dataesr/scientific-paragraphs-categorization huggingface dataset:
3 [10]  Despite the aforementioned improvements, access to these novel compounds in most European countries outside of the context of clinical trials was possible only through early access programs (EAPs), as amivantamab received a conditional marketing authorization by European Medicines Agency on December 9, 2021,  11  and poziotinib and mobocertinib are not yet authorized in the European Union, as of July 2022. Because of the rarity of EGFR exon20ins mutations, randomized trials are difficult, and RWE acquire major importance. There is an immense need for international collaboration to gather an adequate number of patients which would allow firm conclusions to be drawn on this specific population. To address this topic, we created an international registry database for patients with exon 20mutant NSCLC (all mutation types), treated in routine clinical practice or through EAP, outside of clinical trials.
To be eligible for the study, patients had to have received at least one prior treatment for advanced disease, because all exon 20 targeting agents at the time of study design and initiation were available only as second-and beyond-line treatments. There was no restriction on the number of lines of treatment that each patient had received at the time of study entry. EGFR exon 20 mutations may have developed and detected at any time during the disease course, without affecting patient eligibility, provided that the mutation was known at the time of study entry. Each participating center signed a data transfer agreement policy (available as Supplementary Material 1), and the protocol was approved by the institution's institutional review board. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded.
Patient Characteristics Data on 175 patients from 33 centers across eight countries (Greece, Spain, France, Italy, United Kingdom, Germany, Cyprus, and Israel) were included in the final analysis. Basic clinicopathologic characteristics of the study cohort are found in Table  1. Typical for EGFRmutant NSCLC, median age was slightly younger than the average of patients with NSCLC (64. 0 y), and there was a higher prevalence among women (56. 3%), never or past smokers (76. 0%), and those with adenocarcinoma histology (95. 4%). As expected, almost half of the patients had skeletal metastasis at diagnosis (47. 4%) and almost one-third had brain metastases (32%). Tumors were modestly immunogenic: Mean programmed deathligand 1 tumor proportional score was 15. 8% (range: 0-95, N ¼ 110 patients) and mean tumor mutational burden was 7.
Discussion To the best of our knowledge, EXOTIC represents the largest academic effort to report RWE regarding molecular epidemiology and treatment patterns in patients with advanced, exon 20-mutated NSCLC reported to date. This pragmatic registry is representative of daily clinical practice in Europe, because it involved only patients treated outside the context of clinical trials. Given that all the novel exon 20-targeting agents were not authorized in Europe at the time of the study accrual (January 2019-December 2021), this database clearly illustrates the strategy used by treating physicians in Europe during the last three years. In the EXOTIC cohort, CT, alone or combined with IO, accounted for more than half of the cases in first-line treatment, indicating oncologists tend to manage patients with exo-n20in NSCLC as their EGFR wild-type counterparts.
In the latter study,  9  corresponding ORRs were 46% and 0% in the near loop versus the far loop, respectively (p ¼ 0. 0015). In EXOTIC, 83% of the mutations were located in the near loop and 4% within the helix, suggesting that in almost 90% of the cases, novel agents are expected to have high activity. Although EXOTIC was not designed to compare treatment modalities, indirect comparison from subgroup difference analysis suggests that, collectively, use of newer agents in the first line is associated with a survival benefit compared with CT or CT-IO. This is in line with recent data suggesting amivantamab, indirectly compared with real-world therapies, is anticipated to confer an additional 10-month OS. 21 Another recent matching-adjusted indirect comparison between mobocertinib and amivantamab using mathematical projection analysis estimated that both agents are expected to have similar outcomes in terms of PFS and OS.
22 onfirmatory trials, such as the EXCLAIM-2 trial (NCT04129502) comparing directly mobocertinib with platinum-based CT as first-line treatment and trials combining CT with newer agents, including the PAPILLON trial comparing CT plus amivantamab with CT alone (NCT04538664), are currently ongoing. Similar to all RWE studies, our registry harbors some inherent limitations: Data were collected in a retrospective/prospective manner and selection of cases was arbitrary, completely depending on the treating physician. Representation of treatment modalities was subjective and not balanced, largely dependent on the availability of EAP in each one of the participating countries. The latter, together with the exclusion of patients treated within clinical trials, resulted in underrepresentation of some novel agents, such as amivantamab (1.
