dataesr/scientific-paragraphs-categorization huggingface dataset:
2% with graft failure), emphasizing the importance of early management. In comparison, the β-thalassemia-free survival in European children transplanted from matched sibling donors from 2000 to 2010 was about 81%. 9  Nonetheless, a majority of children with TM will require life-long transfusion and iron chelation or, hopefully in the near future, benefit from emerging treatments including gene therapy. This study has a number of limitations. While the enrolment and data are exhaustive regarding children with TM who are regularly transfused, a proportion of patients with TI had missing data. In addition, less symptomatic children may be potentially underdiagnosed and underreported. Importantly, data on quality of life were not collected, so the true burden of the disease could not be captured by this study.
04-0. 12 mbar, or sometimes just gravity flow) and captured by the optical trap, which quickly brings the cell to the micropipette tip. A minute amount of suction was applied to keep the cell stably engage with the tip (so it neither floats away from the tip nor falls back into the optical trap) but without any visible deformation of the cell morphology (as seen in bright field camera). Then following the same bead calibration procedure and membrane tether pulling process as described earlier, consecutive rounds of aspiration and relaxation were performed on the cell for as long as the membrane tethers persist (see Movie S12-13). Image and membrane tension analysis Fiji (NIH), Excel (Microsoft; Redmond, WA), custom Python code, and Prism (Graphpad software, Inc) were used for image and membrane tension analysis.
Average trap force plots (Fig. 1E , 2C, S3A, B, S4A, B) were obtained by aligning trap force traces at time of light induction. Average linked trap force plots were made using Prism Graphpad software, Inc). In Fig. 1F , average trace trap force was measured for 60 seconds before light induction (steady state) and for the duration of the light induction (90 seconds, Light). For Fig. 4F , average trace trap force shown here for 30 seconds before aspiration (steady state) and for the duration of aspiration (15-30 seconds) and intervening recovery periods. Pearson correlation coefficients between T1 and T2 were calculated using Prism Graphpad software, Inc) (Fig. 2H , Fig. S4D , Fig. S5J , and S8G). For Fig. 2H  and S5J, we used 30 seconds before activation for steady state, 30 seconds of light induction for opto-activated protrusion, and ~10-30 seconds of active tether pulling on cell membrane (tether length >30 µm) and on blebs.
Cortical actin flows We reproduce this procedure with actin. We generated kymographs of actin for each cells, and velocity fields from these kymographs. Velocity fields are then averaged across cells (Fig. 3H ). We see the same behavior than with membrane flows: anterograde and then retrograde flows (Fig. 3I ). We provide a (Jupyter Notebook) and the original data for reproducibility on Github. 2 Composite membrane-cortex mechanical model.
National Institutes of Health  grant  GM118167  (ODW),  National Science Foundation/Biotechnology and Biological Sciences Research Council  grant  2019598  (ODW), the  National Science Foundation Center for Cellular Construction  ( DBI-1548297 , ODW), and a  Novo Nordisk Foundation  grant for the  Center for Geometrically Engineered Cellular Systems  ( NNF17OC0028176 , ODW), the  Labex MemoLife, France  under the program " Investissements d'Avenir "  ANR-10-LABX-54  (HBR), the  European Research Council (ERC)  under the European Union's  Horizon 2020 research and innovation programme  (Grant agreement No. 949267 ) (HBR, HT), a  QLife  ( ANR-17-CONV-0005 ) / QBio grant (ODW, HT),  EMBO   ALTF 203-2021  (HDB),  National Institutes of Health  grant  K99GM137074  (SY), and  Howard Hughes Medical Institute (CB).
Reproducibility in organ size and shape is a fundamental trait of living organisms. The mechanisms underlying such robustness remain, however, to be elucidated. Taking the sepal of Arabidopsis as a model, we investigated whether variability of gene expression plays a role in variation of organ morphology. To address this question, we produced a dataset composed of both transcriptomic and morphological information obtained from 27 individual sepals from wild-type plants. Although nearly identical in their genetic background, environment, and developmental stage, these sepals exhibited appreciable variability in both morphology and transcriptome. We identified modules of co-expressed genes in sepals, three of which correlated significantly with morphology, revealing biologically relevant gene regulatory networks.
