dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical analyses The statistical analyses were calculated with GraphPad Prism version 5 (GraphPad software). For comparison between two groups the nonparametric one tailed Mann-Whitney's U test was used and for interpretation between more than two groups the Kruskal-Wallis test was used. The confidence intervals were set at 95%. For correlation the nonparametric two tailed Spearman test was performed. Significance level was always set at p-values less than 0. 05.
1, indicating an impact of transfected DNA on apoptosis induction (Figure  6D ). The redistribution of negatively charged PS to the outer leaflet of the cellular membrane represents another marker for the detection of early apoptosis  [80, 81]. Annexin V, a 36 kDa phospholipid binding protein recognizes PS on cell surfaces of early apoptotic cells  [80]. We investigated the redistribution of PS in A3A transfected HeLa cells with Annexin V by flow cytometry. Dead cells were excluded by additional staining with PI. Figure  6E  shows data in percentage of early apoptosis (Annexin positive and PI negative cells) and late apoptosis/ necrosis (Annexin V and PI double-positive cells). Compared to TOPO3. 1, all constructs scored positive for apoptosis including the cysteine mutants and APOBEC2 (Figure  6E ).
Ethics Statement The research complied with the legal requirements of the Central African Republic and adhered to the research protocol of DSPA. All sample collection from humans was approved by the Anthropology Department Research Ethics and Data Protection Committee; University of Durham, U. K. Only a verbal nonrecorded consent was obtained from all examined persons and the samples were anonymized. We also obtained a verbal nonrecorded permission from the owners of domestic animals to collect animal's faecal samples. The IRB approved this consent procedure. The collection of faecal samples from gorillas, other wildlife and livestock was noninvasive and did not cause any observable distress to the animals. We would like to thank the government of the Central African Republic and the World Wildlife Fund for granting permission to conduct our research in the Central African Republic; the Ministre de l'Education Nationale, de l'Alphabetisation, de l'Enseignement Superieur, et de la Recherche for providing research permits; and the Primate Habituation Programme for providing logistical support in the field.
Phylogenetic analyses The nucleotide sequences of each gene obtained in this study were edited using the ChromasPro 1. 5 software (Technelysium, Pty, Ltd. ) and were aligned with each other and with reference sequences from GenBank using ClustalX 2. 0. 6. Alignment adjustments were made manually to remove artificial gaps using BioEdit. Phylogenetic analyses were performed using the MEGA5 software  [54]. Neighbour joining (NJ) trees were constructed. All ambiguous positions were removed for each sequence pair. The reliability of branches in trees was assessed using the bootstrap analysis with 1000 pseudo-replicates, with values above 50% reported. Phylograms were drawn using MEGA5 and were manually adjusted using CorelDrawX5. ITS, SSU, and TPI sequences have been deposited in GenBank under the accession numbers JQ837793-JQ837800, JQ837801-JQ837802 and JQ837803-JQ837808, respectively.
Statistical analyses To analyse the effect of habituation on the occurrence of microsporidia in gorillas we fitted the generalized linear mixed model (GLMM) with binomial distributions. For the analyses we randomly chose data from 98 gorillas (2009-2010) with each individual represented by one sample to avoid bias from repeated sampling occurring in habituated animals and especially in unidentified gorillas under habituation and from Mayele group. In gorillas under habituation and of Mayele group we chose nest samples from a single day. Unhabituated gorillas were sampled only once. Animals were classified according to the ''group'' (Mayele, Makumba, Wonga, Mata and several unhabituated groups) and ''level of human-ape contact'' (habituated, under habituation, unhabituated). The random factor ''group'' was nested into the fixed factor ''level of human-ape contact''.
