dataesr/scientific-paragraphs-categorization huggingface dataset:
Sequencing data were analyzed using amplimap software  25  (including mapping, coverage analysis, and variant calling), and variants were filtered on the basis of rarity (allele frequency in gnomAD [v2. 1. 1] 26 below 0. 000045),  27  Combined Annotation Dependent Depletion score (≥20 or not reported), and likely consequence (missense or more damaging). The coverage of PRRX1 was assessed in a subset of patients (n = 479) included in the targeted sequencing analysis. These samples were selected because they displayed low variability in normalized mean coverage (see Supplemental Methods for further details). Total coverage for nonoverlapping probe regions (including 20 regions covering all exons) was normalized by the mean coverage for all genes analyzed (n = 41) for each sample, and by the average coverage for all samples for each probe region.
These comprised a loss of the start codon (NM_022716. residue N-terminal to the homeodomain was identified (NM_022716. 4:c. 161A>C; p. (Asp54Ala), Family 3) (Table  1 ). To provide a comparator, we examined data from the gnomAD database (v2. 1. 1) and UK Biobank. 30 In approximately 250,000 alleles in gnomAD, there are 4 LoF alleles and 34 missense substitutions (excluding a known benign substitution, p. (Ser104Gly)) that potentially disrupt the homeodomain. In approximately 735,000 alleles in the UK Biobank, there are 3 LoF variants and 110 missense variants (excluding p. (Ser104Gly)) predicted to disrupt the homeodomain. This indicates a significant overrepresentation (16-fold; Fisher exact test: P <. 000001) in the resequencing study (2 LoF and 5 homeodomain missense variants in 2898 alleles) compared with gnomAD and the UK Biobank, consistent with a causal contribution in the affected individuals.
In this study, we prioritized analysis of variants identified in patients with craniosynostosis; however, there are several other rare homeodomain missense variants reported in population databases, such as gnomAD and UK Biobank, that could be disease causing. Future clinical and functional studies could explore further the effect of rare missense variation across the homeodomain to establish any hidden genotypephenotype correlation. Additionally, though variants outside of the homeodomain could disrupt protein transactivation (as hypothesized for the p. (Asp54Ala) variant), the 3. 5-fold enrichment of rare variants within the homeodomain (based on our resequencing survey), combined with the low disease penetrance of pathogenic variants, indicates that establishing disease causality for variants outside this well-studied domain would be challenging.
Acknowledgments The authors thank all the family members for their participation and the associated clinicians for their help in tissue collection. The authors also acknowledge support from the  National Institute for Health and Care Research UK Rare Genetic Disease Research Consortium  and thank  Jill Brown  for her support with the immunofluorescence analyses,  Fena Ochs  for guidance and technical assistance with the ScanR microscope,  Michael Kern  for sending the original Prrx1 constructs,  Morgan McManus  for assisting with patient information, and  Consolato Sergi  for the provision of material from patients with agnathia-otocephaly, but unfortunately, no usable results could be obtained.
Funding This work was supported by a  Doctoral Training Program studentship  funded jointly by the  Radcliffe Department of Medicine , the  Exeter College (Oxford) Usher Cunningham Scholarship , and the  MRC  (R. S. T. ). The research conducted at the  Murdoch Children's Research Institute  was supported by the  Victorian Government's Operational Infrastructure Support Program ; the " Undiagnosed Diseases Project Victoria" (UDP-Vic ;  RCH HREC 36291A ) acknowledges financial support from the  Murdoch Children's Research Institute  and the  Harbig Foundation  (T. Y. T. ). T. Y. T. was supported by  Victorian Clinical Genetics Services and Murdoch Children's Research Institute  to undertake a sabbatical with A. O. M. W. Work in Oxford was supported by the  National Institute for Health and Care Research Oxford Biomedical Research Centre Program  (A.
CdpB1 is a member of the conserved PRC barrel protein family widely present in archaea CdpB1 is a small protein of 97 amino acids that belongs to the vast PRC barrel protein family widely present in archaea, bacteria and plants (Pfam ID: PF05239)  27. Although most of the PRC barrel proteins remain poorly characterized, four distinct functions have been described: 1) H subunit of photosynthetic reaction center (PRC)  35  ; 2) bacterial RimM protein involved in 30S ribosome maturation  36  ; 3) sporulation proteins YlmC/YmxH in Firmicutes  37  and 4) CdvA component of the crenarchaeal and thaumarchaeal ESCRT-based cell division system  18. Prompted by the role of CdpB1 in haloarchaeal cell division, we reexamined the PRC barrel protein family, focusing on archaeal proteins previously found to be monophyletic in the phylogeny of the PRC barrel family and hypothesized to be involved in translation by analogy with RimM 27 (see Methods).
