dataesr/scientific-paragraphs-categorization huggingface dataset:
Thus, Supplementary Table  S5  includes 16 non-overlapping terms, but on average UK patients have 3. 2 ADRs in VigiBase (De las  Cuevas et al. , 2024). This fact contributes to minor underreporting when comparing UK MHRA data (UK Medicines and Healthcare Products Regulatory Agency, 2023) to the UK data on VigiBase. As the UK has no national registry like the Scandinavians, we do not know how many of the fatal outcomes in clozapine-treated patients have not been reported to the UK MHRA. There is no way to estimate the underreporting of fatal outcomes of clozapine-treated patients who do not have a Yellow Card submitted to the UK MHRA, but there is general agreement that there is significant underreporting of all drug-related ADRs in the UK  (Chaplin, 2006; McLernon et al. , 2010). One of the major differences between UK and other Western European countries is that the UK has a formal registry of clozapine patient and the other countries do not.
Acknowledgements The authors acknowledge  Lorraine Maw, M. A. , from the  University of Kentucky Mental Health Research Center at Eastern State Hospital , who helped in editing the article. The authors are indebted to the national centers which make up the  World Health Organization (WHO) Program for International Drug Monitoring  and contribute reports to VigiBase at the  Uppsala Monitoring Centre. The information comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. However, the opinions and conclusions of this study are not necessarily those of the various centers or of the WHO.
However, the optimized transgene expression cassette including the native GDE cDNA had a size of 5. 3 kb and showed partial efficacy in Agl -/-mice, thus supporting efforts to reduce the size of the GDE transgene. Although no three-dimensional structure of human GDE has been experimentally determined so far, the structure of a GDE homolog from Candida glabrata (PDB id: 5D06 and 5D0F), showing 38% of sequence identity with the human GDE, was solved using X-ray diffraction  (28). With the emergence of AlphaFold2, an artificial intelligence system developed by DeepMind  (29) , high quality models are now available, notably via the AlphaFold2 database  (30) , where a model of human GDE can be found (entry which 2 vectors were coinjected, each encoding half of the expression cassette  (15). By using 2 distinct dual rAAV vector approaches, we demonstrated complete correction of the muscle and heart phenotype, but only partial correction of the liver disease  (15).
org/10. 1172/JCI172018DS1). Mice were i. v. injected with rAAV9 encoding the reporter gene mouse secreted embryonic alkaline phosphatase (mSEAP) under the control of each promoter, and mSEAP expression was assessed in 2 skeletal muscles. MiniCMV, one of the shortest promoters (351 bp), showed the highest mSEAP expression with similar vector genome copy numbers (VGCN) among all tested promoters (Supplemental Figure  1, B  and C ) in triceps and quadriceps. C. glabrata GDE in complex with maltooligosaccharides did not reveal the presence of any sugar binding site in these 2 domains (adapted from PDB id: 5D06 and 5D0F, Supplemental Figure  6B ). These considerations support the assumption that these 2 domains may not play a relevant role in catalysis or ligand binding and could be promising targets to shorten the human GDE protein while retaining activity.
We first generated 4 GDE mutants with deletion in the Cdomain, named ΔC1 to ΔC4, by selecting regions that were less likely to disturb formation of secondary structures, in particular the β-strands mainly composing the C-domain (Supplemental Fig-AF-P35573-F1, Supplemental Figure  6, A  and B ). This model was retrieved from the database and compared with the crystallographic structure of C. glabrata GDE, enabling the identification in human GDE of the different domains described earlier for C. glabrata  (28) , namely M1, GT (corresponding to the assembly of 3 subdomains: A, B and C), M2, and GC (Supplemental Figure  6, C ). The mapping of the missense mutations described in GSDIII patient onto the 3D model revealed the presence of most mutations in the catalytic GT and GC domains  (2, 5, 6, 28, (31) (32) (33) (34) (35) (36) (37) (38) , while almost no mutations were reported in the M1 and C domains (Figure  1A ).
Quantification of images were processed using QuPath 0. 4. 3 Software (51). For the PAS staining, a first pixel classifier was trained on different types of muscle slices for detecting tissue and eliminating artefacts such as folding, bubbles, and tearings. For mice, this PAS contour pixel classifier is a Random Tree with a resolution of 14. 08 μm/pixel, includes 3 channels, 5 scales (0. 5, 1, 2, 4, and 8), 8 features (Gaussian, Laplacian of Gaussian, weighted deviation, gradient magnitude, structure tensor max eigenvalues, structure tensor middle eigenvalues, structure tensor min eigenvalues, and structure tensor coherence), and no local normalization. The quantification of PAS staining was performed using a pixel classifier trained on healthy tissue and impaired tissue. The output parameter is then the ratio of the surface area of impaired tissue over the surface area of the total tissue slice (obtained by the contour pixel classifier).