44, Mayele p = 0. 33, Mata p = 1. 0, Wonga p = 1. 0). Only one of the 48 human stool samples (2. 1%) was positive for Giardia intestinalis and none of the other parasites investigated was detected. Out of the total of 191 samples obtained from other wild and domestic animals 6 (3. 1%) were positive for the presence of specific DNA of screened parasites, including 4 cases of Encephalitozoon spp. (2. 1%), one case of Giardia intestinalis (0. 5%) and one case of Cryptosporidium sp. (0. 5%) (Table  2 ). The alignment of the obtained microsporidial ITS sequences with reference sequences showed 100% homology with GenBanklisted species and their genotypes as follows: 13 E. cuniculi genotype I (AF338410) and 4 E. cuniculi genotype II (GQ422153) (Tables  1  and 2 ). A phylogenetic analysis of all ITS sequences performed on a multiple alignment that included representatives of E.
bieneusi genotypes accessible in GenBank revealed in three cases the presence of previously described pathogenic human E. bieneusi genotype D (AF101200) in gorillas. Moreover, five sequences of our isolates belonged to three new genotypes. While two new genotypes named gorilla 1 and gorilla 2 matched genotype D closely with 99. 1 and 99. 5% similarity, a third new genotype named gorilla 3 is probably unique to gorillas (two cases). When ITS nucleotide sequences of gorilla 3 genotype were compared with other sequences in the GenBank database, the closest matches were 93. 6% similarity to E. bieneusi genotype KB-5 (JF681179) isolated from a captive olive baboon in Kenya and 93. 2% similarity to horse 2 genotype (GQ406054) isolated from a domestic horse in Columbia. The global topology of the tree is shown in Fig.
1. As shown in Fig. 2 , on the basis of the phylogenetic tree based on TPI sequences we were able to resolve G. intestinalis clades of assemblage A originating from humans and gorillas and assemblage E from a sheep. All of the identified assemblage A sequences belonged to A II subgroup forming a well-supported sister group to an isolate from waste water. Three of the five G. intestinalis sequences were identical to GF-2 isolate (AB509383) previously reported from a domestic ferret and another two sequences matched GF-2 isolate most closely, with 99. 4-99. 6% similarity. Phylogenetic analyses based on SSU sequences showed that Cryptosporidium originating from a habituated gorilla was 100% similar to the C. bovis reference sequence listed in GenBank (AY741305). Another Cryptosporidium sequence obtained in this study from a forest buffalo was identical to C.
Acknowledgments We would like to thank the government of the Central African Republic and the  World Wildlife Fund  for granting permission to conduct our research in the Central African Republic; the  Ministre de l'Education Nationale, de l'Alphabetisation, de l'Enseignement Superieur, et de la Recherche  for providing research permits; and the  Primate Habituation Programme  for providing logistical support in the field. The authors wish to thank  Dr. John McEvoy  for his helpful comments and language correction of the manuscript.
Genetic analysis of the BIN1 locus The EADI, GERAD and Belgium-Flanders case-control studies and the imputation methodology are fully described in the Supplementary Method. We imputed single-nucleotide polymorphisms (SNPs) by using MaCH (http://www. sph. umich. edu/csg/abecasis/mach/index. html) and minimac software (http://genome. sph. umich. edu/wiki/minimac). The reference haplotype data is provided by the MaCH website, which was built for the combined Caucasian populations as part of the 1000 Genomes project. In our data set, all individuals were genotyped on the same platform (the Illumina Human660W-Quad Beadchip, San Diego, CA, USA) and we used 492 941 observed SNP genotypes that passed quality filters as follows: genotyping call rateX98%, Hardy-Weinberg equilibrium test P-value X1 Â 10 À 6 and MAF X1%.
We first inferred haplotype combinations of each individual using the 'phase;' option in the MaCH program and then imputed them with minimac. Doses for 7 704 555 SNPs with a MAF 40. 01 were available from the French GWA data set using the 1000 Genomes dataset. 7 We selected 493 SNPs within the BIN1 locus of interest (chr2:127803530-127903530) and evaluated their associations with AD risk in an additive logistic regression model adjusted for age and gender. A graphic representation (Figure  2a ) was then generated with Locuszoom software (http://csg. sph. umich. edu/locuszoom/). Of note, we also used Impute2 package for imputation (mathgen. stats. ox. ac. uk/impute/ impute_v2. html) and found very similar results between minor allele frequency estimation between both methods (R 2 ¼ 0. 99, data not shown) for SNPs in the BIN1 locus.