Sequence comparison, phylogenetic analysis and gene neighborhood analysis for archaeal PRC barrel domain containing proteins The arCOG database  55, 56  that includes annotated clusters of orthologous genes for 524 archaeal genomes covering all major archaeal lineages is available at https://ftp. ncbi. nih. gov/pub/wolf/COGs/arCOG/tmp. ar18/. PSI-BLAST  57  search (e-value cutoff of 0. 01, effective database size of 2*10 7 , no composition-based statistics and no low complexity filtering, 5 iterations) with several selected query sequences from each arCOG consisting of PRC barrel domain proteins (2155, 2157, 2158, 5740, 8023) was used to run searches against all proteins in the arCOG database to identify remotely similar homologs. Proteins identified using this approach but currently not annotated as containing the PRC barrel domain were additionally searched against PFAM, CDD and PDB profiles databases using HHpred  58.
If HHpred searches revealed similarity with known PRC barrel protein profiles with probability greater than 80%, then the query sequences and the respective arCOGs were assigned to the PRC barrel family (Supplementary Table  1 ). Muscle5 program  59  with default parameters was used to construct a multiple sequence alignment of archaeal PRC barrel domains. For phylogenetic analysis, several poorly aligned sequences or fragments were discarded, and the remaining protein sequences were realigned. Columns in the multiple alignment were filtered for homogeneity value 60 0. 05 or higher and gap fraction less than 0. 667. This filtered alignment was used as an input for FastTree program  61  to construct an approximate maximum likelihood phylogenetic tree with the WAG evolutionary model and gamma-distributed site rates (Supplementary File 1).
The same program was used to calculate support values. HHpred and Marcoil 62 were used to search for sequence similarity and prediction of coiled -coil regions, respectively, for protein domains fused to PRC barrel domain. For genome context analysis and search for putative operons, neighborhoods containing five upstream and five downstream genes were constructed for all identified genes encoding PRC barrel domain proteins (Supplementary Table  2 ). CdpB1 colocalizes with known cell division proteins. Exponential phase cultures of H. volcanii H26 carrying plasmid pZS105 (Ptna::cdpB1-gfp-ftsZ1-mCherry), pZS106 (Ptna::cdpB1-gfp-ftsZ2-mCherry) or pZS107 (Ptna::cdpB1-gfp-sepF-mCherry) were diluted 1:100 in fresh Hv. Cab medium with 0. 2 mM Trp, and grown at 45˚C to OD600 ~ 0. 2. 2μL of the cultures was spotted on BSW agarose pads for phase-contrast and fluorescence microscopy.
Acknowledgements We thank members of the  Du lab, Koonin lab, Chen lab and Krupovic lab  for advice and helpful discussions to carry out this study. We thank  Dr. Yan Liao  and  Dr. Iain Duggin  at  University of Technology Sydney  for sending us the ftsZ depletion/deletion strains and plasmids for construction of fluorescent protein fusions. We thank  Dr. Thorsten Allers  at  University of Nottingham  and  Dr. Xipeng Liu  at  Shanghai Jiao Tong University  for sending us the H. volcanii strains and plasmids. We thank  Dr. Ming Li  and  Dr. Hua Xiang  at the  Institute of Microbiology Chinese Academy of Sciences  for providing us with the H. hispanica strains and plasmids. We would also like to thank  Dr. Junfeng Liu  and  Yunfeng Yang  at  Shandong University  for insightful discussions on the function of the PRC barrel domain of CdvA.
b. Numbers of PRC barrel domain proteins in 524 archaeal genomes from the arCOG database. The plot shows the number of distinct PRC barrel domains in all 524 genomes from arCOG database grouped according to their taxonomy and colored using the same color code as in A, except for the gray color, indicating unclassified genomes. c. Selected most frequent domain architectures of PRC barrel proteins. The proteins are shown to scale as indicated. Distinct domains are shown by colored rectangles. The respective protein identifier and arCOG number are indicated on the right. d. Selected neighborhoods of PRC barrel genes. Genes are shown as arrows. Protein name is indicated below each arrow. The numbers inside the arrows indicate the counts of the occurrences of the respective gene in 1675 PRC barrel gene neighborhoods (Supplementary Table2).
