dataesr/scientific-paragraphs-categorization huggingface dataset:
This leads to inaccuracies and may introduce artifacts during post-processing, which requires excellent registration of the acquired volumes. In previous post-mortem experiments in mice  (Li et al. , 2012; Liu et al. , 2012)  and also in humans  (Alkemade et al. , 2020; 2022) , the problem of inconsistent deformations was avoided by keeping the fixed brain within the skull after surgical separation of the head. In the current work, a specific brain mask was derived from the 3D  1 -weighted dataset and a custom-made container was designed consisting of an inner and an outer part (Figure  1B-E ). Based on the mask, the surface of the individual anatomy was reconstructed and split into a top and a bottom mesh using Python (Figure  1B ). The algorithm further allowed for a parameterization of the design, for example, to consider an additional distance from the tissue or modify the wall thickness for sufficient stability.
Stereolithography (STL) files were then produced using CAD (computer-aided design) software (Fusion 360 ® ; Autodesk, San Rafael, CA, USA). The outer container was a spherical structure of sufficient size (16cm diameter) to take up the anatomically shaped inner container, which was rigidly connected via eight adjustable screws (Figure  1E ). The spherical outer shell also consisted of two parts (top and bottom) with further indications of 60 unique orientations on its surface. The orientations were calculated employing an electrostatic repulsion optimization model using MRtrix3  (Jones et al. , 1999; Tournier et al. , 2019). The outer container was then positioned on a custom-made holder that included an additional position indicator (Figure  1E ). The combined setup ensured robust positioning of the specimen in the RF coil with an orientation error ≤3° for all axes.
Image acquisition All MRI experiments were performed at 3 T on a MAGNETOM Skyra Connectom A (Siemens Healthineers, Erlangen, Germany) that achieves a maximum gradient strength of 300 mT/m  (Fan et al. , 2022). In order to avoid damage to the gradient coil during long scanning sessions, a first-order approximation of the acoustic response was computed in Matlab from the simulated gradient time course (IDEA DSV file) of each individual imaging protocol with its specific acquisition parameters  (Labadie et al. , 2013)  and carefully inspected for potentially harmful vibrations. The brain container and holder were then positioned inside a 32-channel receive array coil (Siemens Healthineers), and a complex-valued 3D Fast Low-Angle SHot (FLASH) reference dataset  (Frahm et al. , 1986).
0. 9). Following registration of the GRE and DWI acquisitions to the same reference, voxelwise CSA-ODFs were estimated separately from the orientation-dependent phase or diffusivity data using the DIPY package (Python). The DTI-based FA metric was employed for deriving a mask including only regions of sufficient tissue anisotropy (FA > 0. 2). Further processing of the local phase data included outlier exclusion by thresholding and normalization to [0,1] prior to the ODF estimation (Figure  2 ). For quality assessment, the SNR was calculated for each registered GRE volume based on the magnitude images. Briefly, GM and WM masks were calculated using thresholding on the reference GRE dataset, and a 3D region of interest (ROI) was defined within ranges of ±20 voxels in anterior-posterior, ±50 voxels in inferior-superior and ±25 voxels in right-left direction around the center (Figure  3A-C ).
Tensor-based analyses The high-angular GRE phase dataset provided unprecedented susceptibility tensor quality (Figure  5A ). Similarly, an excellent diffusion-tensor quality was obtained with DWI, which was of equivalent spatial and angular resolution as the GRE acquisitions (Figure  5B ). Consistently, the eigen-analysis of the diffusion data yielded a high quality of the MD and FA. The corresponding susceptibility metrics, MMS and MSA, yielded robust differentiation between WM and GM. The MMS exhibited local differences also within WM, indicating a particular sensitivity to the underlying microstructure of the voxels. The MSA results suggested a high sensitivity to microstructural changes but also to spurious noise from residual artifacts. Due to this slightly enhanced noise sensitivity of MSA, the DTI-derived FA map was selected as a more robust indicator of anisotropy.