5 hours). Absorbance data required the use of extinction coefficients to calculate the molar concentration and the percent value of the empty and genome-containing capsids. Molar concentrations of both genome-containing and empty capsids were calculated using Beer's law, and percentages of full genome-containing and empty capsids were calculated. Viral genome analysis on agarose gel. DNA was extracted using the High Pure Viral Nucleic Acid Kit (Roche). Purified viral DNA was then loaded on a 1% agarose gel (Eurobio Scientific) stained with SybrSafe Gel Stain (Invitrogen) to visualize the viral DNA. Western blot analysis. Mouse and rat tissues were homogenized with FastPrep lysis tubes (MP Biomedicals) in PBS with cOmplete protease inhibitor cocktail (Roche). Protein concentration was determined using the Pierce BCA Protein Assay (Thermo Fisher Scientific) according to the manufacturer's instructions.
Cell imaging was carried out with a Zen Black software-associated LSM-800 confocal microscope (Zeiss) with a 20× objective. PAS staining on skMt. PAS staining on hiPSC-derived skMt was performed with the PAS Staining Kit (Sigma-Aldrich) following the manufacturer's instructions. Briefly, cells were fixed with 4% paraformaldehyde for 10 minutes at room temperature. After 2 washes in PBS, cells were treated with PAS for 5 minutes at room temperature. After 3 washes in distilled water, cells were treated with Schiff 's reagent for 15 minutes at room temperature. Finally, after 4 washes in tap water, staining was visualized using an EVOS XL Core microscope (Invitrogen). Images were processed and analyzed using FIJI custom-made scripts  (54). First, colors were split and only the green channel was kept as it was the most contrasted channel.
Images were manually thresholded into binary images where PAS signal was black and background white. The threshold was set for maximizing the difference between genotypes, and, once calculated, the same threshold was applied to all images to quantify. The quantification of PAS staining was obtained using this formula: Area of PAS staining / Total area of image × 100, giving a percentage of PAS staining within the image. Molecular modelling. A three-dimensional model of the full-length human GDE was retrieved from the AlphaFold2-database  (30). The 3D model of ΔNter2-GDE was predicted using AlphaFold2 v. 2. 1  (29)  and the default parameters. Molecular dynamics simulations were performed using Gromacs 2021. 3  (55)  with CHARMM36 forcefield  (56). Solvation was done using explicit TIP3 water model.
RESEARCH IN CONTEXT Evidence before this study: We searched PubMed for articles on Parkinson's disease (PD) with no language restrictions from database inception up to February 9, 2022. We used the search terms "Parkinson disease AND genetics" and "disease progression OR survival OR mortality OR prognosis OR longitudinal studies". We also conducted this search with the addition of "genome-wide association study" (GWAS) to focus on these genome-wide analyses. There are now three published large-scale GWASs.
4 In addition, many candidate gene studies have shown that variants in GBA, APOE, and potentially MAPT, are associated with the rate of PD motor and cognitive progression. 5  progression may be determined by differential cellular susceptibility, related to mitochondrial function or proteostasis, differential cell to cell spread of pathology, or novel pathways and mechanisms. Risk factors determined from case control studies indicate aetiological pathways and guide future preventive trials, these may or may not differ from risk factors that determine disease progression. Currently disease modifying treatment trials focus on intervention in recently diagnosed patients, related to disease progression after diagnosis. Work on large scale longitudinal cohorts over the last ten years has now enabled the collaborative study of large clinico-genetic datasets.
PD Progression GWAS Tan and colleagues p13/30 GWAS of H&Y stage 3 or greater 3,299 individuals were analysed for progression to H&Y stage 3 or greater. The Oslo cohort was excluded as the genomic inflation factor was greater than 1. 2. After exclusion of the Oslo dataset, 872 individuals (26. 4%) met the outcome of H&Y stage 3 or greater, with a median time to H&Y 3 of 5. 5 years. 6,553,504 SNPs passed filtering for heterogeneity and MAF variability. The genomic inflation factor of the meta-analysis was 1. 01. The top ten independent SNPs from FUMA are reported in Table  4. One locus in Chromosome 22 was significantly associated with progression to H&Y stage 3 or greater, with the lead SNP rs112809886 (p=1. 9x10 -9 ), close to GGT5 (Figure  3 ). The regional association plot is shown in Supplementary Figure  4.
