dataesr/scientific-paragraphs-categorization huggingface dataset:
Clinical and epidemiological features Data are shown in  Ethnicity 2 = Hmong ethnic minority f) Severity is classified according to five scores: 1, 2a, 2b, 3 and 4. 1 and 2a are mild cases and 2b to 4 are severe cases. The description of each stage is given in Additional file 1: Table  S1  g) "0" means that admission occurred the same day as onset cases, 59 (71. 08%) belonged to main Vietnamese ethnicity (Ethnicity 1) while the rest of patients belonged to the minority Hmong ethnicity (Ethnicity 2) (Table  1 ). All severity levels were reported for the patients. Mild forms (severity level 1) made the majority of cases (57 cases, 61. 29%) while 15 patients displayed severe symptoms (16. 13%). Among this group, 3 patients displayed a severity score of 3. No case with the highest level of 4 was recorded.
The function of IR is conserved over 430 million years We have shown previously that IR affects similar biological processes during hematopoietic differentiation in human and mouse  [3]. To study the functional conservation of IR events in species spanning 430 million years, we identified IR in terminally differentiated granulocytes using the IRFinder algorithm  [26]  (see "Methods"). For every intron the algorithm computes the IR ratio (in the range of 0-1), which is an approximation of the proportion of total transcripts that retained the given intron. More specifically, the IR ratio is the ratio of the median read coverage of the intron to that of its flanking exons. We defined a threshold for the IR ratio (IR_ratio = 0. 1) in order to consider only biologically meaningful cases of IR for further analysis.
Of the five species, the representative of the ray-finned fishes (zebrafish) has the lowest fraction of expressed genes that are affected by IR (7. 8%). The group of more closely related mammalian species have a similar IR abundance with 13. 6% of the expressed genes affected in Sources of information are indicated in the "Methods" section. Data on introns were determined using the featureBits program of the UCSC genome browser. a Percent of the genome pc protein-coding, nc non-coding, sRNA small RNA, lncRNA long non-coding RNA mouse, 17. 4% in human, and 18. 6% in dog. The exception in this study is the avian representative, in which a great proportion of expressed genes (40. 8%) retained one or more introns in their mRNA transcripts (Fig. 1a ). Taken together, in all five species we found a considerable fraction of expressed genes that are affected by IR (see Additional file 1).
Post-transcriptional control of gene expression including IR is more dominant in cases where many genes are expressed (chicken). In order to reinforce this thesis, we extracted the number of transcriptional regulators (transcription factors, transcription co-factors, and chromatin remodeling factors) for each species from the AnimalTFDB database  [33]  and found that this number anti-correlates (r = -0. 73, Pearson correlation) with the number of expressed genes in our samples. In zebrafish, where there are abundant transcriptional regulators, the number of expressed genes is low. We argue therefore in zebrafish that IR is not as important comparatively as it is in organisms like avian species where IR is a dominant mechanism of post-transcriptional gene expression control. Of note, intra-sample comparisons of gene expression values resulted in no consistent picture, showing lower median expression levels (FPKM values) of intron-retaining genes only in dog, chicken, and zebrafish (Additional file 2: Figure  S3 ).
With retained introns in the 3′ UTR, the number of predicted miRNA binding sites increases further by 186. 3, 124. 1, 18. 1, 70. 4, and 28. 9 additional sites, on average, in human, mouse, dog, chicken, and zebrafish, respectively. This leads us to hypothesize that the expression of genes subject to IR is also controlled by miR-NAs. MiRNA target prediction also revealed a significantly higher density of putative miRNA binding sites in sequences of retained introns compared to nonretained introns (Additional file 2: Figure  S13 ). IR transcripts could therefore function as miRNA sponges to indirectly regulate other transcripts by modulating the available pool of miRNAs (Fig. 5e ). Six examples in which retained introns may facilitate a miRNA sponge effect were derived from our previous data comparing promyelocyte against granulocyte transcriptomes in mice (Additional file 2: Figure  S14 ; GEO accession numbers: GSE48307  [53] , GSE57624  [54] ).