1% in EXOTIC). These numbers, however, reflect the actual pragmatic situation in each country on the basis of the availability of EAP during the last three years. Amivantamab was authorized by the European Medicines Agency in December 2021 and is now expected to be widely available in most European countries. Finally, similar to all RWE studies, analysis of clinical outcomes is restricted by missing data for some patients, and thus results in terms of disease control rate and OS should be interpreted with caution, until definitive results from ongoing prospective clinical trials become available. In conclusion, EXOTIC is an important multinational RWE study in reflecting clinical practice patterns of treating physicians in patients with rare EGFR mutations in the precision oncology era. Our data suggest that in patients with EGFR exon 20-mutated NSCLC, first-line CT with or without IO will be gradually replaced by the use of novel, exon 20-targeting agents that are expected to herald a new standard in the management of this challenging disease entity.
(ASO for short)  [LCBM21]. Note that we use a similar experimental setting as Lejemble et al. , who have already shown that ASO outperforms many existing approaches from the related works (such as algebraic point set surfaces  [GG07] , wavejets  [BDC18] ). As the JetFitting approach returns absolute curvature values, intervals are clamped to zero for this estimator. For performance evaluations, timings have been measured after the neighbors have been retrieved for the NN data structure, i. e. after the K-NN search for JetFitting, ASO, CNC-Delaunay (skipping the local Delaunay construction as well), CNU-Uniform, and CNC-Avg-Hexagram, and the six NN requests for CNC-Hexagram. Note that for all methods, we have used the same number of neighbors K. For the JetFitting approach, a polynomial surface of degree 4 has been considered.
Additional results Figures  7  and 8  illustrate the stability and the efficiency of our approach on point clouds from scans of historical pieces. Figure  7  displays results computed with CNC-Avg-Hexagram from 50 to 300 neighbors only (K = 50 for the first two objects of 500k points, K = 300 for the third one with 1. 7M points). Overall timings (NN requests and curvature measure estimation) for these three point clouds are respectively 10. 2s, 4. 6s and 85. 5s with a nonoptimized NN data structure. Focusing on the curvature estimation only, timings are respectively 252ms, 258ms and 3991ms (2. 5% to 5. 6% of the total time). Figure  8  shows results computed by CNC-Hexagram, in order to evaluate the quality of the estimation using only six NN requests on a real dataset. As we increase K, which submitted to Eurographics Symposium on Geometry Processing (2023) parisons (for goursat and torus with different neighborhood sizes).
Evidence of positive, diversifying selection in MiMSPs To first test which of the 27 previously identified pioneer MiMSP genes  (Abad et al. , 2008)  have homologs in current genome assemblies of M. incognita  (Kofoid & White, 1919)  and other root-knot nematodes, we used their predicted mRNA sequence to query the Wormbase Parasite cDNA database with the BLASTN algorithm (at parasite. wormbase. org, accessed in May 2020). Hits with a BLASTN score below 100 were disregarded as being false positives. The genome assemblies of the root-knot nematodes referred to in this analysis are available at NCBI under the following accession codes: PRJEB8714 dataset for Meloidogyne arenaria, M. incognita, and M. javanica  (Blanc-Mathieu et al. , 2017) ; the PRJNA340324 dataset for M. arenaria, Meloidogyne enterolobii, Meloidogyne floridensis, M.
incognita, and M. javanica  (Szitenberg et al. , 2017) ; the PRJNA438575 dataset for M. arenaria  (Sato et al. , 2018) ; the PRJEB6016 dataset version nMf. 1. 0 from nematodes. org for M. floridensis; and the PRJNA29083 dataset for M. hapla  (Opperman et al. , 2008). For MiMSPs with three or more hits in the genome assembly of M. incognita PRJEB8714, we generated a multiple sequence alignment of the coding sequences of the paralogous genes using CLUSTALW2. The resulting alignment was used to construct a cluster tree based on the Tamura-Nei genetic distance model. MiMSPs with three or more paralogs in the PRJEB8714 genome assembly of M. incognita were also tested for signatures of positive selection using the CODEML algorithm of PAML 4. 7 (phylogenetic analysis by maximum likelihood;  Yang, 1997 Yang, , 2007;; Yang & Bielawski, 2000)  within EASYCODEML v.