Acknowledgements This research was funded in whole or in part by  Aligning Science Across Parkinson's  [Grant number:  ASAP-000478 ] through the  Michael J. Fox Foundation for Parkinson's Research (MJFF). For the purpose of open access, the author has applied a CC BY public copyright license to all Author Accepted Manuscripts arising from this submission. This research has been conducted using the UK Biobank Resource under Application Number  46450.
Acknowledgements The authors would like to thank  G. Gadea  and  C. Teyssier  for input and critical reading of the manuscript. We thank the  CRB-ICM  ( BB-033-0059 ) for the tumor samples supplied for this study. We thank all members of the animal, imaging, and histology facilities ( Unité Mixte de Service, UMS3426 Montpellier BioCampus)  for technical help. Funding: This research was supported by grants from the  Fondation ARC , the  Ligue contre le Cancer, INSERM, Onward therapeutics  and INCA. G. M. was supported by a fellowship from the  INSERM and Région Occitanie , J. P. R. was supported by  "La Ligue Contre le Cancer".
Search for candidate venom RhoGAPs in Leptopilina transcriptomes L. victoriae venom apparatus, corresponding to venom glands and associated reservoirs, were dissected in Ringer's saline (KCl 182 mM; NaCl 46 mM; CaCl 2 3 mM; Tris-HCl 10 mM). Total RNA was extracted from 100 venom apparatus using TRIzol reagent (Invitrogen) followed by RNeasy Plus Micro Kit (QIAGEN) according to the manufacturers' instructions. The quality of total RNA was checked using an Agilent BioAnalyzer. Illumina RNASeq sequencing (HiSeq 2000, 2 × 75 pb) and trimming were performed by Beckman Coulter Genomics. The raw data are available at NCBI under the BioProject ID PRJNA974978. Sequence assembly was performed using the "RNASeq de novo assembly and abundance estimation with Trinity and cdhit" workflow available on Galaxy at the BIPAA platform (https://bipaa.
genouest. org). Leptopilina clavipes (whole body), Ganaspis sp. G1 (female abdomen), Andricus quercuscalicis (whole body) and Synergus umbraculus (whole body) transcriptomes were obtained from NCBI under accession numbers GAXY00000000, GAIW00000000, GBNY00000000 and GBWA00000000, respectively. Coding regions in the transcripts were identified and translated using TransDecoder  (Haas et al. , 2013) , which is available on the BIPAA Galaxy platform. Searches for RhoGAP domain-containing sequences in translated coding sequences were performed using hmmsearch from the HMMER package  (Eddy 2009)  with the RhoGAP (PF00620) HMM profile.
Completion of L. boulardi and L. heterotoma venom RhoGAP sequences Venom apparatus, corresponding to venom glands and associated reservoirs, were dissected in Ringer's saline. Total RNA was extracted from venom apparatus using the RNeasy Plus Micro Kit (QIAGEN) according to the manufacturers' instructions. To obtain the full-length coding sequence of LbGAP1. 3, LbGAP5, LbGAPy6, LhGAP1 and LhGAP2, rapid amplification of cDNA ends (RACE) was performed using the SMART RACE cDNA Amplification Kit (Clontech). For LhGAP3, 3' RACE could not be applied due to the presence of poly(A) stretches in the sequence. LhGAP3-matching sequences were searched for in the transcriptome assembly obtained by  Goecks et al. , 2013)  from the abdomen of L. heterotoma females (GenBank accession number GAJC00000000) using the command line NCBI-BLAST package (version 2.
Obtention of the genomic sequences of Leptopilina venom RhoGAPs and RacGAP1 The genomic sequences of Leptopilina venom RhoGAPs and RacGAP1 were obtained by BLAST and Exonerate searches  (Slater & Birney 2005)  using the corresponding coding sequences as queries. L. boulardi ISm, L. boulardi ISy, L. heterotoma and L. clavipes genome assemblies were obtained from NCBI under accession numbers GCA_011634795. 1, GCA_019393585. 1, GCF_015476425. 1 and GCA_001855655. 1 respectively.