RNA-seq data analysis and identification of IR events Reference genome files were built and mRNA-seq reads were mapped to the respective reference genomes using STAR (Version 2. 4)  [77]. Details on sequencing depth and read mapping statistics for each sample are provided in Additional file 2: Table  S5  and Figure  S22. Gene body coverage was determined using the geneBody coverage module from the RSeQC package (v2. 6. 3) [78]. We used the IRFinder algorithm  [26]  for the detection of IR events in all known introns. IRFinder estimates the abundance of IR by computing the ratio between gene transcripts retaining an intron and the sum of all transcripts of the respective gene. We refer to this measure as the "IR ratio," while others have also used the term "percent IR" (PIR)  [2]. The IR ratio is in the range of 0-1; however, we only considered introns with an IR ratio ≥ 0.
Annotation enrichment analysis Gene annotation enrichment was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID 6. 7)  [80]. In order to make the analyses comparable across species, we used the set of orthologous genes shared among all species as background. Enriched terms with a p value < 0. 05 were considered significant. Most commonly enriched terms are SwissProt and Protein Information Resource keywords (SP_PIR_KEYWORDS). All enriched functional annotations for each cluster of intron-retaining orthologs illustrated in Additional file 2: Figure  S1  can be found in Additional file 3. The Circos plot in Fig. 1c  was generated using the R package GOplot  [81]. We have additionally performed a functional enrichment analysis of all intronretaining genes using expressed genes as background in each species.
Gene orthologs Orthologs of intron-retaining genes were determined based on orthology relationships extracted from the Ensembl BioMart interface. Venn diagrams were drawn with the VennDiagram R package. miRNA target site analysis miRNA sequences and genomic coordinates were downloaded from the miRBase database (release 21)  [82]. miRNA target site predictions were performed using mi-Randa v3. 3a  [83]  with the energy threshold set to -14 kcal/mol and requiring strict alignment in the seed region (offset positions 2-8). Seed site enrichment analysis was performed using Sylamer  [55] , which calculates cumulative hypergeometric p values associated with small word occurrences in a sequence repository. 3′ UTR sequences of intron retaining genes were tested for 6mer seed site enrichment using the 3′ UTR sequences of all genes as background.
Acknowledgements We thank  Kim Baker  and  Elanco  (formerly  Novartis Animal Health)  for providing the peripheral blood from dogs. We thank  Steven Allen ,  Frank Kao , and  Suat Dervish  for FACS. The authors acknowledge the  Sydney Informatics Hub  and the  University of Sydney 's high-performance computing cluster, Artemis, for providing the high-performance computing resources that have contributed to the research results reported within this paper.
A1 ). After drying, the base agar was covered with 10 ml of Dolichospermum suspended in 1% agar, incubated at 28°C at 80 mmol photons m -2 s -1 for seven Table  1. Freshwater plant species used in the analyses. Species were classified into clades (monocot, eudicot and 'other' in case of taxa outside these clades, Fig. 1 ), plant origin described as native status to northwestern (NW) Europe, native range (ARS-GRIN database at < www. ars-grin. gov > and Hussner 2012), growth strategy (emergent and floating plants versus submerged plants), greenhouse acclimation (whether species were held in the greenhouse) and plant part (which part of the plant was sampled).
Allelopathic potential and explanatory factors The 34 tested aquatic plant species varied considerably in their allelopathic potential (Fig. 1 ). Plant phylogeny, growth strategy and plant origin significantly affected the allelopathic potential when tested together in a three-way days  (Gross et al. 1991) , and all plates were subsequently scanned to a photo using a digital scanner. Scans were then analysed to calculate the surface area in millimetres of individual clearing spots using ImageJ software. In addition to the plant extracts, we used a negative (70% aqueous MeOH v/v) and a positive control (3 ml of 1. 5% NaClO in water, w/w) in the ADAs. Negative controls did not show clearing spots, whereas positive controls showed clearing spots (average of 258 mm 2 per spot).
Acknowledgements -We would like to thank  Yvonne Roijendijk  and  Roos Plak  for practical assistance and  Nico Helmsing  and  Ciska Raaijmakers  for help with chemical analysis. Funding -This work was financially supported by  NWO-ALW Biodiversity  works grant  841. 11. 011. This is publication 6309 of the  Netherlands Inst. of Ecology (NIOO-KNAW ).
We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%).
The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes.