Nematode-containing 6-well plates were incubated at 24°C under dark conditions for the duration of the bioassay. Data collection and statistical analysis The number of root tips was counted for each plant at the time of inoculation. Data were collected in at least three independent experiments and pooled for statistical analysis and visualization. The number of nematodes inside the roots was counted at 7 dpi by means of acid fuchsin staining on the whole root system. Therefore, clean roots were incubated for 5 min in 2. 5% household bleach followed by rinsing for 10 min in tap water. Next, roots were incubated in fuchsinstaining solution (0. 2 M acid fuchsin and 0. 8% glacial acetic acid in tap water) for 30 s in a microwave oven at maximum power. Finally, roots were transferred to 40% glycerol and nematodes could be counted visually using a dissection microscope.
Counting data from tomato or Arabidopsis were collected in at least two independent experiments with n ≥ 16 and combined for statistical analysis and visualization. To be able to pool the data of independent experiments, we normalized the counts for batch effects (Fig. S1d ). To this end, the actual counts were corrected based on the average of counts on wild-type plants from a single independent experiment against the average of counts on wild-type plants over all experiments using T norm ¼ T i À T i,ColÀ0 ÀT total,Col À0 À Á where T norm is the normalized number of nematodes or nematode-induced galls, i is the individual experiment, and T is the averaged number. The batch-corrected data for nematode numbers, gall numbers, and root tip numbers were analyzed in R v. 3. 6. 1. x64. Extreme outliers in the dataset outside the interquartile range of 1.
For constructs carrying a mCherry tag, imaging was done using a 543 nm HeNe laser for excitation and mCherry emission was selected by a 600-650 nm band-pass filter. Chlorophyll emission was detected using a 650 nm long-pass filter. Images were equally enhanced in brightness for publication in print. To quantify differences in subcellular localization, the ratios in fluorescence intensity between cytoplasm and nucleus were calculated in IMAGEJ. Normality of the data was checked using qq-plots from the GGPUBR package in R v. 3. 6. 1 x64, and a oneway ANOVA with post hoc Tukey's HSD was used to determine statistical differences.
Evidence of positive selection in putative M. incognita effectors Twelve years after the publication of the first M. incognita genome sequence  (Abad et al. , 2008) , we revisited the status of 27 previously identified 'pioneer genes' isolated from gland-specific cDNA libraries by  Huang et al. (2003)  using the latest root-knot nematode genome assemblies available  (Blanc-Mathieu et al. , 2017). Querying the WormBase ParaSite nucleotide sequence database with these 27 genes, hereafter named MiMSPs, yielded significantly matching sequences from one or more rootknot nematode species (Fig. 1a ). Surprisingly, for only 19 MiMSPs originally identified in M. incognita, we found at least one significantly matching gene prediction in the latest genome assembly of M. incognita (Meloidogyne_incognita_V3; Fig.
Aligning the clone inserts with the best matching predicted full-length proteins in sequence database of tomato genome version SL2. 50 enabled us to identify the six corresponding genes as Solyc06g073580. 2. 1 (SlH6D; hyoscyamine 6-dioxygenase), Solyc10g074940. 1. 1 (SlALA1; phospholipidtransporting ATPase 1-like), Solyc12g010040. 1. 1 (SlLAPA2; leucine aminopeptidase), Solyc01g103390. 2. 1 (SlOPR2; oxophytodienoate reductase 2), Solyc03g025610. 1. 1 (SlTPPII; tripeptidyl-peptidase 2), and Solyc10g081020. 1. 1 (SlSTP6; transcription elongation factor SPT6-like) (Table  S5 ). Next, we analyzed predicted physiochemical properties of the six interacting protein fragments that could result in nonspecific binding in the Y2H screen (Table  S6 ). We also determined the positions of the interacting fragments relative to predicted subcellular localization signals and conserved protein motifs and domains in the matching full-length proteins  (Marchler-Bauer et al.
Acknowledgements This work was financially supported by the  Dutch Research Council (NWO) Domain Applied and Engineering Sciences (AES/TTW)  grant  11042. MGS was supported by the  NWO domain Applied and Engineering Sciences VENI  grant ( 17282 ). MQ was supported by the  'Investments for the Future' LabEx SIGNALIFE: program  reference # ANR-11-LABX-0028-01  and by the  INRAE-Syngenta  ' Targetome ' project. IFK was supported by the  NWO domain Applied and Engineering Sciences  grant ( 13551 ). We wish to thank  Drs R. Solano  and  A. Chini  for the opr3-3 and opr2-1/opr3-3 seeds. The authors would like to thank the  Wageningen Microspectroscopy Research Facility , for access Ó 2022 The Authors New Phytologist Ó 2022  New Phytologist Foundation New Phytologist  (2023) 237:  2360-2374  www.
