dataesr/scientific-paragraphs-categorization huggingface dataset:
CRITICAL: While it is acceptable to perform micro-adjustments for thresholding, it is paramount to be consistent with the filtering/removal of debris during post-processing in Imaris. Removing more/less debris can confound your data analysis. Thus, we recommend using the volume filter and consistently filtering out debris smaller than 100-200 mm 3. 68. The final step before collecting data on astrocyte surface parameters is to isolate astrocytes so that the software recognizes them as individual entities. To do so, click on each astrocyte individually. Selected astrocytes will appear in yellow (see Figure  6A ). As astrocytes contact each other quite frequently, you will often see that 2 or more astrocytes will be selected at the same time, as their surface reconstructions will be connected to each other.
To overcome this issue, you need to manually cut astrocyte processes at the contact points of two different cells. Use the Cut function, which you can find by clicking on the orange pencil icon. Cuts will always be done perpendicular to the 3D arena, so make sure that you bring your astrocytes in the correct position prior to cutting. Left click and a thin blue line will appear that tells you where the cut will be made (Figure  6A ). 69. At this point we also recommend manually deleting astrocytes that are too close to the x, y or z plane. Not removing incomplete astrocytes can confound the data set and lead to inconsistent data collection. Left click on the respective astrocytes and click delete on your keyboard or left click delete in the orange pencil tab. Fused astrocytes will now be separated (Figure  6B ).
QUANTIFICATION AND STATISTICAL ANALYSIS Imaris-generated data files are compatible with both Excel and Numbers and generated data sets can be easily imported to either software. For the statistical analysis common programs such as Graphpad Prism or SPSS can be used. In addition to the exported astrocyte parameters, Imaris also allows you to measure the signal intensity of astrocyte-confined mRNA transcripts. This can be achieved by manually creating spheres that precisely engulf the astrocytic soma and, thus, the mRNA signal. Use the Spot function (top left, orange symbol) and then clicking on the create tab (orange pencil). You can place the sphere via shift+left mouse click and manually adjust the size by rotating the mouse wheel or adjusting the diameter of the selected spot. You can now click on any spot and export data in analogy to step 70.
ACKNOWLEDGEMENTS This work was supported by  DFG  Postdoc Fellowship AL 2466/1-1 to F. A. ,  National Heart, Lung, and Blood Institute  Grant  NIH HL090948  to J. E. S. ,  National Institute of Neurological Disorders and Stroke  Grant  NIH NS094640  to J. E. S. , and funding provided by the  Center for Neuroinflammation and Cardiometabolic Diseases (CNCD) at Georgia State University , the  German Research Foundation (DFG)  grants  GR 3619/8-1 ,  GR 3619/13-1 ,  GR 3619/15-1 ,  GR 3619/16-1 , Training Research Group (GRK) 2174 and SFB Consortium  1158-2  to V. G. , the  Centre National de la Recherche Scientifique  contract  UPR3212 , the  Universitede Strasbourg  contract  UPR3212 ,  ANR JCJC  grant  19-CE16-0011-0  to A. C. , and  ANR-DFG  grant  GR 3619/701  to A. C. and V. G. , National Heart, Lung, Blood Institute Grants  NIH HL150750  and  HL136595  to E.
Search for DUF239-encoding loci in the Arabidopsis genome The Arabidopsis Information Resource (TAIR) was queried using "DUF239" as a key word in the gene data type (https:// www. arabidopsis. org/index. jsp). In this way, 45 loci were recovered. Then a first phylogenetic tree was constructed (see after) and one or two protein sequences of each cluster were used to search for additional sequences using Blastp with default parameters in the Arabidopsis-restricted NCBI Database (https://blast. ncbi. nlm. nih. gov/Blast. cgi). Five nonredundant additional sequences were recovered and integrated in this article. The DUF239 presence was confirmed by querying the InterproScan domain prediction website (http:// www. ebi. ac. uk/interpro/). The TAIR definitions were used for the description of the sequences in.
Domain organization of the DUF239-containing proteins Identification of the domain organization of the 50 DUF239 proteins was performed by querying the InterproScan database (http://www. ebi. ac. uk/interpro/). The positions of each identified domain were collected, and protein domain organization were drawn using PowerPoint software. By this way, we also confirmed the presence of DUF239 in the five protein sequences identified in this article (encoded by At4g23355, At4g23360, At4g23365, At4g23370, At4g23373).