INTRODUCTION Monogenic diabetes syndromes are characterized by glucose intolerance together with extrapancreatic features, and result from one or more defects in a single gene. There are about 40 different genetic subtypes identified so far, with an estimated prevalence of 2%-5% of all patients with diabetes  (Schwitzgebel, 2014). The wide phenotypic and genetic heterogeneity poses significant problems for our understanding of disease mechanisms, and for providing prognostic information. This is compounded by the identification of diabetes syndrome gene variants of uncertain significance, in isolated diabetes through the widespread application of next-generation sequencing  (Alkorta-Aranburu et al. , 2014; Ellard et al. , 2013; Philippe et al. , 2015). There are no up-to-date variant databases for most monogenic diabetes syndrome genes; those that do exist contain limited historical variants on publicly available Websites (HGVS: http://www.
A number of projects including Orphanet, EUROPLAN, and EURORDIS have made progress in this field. The EURO-WABB project is an EU initiative to widen access to genetic testing, clinical information, and research for the overlapping rare diabetes syndromes  Wolfram, Alström, Bardet Biedl syndrome, and others, in Europe (www. euro-wabb. org). As part of this project, we have created a new locus-specific database to provide catalogs of gene variations involved in monogenic diabetes syndromes. By building on the existing generic frameworks and platforms for rare diseases, this gene variant database operates at a disease-specific level to support efficient diagnosis and research for these syndromic diabetes diseases.
THE GENES This report focuses on four genes in the EURO-WABB locus-specific database, namely ALMS1, WFS1, CISD2, and SLC19A2. Pathogenic variants in the gene ALMS1 (MIM# 606844) on chromosomes 2p13. 1 have been identified in patients with Alström syndrome (AS), an autosomal-recessive disease characterized by retinal dystrophy, childhood obesity, type 2 DM, and sensorineural hearing loss  (Collin et al. , 2002; Hearn et al. , 2002; Marshall et al. , 2005; Marshall et al. , 2007; Marshall et al. , 2015). Other features include dilated cardiomyopathy (70% of patients), hepatic diseases, and urological abnormalities  (Alstrom, Hallgren, Nilsson, & Asander, 1959; Marshall et al. , 2005; Marshall et al. , 2007). ALMS1 consists of 23 exons encompassing over 224 kb of genomic DNA encoding a centrosomal protein of 4,169 amino acids, which contain a large tandem-repeat domain consisting of 47 amino acids and has been implicated in the assembly and maintenance of primary cilia  (Hearn et al.
THE DATABASE We followed the guidelines for establishing locus-specific databases  (Celli, Dalgleish, Vihinen, Taschner, & den Dunnen, 2012; Vihinen, den Dunnen, Dalgleish, & Cotton, 2012). We formed a consortium of scientists and clinicians working with these diseases through the EUfunded EURO-WABB European Registry project  (Farmer et al. , 2013). The database is based on the Leiden Open-source Variation Database (LOVD) platform V2. 0-36  (Fokkema et al. , 2011)  and stores both published and submitted variants. Variations in the databases are named according to the HGVS nomenclature  (Den Dunnen et al. , 2016; http://varnomen. hgvs. org) and include descriptions at DNA and protein levels. Variants are numbered and described with respect to the NCBI reference sequences NM_015120. 4 (NP_055935.
4), NM_006005. 3 (NP_005996. 2), NM_001008388. 4 (NP_001094344. 1), NM_006996. 2 (NP_008927. 1) for ALMS1, WFS1, CISD2, and SLC19A2, respectively, with +1 = A of ATG start codon. Previously published variants that do not conform are renamed accordingly with the original description included in the entry to facilitate cross-reference. Mutalyzer  (Wildeman, van Ophuizen, den Dunnen, & Taschner, 2008)  is used to verify variant description. We included the following minimum data item set: pathogenicity, DNA change, genomic position in the reference sequence and genome assembly (GRCh 38), predicted protein change, mutation type, variant remarks (other information available for the variant), technique used, link to published reference if applicable, and the following anonymized clinical data: ethnic origin, gender, consanguinity, and clinical features.