Effect of substitutions on the structure of mutant VHHs in complex with their peptide epitope To rationalize the potential effect of the mutations on the interaction, and particularly the effect of the most abundant mutations in the screen, G115E and R47K, we have solved the structures of mutants 1 (G115E), 3 (R47K) and 20 (G115E + R47K) in complex with a Tau[301-312] peptide by X-ray crystallography. We previously reported the crystallographic structure of Z70 in complex with the same peptide containing the PHF6 motif (  16 ) (pdb code : 7QCQ), allowing a straightforward comparison. The structures obtained at a resolution of 1. 83 Å, 2. 35 Å and 1. 54 Å for mutant 1, 3 and 20, respectively, showed no major conformational differences with the parent Z70 bound to its epitope with backbone RMSD values of 0.
Inhibition of in vitro Tau aggregation Z70 was primarily selected for its ability to inhibit Tau aggregation both in vitro and in vivo  (16). Z70 shows a very potent inhibition of in vitro Tau aggregation in the heparin mediated assay in the presence of thioflavin as a fluorescent reporter of the aggregation. We therefore used this assay to evaluate the efficiency of the different mutants to inhibit Tau aggregation in comparison with Z70 at sub-equimolar ratios (Fig. S6, S7 ). To facilitate comparison between the different VHHs, the data from the different aggregation tests were analyzed as a ratio of Thioflavin T fluorescence intensity in the presence of VHH compared to the positive control (Tau alone) for all points in the dynamic range of fluorescence corresponding to an intensity between 10 and 90% of the maximum fluorescence obtained for the positive control, in the absence of any VHH.
Nuclear Magnetic Resonance Spectroscopy Experiments Analysis of the 15 N Tau/VHH interactions were performed at 298K on a Bruker Avance Neo 900MHz spectrometer equipped with cryogenic probe. TMSP (trimethyl silyl propionate) was used as internal reference. Lyophilized 15 N Tau were diluted in NMR buffer with 10% D 2 O and mixed with a VHH at 100 μM final concentration for each protein. 200 μL of each mix in 3 mm tubes were sufficient to obtain the 2D 1 H, 15 N HSQC spectra with 32 scans. 1 H, 15 N HSQC were acquired with 3072 and 416 points in the direct and indirect dimensions, for 12. 6 and 25 ppm spectral windows, in the 1 H and 15 N dimensions respectively. Data were processed with Bruker Topspin 3. 6 and analyzed with Sparky (T. D. Goddard and D. G. Kneller, SPARKY 3, University of California, San Francisco).
FRET Flow Cytometry Cells were recovered with trypsin 0. 05% and fixed in 2% PFA for 10 min, then suspended in PBS. Flow cytometry was performed on an ARIA SORP BD (acquisition software FACS DIVA V7. 0 BD, Biosciences). To measure CFP emission fluorescence and FRET, cells were excited with a 405 nm laser. The fluorescence was captured with either a 466/40 or a 529/30 nm filter, respectively. To measure YFP fluorescence, a 488 nm laser was used for excitation and emission fluorescence was captured with a 529/30 nm filter. mCherry fluorophore was excited with a 561 nm laser and fluorescence was captured with a 610/20 nm filter. To selectively detect and quantify FRET, gating was used as described  (35, 51). The FRET data were quantified using the KALUZA software analyze v2 and an in-house python script using FlowKit  (52).
Acknowledgements We thank  Dr Z. Lens  for support on the T200 biacore measurements and  P. Legrand  for valuable support during data collection at beamline PX1 at the  SOLEIL synchrotron facility (Paris, France). We acknowledge  SOLEIL  for the provision of synchrotron-radiation facilities. We also thank the  BiCel  platform from  US 41 -UAR 2014 -PLBS  for microscopy and FRET data acquisition. The NMR facilities were funded by the  Nord Region Council ,  CNRS ,  Institut Pasteur de Lille ,  European Union ,  French Research Ministry,  and  Univ. Lille. Financial support from the  IR INFRANALYTICS   FR2054   CNRS  for conducting the research is gratefully acknowledged. This study was supported by the  LabEx (Laboratory of Excellence) DISTALZ ( Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease   ANR-11-LABX-01 ), by I-site  ULNE  (project  TUNABLE ) and by the  ANR  (project  ToNIC ,  ANR-18-CE44-0016 ).