A unique dataset to analyze the association between gene expression and morphology Our goal was to analyze the variability of both the morphology and the transcriptome of individual sepals from wild type plants grown in standard conditions. On a single inflorescence (flowering stem) of Arabidopsis, flower buds initiate at regular time intervals in a continuous manner. Each flower bud contains four sepals that are formed in a defined order, the first one to emerge being called the abaxial sepal (it forms on the flower-bud side furthest away from the meristem). Previous studies  (Hervieux et al. , 2016; Hong et al. , 2016)  have shown that arrest of sepal growth begins at stage 11 (according to staging of Arabidopsis flower development described in  Smyth et al. , 1990). We therefore chose early stage 11 to collect sepals and to minimize stage heterogeneity.
Highly variable genes are enriched in response to stimulus and cell-wall functions We have classified our set of 14,085 genes according to their variability by measuring their CV 2 across 27 samples. Given the higher variability (both technical and biological) found in lowly expressed genes, one can correct CV 2 to account for this association  (Cortijo et al. , 2019). However, the gene expression threshold that we have set has eliminated most lowly expressed genes from our dataset and essentially, there is no correlation between CV 2 values and average gene expression. Hence, we have ordered genes by their raw CV 2 values and have selected highly variable genes (HVGs: top 5%, top 5-to-10%, and top 10-to-15%), and lowly variable genes (LVGs: bottom 5%, bottom 5-to-10%, and bottom 10-to-15%) in order to see if these groups of genes were enriched in particular biological functions (Figure  5A ).
A curated cell-wall related gene list to assess gene ontology Highly variable genes are enriched in cell-wall functions. Additionally, cell-wall related genes are over-represented in modules of coexpressed genes which have the strongest correlation with morphological parameters. These two observations might be related. Importantly, they are both driven by GO annotations which are known to be incomplete and biased  (Timmons et al. , 2015). In order to use an alternative approach to assess cell-wall related gene expression in sepals, we have compiled a non-exhaustive but rather comprehensive list of cell-wall related genes centered on genes encoding proteins involved in structure, biosynthesis and cell-wall remodeling. To produce this list, first, we referred to a review describing all the enzymes acting on the cell wall (Frankova and Fry, 2013) and identified the corresponding genes in the TAIR Arabidopsis database (www.
tair. com). Second, we used the CAZy database (www. cazy. org) describing families of structurally-related catalytic and carbohydrate-binding modules of enzymes that degrade, modify or create glycosidic bonds to find corresponding genes in the Arabidopsis genome. Finally, we manually enriched the list with proteins known to directly interact with those enzymes in the cell wall, such as pectin methylesterase inhibitors or interactors of cellulose synthase, also adding the extensins, which are non-enzymatic proteins highly abundant in the cell wall and important for its biosynthesis. After removing duplicates, we recovered a list of 1585 genes (Supplementary Table  4 ) that we will refer to as "cell-wall related gene list". Our cell-wall related gene list was compiled from the whole Arabidopsis genome.
Among these genes, 718 are expressed in sepal since they are within our 14,085 sepal gene set. We tested for enrichment of cell-wall related genes within this list across our modules and confirmed that the magenta and orange modules are enriched in cell-wall related genes (Figure  6A ). Additionally, CV 2 values of genes within our cell-wall related gene list are higher compared to the entire gene dataset (Figure  6B ) confirming our results on variability of expression based on GO term enrichment.
Variability of cell-wall mutant morphology correlates with average expression of corresponding genes in wild-type plants To further explore the link between cell-wall related gene expression and sepal morphology, we decided to exploit an unpublished mutant dataset previously produced in our team  (Dumond, 2017). This mutant dataset had been generated in the context of sepal phenotype exploration and contained data for 16 of the 718 cell-wall related genes expressed in sepal. The mutants had been selected based on the level of expression of the corresponding genes in sepals at stage 12 (from publicly available datasets, not from our RNA-Seq data) and on availability of mutants with T-DNA insertions in exons. Because it is difficult to compare developmental stages between mutants and wild-type, we focused on sepals that had ceased growing (stage 12).