Expression pattern analyzes RNAseq expression values of the 50 DUF239 coding loci were recovered from the Klepikova atlas  (Klepikova et al. , 2016)  at the Transcription Variation Analysis (TRAVA) website (http://travadb. org/browse/). Raw absolute expression data were centered and scaled per gene and the heatmap was generated with the Excel software. Hierarchical classification of loci was carried out by using XLSTAT software. Seed specific expression patterns of each locus were sought from the Bio-Analytic Resource (BAR) Expression browser (http:// bbc. botany. utoronto. ca) by querying the microarray database of the Seed Development data source. Sixteen of the 50 DUF239 loci could not be found in ATH1 datasource, so we recovered 34 patterns.
Nevertheless, none of the E. R. -predictions are confirmed querying the PREDOTAR prediction server (https://urgi. versailles. inra. fr/ predotar/; data not shown). At4g23080 prediction to mitochondrion is also not confirmed, but PREDOTAR associate At1g70550 (Mt according to SUBA prediction) to the chloroplast (score 0. 69). So, although most sequences are predicted to the extracellular space, we cannot exclude that few PUF239 proteins localize in another compartment. In the Nepenthes genus, Neprosins share the same domain organization (Figure  1 ) that consists in an N-terminal α-helix, a DUF4409 and a DUF239. Association of those three domains is required for functional Neprosins  (Rey et al. , 2016)  in which DUF239 confers the proteolytic activity and DUF4409 is presumed to act as a peptidase-activating sequence  (Rey et al.
Specificity of Arabidopsis DUF239 family expression pattern Expression data of the 50 DUF239 loci were recovered from the RNAseq Klepikova Arabidopsis Atlas  (Klepikova et al. , 2016). It consists of 79 values per locus that are basically distributed in three datasets: seed/silique, flower, and vegetative stages (Supplemental Figure  S6 ). In order to understand whether DUF239 gene expression relies on their phylogenetic distribution, expression patterns of the 50 DUF239 loci were compared according to their phylogenetic cluster. The heatmap generated in Figure  7  reveals that DUF239 genes are widely expressed in all plant developmental stages. Nevertheless, for Clusters I, II, III, and IV, gene expression is mainly observed in the seed-related datasets. Cluster V genes display the higher diversity in their expression patterns but 3 of the 16 genes of this cluster are also mainly expressed in reproductive organs.
Toward a possible role of DUF239-containing proteins in seed We investigated the expression pattern of the seed-related DUF239 loci (i. e. , group 1, Supplemental Figure  S7 ) using the Seed Development Datasets of the Arabidopsis eFP Browser that explores six different tissues of seeds during five developmental stages  (Le et al. , 2010). Among the 39 DUF239 loci expressed in reproductive organs (Figure  7 ), 13 loci are absent of the ATH1 array. Nevertheless, regarding the 26 remaining loci, 3 (At2g23360, At4g17860, and At5g46200) are expressed in embryo or in seed tissues and 23 are specifically expressed in the endosperm (Figure  8  and Supplemental Figure  S8 ). The endosperm is a peculiar trinuclear tissue that develops, in parallel to the embryo, from the two polar nuclei of the female gametophyte central cell  (Dumas & Rogowksy, 2008).
R E F E R E N C E S Bassel, G. W. (2016). To grow or not to grow? Trends in Plant Science, 21(6), 498-505. https://doi. org/10. 1016/j. tplants. 2016. 02. 001 Blum, M. , Chang, H. Y. , Chuguransky, S. , Grego, T. ,  Kandasaamy, S. , Mitchell, A. , Nuka, G. , Paysan-Lafosse, T. , Qureshi, M. , Raj, S. , Richardson, L. , Salazar, G. A. , Williams, L. , Bork, P. , Bridge, A. , Gough, J. , Haft, D. H. , Letunic, I. , Marchler-Bauer, A. , & Finn, R. D. (2021). The interpro protein families and domains database: 20 years on. Nucleic Acids Research, 49(D1), D344-D354. https://doi. org/10. 1093/nar/gkaa977 Bonetta, D. , Bayliss, P. , Sun, S. ,  Sage, T. , & McCourt, P. (2000). Farnesylation is involved in meristem organization in Arabidopsis. Planta, 211(2), 182-190. https://doi. org/10. 1007/s004250000283 Buch, F.