European forests are threatened by increasing numbers of invasive pests and pathogens. Over the past century, Lecanosticta acicola, a foliar pathogen predominantly of Pinus spp. , has expanded its range globally, and is increasing in impact. Lecanosticta acicola causes brown spot needle blight, resulting in premature defoliation, reduced growth, and mortality in some hosts. Originating from southern regions of North American, it devastated forests in the USA's southern states in the early twentieth century, and in 1942 was discovered in Spain. Derived from Euphresco project 'Brownspotrisk,' this study aimed to establish the current distribution of Lecanosticta species, and assess the risks of L. acicola to European forests. Pathogen reports from the literature, and new/ unpublished survey data were combined into an open-access geo-database (http://www.
portaloff orestpathology. com), and used to visualise the pathogen's range, infer its climatic tolerance, and update its host range. Lecanosticta species have now been recorded in 44 countries, mostly in the northern hemisphere. The type species, L. acicola, has increased its range in recent years, and is present in 24 out of the 26 European countries where data were available. Other species of Lecanosticta are largely restricted to Mexico and Central America, and recently Colombia. The geo-database records demonstrate that L. acicola tolerates a wide range of climates across the northern hemisphere, and indicate its potential to colonise Pinus spp. forests across large swathes of the Europe. Preliminary analyses suggest L. acicola could affect 62% of global Pinus species area by the end of this century, under climate change predictions.
Current geographic distribution of Lecanosticta species The occurrence of Lecanosticta species in some countries is well documented, with high confidence in the diagnosis, whilst in other areas, identification of the pathogen has been less reliable. For this review, information from published and grey literature was re-examined, considering advances in morphological and molecular diagnostic tools. These data have been incorporated with new, previously unpublished records to produce a contemporary, global dataset of Lecanosticta species. The approaches used to generate this geo-database for Lecanosticta follow those used by  Drenkhan et al. , (2016a)  for Dothistroma species and Fusarium circinatum  (Drenkhan et al. , 2020)  where a global map of records is available (https://www. portalofforestpathology.
com), and users can navigate between pathogens by clicking on the 'layer' tab. Researchers from across the world, particularly from countries where the distribution of Lecanosticta appears to be less well established, were approached and strongly encouraged to participate in data collection. The objective of the resulting geo-database was to collate records and locations of known Lecanosticta species (including L. acicola), worldwide and with a particular focus on Europe. Certain data entry fields were compulsory, including pathogen presence/absence, host species and forest type (urban versus natural versus plantation). Voluntary fields allowed entry of more detailed data on disease intensity, presence of other pathogens, local climate, soil type and management practices such as thinning, pruning and chemical interventions.
A dedicated web site hosts contact details, the data collection template (in Excel) and an instruction manual for the Lecanosticta geodatabase. All data were compiled and uploaded to an interactive internet-based map hosted by Mendel University in Brno, Czechia (See https://www. portalofforestpathology. com) and further technical information on mapping and analysis is included in Supplementary material (Table  S1 ). Fig. 2  shows a time series illustrating when Lecanosticta species were first recorded in each country. (Supplementary Figure  S1  presents a global overview of L. acicola and other Lecanosticta species presence/ absence). The database currently incorporates geographic coordinates from 3205 records, including both positive (9 4 7) and negative (2258) reports of Lecanosticta species.
and Harn. ) Lindau, Engl. and Prantl on P. ponderosa Douglas ex Lawson  (Offord, 1964; Bonar, 1965)  and a Lecanosticta sp. on P. monticola Douglas ex. D. Don. (Cobb and Miller, 1968) , together with reports of a single specimen of Scirrhia acicola (Dearness) Siggers on P. attenuata from Oregon  (Siggers, 1944) , need clarification and confirmation. Most geo-database records from Canada, Cuba, Jamaica, Mexico and USA are based predominantly on morphological methods. Molecular confirmation has also been used in Canada (in 1 province), Mexico and USA (7 out of the 28 states with L. acicola recorded present). In Central America, morphological examination confirmed Lecanosticta spp. causing minor foliar browning in Belize, Costa Rica, Guatemala, Honduras, and Nicaragua on native pine species including P.