, 2020; Fan et al. , 2022). In comparison, QSM acquisitions are less demanding on the hardware, and the signal loss at TEs in the order of 25 ms at 3 T or 12 ms at 7 T that are required for sufficient phase evolution is smaller than that inherent to DWI. Consequently, human whole-brain (magnitude) GRE datasets at 100-200 µm are available as digital resources  (Alkemade et al. , 2022; Ding et al. , 2016; Edlow et al. , 2019). Although the precise registration of multi-orientation phase data remains challenging, the HARSI approach introduced here as a proof of concept holds great potential to go beyond current (spatial) resolution limits of diffusion-based investigations of connectivity patterns. Currently existing histological methodologies to obtain 3D information on the fiber architecture require complicated preparations  (Morawski et al.
Acknowledgements This work was funded by the  EU  through the  ITN "INSPiRE-MED " ( H2020-MSCA-ITN-2018 , # 813120 ). Chunlei Liu  and  Jingjia Chen  were supported in part by the  National Institute of Aging of the National Institutes of Health  (Award No. R01AG070826 ). We particularly thank  Angela D. Friederici  and  Nikolaus Weiskopf  and further  Evolution of Brain Connectivity (EBC)  project organizers, the  Ministère de l'Enseignement Supérieur et de la Recherche Scientifique  and the  Ministère des Eaux et Fôrets, Côte d'Ivoire , the  Office Ivoirien des Parcs et Réserves , and the staff of the  Taï Chimpanzee Project  for permitting and supporting this research. Appreciation is extended to  Michael Paquette ,  Riccardo Metere  and.
Baseline assessment and data collection The following parameters were recorded in the electronic case report form of each subject: age, sex, body mass index, comorbidities, dates of first COVID-19 symptoms, RT-PCR positivity, and hospital and ICU admission. Baseline respiratory parameters included oxygen saturation measured by pulse oximetry (S pO 2 ), respiratory frequency, O 2 supply, arterial blood gas (ABG), P aO 2 :F IO 2 and Borg scale ranking. P aO 2 :F IO 2 was calculated with F IO 2 for patients who received O 2 with a high-flow nasal cannula or estimated for those who received O 2 through non-rebreathing masks with the following formula  [16] : F IO 2 =21%+oxygen flow rate in L•min -1 ×3 Thoracic computed tomography (CT) scan was performed as routine exam at ICU admission, and findings were collected.
Statistical analysis The methodology of analysis complies with the Consolidated Standards of Reporting Trials Statement (CONSORT, http: //www. consort-statement. org/consort-statement/). The statistical analysis and figures were generated using SPSS Version 20 (IBM SPSS Inc. , Chicago, IL, USA). We postulated that PP would be associated with a decrease in the GI index of 20% (with a standard deviation of 20%). With a power of 80% and α risk of 5%, we needed to include 10 patients in each group. A crossover design was chosen to avoid the risk of important inter-individual heterogeneity and was sufficient with a global cohort of 10 patients. A washout period of 30 min was used to decrease the risk of sequence effect (carryover effect). However, in case of a sequence effect, a higher number of anticipated patients (10 patients for each sequence) counteracted this risk of loss of power.
Results A flow chart of the study is shown in figure  2. Initially, 22 patients gave their consent and were included in the study. One patient was rapidly intubated after consent, and another withdrew his consent; therefore, data were available for 20 patients. Table  1  shows the demographics, medical history, gravity scores, thoracic CT scan findings, respiratory function and support at ICU admission and clinical outcomes of the studied population. Three patients were intubated during their ICU stay, and one of them died. The overall ICU and hospital mortality rate was 5%. 10 patients were randomised into each group (SP-aPP and aPP-SP). One patient in the SP-aPP group could not tolerate aPP, so all time points were available for only nine patients in this group. An example of EIT measurements for one patient in each group is provided in figure  3.