The tetrapeptide sequence of the putative CaaX-box identified on At2g20170 is Cys-Thr-Iso-Thr (CTIT). It may be F I G U R E 7 Expression pattern of the domain of unknown function 239 (DUF239) gene family. RNAseq data were recovered thanks to the Klepikova atlas (Klepikova et al. , 2016). The 79 datasets are classified in three categories : Seed-related (i. e. , seed/silique), Flowers, Vegetative organs (see Supplemental Figure S4 for details). Values in brackets indicate the numbers of expression values by category. Loci are ordered according to their phylogenetic clusters. The black frames indicate the loci that are preferentially expressed in seed. An arrowhead indicates At2g03930 in Cluster V.
html Software available at FreeFem-sources/examples/ffddm (ffddm) within FreeFEM, https: //github. com/hpddm/hpddm (HPDDM), and https://www. mcs. anl. gov/petsc (PETSc). two scenarios: the under-resolved case with a discretisation of 5 points per wavelength (Table  1 ) and the over-resolved case with a discretisation of 10 points per wavelength (Table  2 ) and vary the frequency and the number of subdomains. Low resolution is motivated by applications where high precision is not needed, especially when solving inverse problems by FWI (Full Waveform Inversion). In this case, since the test cases are large, one needs to find a good trade-off between precision and the size of the system to be solved. We refer the reader to the references  [11, 12]  where a more extensive numerical study was performed.
Methods First, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the ndings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical pro le of CNTN5 CNV carriers in the DECIPHER database.
Finally, we determine the clinical signi cance of CNTN5 CNVs by comparing their prevalence in cases with ASD to patients with suspected neurodevelopmental disorders (NDDs) (n ≈ 16,500), and assess their prevalence in DECIPHER, a rare disease genomic database. Our study outlines an approach for investigating the role of intermediate effect size candidate variants using large-scale data. Our results implicate the possible role of CNTN5 CNVs in ASD-susceptibility.
Exploration of a multiplex ASD family A multiplex family with ASD, consisting of ve brothers, a sister, and two parents was identi ed and recruited in Pakistan by a local psychiatrist (Dr. Brohi Qasim). Following a face-to-face standardized evaluation based on DSM-IV, three brothers were given a diagnosis of autism, and a fourth brother was diagnosed with a learning disorder (Supplementary Figure  A ). Following standard DNA extraction and genotyping protocol, CNVs across all family members were annotated and called (Supplementary Note). In the interest of identifying candidate ASD-risk variants, an in-house Python script, SV-Segregation, was used to identify CNVs that were shared by all three brothers with ASD.
Cohorts ASD cohorts We included individuals with ASD from the Simons Simplex Collection (SSC) (n = 2,585) [16], MSSNG (n = 3,289)  [17] , and Simons Foundation Powering Autism Research for Knowledge (SPARK) (n = 8,423) [18] cohorts as cases in this study. The SSC is a cohort of simplex families consisting of trios (one proband with ASD and unaffected parents) and quads (one proband with ASD, unaffected parents, and unaffected sibling(s)). The MSSNG database includes simplex and multiplex (multiple affected family members with ASD) from the Autism Speaks whole-genome sequencing (WGS) project. The SPARK database is a newly established genetic cohort that includes genotyping data of over 8,000 families or singletons with ASD. Parents diagnosed with ASD or half-siblings were excluded from the study.
We also included individuals with ASD reported in Mercati et al. (n = 1,534)  [12]  and the BBGRE database (https://bbgre. brc. iop. kcl. ac. uk/) (n = 776) in our meta-analysis. In total, 16,607 cases with ASD were studied. When available, the unaffected siblings and unaffected parents of probands with ASD from the SSC, MSSNG, and SPARK cohorts were used as intrafamilial control subjects. Parents diagnosed with ASD from the SPARK cohort (n fathers = 48; n mothers = 101) were excluded from the analyses. In total, we studied 5,290 unaffected siblings and 21,767 unaffected parents from the SSC, MSSNG, and SPARK cohorts.