As standard for the LOVD system, the database has links to other services such as PubMed, HGNC, Entrez Gene, OMIM, and GeneCards, in addition to sequence databases. The databases catalogs variants identified in patients reported to have been diagnosed with AS, WS type 1/type 2, and TRMA syndrome. In predicting variant pathogenicity, we followed guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP)  (Richards et al. , 2015)  and considered other supporting information such as experimental evidence, presence in multiple families, segregation with disease  2 and exon 1, respectively  (Mozzillo et al. , 2014; Rondinelli et al. , 2015). The exon 2 deletion of CISD2 is predicted to abolish the transmembrane domain of the protein.
WFS1 genotype-phenotype analysis We collected information on the age of onset of DM, OA, deafness, DI, and other reported clinical features from patients in the database and categorized the disease by phenotype and genotype. Table  S1 ). We defined the WFS1 N-terminal as amino acids at positions 1-652 (cytosolic and transmembrane domain) and the C-terminal as amino acids at positions 653-890 (ER lumen) (Fig. 1 ). Patients whose phenotype could clearly be identified were then assigned into respective genotype and phenotype categories (Supp. (Krogh, Larsson, von Heijne, & Sonnhammer, 2001)  and SMART  (Letunic, Doerks, & Bork, 2015). ER, endoplasmic reticulum Notes: Group 1: variants predicted to cause complete or partial loss of function (N-terminal nonsense and frameshifts, splice-site variants predicted to cause exon skipping/deletions; C-terminal nonsense and frameshift; N-terminal small in-frame deletions/duplications/insertions/indels); or compound heterozygous where one variant is predicted to cause complete and the other a partial loss of function.
Future prospects and database update The clinical overlaps and complexity exhibited by the syndromes mentioned in this report may lead to delayed or misdiagnosis. We have demonstrated that a more detailed description of clinical phenotypes in the patients coupled with genotype information can provide insight into genotype-phenotype correlations of these syndromes. Unfortunately, the clinical phenotypes are difficult to access, not always available, and can be unreliable sometimes in terms of age of onset. We hope that the information available for some of the patients in our databases will allow for better understanding of the disease and reliable genetic counselling for the patients and their families. Ultimately, functional studies of the variants will be necessary to further our understanding of disease mechanisms that will lead to the development of personalized therapies.
The EURO-WABB LOVD locus-specific databases for ALMS1/WFS1/CISD2/ SLC19A2 have been available online since 2012 and have received submissions of variants identified in patients. Future contributors can submit their variants online or by contacting and providing curators with the necessary information. When referring to the EURO-WABB ALMS1/WFS1/CISD2/ SLC19A2 LOVD databases, we kindly ask users to cite this article.
UK, Italy, Germany, France, Denmark, Spain, the Netherland, Finland,   Hungary, Poland, Russia), Americas (USA, Canada Brazil), North Africa, Middle East, and Asia (Lebanon, Iran, Iraq, Turkey, Japan, China, India, Pakistan), and Australia. To date, the CISD2 database contains three unique variants identified in 13 individuals, namely, c. 109G>C (p. Glu37Gln), c. (103+1_104-1)_(318+1_319-1)del, and c. 103+1G>A. All result in exon deletion of CISD2 leading to early termination of the ERIS protein. The first CISD2 mutation (c. 109G>C, p. Glu37Gln) was identified in 10 family members of three consanguineous Jordanian families (Amr et al. , 2007)  who presented with DM, sensorineural hearing loss, optic neuropathy, peptic ulcer, and defective platelet aggregation. The variant caused missense changes in a conserved amino acid as well as aberrant splicing resulting in the deletion of exon 2.
ACKNOWLEDGMENTS We sincerely thank referring clinicians, patients, and their family and past contributors for submitting their variants to our databases. We are very grateful for the support of  Alström Syndrome UK, Association du syndrome de Wolfram, Wolfram syndrome UK , the  NIHR Wellcome Clinical Research Facility (Birmingham) , and the  NIHR Translational Research Collaboration for Rare Diseases. We would like to dedicate this manuscript to  Professor Jan D Marshall , who made an outstanding contribution to our understanding of AS.