Acknowledgements: We would like to thank the patients and their families and all the frontline caregivers involved in the COVID-19 pandemic. We also thank  Basile Puech  for the computed tomography scan analysis. This study is registered at www. clinicaltrials. govwith identifier number  NCT04632602. Individual patients' data reported in this article will be shared after de-identification (text, tables, figures and appendices), beginning 6 months and ending 2 years after article publication, to researchers who provide a methodologically sound proposal and after approval of the corresponding author. The datasets generated and analysed during the study are available from the corresponding author upon reasonable request.
These data correlated with the mobilization of intracellular calcium, another proximal signaling event (Figure  5D ). These data reveal the defective nature of early TCR-mediated signaling events in T cells expressing the R170C ZAP-70 mutant. Previous studies have revealed the importance of the R192 residue in the function of ZAP-70 as an R192W mutation, also in the SH2-C domain, results in impaired binding of the mutant ZAP-70 to the phosphorylated z-chain  (41, 42). To assess the potential of the R170C ZAP-70 to bind to TCR-z, we performed TCR-z immunoprecipitations on parental Jurkat (E6-1) as well as the ZAP-70 -/-/Syk -/-p116 cells reconstituted with EGFP, WT ZAP-70, and R170C ZAP-70. As shown in Figure  5E , ZAP-70 only coimmunoprecipitated with TCR-z in cells harboring a WT ZAP-70. Thus, these data highlight the importance of the R170 residue in mediating association with the TCR-z chain.
Indeed, recent work highlights a network of non-covalent interactions that result in the coupling of the two SH2 domains to the doubly-phosphorylated ITAMs  (46). Using PyMOL  (47)  to generate a structural representation of the ZAP-70 SH2 domains associated with the TCR-z chain, the prominent positioning of these three arginine is highlighted (Figure  6A ). Furthermore, using the AlphaFold2 protein structure database  (48, 49) , the predictions reveal changes in the structure of the residues associating with TCRz upon mutation of arg-170 to cys and arg-192 to trp (Figure  6B ). These results strongly suggest that the pathological consequences of mutations in R170 and R192 of ZAP-70 are due to changes in the binding of ZAP-70 to TCR-z.
High resolution melting analysis by qPCR Genomic DNA was extracted as described above. Detection of the R170C mutation and the 13bp deletion was performed by Real-Time qPCR using the LightCycler 480 High Resolution Melting Master mix (Roche) on the LightCycler480 machine (Roche). Briefly, genomic extract (10ng) was amplified with exon 4 primers specifi c for the R170C mutation (Forward: CTGGAGCAGGCCATCATCAGC; Reverse: GCCCCACATACA GGAACTTG) and exon 12 primers specific for the 13bp deletion (Forward: GATCCAGCAGCATCTCCC; Reverse: CCTCCCA CATGGTGACC) using the following program; 5 sec 95°C, 10 sec 60°C, 10 sec 72°C, for 30 cycles. An extensive HRM curve (from 62 to 95°C, rate 0. 02°C/sec) was analyzed using LightCycler 480 II software.
For evaluation of TCR signaling, Jurkat cells transduced with the indicated vectors were starved overnight in RPMI media containing only 1% FCS. Cells (1x10 6 ) were then activated in 100 µl RPMI with anti-CD3 (clone OKT3, 1 µg/ml) and anti-CD4 (clone 13B8. 2, 1 µg/ml) mAbs for 1 min, and crosslinked by goat anti-mouse Fab'2 fragment (1:100) for 2 min. Cells were assessed on a FACS-CantoII or BD LSRII-Fortessa (BD Biosciences) and data were analyzed using Diva (BD Biosciences) or FlowJo (Tree Star) software.
