community Councils, local government units, and/or regional offices of the National Commission on Indigenous Peoples (NCIP) (SI Appendix, section 10).
Mantel tests were performed to determine statistical significance on correlations between genetic and linguistic and between genetic and geographic distances. ADMIXTURE v1. 3  (44)  and CLUMPP (45) were used to analyze population structure, which was subsequently visualized using Pong v1. 4. Outgroup f3 statistics and formal tests of admixture were performed using qp3Pop and qpDstat of the AdmixTools v5. 0 package  (46). We used qpF4Ratio and qpAdmin of the AdmixTools v5. 0 package for estimating admixture proportions in populations, and qpGraph for fitting populations in an admixture graph with baseline framework based on earlier publications  (47). For estimating dates of admixture, we utilized a weighted linkage disequilibrium (LD) statistic-based method, MALDER  (48) , which also allows detection of multiple admixture events.
Blunt-end Illumina libraries were generated for both Liangdao-1 and Liangdao-2 DNA samples, and, additionally, uracil-DNA-glycosylase (UDG)-treated libraries were generated for a higher quality Liangdao-2 sample. The libraries were shotgun sequenced using Illumina HiSeqX with a 150-base pair (bp) paired-end length and v2. 5 chemistry at the SNP&SEQ Technology Platforms at Uppsala University. Processing of aDNA Data (SI Appendix, Section 1. 8). For processing of aDNA data, paired-end reads were merged, and their adapters were trimmed and subsequently mapped to the human reference genome using BWA  (53). PCR duplicates with identical start and end coordinates were collapsed into consensus sequences  (54). Both Liangdao-1 and Liangdao-2 possessed the characteristic deamination pattern toward the read fragment-ends  (55).
The level of contamination was estimated using the Green  (56) , Contamix  (56) , and Schumtzi (57) methods for mitochondrial DNA and VerifyBamID for autosomal DNA. Data Availability. Anonymized SNP genotype data have been deposited in the European Genome-Phenome Archive (EGAS00001005083), and will be made available upon request from the Data Access Committee, provided that the request is intended for academic purposes only and is in accordance with the consent provided by the study participants. Ancient DNA sequence data have been deposited as publically available in the European Nucleotide Archive (PRJEB43078).
ACKNOWLEDGMENTS. We thank all of the volunteers and indigenous cultural communities who participated in this research. The project is recognized by, and implemented in partnership with, the NCCA of the Philippines, in accordance with the provisions of Philippine Republic Act 7356, or the Law Creating the  NCCA. The project was reviewed and approved by the  Regional Ethical Review Board in Uppsala, Sweden  ( Dnr 2016/103 ). We thank  Felipe Mendoza de Leon Jr. , NCCA chairperson 2010 to 2016, for his support. We also thank the  NCIP , local government units, and regional cultural organizations for facilitating fieldwork. We thank  Suei-Sheng Yang , former Lienchiang County Governor, and the  Lienchiang County Cultural Affairs Department , and  Marie Lin  ( Mackay Memorial Hospital ) for the provision of Liangdao archaeological samples.
RAD-Sequencing Twelve RAD libraries were prepared according to the protocol described in The STACKS pipeline  (Catchen et al. , 2011 (Catchen et al. , , 2013) )  was used for the loci de novo assembly and genotyping. Quality filtering and demultiplexing were performed with the process_radtags module with default parameters which enables to remove any read with uncalled base and to perform a phred-33 quality filtering of raw reads. Exact-matching RAD loci (putative orthologous tags) were individually assembled using ustacks with a minimum depth of coverage of five reads per allele (m = 5) and a maximum of five nucleotide mismatches between allele (M = 5). These parameters were optimized during preliminary runs. Cstacks was used to build a catalog of consensus loci from all individuals, with five mismatches allowed between individuals at the same locus (n = 5).