Modules and enriched gene ontology categories To recover modules of co-expressed genes, we used the WGCNA package  (Langfelder & Horvath, 2008)  which allows this with relatively few parameters to adjust. Other tools, such as sPLS  (Lê Cao et al. , 2008) , also allow for the association of two-block data, such as gene expression and morphology. However, sPLS recovers individual genes instead of modules. Given the risk of false positives when focusing on small subsets of genes, we considered that associating morphology to modules of co-expressed genes instead of individual genes was a more conservative approach. Based on our morphology analysis, we predicted that area and aspect ratio were the most informative parameters to describe sepal size and shape. However, our WGCNA results show width as the most highly correlated parameter.
Segmentation and extraction of geometrical parameters Images are pretreated in the xy plane using a Gaussian filter of sigma of the order of the z direction voxel size. Then a normalizing procedure is performed on the whole filtered sample. The linear normalization is constructed in such a way that it superimposes the background value and the Otsu threshold value of the output images. The sepal's contour detection procedure is based on the Edge Detect Morphology process of the MorphoGraphX software. First, a rough contour is assessed as the intersection of the top-down and the bottom-up contours given by Edge Detect. Then a dilation in the xy direction is performed in order to recover the weakly marked margin cells of the sepals. The principal directions of the sepal contour are computed, and sepals are placed in the frame where their center of mass is in the origin (their first principal axis is along the Oy axis and the second principal axis is along the Ox axis).
The length measurements are done on the longitudinal and transversal principal sections using a python script. The sepal's abaxial and adaxial surfaces are separated by watershed segmentation of the maximal curvature map constructed on the sepal's whole surface. Then the area of the abaxial surface is computed as areas of cells on a tissue surface mesh in MorphoGraphX. The morphological parameters measured are length, width, area, longitudinal curvature and transversal curvature. Aspect ratio is length divided by width and Gaussian curvature is the product of longitudinal and transversal curvatures. In order to validate geometrical measurements, we compared a sample of 10 images from 10 different sepals with a sample of 10 images of the same sepal that was manipulated between consecutive shootings.
GO enrichment analysis Gene ontology enrichment analysis was performed with PANTHER17. 0 (Mi et al. , 2021) at http://pantherdb. org (last accessed on 2022-03-30) with the following parameters: Analysis Type: PANTHER Overrepresentation Test (Released 2022-02-02); Annotation Version and Release Date: GO Ontology database DOI:10. 5281/zenodo. 5725227 Released 2020-11-01; Test Type: FISHER; Correction: FDR. Background used was our 14,085 gene dataset (Supplementary Table  2 ), and Arabidopsis whole genome (Supplementary Table  3 ). Top hierarchy GO terms were obtained by filtering the PANTHER output with the following criteria: only positive enrichment terms were kept, only top hierarchy terms in each block (as output by PANTHER) were kept according to total number of genes associated with each GO term, terms were ordered according to their false discovery rate (FDR) starting from the smallest rate, only the top five resulting terms were kept for each highly-variable group (HVG) or lowly-variable group (LVG) group unless a term in the top five in one group also appeared in another group, in which case it was kept in both.
Gene regulatory networks Gene regulatory network reconstruction was performed with GENIE3  (Huynh-Thu et al. , 2010)  with the Random Forest method and default parameters. The weighted adjacency matrix obtained was modified by setting all adjacent values above 0. 045 to 1 and below 0. 045 to 0. The 0. 045 threshold was chosen to improve visibility and to include all cell-wall related genes in the magenta module. Graph visualization was performed by using the graph_from_adjacenty_matrix function from the igraph (version 1. 2. 11) package and the ggnet2 function in R. Genes under the GO term "cell wall organization or biogenesis" (GO:0071554) were extracted from Agrigo2. 0  (Tian et al. , 2017)  at http://systemsbiology. cau. edu. cn/agriGOv2/ (last accessed on 2022-02-20) and are listed in Supplementary Table  7.