Proliferation assays Proliferation was monitored as a function of CFSE dilution. CD3 + T cells were stained with 1mM CFDA-SE (Cell Trace CFSE kit, ThermoFisher) for 3 min and washed twice with PBS 2% FCS. T cells (1x10 6 ) were subsequently plated into anti-CD3/anti-CD28 coated wells (clones OKT3 and 9. 3 respectively, BioXCell) or stimulated with PHA (1mg/ml-Sigma) and rhIL2 (100IU/ml-Proleukin). Proliferation was evaluated at day 5 following staining with anti-CD4 APC (clone 13B8. 2) and anti-CD8 PeCy7 (clone SFC121Thy2D3) mAbs and data acquired on a FACSCanto II Flow Cytometer (Becton Dickinson). Analyses were performed using FlowJo Software (v10-10. 6. 2).
Calcium flux analyses ZAP-70 -/-/Syk -/-p116 cells (2x10 6 ) expressing EGFP, WT ZAP70, or R170C ZAP70 were loaded with 1µM of the ratiometric calcium indicator Indo-1 (Molecular Probes) for 30min at 37°C. Cells were then washed and analyzed; after 1 min of acquisition on a BD FACSAria (Becton Dickinson), cells were activated by addition of anti-CD3 (clone UCHT1) and anti-CD4 (clone 13B8. 2) mAbs for 1 min followed by crosslinking using an anti-mouse Fab'2 fragment for 2 min. Calcium flux was analyzed as a function of the ratio of the green (filter BP 530/30nm) and violet emissions (filter BP 450/50nm) of Indo-1 using FlowJo software.
Funding CM and VZ are supported by the  CNRS. RV was supported by a fellowship from the  Portuguese Foundation for Science and Technology  ( SFRH/BD/23553/2005 ) and the  Association Francaise contre le Myopathies (AFM-Telethon ). NN and NT were supported by  INSERM  and  NT  is presently supported by  NCI  intramural  NIH research program  ( ZIA BC 011924 ). This work was funded by grant  R01AI059349  from the  NIAID ,  NIH , the  AFM ,  ANR ,  ARC  and  INCa  (to NT and VZ) as well as David's  Dream Research Funds  (to JC).
6 6 FIGURE 6 Pathological arginine mutations in the ZAP-70 C-terminal SH2 domain interact with the TCR-z-ITAM binding pocket. (A) Ribbon representation of the 3-dimensional structure of human ZAP-70 highlighting the interaction with a 19-mer TCR-z peptide containing phosphotyrosine 304. The binding of ZAP-70 to the phosphate within TCR-z (purple) occurs via hydrogen binding to three residues; arginine 170, 190 and 192 and the positions of these amino acids relative to TCR-z are presented (pdb entry 2OQ1). (B) Alphafold2-predicted structures of the ZAP-70 SH2 domains are presented for WT ZAP-70 as well as the R170C and R192W mutants. Amino acids in the TCR-z binding pocket are shown in red.
Participants We analyzed patients younger than 55 years who were referred to the clinic for osteoporosis and/or history of fracture. We excluded patients taking medications that interfered with bone metabolism. Extensive radiological and biochemical investigations allowed excluding secondary causes of osteoporosis. Tests included serum levels of total calcium, phosphorus, 25OH vitamin D and parathyroid hormone, electrophoresis of proteins, Creactive protein, thyroid-stimulating hormone, and serum creatinine. Patients were <55 years old at diagnosis and had a BMD Zscore <À2 standard deviation (SD) at the spine or total hip  (21, 30)  associated with osteoporotic fractures. For each patient, the following data were collected: age at diagnosis, number and site of fractures, family history of fracture, and bone marker levels before any treatment.
Microarchitecture analysis by HR-pQCT Microarchitectural parameters were assessed at the right distal radius and tibia by HR-pQCT (XtremeCT, Scanco Medical AG, Brüttisellen, Switzerland), as previously described. The resolution (voxel size) was fixed at 80 μm. Quality control was performed by daily scans of the manufacturer's phantom. The volume of interest (VOI) was automatically separated into trabecular and cortical regions using a threshold-based algorithm (Scanco software version, V 6. 1) to provide all parameters of interest. (31).