Matches of individual RAD loci to the catalog of loci were searched using sstacks. Finally, the population module was used to obtain the loci that were successfully genotyped in at least 75 % of individuals from all populations. We observed an increase in the number of SNPs from position 86 bp to 91 bp and we removed these positions from the analysis which were due to sequencing problems. In order to filter for poor-quality SNPs and artifacts due paralogous sequences, we used VCFtools  (Danecek et al. , 2011)  to remove SNPs that were not at the Hardy-Weinberg equilibrium within at least one of the 12 populations with a p-value threshold of 0. 01. SNPs with a minor allele frequencies below 0. 01 were removed using VCFTools. Individuals with more than 30 % of missing genotypes were discarded.
Diversity and neutral genetic structure Global F IS over alleles and expected heterozygosity were estimated using GENEPOP and ARLEQUIN v. 3. 5  (Rousset, 2008; Excoffier and Lischer, 2010). The C. rubrum genetic structure was first analyzed by principal component analysis (PCA) using the package adegenet in R  (Jombart, 2008; R Core Team, 2016). This analysis was performed on the total dataset (12 populations) and inside each of the three studied geographical regions (four populations in each). The dataset was centered and missing data were replaced by the mean allele frequency for each locus (http://adegenet. r-forge. r-project. org/files/tutorial-basics. pdf). In a second step, we performed a Bayesian population clustering implemented in the program STRUCTURE v. 2. 3. 4  (Pritchard et al.
Finally, we conducted an analysis of molecular variance (AMOVA) in ARLEQUIN v. 3. 5  (Excoffier and Lischer, 2010)  with 10 000 permutations. The hierarchy for this analysis was chosen to follow the three geographical regions of our samples (Marseille, Corsica and Banyuls). This choice was justified by the PCA on the overall dataset. Finally, we performed the PCA and F ST calculation using a dataset comprising only putatively neutral SNPs (without the SNPs detected as outliers by F ST outlier methods, see below).
Detection of local adaptation In order to search for loci potentially involved in local adaptation, we first used BayeScEnv  (Villemereuil and Gaggiotti, 2015). This method identifies F ST outlier loci that show a relationship between genetic differentiation and environmental differentiation. Runs were performed using default parameters, except the number of pilot runs that was set at 40. The maximal temperature recorded in each site was used as environmental variable (Table  2 ). We tested other descriptors of the thermal regime and we got similar results (data not shown). The convergence of runs was checked with the Gelman and Rubin's diagnostic using the R package coda  (Plummer et al. , 2006). Second, we searched for F ST outliers among red coral populations using ARLEQUIN v. 3. 5  (Hofer et al.
Significant differences were identified by using a false discovery rate of 0. 05  (Benjamini and Hochberg, 1995). Finally, we used the R package pcadapt to search for outliers loci by taking into account population structure and individual admixture  (Luu et al. , 2017). This method is recommended in cases of hierarchical genetic structure for a better control of the false positive rate. By identifying outliers loci linked with a particular principal component, pcadapt enabled us to focus on candidates linked with our biological question. From the pcadapt analyses, we selected outliers candidates linked with the relevant principal components with a q-value cutoff of 0. 01.
Functional annotation and enrichment tests The RAD tags were aligned on the red coral transcriptome  (Pratlong et al. , 2015)  using the Burrows-Wheeler Alignment Tool (BWA;  Li and Durbin, 2009). Blast2GO was used for the annotation of resulting contigs and functional enrichment analysis  (Conesa et al. , 2005). First, a blastp was first performed on the NCBI nr database with an e-value threshold of 10 -10 (  Altschul et al. , 1990). Then, Blast2GO retrieved Gene Ontology (GO) terms associated with the obtained BLAST hits. Finally, in order to identify function potentially over-represented in outliers, we performed an enrichment analysis using a Fisher's exact test corrected using a false discovery rate of 0. 05  (Benjamini and Hochberg, 1995).