Unselected control cohorts Loading [MathJax]/jax/output/CommonHTML/jax. js In our discovery cohort, we included 1,802 individuals from the IMAGEN Study  [19]  and 14,160 individuals from Generation Scotland Scottish Family Health Study (GS)  [20]  to represent unselected controls from the general population. We also included the 8,936 unaffected controls reported in Mercati et al, which are detailed in their Supplementary Materials. In total, we used 24,898 individuals as independent unselected controls in our discovery cohort. We used the genetic data of 459,855 individuals from the UK Biobank (UKBB)  [21] , a large-scale population-based study, as an independent replication cohort to validate our ndings.
Statistical Analysis To assess whether CNTN5 CNVs were over-transmitted in cases with ASD, in comparison to their unaffected siblings, we used a generalized linear mixed-effects model, accounting for relatedness as a random effect, with ASD diagnosis as the outcome variable and CNTN5 CNV presence as the predictor variable. The analysis was done using the R package ("lme4")  [24]. Enrichment of exonic and intronic CNTN5 CNVs in cases compared to unselected controls and individuals from the clinical cohort was assessed using a Fisher's exact test (" sher. test") in the R ("stats") package. All analyses were performed on the R version 3. 6. 1  [25].
Frequency CNTN5 CNVs cases with ASD and controls We rst compared the frequency of all combined (exonic and intronic) CNTN5 deletions and duplications in cases with ASD (30 out of 14,297; 0. 201%) and controls (4 out of 15,962; 0. 025%), which excluded samples from Mercati et al. and the BBGRE database, where intronic CNV information was unavailable (Table  3A ). A signi cant enrichment of CNTN5 deletion and duplication for all CNVs (exonic and intronic) in ASD was observed (Fisher's exact test; p = 0. 0001; OR = 4. 13; 95%CI = [0. 85-10. 44]). To determine which CNVs were driving the association signal, we assessed the differential enrichment across deletions or duplications, and CNVs localized in the exonic or intronic regions (Table  3  details the results of the nine tests). Intronic deletions were signi cantly enriched in cases with ASD (0.
6kb deletion (chr11:99675192-99728831), both restricted to CNTN5. They did not carry any other pathogenic CNV that could explain their clinical presentation. A carrier with a 29. 52 Mb deletion encompassing 119 genes, including CNTN5, was excluded from the analysis. A Fisher's exact test revealed no signi cant enrichment of CNTN5 CNVs in individuals with ASD in comparison to individuals with NDDs from the CHU-SJ cohort (p ≥ 0. 05). In the DECIPHER database v10. 3 (https://decipher. sanger. ac. uk/), 30 CNTN5 CNV carriers (deletions and duplications) are listed among 36,530 patients (0. 082%). The phenotype for autism is indicated 3 times out of 30 carriers (10%). Of the three individuals with autism, 1 individual has a duplication inherited from a deemed to be unaffected parent and the other two are deletion carriers with unknown transmission.
We observed a signi cant association of intronic deletions in ASD compared to unselected individuals from the general population. These ndings replicated in another independent control cohort. Interestingly, the three brothers with ASD and the fourth brother with a learning disorder from the multiplex Pakistani family we originally identi ed shared an intronic CNTN5 deletion as well. According to Ensembl, this intron is a retained intron, thus it may encode the protein depending on its alternative splicing. Intronic CNVs have been associated with signi cant difference in gene expression levels in the population and may be associated with expression differences of other genes through intron-promoter 3D interactions  [27]. We investigated the clinical impact of CNTN5 CNVs and observed no signi cant difference in CNTN5 CNV frequency between individuals with ASD and those with suspected NDDs from the CHU-SJ pediatric cohort.
Loading [MathJax]/jax/output/CommonHTML/jax. js Limitations Despite the large-scale case-control study design, the rareness of the CNV, as well as their incomplete penetrance, limits the signi cance of the results for clinical practice. There is a noticeable difference in CNTN5 CNV frequency across cohorts which may be attributed to difference in genotyping or sequencing technologies used. Most (24 out of 25) of the intronic CNTN5 deletions in the ASD cohort came from carriers in SPARK. While all SPARK CNVs were manually visualized by plotting their Log R ratio (LRR) and B-allele frequencies (BAF) to ensure their validity, the ASD-risk association signal is mostly driven by this cohort. Furthermore, different CNV calling, annotation, and ltering parameters in Mercati et al. , the BBGRE database, and the DECIPHER database may limit the ability to comprehensively compare the prevalence of CNTN5 CNVs across cohorts.