Acknowledgements We wish to acknowledge  A. Roeder  for constructive discussion and for suggestions on a first version of the manuscript,  A. Ahmed  for work on a pilot project, PLATIM for provision of microscope facilities, Helixio for their excellent service and assistance in the RNA sequencing,  J. Pelloux  for sharing mutants and discussion on cell wall,  Y. Long ,  P. Das ,  A. Fruleux  and  S. Bovio.
The present results show that at least two protomers should be considered as representative structures of the protonated ATP molecule, instead of just one typically presumed in the literature. Moreover, the remarkable resemblance between gasphase and solvated (at low pH) ATP suggests then that such calculated structures could also be relevant as a starting point in modeling the structure of hydrated and solvated ATP, as discussed in more detail in section S6 of the Supporting Information, where the effect of water molecules on structures and spectra is discussed. However, our combined theoretical/ experimental study shows that NEXAFS data at the N K-edge alone are thus far not sufficient to unambiguously identify one of the protomers as the only (or most abundant) species. Further analysis of C spectra is therefore required to gain more   24  of protonated ATP (light blue), solvated ATP at pH 2.
■  ACKNOWLEDGMENTS Giuseppe Mattioli  is extremely glad to thank  Lorenzo Avaldi  for many years of fruitful discussions on core-level spectroscopies. The authors thank  O. Plekan  and  D. N. Kelly  for sending their published results as tabulated data. The work of  Robin Schurmann  was supported by a postdoc fellowship of the  German Academic Exchange Service (DAAD). The work of  Giuseppe Mattioli  was financially supported by  ICSC-Centro Nazionale di Ricerca in High Performance Computing ,  Big Data  and  Quantum Computing , funded by  European Union-NextGenerationEU  (Grant  CN00000013 ). The SOL-EIL synchrotron radiation facility is acknowledged for providing beamtime under Projects  20190201  and  20200345. This work was performed within the frame of  COST Action   CA18212 MD-GAS.
Background: The diagnostic strategy for pulmonary embolism (PE) includes a D-dimer test when PE probability is low or intermediate, but false-positive D-dimer results are frequent and can result in an unnecessary computed tomography pulmonary angiogram. The PE rule-out criteria (PERC) rule excludes PE without D-dimer testing when pretest probability is <15%. The aim of this study was to assess the safety of the PERC rule strategy in patients included in the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry. Methods: This retrospective cohort study used data from the RIETE registry, an ongoing, international prospective registry of patients with objectively confirmed venous thromboembolism. The primary outcome was the failure rate of the PERC strategy, represented by the proportion of PERC-negative (PERC-N) patients with a PE included in the registry.
23 Finally, a large European prospective observational study found that the PERC failure rate was only 1. 2%, with a PE prevalence of 11. 4%. 24 Although the UK National Institute for Health and Care Excellence (NICE) guidelines encourage clinicians to consider using the PERC rule if clinical suspicion of PE is <15% based on their gestalt,  23  it is not yet recommended in the latest European guidelines. 1  Evidence regarding the PERC rule is based on publications from clinical trials, but their generalizability to the real-life clinical setting may be limited. 25 The Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry provides data on the management of venous thromboembolism (VTE) in such a setting with an unselected patient population. 26 Notably, the registry offers a unique opportunity to assess the performance of the PERC rule by using its large international database of VTE patients enrolled in diverse types of hospitals over the past 20 years.
Study design This retrospective cohort study used data from the RIETE registry from March 1, 2001, through December 31, 2021. The methodology of the RIETE registry has been described elsewhere. 27 Briefly, this ongoing, international prospective registry has enrolled consecutive patients with objectively confirmed VTE since 2001. At each Conclusions: A low failure rate of the PERC rule was observed in the RIETE registry, thus supporting its use to safely identify patients with an unlikely probability of PE. participating site, consecutive patients are screened by the site investigators and checked for eligibility. Regular audits are conducted to check for the sequential inclusion of patients, data completeness, and accuracy. Patients are excluded if they are currently participating in a therapeutic clinical trial involving blinding of their medication or if they are unavailable for a 3-month follow-up.