RAD-Sequencing and genotyping An average of 191 ± 21 millions of reads by library was obtained after sequencing. After the demultiplexing and cleaning processes of the STACKS's process_radtags module, an average of 180 ± 22 millions of reads by library was obtained. From these reads, we were able to assemble 138 810 unique consensus RAD-tags present in at least 75 % of our 360 individuals. After all quality filter steps (Table  3 ), 27 461 SNPs were available. The mean proportion of missing data per locus before filtering for MAF 0. 01 was 4. 22 % (standard error : 2. 78%). Finally, we removed six individuals presenting more than 30 % of missing data (one individual from the MEJ40 population, two from the BANN40 population, two from the GAL20 population and one from the GAL40 population). Our final dataset used for further analysis consisted in 359 individuals genotyped on 27 461 SNPs.
In Corsica and Banyuls, no PCA axis showed clear association with depth. Individuals from the two depths of the Galeria (GAL) site of Corsica were separated along the second axis (4. 02 % of the total genetic variance) but this was not the case for individuals from the two depths of the Porto site (POR). Individuals from Banyuls showed much less structure than individuals from Marseille and Corsica (Fig. 1D ). The first axis (2. 99 % of the total genetic variance) separated individuals from the two sites (north and south). The second axis (2. 46 % of the total genetic variance) separated individuals according to their sex  (Pratlong et al. , 2017). The PCA on the overall dataset and inside each geographical region gave similar results when only putatively neutral SNPs were considered (Fig.
S2 ). The delta(K) criterion  (Evanno et al. , 2005)  indicated K = 2 as the most informative number of clusters for the STRUCTURE analysis. We present here the results for K =2 to K =4 which captured the main information (Fig. 2 ). In all cases, all clusters corresponded to the main geographical boundaries and the two depths of each site always clustered together. For K = 2, a clear separation between the Marseille regions and the Corsica / Banyuls regions was observed, confirming the separation of populations along the first PCA axis (Fig. 1 ). The clustering at K = 3 separated the three geographical regions in 7/10 replicates, and the remaining replicates grouped either one or the other Corsican sites with Banyuls populations (Fig. S3 ). Finally, K = 4 separated the two Corsican sites. The overall multilocus F ST of the total dataset was 0.
13. Pairwise F ST values ranged from 0. 01 (BANS20 vs BANS40, BANS20 vs BANN40 and BANN40 vs BANS40) to 0. 24 (ELV12 vs GAL20 and FIG8 vs GAL20; Table  5 ). The exact test of genetic differentiation was highly significant for all pairwise comparisons (p < 0. 001), even for the Banyuls and Galeria populations separated by 10 m depth (F ST = 0. 022 for BANN20 vs BANN40, F ST = 0. 012 for BANS20 vs BANS40 and F ST = 0. 10 for GAL20 vs GAL40). Considering the F ST between depths, high F ST values can be observed for different loci and different samples comparisons (Fig. S4 ). The average F ST between the two depths of the same site was 0. 04 in Marseille, 0. 08 in Corsica and 0. 02 in Banyuls (0. 04 for the total dataset). Considering only putatively neutral loci (see below for outliers loci), the overall F ST of the total dataset was 0.
Outliers SNPs We identified 82 outliers with BayeScEnv. However, we noticed that all these outliers seemed to be driven by the divergence between particular populations, with one allele being always fixed in one or several Considering only these outliers, the overall F ST of the total dataset was 0. 25 and pairwise F ST values ranged from 0. 02 (BANS20 vs BANS40) to 0. 42 (GAL20 vs POR40) (Table  S2 ). and 2 where also respectively detected with the ARLEQUIN analysis. The numbers of outlier loci were correlated with the variance and the average of F ST values inside each geographical regions (correlation coefficient of 0. 97). The second axis of the PCA using the Marseille individuals showed apparent association with depth and appeared to be influenced by the variation of the candidates for local adaptation to depth detected by ARLEQUIN: 51 % of these loci were in the top 1 % of the contributions to this second axis, and 86 % were in the top 5 %.
Genetic diversity and structure Our results confirm at a genomic scale the high genetic structure of the red coral, which was observed with a small number of microsatellite loci  (Costantini et al. , 2007; Ledoux et al. , 2010b). Here the differentiation was significant for all comparisons, even with low average F ST in some cases (0. 01 or 0. 02 between depths in Banyuls). Such low but significant F ST can be explained by the high number of loci used here, and by the high variance in F ST values. Indeed for all comparisons some important F ST were observed in the dataset (see below). This significant differentiation at all distances could be the consequence of reduced mean larval dispersal distance, despite a quite long pelagic larval duration estimated in aquarium (from 16 to 42 days;  Martínez-Quintana et al.