Genetic analysis of the LD block of interest in the BIN1 locus Sequencing of the LD block of interest was performed using genomic DNA extracted from 47 AD cases and 47 controls. Oligonucleotides are available upon request. The Polymorphisms not initially imputed (four SNPs and four Indels, MAF 40. 05) were genotyped in a sample of 350 healthy French controls used as a panel reference for imputation in the EAD1 GWAS. After obtaining doses for the eight genetic variations from EADI1 GWA data set, we evaluated their associations with AD risk in an additive logistic regression model adjusted for age and gender. rs59335482 was also genotyped by direct sequencing in EADI1 (data presented across the manuscript), the Flanders-Belgian population and the brain samples. In order to avoid any genotyping bias, cases and controls were randomly mixed while genotyping and laboratory personnel were blinded to case/control status.
The UAS-Tau (human 2N4R Tau), UAS-Ab42, Amph 5E3 and the Eq-GAL4 lines were a kind gift from GR Jackson, D Crowther, GL Boulianne and H Sun, respectively. Flies were reared under controlled temperature conditions of 25 1C and were fed standard fly medium. Pictures of external eye morphology were taken at different focus points, with a DP70 camera mounted on an Olympus BX61 (Hamburg, Germany), in a way that an array of images with overlapping depth of fields is obtained. These stacks were focused using ImageJ software with the 'stack Focuser' plugin (National institutions of Health, Bethesda, Maryland). To measure eye size female flies were photographed with an Olympus SZX12 stereomicroscope fitted with a XC30 camera. Measurements were performed using AnalySIS FIVE software (Olympus soft Imaging solutions, GmbH, Mu ¨nster, Germany).
A Kruskal-Wallis test was performed followed by a Dunns post-hoc test on Prism 5. 0b for MacOS (Graphpad software, La Jolla, CA, USA). To count notal bristles, flies were mounted on glass slides and photos were taken with the SZX12 stereomicroscope/XC30 camera. Bristles of a well-defined area were counted in a non-automated manner. A Kruskal-Wallis test was performed followed by a Dunns post-hoc test on Prism 5. 0b for MacOS (Graphpad software). Drosophila adult brains were dissected and processed for immunohistochemistry with a mouse monoclonal antifasciclin 2 antibody to visualize mushroom body a-, band g-lobes and the ellipsoid body, as described previously. 8 The immunostaining was documented using an Olympus BX61 epifluorescence microscope equipped with a DP70 digital camera controlled with analySIS FIVE software.
Quantitative real-time PCRs were performed on an ABI7000 instrument with qPCR Mastermix Plus for SYBR Green I (Eurogentec, Seraing, Belgium) with primers designed by PrimerExpress software (Applied Biosystems, Foster City, CA, USA). Expression levels of transcripts from the various samples were normalized to the housekeeping genes gadph and Rps13. Primers used: CAGCCCCGACATGAAGGT-forward and CGATCTCGAAGTTG TCATTGATG-reversed for Gadph, GGGTCTGAAGCCCGACATT-forward and GGCGACGGCCTTCTTGAT-reversed for RpS13, TCAGAATCTGCAGG CCAATG-forward and CGCGTCCTTTGGTTAGTTTGAC-reverse for dAmph. Cell culture and western blot analyses HEK293 and neuroblastoma SKNSH-SY5Y cell lines were maintained in DMEM supplemented with 10% fetal bovine serum, penicillin and streptomycin at 37 1C in a humidified atmosphere with 5% CO 2.
Endophenotype analyses We extracted BIN1 mRNA levels measured in lymphoblastoid cell lines from the public MTAB-198 database (http://www. ebi. ac. uk/arrayexpress/ experiments/E-MTAB-198). These lymphoblastoid cell lines were derived from 109 caucasian HapMap 3 individuals and mRNA levels were measured using a whole-genome expression array (Illumina Sentrix WG-6, Version 2). 5 rs59335482 imputation was successfully performed as described in the imputation section for 98 individuals (info measure ¼ 0. 94) and association study of rs59335482 with BIN1 lymphoblastoid cell lines mRNA levels were performed using a general linear model. Comparison of BIN1 mRNA amounts in the brain of AD cases and controls, and the association study of rs59335482 with BIN1 cerebral mRNA levels were performed using a general linear model adjusted for RNA degradation level (28 s/18 s ratio).