( UK, Italy, Germany, France, Denmark, Spain, the Netherland, Finland,   Hungary, Poland, Russia), Americas (USA, Canada Brazil), North Africa, Middle East, and Asia (Lebanon, Iran, Iraq, Turkey, Japan, China, India, Pakistan), and Australia. To date, the CISD2 database contains three unique variants identified in 13 individuals, namely, c. 109G>C (p. Glu37Gln), c. (103+1_104-1)_(318+1_319-1)del, and c. 103+1G>A. All result in exon deletion of CISD2 leading to early termination of the ERIS protein. The first CISD2 mutation (c. 109G>C, p. Glu37Gln) was identified in 10 family members of three consanguineous Jordanian families (Amr et al. , 2007)  who presented with DM, sensorineural hearing loss, optic neuropathy, peptic ulcer, and defective platelet aggregation. The variant caused missense changes in a conserved amino acid as well as aberrant splicing resulting in the deletion of exon 2.
TA B L E 1 Summary of the types of variants in ALMS1, WFS1, CISD2, and SLC19A2 database Gene ALMS1 WFS1 CISD2 SLC19A2 Chromosomal 2p13. 1 4p16. 1 4q24 1q24. 2 location Disease Alström syndrome Wolfram syndrome Wolfram syndrome Thiamine- type 1 type 2 responsive megaloblastic anemia (TRMA) syndrome Number of unique 268 309 3 48 variants Substitutions 133 208 2 30 Deletions 90 64 1 13 Duplications 34 28 0 2 Insertions 7 5 0 1 Indels 3 4 0 2 T r a n s l o c a t i o n s 1 0 0 0 phenotypes, as well as the prediction algorithm SIFT (Ng & Hanikoff, 2003), and PolyPhen-2 (Sunyaev et al. , 2001). The database is implemented on a secure server held by University of Melbourne, Australia, with only curators being able to modify contents. All components of the server service are checked regularly to ensure the long-term integrity of the server and the information stored in it (LSDB software, operating system, back-end database, and Web server).
Submitted variants are accepted and published after curation. The databases are updated regularly, are publicly accessible (https://lovd. euro-wabb. org), and have been included in the Human Genome Variation Society (HGVS) list of locus-specific databases. The summary of the types of variants stored in the ALMS1, WFS1, CISD2, and SLC19A2 databases are shown in Table 1. The ALMS1 database contains 268 unique variants, identified in 334 patients, including 17 previously unreported variants. The major- ity (49. 6%; 133/268) are single-nucleotide substitutions, of which 104 (78%; 104/134) of the base substitutions lead to codon termination. Deletions make up 34% (90/268) of the total variants reported (83 frameshift, six nonsense, and one in-frame), with six variants having deletions of more than 10 bases.
The rest of the variants are duplica- tions (13%; 34/268), insertions (2. 6%; 7/268), insertion/deletions or indel (1%; 3/268), and translocations (1/268). The majority of vari- ants are reported in exons 8 (51. 5%; 137/268), 16 (17. 3%; 46/268), and 10 (16%; 43/268). The most frequently reported variant is the Val415del) reported 33 times c. 10775delC (p. Thr3592Lysfs6*) located in exon 16 that is reported in 22 patients, and c. 1230_1233del (p. Val412Serfs*29) reported 30 exclusively in 28 patients with English ancestry. Missense variants are times in 26 patients. In 233 (44%) of WS patients in the database, uncommon. Among the 24 missense variants in the ALMS1 database, variants occur in the homozygous state. 11 (45. 8%) are predicted to be pathogenic, four (16. 7%) are likely The geographic origin of WS patients reported includes Europe pathogenic, four (16.
7%) are benign or likely benign, and five (21%) are variants of uncertain significance. The geographic origin of reported AS patients includes Europe (UK, Italy, Portugal, Sweden, Spain, France, Belgium, Germany, the Netherland, Norway, Serbia, Macedonia, Romania, Bulgaria, Slovakia, Yugoslavia, Poland, Ireland), North Africa (Morocco), the Americas (US, Canada, Brazil, Argentina, the Caribbean), and Asia and Oceania (Turkey, Israel, Iran, Iraq, Saudi Arabia, Lebanon, Japan, Taiwan, China, India, Korea, Melanesia). The gender of 194 patients is known and consists of 109 males (56. 2%) and 85 females (43. 8%). The WFS1 database currently contain 309 unique variants identified in 531 patients, including 23 previously unreported variants. The frequency of WFS1 variant types consists of 67. 3% (208/309) substitutions, 20.