Acknowledgements We would like to thank  Brohi Qasim  who recruited the Pakistani family and  Lydia Werhli , who contributed to the analyses about the Pakistani family during her IFMSA Exchange program. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher. sanger. ac. uk and via email from decipher@sanger. ac. uk. Funding for the project was provided by the  Wellcome Trust. Generation Scotland received core support from the  Chief Scientist O ce of the Scottish Government Health Directorates  [ CZD/16/6 ] and the  Scottish Funding Council  [ HR03006 ] and is currently supported by the  Wellcome Trust  [ 216767/Z/19/Z ]. Genotyping of the GS:SFHS samples was carried out by the  Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland  and was funded by the  Medical Research Council UK  and the  Wellcome Trust  ( Wellcome Trust   Strategic Award  " STratifying Resilience and Depression Longitudinally " ( STRADL ) Reference  104036/Z/14/Z ).
Further support was provided by grants from: -the  ANR  ( ANR-12-SAMA-0004 ,  AAPG2019 -GeBra ), the  Eranet Neuron  ( AF12-NEUR0008-01 -WM2NA ; and  ANR-18-NEUR00002-01 -ADORe ), the  Fondation de France  ( 00081242 ), the  Fondation pour la Recherche Médicale  ( DPA20140629802 ), the  Mission Interministérielle de Lutte -contre-les- Drogues-et-les-Conduites-Addictives   (MILDECA) , the  Assistance-Publique-Hôpitaux-de-Paris  and  INSERM  (interface grant),  Paris Sud University IDEX   2012 , the  Fondation de l'Avenir  (grant  AP-RM-17-013  ), the  Fédération pour la Recherche sur le Cerveau ; the  National Institutes of Health, Science Foundation Ireland  ( 16/ERCD/3797 ), U. S. A. ( Axon ,  Testosterone   and Mental Health during Adolescence ;  RO1 MH085772-01A1 ), and by  NIH Consortium  grant  U54 EB020403 , supported by a cross -NIH alliance  that funds  Big Data  to  Knowledge Centres of Excellence.
Funding The analysis of the Pakistani family was supported by a  CIHR  operating grant to  Lan Xiong , and  Guy A. Rouleau. Bioinformatic analyses were supported by the  Canadian Institutes of Health Research (CIHR). ZS is funded by the  Transforming Autism Care Consortium , a thematic network supported by the  Fonds de Recherche Québec-Santé. CL is funded by the  Vanier Graduate Scholarship. JPR is funded by a  Canadian Institutes of Health Research (CIHR)   Frederick Banting & Charles Best Canada Graduate Scholarship  ( FRN159279 ). CH was supported by an  MRC Human Genetics Unit programme  grant ' Quantitative traits in health and disease ' ( U. MC_UU_00007/10 ). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Pen eld Chair in Neurosciences and is supported by a  Canadian Institutes of Health Research Foundation Scheme  Grant # 332971.
) and replication (unselected controls from the UKBB cohort) cohorts. a Samples exclude cases with ASD from Mercati et al. and the BBGRE database, where intronic CNV information is unavailable. b Samples exclude controls from Mercati et al. and the BBGRE database, where intronic CNV information is unavailable. Loading [MathJax]/jax/output/CommonHTML/jax. js CNTN5 CNVs are not speci c to ASD.
The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains. eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation.
EBRAINS addresses these challenges by offering modelling and simulation services for collaborative brain research, databases with annotated and curated data of many modalities, atlases of human and rodent brains, image processing workflows, supercomputing resources, neuromorphic systems, and virtual robots. EBRAINS was developed by the Human Brain Project, a research initiative funded by the European Commission with the mission to decode the human brain  ( Amunts et al. , 2019 ( Amunts et al. , , 2016 ) ). TVB cloud services ( Tables  1 , 2  ) were developed by the Human Brain Project subproject "The Virtual Brain" in collaboration with the two Human Brain Project partnering projects TVB-Cloud (virtualbraincloud-2020. eu) and TVB-CD (bit. ly/3ogLYtb). To provide supercomputing resources, the Human Brain Project offers as part of the Interactive Computing E-Infrastructure project access to compute and storage resources of the Fenix infrastructure (fenix-ri.