BIN1 expression is increased in AD brains when compared with controls We first analysed BIN1 expression in the human brain and observed increased BIN1 transcript levels in brains of AD cases when compared with controls (Figure  1 ). From this observation, we hypothesized that altered BIN1 expression might constitute the genetic mechanism by which BIN1 increases AD risk. This hypothesis is in line with the fact that the Index signal rs744373 observed in the initial publication of Seshadri et al. 3   EADI1 2 cohort using the 1000 Genomes data set (http://www. 1000genomes. org). We analysed 493 SNPs and after Bonferroni correction (Po10 À 4 ), we observed two SNPs, rs4663105 and rs6733839, associated with AD risk ((Figure  2a ). We therefore investigated these two SNPs for their potential to modify transcription in vitro using luciferase reporter assays.
However, none of them showed evidence for allele-specific differences in transcriptional activity in both SKNSH-SY5Y and HEK293 cells (Figure  2b ). To further fine-map the BIN1 locus, we performed linkage disequilibrium (LD) block analysis by using Haploview software (MIT, Cambridge, MA, USA) and by applying Gabriel's criteria to define these LD blocks. This indicated that rs4663105 and rs6733839 were encompassed in a small 6. 7 kb LD block (from rs11680911 to rs6431223) (Figure  2c ; Supplementary Table  S1 ). This LD block also includes rs744373, which is the index signal observed in the initial publication of Seshadri et al. 3  These data suggested that this LD block might harbour (a) functional risk variant(s). We therefore fully sequenced this 6. 7 kb region in 47 AD cases and 47 controls and observed eight new polymorphisms including four SNPs and four insertion/deletion variants (Indel) (Figure  2d  and Supplementary Table  S2 ).
ACKNOWLEDGEMENTS The work was made possible by the generous participation of the control subjects, the patients, and their families. This work was supported by the  National Foundation  for Alzheimer's disease and related disorders, the  Institut Pasteur de Lille , the  Centre National de Genotypage, Inserm ,  FRC  (fondation pour la recherche sur le cerveau) and  Rotary. 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). FH was funded by the  Alzheimer's Association  (Grant  IIRG-06-25487 ) and the 'Ligue contre la Maladie d'Alzheimer (LECMA; Grant  09705 ). MG and LVB are PhD fellows of the  Institute for the Promotion of Innovation by Science and Technology (IWT)  in Flanders.
CB received funding from the fondation pour la recherchemedicale. AM received funding from the  INSERM  and the  Nord-Pas de Calais Regional Council. JC was funded by the  MEDIALZ  Project (Grant  11001003 ) financed by  ERDF  ( European Regional Development Fund)  and  Conseil Regional Nord Pas de Calais. FL received funding from the  university of Lille II  and the  Nord-Pas de Calais Regional Council. BD received support from the  Foundation for Alzheimer Research (SAO/FRMA) in Belgium , the  Foundation for Research Flanders in Belgium (FWO). Research on Drosophila dementia models at INSERM U744 is supported by grants from the  Region Nord/Pas-de-Calais and European Regional Development Funds ERDF  ( N0 11005007 ), France, to  B D  and from the  Fondation Plan Alzheimer, France , to J-C L and BD.
The Fondation pour la  Recherche Me  ´dicale funded the preparation and initiation of the study. The 3C Study was also funded by the  Caisse Nationale Maladie des Travailleurs Salaries ,  Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Franc¸aise de SecuriteSanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils ,  Fondation de France  and the joint  French Ministry of Research/ INSERM 'Cohortes et collections de donnees biologiques' programme. Lille Ge  ´nopole received an unconditional grant from  Eisai. This study incorporated summary results from the GERAD1 genome-wide association study. GERAD1 Acknowledgements: Cardiff University was supported by the  Wellcome Trust, Medical Research Council (MRC) ,  Alzheimer's Research Trust (ART)  and the  Welsh Assembly Government.