Susceptibility of Pinaceae to Lecanosticta species Fifty-three host taxa were recorded for L. acicola by  van der Nest et al. , (2019a) , mostly within the genus, Pinus, but including Picea glauca (Moench) Voss. Reports from 91 taxa were examined during the construction of the current Lecanosticta geo-database and 70 listed as susceptible to Lecanosticta species.
Data collated from reports in peer-reviewed and 'grey' literature and previously unpublished surveillance records were entered into the geo-database disease impact fields. Most reports are derived from trees growing in natural forests, plantations, botanic gardens, arboreta and field trials. Where susceptibility ratings for some hosts are based on one region only, they should be considered preliminary. Fifteen host taxa with more than one susceptibility 'rating' are marked accordingly in Table  1. Susceptibility may vary between reports written at different time periods throughout the twentieth to twentyfirst century as silvicultural practices, inoculum pressure, and climate, are all likely to have changed. Observations have also been made on host species growing within and outside their native ranges, where physiological stress may have affected resilience to infection.
Relatively few observations entered into the geo-database contained quantitative information on the extent to which individual trees or forest stands were affected by the pathogen. The majority of positive records (3 2 4) were recorded on P. mugo and its variants, and infection ranged from trees with less than 1 % needle infection  (Switzerland -Dubach et al. , 2018)  to 51 -75 % needle infection (again Switzerland  -Dubach et al. , 2018; Austria -Cech, unpublished data). Sixty-nine % of the P. mugo observations recorded crown infection greater than 25 %. Similarly, needle infection of P. nigra (and its subspecies) ranged from 5 to 10 % (Bulgaria -Georgieva, 2020) to over 75 % (Turkey -Oskay et al. , unpublished data), and over 86 % of records illustrated greater than 25 % needle infection.
Only nine P. sylvestris records from Austria, Bulgaria and Spain included information on the extent of infection, but of these, seven observations recorded crown infection of over 25 %. Thirty-six % of P. radiata suffered greater than 25 % needle infection, all of these records originating from Spain. There is currently insufficient information to evaluate the susceptibility of nine host taxa reported to be infected by L. acicola and all inferences on the susceptibility of hosts relevant to European forestry will benefit from further field data from across Europe.
are informative  (Watt et al. , 2011; Woods et al. , 2016) , our understanding of future behaviour of L. acicola is currently limited. A geo-database was therefore developed to facilitate and promote future disease modelling efforts by providing a global synthesis of available data via an easily accessible platform. Global records of L. acicola were analysed alongside fine scale climatic and topographical variables at 1 km spatial resolution (https://www. portalofforestpathology. com;  Fick and Hijmans, 2017). Only data points from confirmed reports of L. acicola in the wider environment were used, nursery records were omitted and, given the presence of multiple Lecanosticta species in Mexico and Central America, only molecularly confirmed reports of L. acicola were included from these two regions.
Comm. 2022). Ascospores of L. acicola have also been trapped in the field at temperatures as low as 4 • C  (Kais, 1971) , but as they have yet to be recorded north of Ashland, Missouri (P. ponderosa,  Luttrell 1949) , it is probable that temperature is a significant, limiting factor in their production  (Kais, 1971). The distribution of L. acicola geo-database records in relation to maximum monthly temperature was bimodal, with a peak in numbers of record between 22 and 23 • C, and a second between 32 and 33 • C (Fig. 3 ). Records from locations with Alpine and Subalpine climates and the Baltic countries, as well as the northern USA and southern Canada form the majority of data points in the first peak. A second peak includes L. acicola records from Mediterranean and east Asian countries and states surrounding the Gulf of Mexico.
Supplementary Figures S2 to S6 illustrate the distribution of L. acicola records according to precipitation values in the driest and wettest months, annual precipitation, the minimum temperature of the coldest month, and annual mean temperatures. Although the L. acicola records span a wide range within each of these climatic variables, there was no further evidence of bimodal responses, as described above. The geodatabase records clearly demonstrate the wide variation in temperature and precipitation tolerated by L. acicola. One ongoing study arising from this collaboration is utilising the geo-database resource to develop a model predicting the potential global distribution of L. acicola. Preliminary results utilising different climate change scenarios (five Global Climate Models (GCM), three combined pathways of shared Socioeconomic Pathway and Representation Concentration Pathway (SSP-RCP) models) illustrate a positive trend in expansion of L.