The Advisory Board members, who included Prof. Orla Hardiman, Trinity College, University of Dublin, Prof. Paola Minghetti, University of Milan, Italy, Dr Graziella Filippini, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy and Dr Ettore Beghi, IRCCS "Mario Negri" Pharmacological Research Institute, Milan, Italy, approved the protocol. 34 he study protocol was approved by the Ethics Committee of IRCSS Fondazione Istituto Neurologico "Carlo Besta" of Milan on 28 October 2015 (Eudract Number 2014-005367-32) and then by the Ethics Committees of all the participating centres. The authorization of the Agenzia Italiana del Farmaco (AIFA) was obtained on 1 March 2016 (protocol number AIFA/RSC/P/20735). Patient enrolment began on December 2016. The protocol was designed adhering to the SPIRIT recommendations and Declaration of Helsinki.
Trial procedures After obtaining informed consent, participants underwent a screening visit to provide demographic data and undergo ECG and haematological exams, assessment according to the revised Hamilton depression rating scale  36  and blood pressure recording. After verification of eligibility, a randomization code was generated using an automated web-response system. Monthly visits were planned to record end points and adverse events. During the titration period, participants were asked to measure their blood pressure at least twice a week and were contacted weekly to record values, adverse events and symptoms of overdose (e. g. dizziness, irritability, nervousness, pinpoint pupils, slow heartbeat, unusual tiredness or weakness). Participants who withdrew from treatment for any reason (except consent withdrawal) were followedup with monthly visits to record the ALSFRS-R score until the end of the study.
85. For this purpose, and assuming a loss to follow-up of 5%, 208 patients were calculated as the target size for randomization. The primary analysis of efficacy was performed in the intention-to-treat population with available data at 6 months (175 of 200 enrolled in the trial and 178 of 200 in the historical cohort). Per protocol analysis was carried out after excluding non-compliers (e. g. patients who had taken 580% of the therapy). Statistics were tabulated by treatment arm. Measures of central tendency for continuous metrics were presented as mean ± standard deviation (SD) and median with interquartile range (IQR). All primary and secondary analyses were based on the comparison of the guanabenz 64 mg and 32 mg arms alone and combined versus the historical cohort alone and combined with the placebo.
The disproportionate dropout rate in the top dosing arms relative to the placebo may have confounded the ability to identify an even stronger signal both in the bulbar subgroup and the full study population inclusive of spinal onset patients. The ability of guanabenz to induce hypotension in the non-hypertensive patient clearly limits its practical application in further assessment in ALS. We note, however, that most of the confounding issues associated with testing the hypothesis of unfolded protein response regulation on the outcome of ALS progression can be avoided with the use of agents that similarly act to prolong eIF2a phosphorylation. Sephin1, a synthetic molecule lacking alpha-2-adrenergic receptor activity, which selectively binds to and inhibits the ER stress-induced PPP1R15A phosphatase complex, has already completed a phase 1 clinical trial under the name of IFB-088 (NCT03610334) and has demonstrated a strong effect in preventing in vitro motor neuron degeneration and in vivo ALS progression.
5 and a corresponding cut-off of P = 0. 0375. P-values for specific tests are provided directly in tables and figure or their captions. All statistical analyses were performed using STATA statistical software, version 16 (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC). Two additional statisticians (J. M. N. and E. A. ) independently reviewed the anonymized dataset and validated all statistical results. Neither of the independent statisticians participated in the trial design or randomization process.
Funding The study was funded by a competitive grant to G. L. from the Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA) (grant no. FGCR 01/2013; Eudract no. 2014-005367-32) and partly by intramural funds from the Ricerca Corrente of the Ministry of Health to the Fondazione IRCCS Istituto Neurologico "Carlo Besta" of Milan, Italy.