Search for candidate V. canescens RhoGAP calyx sequences Coding regions were identified from the V. canescens calyx transcriptome published by  Pichon et al. , (2015)  and translated into protein sequences using TransDecoder  (Haas et al. , 2013). The search for RhoGAP domain-containing sequences was performed using hmmsearch from the HMMER package  (Eddy 2009)  with the RhoGAP (PF00620) HMM profile. The identified RhoGAP calyx sequences were used as a database for Mascot to explore MS/MS data obtained from purified V. canescens VLPs  (Pichon et al. , 2015)  with a false discovery rate of 1%. Only proteins identified by two or more peptides were considered. The V. canescens RacGAP1 coding sequence was obtained by BLAST searches in the V. canescens calyx transcriptome using the N. vitripennis RacGAP1 sequence as query.
Phylogeny of Leptopilina venom and Venturia calyx RhoGAPs Searches for N. vitripennis RhoGAP sequences were performed using BLASTP at NCBI (http://www. ncbi. nlm. nih. gov/blast/) and hmmsearch from the HMMER package  (Eddy 2009)  with the RhoGAP (PF00620) HMM profile on the N. vitripennis v1. 2 proteome database  (Rago et al. , 2016). Multiple amino acid sequence alignments were performed using MAFFT with the --auto option  (Katoh and Standley 2013). For codon-based analysis of selection (see below), codon-based alignments of complete coding sequences were performed using RevTrans (https://services. healthtech. dtu. dk/service. php?RevTrans) with the amino acid alignments as templates. Poorly aligned regions were removed using trimAl with the -automated1 option  (Capella-Gutierrez et al. , 2009).
Structural analysis Molecular modeling of VcVLP2 RhoGAP was performed using the Phyre server with default parameters (http://www. sbg. bio. ic. ac. uk/phyre2/)  (Kelley et al. , 2015). The model with the highest confidence (100%) and coverage (46%) was obtained using the crystal structure with PDB code 2OVJ as a template. Model quality was evaluated using the QMEAN server (http://swissmodel. expasy. org/qmean/) (Benkert et al. , 2011). Briefly, the QMEAN score is a global reliability score with values ranging between 0 (lower accuracy) and 1 (higher accuracy). The associated Z-score relates this QMEAN score to the scores of a non-redundant set of high-resolution X-ray structures of similar size, with ideal values close to 0. Visualization of LbGAP  (Colinet et al. , 2007)  and VcVLP2 structures and mapping of sites under selection were performed using PyMol (http://sourceforge.
The absence of a predicted nuclear localization signal for VcGAP7 may be explained by the incomplete coding sequence at the 5' end (Table  2 ). There is greater variation in domain organization for V. canescens calyx RhoGAPs compared to Leptopilina venom RhoGAPs (Figure  3B  and Supplementary Figure  S4 ). Eight V. canescens calyx RhoGAPs have retained the C1 motif. In addition, VcGAP12 still contains a CC region in the N-terminal part of the sequence although the total sequence length is shorter than RacGAP1 (Figure  3B  and Supplementary Figure  S4 ). Table  2. Motif and domain organization of Venturia calyx RhoGAP proteins associated with VLPs. The coiled-coil (CC) region was predicted using COILS  (Lucas et al. , 1991). The protein kinase C-like zinc finger (C1) motif (PS50081), the RhoGAP domain (PF00620) and the RacGAP1 domain (PTHR46199) were identified using InterProScan.
(Perez-Riverol et al. , 2022) sequences of the Leptopilina venom RhoGAP sequences. Data validation criteria were (i) one peptide with individual ion score greater than 50 or (ii) at least two peptides of individual ion score greater than 20. The mascot score is calculated as -10Log (p). The calculated FDR (based on an automated decoy database search) was less than 1%. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE(Perez-Riverol et al. , 2022)partner repository with the dataset identifier PXD041695.
Acknowledgements We are highly grateful to  Christian Rebuf  for help in insects rearing. We also thank  Pr. M. T. Kimura  ( Hokkaido University, Japan ) for providing biological material. We would also like to thank  Anthony Bretaudeau  ( INRIA, Rennes, France ) for help in the use of the workflows available at the BIPAA platform, the genotoul bioinformatics platform  Toulouse Occitanie  ( Bioinfo Genotoul , https://doi. org/10. 15454/1. 5572369328961167E12 )for providing computing resources and the  BIG bioinformatics platform from the PlantBios infrastructure  for providing facilities and technical support.
Data and supplementary information availability Raw data from the Illumina RNASeq sequencing of the L. victoriae venom apparatus are available at NCBI under the BioProject ID PRJNA974978. The mass spectrometry proteomics data from L. boulardi and L. heterotoma venosomes have been deposited to the ProteomeXchange Consortium via the PRIDE  (Perez-Riverol et al. , 2022)  partner repository with the dataset identifier PXD041695.