Wider surveys: Phytosanitary inspectors from regional authorities have conducted specific surveillance for L. acicola in forest stands, parks, urban areas, nurseries, and gardens, sending samples to BFW for analysis using morphological and molecular methods. Inspections have been annual in Tyrole (2014-present) but more sporadic in other areas, including Upper Austria  (2010 -2013 ), Saltzburg (2011 -2020 ), Vorarlberg (2011 only)  and  Styria (2006 Styria ( -2017)). Infections have been found on P. sylvestris, P. uncinata and P. mugo subsp. mugo  (Kessler and Krehan, 2011). All L. acicola infected needle samples are stored in the herbarium of BFW and entered in the database of BFW's damage diagnosis system (SDIS -https://bfw. ac. at/ws/sd. web?kat=Aandlang=1andgmp=2020). Eradication in urban areas and public spaces has relied on felling and burning of all residues on site by the phytosanitary services or designated contractors, in accordance with the former EU plant protection legislation.
mugo, P. mugo subsp mugo and P. mugo subsp. rotundata were felled and burnt. Between 2011 and 2016 further specimens of these species and the closely related P. uncinata, P. pumila and Pinus × rhaetica  (Adamson et al. , 2015 (Adamson et al. , , 2018) )  were also found to be infected in the Botanic Gardens and wider environment. All pine specimens in the gardens are currently inspected at least once per year, and samples of needles, shoots and cones (if present) collected. Between 2008 and 2013 a range of fungicide actives (chlorothalonil, propiconazole azoxystrobin and prochloraz;  Kaur & Hermann, 2021)  were applied every-three to four weeks throughout the growing season. This was reduced to Spring and Autumn applications of azoxystrobin, propiconazole and mancozeb from 2014, collecting and burning fallen needles under infected trees, and felling the worst affected trees.
Discussion Lecanosticta acicola is just one amongst an increasing number of pests and diseases affecting Europe's forests but the EUPHRESCO Brownspotrisk project underpinning this study contributed significantly to raising the profile of this significant foliar pathogen. Data from 44 countries were compiled into the Lecanosticta species geo-database, and numerous scientific publications (e. g. Piškur, 2018; Sadiković et al. , 2019a; Laas et al 2022; Raitelaityt ė et al. , 2022) , national P&D updates  (Steyrer et al. , 2018 (Steyrer et al. , , 2020 (Steyrer et al. , , 2021)) , presentations  (Cech, 2018; Sadiković et al. , 2019b; Piškur et al. , 2020) , risk analyses, management guidelines, training events and provision of up to date advice for government ministers  (Jurc and Piškur, 2018; Benko-Beloglavec et al.
, 2019; Piškur et al. , 2019a,b)  have been facilitated by the collaboration. Despite a downgrading of the quarantine status of the pathogen across much of Europe, L. acicola continues to be included in training for plant health inspectors in many countries, and surveillance activities in nurseries and forests are ongoing. Currently, Lecanosticta species appear to be more restricted in their range than the similar Dothistroma species which are now found almost everywhere that susceptible hosts grow  (Watt et al. , 2009; Drenkhan et al. , 2016a). However, over the past twenty years, Lecanosticta species' range has increased dramatically, with over half of the current 44 country reports received within this timeframe. This literature review combined with new records in the Lecanosticta geo-database have added eight countries (Belarus, Ecuador, Georgia, Jamaica, Poland, Slovakia, Turkey and Ukraine) to the global distribution of L.
sylvestris plantations in the 1970s  (Skilling and Nicholls, 1974)  manifest in the original varietal locations in France, Austria, Spain and Germany. Pinus nigra originates from a narrower geographic range than P. sylvestris, and is largely restricted to Europe. Many regional varieties exist, including two particularly distinct P. nigra 'types' delineated by a large gap across the Adriatic Sea and the Po valley of Northern Italy  (Olsson et al. , 2020). There is no evidence yet to suggest these 'types' influence susceptibility to L. acicola, with heavy infection reported in sites as distant as Turkey and Spain. Encouraging future contributors to input more data on host provenance and disease impact into the developing geo-database, may highlight trends, allowing the development of a more robust risk assessment for European forests.