Determination of alkaline phosphatase activity was performed through alkaline phosphatase staining after 14 days of culture in osteogenic medium, using SigmaFast BCIP/NBT tablets (Sigma). Mineralization was assessed by alizarin red staining after 21 days of culture in osteogenic medium. Mean intensity was measured with the ImageJ software in arbitrary units and normalized to the mean value obtained for CTL. Reverse transcription and real-time quantitative PCR mRNA was extracted using the Isolate II RNA Mini Kit (Bioline, London, UK), in accordance with the manufacturer's instructions. For each sample, 1 μg of total mRNA was reverse transcribed using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Carlsbad, CA, USA) following manufacturer's instructions. Samples were subjected to quantitative PCR with SensiFAST SYBR (Bioline) on a Light Cycler 480 thermocycler (Roche).
5 mm. NRecon, DataViewer, CTAn, and CTVox softwares were used for 3-dimensional (3D) image reconstruction, analyzed, and expressed according to international guidelines. (33) The following morphometric parameters were computed: bone volume/tissue volume (BV/TV, %), trabecular thickness (Tb. Th, μm), trabecular number (Tb. N, 1/μm), trabecular separation (Tb. Sp, μm), cortical thickness (Ct. Th, μm), and cortical area (Ct. Ar, μm 2 ).
Acknowledgments Investigation of bone material properties was performed in the HiMolA platform -INSERM U1229 (Angers, France). This work was supported by the  Fondation pour la Recherche Médicale  (AD [M2R202106013349] and SF),  French  state funds managed by the  Agence Nationale de la Recherche  within the  Investissements d'Avenir program IHU FOReSIGHT  ( ANR-18-IAHU-0001 ), and  Novartis DREAMER  grant.
Oropharyngeal pH-monitoring Patients with RSS-12 > 11 underwent 24-h oropharyngeal pH-monitoring (Restech Dx-pH, Restech, San Diego, CA). The probe was placed in the oropharynx of fasting patient at 9:00 A. M. through a standardized and recommended method by the provider. According to a recent meta-analysis, the LPR diagnostic was based on the presence of > 1 pharyngeal reflux event  [14]. The following data were collected from the analysis: total number of reflux event lasting > 5 min; Ryan score; pH total time below/at pH 6. 5. , 6. 0, 5. 5 and 5. 0 in both upright and supine position.
Sleep findings Polysomnography (PSG) was carried out at home during the 24-h pH-monitoring period with the Cidelec CID-LXe (Cidelec, Loire, France) that is composed of 20 channels. Patients fulfilled the French version of Epworth Sleepiness Scale (ESS)  [17]  and the Pichot fatigue scale  [18]. The following PSG data were extracted by a boardcertified sleep physician using the Cidelec software (Cidelec v2. 2. 6. , Loire, France): Apnea-Hypopnea Index (AHI; Chicago scoring system)  [11] ; total number of arousals; number of arousals/hour; % of time with O 2 saturation level < 90%; and the 4 sleep phases including the paradoxical sleep. OSA status was retrieved from the home sleep study findings considering an AHI ≥ 5 per hour as a positive OSA diagnosis. The degree of obstructive sleep apnea was rated regarding the report of the American Academy of Sleep Medicine based on the patient's AHI: mild (5-14 events/hour); moderate (15-30 events/hour); or severe (> 30 events/hour)  [11].
Material and methods Forty-two healthy males participating in a previous trial  [13]  took part in the present study. Table  1  summarizes the main clinical parameters and their evolution during the trial. All participants were given written and oral information before the study and written consent was obtained. The protocol was approved by the ethic committee of Lyon Sud-Est according to the French "Huriet-Serusclat" law and the Second Declaration of Helsinki According to the International Committee of Medical Journal Editors. The protocol was registered at clinicaltrials. gov (NCT02145780). The participants were enrolled in a 31 days overfeeding trial during which they were required to add an excess of 0. 5 * total energy expenditure to their usual diet. Briefly, subjects added sodas, chocolate bread, chips, and chocolate bars in between their usual meals.