ART supported sample collections at the  Kings College London , the  South West Dementia Bank ,  Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the  Alzheimer's Society ,  Ulster Garden Villages ,  N. 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.
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 KORA F4 studies were financed by  Helmholtz Zentrum Mu  ¨nchen; 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  ( Dr jur G Schmidt , Chairman) and  BMBF. Coriell Cell Repositories is supported by  NINDS  and the  Intramural Research Program  of the  National Institute on Aging.
M E T H O D S Criteria for considering studies for this review Types of studies 1. Patient or cluster randomised controlled trials (RCTs) 2. Patient or cluster controlled clinical trials (CCTs) 3. Controlled before and after studies (CBAs) 4. Interrupted time series analyses (ITSs) We defined 'randomised' as studies that were described by the authors as 'randomised' anywhere in the manuscript except in cases where the term was misused (e. g. referring to a random sample). We included CBAs that had at least two intervention sites and two control sites. We included ITSs with a defined point in time when the intervention started and at least three data points before and three after the intervention. The economic component of the review was restricted to economic analyses conducted alongside the studies meeting eligibility criteria for the effectiveness component of the review.
Results of the search We identified 7594 records through searches of databases, excluding duplicates. After screening the titles and abstracts, we excluded 6986 (see reasons in Figure  1 ). We reviewed the full text of the remaining 608 records for a more detailed evaluation. Of these, 53 reports (of 23 studies) met our inclusion criteria and were included in the review. The search of reviews and textbooks identified no new studies but found 10 additional references reporting on the already included studies. Searches of conference proceedings added two records to an already included study (one conference abstract and one paper). Personal contact with investigators added no new studies (yet identified one additional reference on an already included study). These additional 13 records were included in the review.
Sample sizes The studies' sample sizes varied between 42 and 747 participants, except for two non-randomised studies (Greer 1986 with 1754 cancer patients and their caregivers and Ward 1987 with 31,890 cancer deaths). Excluding the latter study, which covered a period of six years, recruitment length ranged from 1 to 50 months. In total, we analysed data from studies involving 41,603 participants (37,561 patients and 4042 caregivers). Eleven studies were guided by power calculations (details in 'Characteristics of included studies'): three powered the study on quality of life (one also performed calculations on care costs and one on symptom intensity and depression), two on place of death, two on pain (one also performed calculations on nausea), one on overall palliative care outcomes, one on caregiver general health and one on care costs.
Economic data Sixteen studies measured the resource use associated with receiving the intervention and the control. This included ED visits; stays in intensive care; admission, days and proportion of time spent in nursing homes and hospitals; length of hospital admissions including the last one before death; overall institutional days; outpatient clinic visits; a range of community services; informal care; medication and other resources; caregiver post-bereavement healthcare use and absenteeism from work. Eight of these 16 studies calculated the costs associated with the resources used; six reported on total costs. Higginson 2009 provided cost-effectiveness planes for the primary outcome (palliative outcomes) and a secondary outcome (caregiver burden). Tramarin 1992 (the only full economic evaluation) calculated cost-utility ratios.
However, two studies provided limited currency and price data (Zimmer 1985 and Greer 1986) and details of currency or price adjustments for inflation or currency conversion were only given in one study  (Tramarin 1992). None of the six studies discussed productivity changes (time off work because of illness, therapy or caregiving). In terms of analysis and interpretation of results, all studies were clear about the time horizon of costs and benefits, they all answered to the study question given, and the conclusions followed from the data reported. Downpoints were the lack of detail about statistical tests and confidence intervals, about the ranges over which the variables varied, and about disaggregated outcome data. The majority of participants in all seven trials in the meta-analysis had cancer but three also included non-cancer conditions (Brumley 2007; Grande 1999; Zimmer 1985).