Measures The primary outcome of our study was the overall percentage of PE patients included in the RIETE registry who were PERC-N and therefore represented the failure rate of the PERC rule. The registry does not provide all the items required to estimate the pretest probability of PE as clinicians' gestalt, "PE as the most likely diagnosis" in the Wells' score, and "unilateral lower leg pain" in the revised Geneva score are not recorded. Therefore, we draw a parallel with the two-tier Wells' score: given the shared criteria between the Wells' score and the PERC rule, PERC-N could have a maximum of 4 points (Appendix S1), i. e. , PE unlikely using the two-tier rule with a prevalence of <15%. 28 condary outcomes were: (1) to identify if specific characteristics suggested by others,  12, 24  such as chest pain, pregnancy, or postpartum status, were associated with PERC-N cases; (2) to compare the localization of PE, a mandatory item since 2012 in the database, its hemodynamic repercussion on the right ventricle, treatment strategies, and outcome at 3 months of PERC-N versus PERC-positive (PERC-P) patients, with the aim to determine the clinical significance of missed PE in both patient groups  12  ; and (3) to assess if the proportion of PERC-N patients had decreased over the years in the registry, a potential indicator that more PEs had been left undiagnosed as the PERC rule has been more widely applied.
Data analysis Descriptive statistics are presented as the mean and standard deviation for continuous variables or as proportions for categorical variables. Baseline characteristics between groups were compared using the chi-square test or Fisher's exact test for categorical variables and Student's t-test for continuous variables. We excluded multiple patient visits and verified the normal distribution of continuous variables. We used a chi-square test to compare the burden of the index PE (the proportion of patients with PEs in subsegmental only, segmental, more proximal arteries, or not provided) and also the proportion of patients in each of the four categories. For clinical outcomes, odds ratios and corresponding 95% CIs were calculated. Incidence rates were calculated as the cumulative incidence (events per 100 patient-years of follow-up) and compared between PERC-N and PERC-P patients.
22, 24  However, the prevalence of PE was <5% in these studies and they had probably very few PERC-N patients. Our study showed that PERC-N patients had nonnull rates of recurrent PE or death, albeit much lower than in PERC-P patients during anti-   [48] [49] [50]  An increased proportion of large hospitals participated in the RIETE database during this period and were probably associated with a higher proportion of PERC-N patients. A higher adherence to guidelines may have played a role in this increase, such as the use of the PERC rule. 51.
S TRENG TH S AND LIMITATI ON S The strength of our study lies in the use of the RIETE registry, a large-scale, multinational, observational study that has been ongoing for the past 20 years, with the inclusion of PE patients covering the whole spectrum of PE severity managed in various international settings, all of which provide a good external validity to our results. However, our study has several limitations. First, the number of PERC-N patients was relatively small, with additional loss-tofollow-up or missing data. Nevertheless, to the best of our knowledge, this study has included the largest number of PERC-N patients to date. Second, the RIETE registry is an ongoing observational registry with data collected from multiple international hospitals on a voluntary basis, which may differ from nonparticipating ones.
Study design and population JADE (56136379HPB2001; ClinicalTrials. gov Identifier: NCT03361956) was a phase 2, randomised, partially-blinded, multicentre, interventional, placebo-controlled, two-part study in patients with CHB evaluating oral JNJ-56136379 administered as monotherapy or in combination with ETV or TDF (figure  1 ). Two, otherwise identical parts, explored 75 mg (part 1) and 250 mg (part 2) of JNJ-56136379 administered qd. The study included patients with non-cirrhosis aged 18-70 years with documented hepatitis B e-antigen (HBeAg) positive or negative CHB infection who were not currently treated at study start (NCT) or virologically suppressed (VS) with TDF or ETV at study start (inclusion and exclusion criteria provided in online supplemental table  S1 ). Each part comprised a screening (≤8 weeks), treatment (24 weeks plus a 24-week extension, depending on response) and follow-up phase (24 weeks or 48 weeks, depending on response).
Hepatology Efficacy and safety analyses were conducted for all randomised patients who received ≥1 dose of study drug. Comparisons among the pooled placebo+NA, JNJ-56136379 75 mg+NA and JNJ-56136379 250 mg+NA treatment arms were described. Non-compartmental PK analyses of plasma and urine concentration-time data were performed. Descriptive statistics were used to compare plasma PK parameters for different treatments.