Bioinformatic analysis of the RNA-sequencing Sequencing data were demultiplexed with Bcl2FastQ Demux Pipeline (UBP). Reads were trimmed with BBDuk (BBTools version 35. 85). Mapping to the human genome (built GRCh38. p2) was performed with RNA STAR version 2. 3. 0e using default parameters. A total of 78. 3% of the reads in average were mapped. Gene count was performed with HTSeq version 0. 5. 4p3. Raw data were processed with the open-source software Rstudio (V. 2022. 02. 1), implemented with the Deseq2 package (V. 1. 34. 0). After filtering low count reads, statistical models addressing time effect (Basal as reference), group effect (PCB or PP) and patient effect were used. Using this approach, we were able to identify genes regulated by the diet in the PCB or PP group as well as genes differentially regulated during the nutritional intervention between both groups.
The staining is then revealed using DAB substrate/3,3 -Diaminobenzidine (VectorLabs, ref SK4100), for 10 minutes at room temperature, followed by hematoxylin counterstain and mounting. The stained biopsies are observed under a microscope (Olympus). Due to tissue quality, adipose tissue samples from 16 PCB and 17 PP volunteers were analyzed. The subjects from this subgroup did not differ from those from whom the RNA sequencing data were obtained (Supplementary Table  1 ) nor from the whole cohort of volunteers who performed the trial (data not shown).
Statistical analysis All data are presented as mean ± SEM unless otherwise stated. Principal component analysis (PCA) was used to identify outliers according to the baseline gene expression For the clinical data, differences within and between groups were analyzed using a linear mixed model (Lme4 package V. 1. 1-29). For the CD31 quantification, the differences within and between groups was analyzed using a linear mixed model (Lme4 package V. 1. 1-29) and post-hoc tests were used (emmeans package V1. 7. 5) with a Tuckey adjustment. Differences between cohorts were assessed with a Wilcoxon test on the deltas. In vitro data were analyzed using a Kruskal-Wallis statistical test and post-hoc analyses were made with a Wilcoxon test using R (V. 2022. 02. 1).
ADHD symptoms were screened according to DSM-5 criteria, and attention tests were added when appropriate. Comorbid NDDs were diagnosed according to DSM-5 criteria, including speech and language evaluation (reading disability), clinical and neuropsychological evaluation (ADHD), or multidisciplinary assessments (autism spectrum disorder) when appropriate. The study was approved by the Robert-Debré Hospital Ethics Committee and the French National Data Protection Agency (Commission Nationale de l'Informatique et des Libertés). Parents provided written informed consent.
Data collection Clinical data were obtained from medical records. The Developmental Coordination Disorder Questionnaire and MABC-2 checklist were completed by the parents. All the children had received a detailed neurological examination with a focus on motor aspects. Brain magnetic resonance imaging (MRI) was available if there was a history of perinatal injury, head circumference less or more than 2 standard deviations (SD), or specific skin or ophthalmological abnormalities. Neuropsychological data included three sets of variables: (1)  psychometric assessment by the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V); (2) motor skill, manual dexterity, visuospatial, and graphomotor tests by Developmental Neuropsychological Assessment, Second Edition (NEPSY-II) subtests, the Movement Assessment Battery for Children, Second Edition (MABC-2), the Rey-Osterrieth Complex Figure Test for children aged 9 years or more or Developmental Test of Visual Perception, Second Edition, spatial relation subtest for those younger than 9 years, and the Concise Evaluation Scale for Children's Handwriting (the French criterion standard test for dysgraphia); and (3) attention tests by the Test of Everyday Attention for Children and NEPSY-II subtests when clinically appropriate.