(Perez-Riverol et al. , 2022) sequences of the Leptopilina venom RhoGAP sequences. Data validation criteria were (i) one peptide with individual ion score greater than 50 or (ii) at least two peptides of individual ion score greater than 20. The mascot score is calculated as -10Log (p). The calculated FDR (based on an automated decoy database search) was less than 1%. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE(Perez-Riverol et al. , 2022)partner repository with the dataset identifier PXD041695. MS/MS data analysis was performed with Mascot software (http://www. matrixscience. com), licensed in house.
Acknowledgments We thank  Dr. Philippe Benaroch  ( Institut Curie INSERM U932, Paris ) for the Env-mutated pNL4. 3. Gag-mCherry (R5 tropic). We acknowledge the imaging facility MRI, member of the national infrastructure "France- BioImaging infrastructure " supported by the  French National Research Agency  ( ANR-10-INBS-04 ,  «Investments  for the future»)". This work was supported by the " ANRS-Maladies Infectieuses Emergentes » , by  SIDACTION , by the  Centre National de la Recherche Scientifique (CNRS)  and by the  University of Montpellier.
40  , the snap trap protocol from Woodman et al. 39  and the "Levantamento Rapido de Indices para Aedes aegypti -LIRAa" protocol by Brasil  55  to develop speci c protocols that remedy the aws identi ed in the previous protocol and suitable to The Bahamas condition. These Bahamas-speci c protocols are described in detail under "preparation of protocols" and included the following components: de nition of sampling size; preparation of maps; preparation of databases; approaching residents;household survey protocol, track plate and snap trap protocols as well as a road map for community collaborative engagement. The protocols were also used to train the course participants about different rodent survey techniques such as exterior and interior household rodent inspection, track plate and snap trap application.
Preparation of maps and database Following the proliferation of rodents in the study areas after the occurrence of Hurricane Dorian in 2019, 50% of the affected areas (7 areas) were selected for pilot rodent surveillance as de ned by the sampling strategy above. A map of the study areas containing the randomly selected blocks from each area was produced using spatial analysis software QGis Version 3. 22 (Fig. 3 ). Additional maps containing the selected blocks from each study area were produced to assist the eld teams in identifying the households to be visited and monitored during the eldwork. Each area contained between 4 and 9 blocks depending on the size of the area. Figure  3  was also used during the community collaborative mapping to indicate possible rodent foci as identi ed by the residents.
Acknowledgements: The authors appreciate The  Bahamas Department of Environmental Health Services, WHO, PAHO  and the community members of the study areas for their support during the training program and eventual rodent survey. Also, the authors are grateful to  Tshewang Dorji ,  Brittney Jones  and  Carlyne Smith-McKenzie  for their contribution towards the success of the training and the training participants for their cooperation during the training and eld study. Lastly, we are grateful to all the specialists for their constructive contribution during the one-day experts' meeting.
Neurological characteristics We collected the following data related to PD: age of PD onset, PD duration, and current DRT (medication, dosage, number of pills per day). The standardized conversion formula described by Tomlinson et al. 20  was used to calculate the levodopa equivalent daily dose (LEDD), which reflects the levodopa requirement. 21, 22  During the inclusion process, a face-to-face interview with a trained examiner explored the presence of lifetime and current ICBs (Minnesota Impulsive Disorder Interview,  23  Giovanni criteria  24  ) to establish the initial "ICB+" and "ICB-" groups. During the follow-up visit, the presence of current ICBs (de novo ICBs, ICB recurrence or persistence diagnosed at inclusion) was assessed using an adapted version of the initial interview, shortened  25  and designed to be completed as a self-report question- naire exploring the period of the last 12 months.
However, for descriptive and exploratory purposes, we calculated the mean score for each item, according to the absence or presence of a current ICB and the type of ICB (a persistent/recurrent or de novo ICB) (Supplementary Figure  1  in the online-only Data Supplement). The highest score was obtained for the Bodily Discomfort item, especially when an ICB was present. The links among PD, ICBs and HRQOL are probably complex and likely to be bidirectional. According to some authors, the unpredictable nature of PD and the inability to stop or slow its progression may result in uncertainty and psychological stress. 32  One might imagine that the development of ICBs is a coping mechanism against the stigma, distress, anxiety, or depression associated with the evolution of the disease for some patients.