Data availability Raw data are deposited in zenodo database (https://doi. org/10. 5281/zenodo. 8083246) or can be shared upon request. Three-dimensional crystallographic structure coordinates and electron densities are available for mutant 1 at https://www. rcsb. org/structure/8OPI, for mutant 3 at https://www. rcsb. org/structure/8OPII and mutant 20 at https://www. rcsb. org/structure/8OP0.
Digital volume correlation DVC is a powerful analysis method to quantify the internal displacement field from high-resolution reconstructed micro-CT images, and thereby determine the strain induced between load increments. In this study the open-source DVC package kintsugi 1  was used. This DVC implementation is based on a global approach  [21]  in which the entire Volume-of-Interest (VOI) is considered and a shared set of parameters is used for displacement interpolation via a finite element (FE) mesh  [22]. This ensures continuity in the resulting displacement field and overcomes the challenges associated with the use of multiple local VOIs, which can be difficult to reliably integrate into a final result when using a local approach  [23, 24]. Accordingly, despite sometimes being more processor intensive, the accuracy of the global DVC approach is typically much higher than a local equivalent  [25] [26] [27].
Experimental setup Micro-CT image acquisition was performed at the I13-2 beamline at Diamond Light Source. A pink beam of peak energy 19 keV was obtained through a series of Pyrolytic graphite filters and an aluminium filter, and the beam was collimated to 10 mm × 10 mm using beamdefining slits. The PCO. edge high speed 5. 5 X-ray camera was used to capture radiographs at each load increment at a resolution of 2560 × 2560 px. Micro-CT data was collected via a flyscan over 180 • at an increment of 0. 01 • (18,000 projections) with an exposure time of 50 ms. A ×2 objective lens was selected in addition to the detectors ×2 predefined magnification (×4 total magnification), resulting in a FOV of 4. 2 mm × 3. 5 mm with an effective pixel size of ∼ 1. 625 μm. This pixel size is sufficient to distinguish individual fibres with 𝜙 𝑓 = ∼ 7 μm in diameter.
To enhance the phase contrast between the fibres and matrix, an in-line phase propagation study was employed by collecting micro-CT data sets at a range of sample to detector distances  [35]. The reconstructions were then analysed to determine an optimised sampleto-detector distance of 580 mm. A schematic representation of the synchrotron experiment is shown in Fig. 2. A Deben CT5000 5kN load cell, co-axially fixed onto a tomography tower, was used to perform in-situ compressive testing of baseline and defect-rich samples. The tower was composed of an Aerotech goniometer, along with multiple Huber and Newport motors, to facilitate sample rotation and the translation required for synchrotron micro-CT at the location of interest. A compressive load was applied at a rate of 0. 1 mm/min along the primary fibre axis of the sample.
Micro-CT data were collected at each increment load while the motors held stationary, and the increment was reduced close to the expected failure loads for all samples until they failed. This ensured that the initiation of failure and subsequent failure (e. g. fibre kinking, matrix shear and fibre fracture) were captured during the experiment. The samples were held using steel grips that were able to load the sample via the resin blocks on either end. Estimates of the expected failure load were obtained by loading 10 nominally identical samples of each type before the start of the synchrotron experiment. These results were used to determine the load increments applied to the sample during the micro-CT study.
Image processing 3. 3. 1. Image reconstruction The parallel-beam tomography data collected at the synchrotron was reconstructed via a back projection algorithm implemented within Savu  [37] , which included dark-and flat-field correction. Ring artefact correction was performed to minimise artefacts in the micro-CT scans. The centre of rotation (COR) of the image was determined manually from an iterative process by processing a single slice in which the COR was iteratively shifted by 0. 5 px. This allowed a visual determination of optimal COR, which overcomes some of the limitations of the automated process.
Fibre orientation determination Structure-tensor analysis was implemented on the micro-CT datasets collected at different load increments in order to estimate the fibre's orientation distributions and changes. The structure tensor can be defined as a product of ∇𝑓 ⨂ ∇𝑓 at each voxel, where ∇𝑓 is the image gradient computed from an optimal kernel for the fibres  [26, 38, 39]. In order to determine the first order estimate of this structure tensor,  neighbouring voxels are convoluted with a Gaussian kernel to reduce noise and other artefacts which can significantly impact the estimates obtained. Optimisation of the kernel size was incrementally performed on the data set, in order to determine a value that effectively suppressed noise whilst not over smoothing the underlying data. From this analysis the optimal window size was determined to be 9 × 9 × 9 voxels.