dataesr/scientific-paragraphs-categorization huggingface dataset:
(  4   10 ) Create an empty folder to store the execution reports, outside of any of the Brainstorm folders (reports_dir). (  11 ) The total size of the Brainstorm database after processing will be around 130 Gb, make sure enough space is available on the hard drive. (  12 ) In your Matlab command window, type: tutorial_ frontiers2018(tutorial_dir, reports_dir). This will run all the scripts mentioned in this article: tutorial_ frontiers2018_single. m, tutorial_frontiers2018_copy. m, tutorial_frontiers2018_group. m. All these scripts are located in the folder brainstorm3/toolbox/script, which is created and added to the user Matlab path after starting Brainstorm. Execution time is typically between 10 and 30 h, depending on hardware. For detailed execution times on the reader's system, please refer to the reports saved in reports_dir; examples for the execution on a Dell XPS 2016 laptop are available from the online tutorials 45.
As functionally lateralised regions would need to inhibit the opposite hemisphere more than non-lateralised regions, they could be more connected by the corpus callosum. Preliminary anatomical  16  and functional magnetic resonance imaging (fMRI)  17  studies provide support for both theories. However, the small range of functions investigated and shortcomings in the methods often limit the interpretability of the findings  13. Overall, the generalisation of these theories and findings to the whole brain's functional organisation remains unknown. Here, we took advantage of combining the largest fMRI metaanalytic dataset  18  with the highest quality structural connectivity data  19  to produce, for the first time, a comprehensive map of the functional brain architecture of lateralised cognitive functions, characterise its low-dimensional structure, and examine its relationship to corpus callosum connectivity.
Results Functional lateralisation maps and their low-dimensional structure. We selected 590 terms related to specific cognitive processes out of the whole Neurosynth database (see Supplementary Table  1 ). A functional lateralisation map was computed for each term by calculating the difference between hemispheres for each pair of homologous voxels. Homologous functional regions may be displaced in the two hemispheres because of anatomical factors, e. g. the Yakovlevian torque  4, 20  , the size of the planum temporale  21  and motor cortex  22, 23. Here we adjusted for main anatomical asymmetries in the two hemispheres by registering the maps to a symmetric atlas  24. We first sought to determine which regions show a significant functional lateralisation. Given that selected terms could be either correlated or related in a trivial way (e.
Out of the 300 most relevant studies for the term "emotion" in the Neurosynth database, 36% used face stimuli, 28% visual scenes, 16% language-related material, 4% movies, 4% memories, 2% odour and 10% used other materials such as music, conditioned stimuli or inkblots. This appeared to have had a limited effect on our results, because the maps driving the emotion axis did not involve the face fusiform area that is specialised in face perception  57. However, we cannot rule out the possibility that biases in label selection by the experimenters that ran the studies housed in Neurosynth may in part affect our findings. Another issue concerns whether the left lateralisation of some functions, such as finger tapping, movement and touch, could be related to the laterality of stimulus presentation or response.
Methods Datasets. In this study we used a meta-analytic approach to the functional MRI studies described by Yarkoni et al. 18  (http://Neurosynth. org). We downloaded the Neurosynth database that contained 3107 reversed unthresholded functional maps and the details of 11,406 literature sources as of the 25th of September 2017. Structural connectome data were derived from the diffusion-weighted imaging dataset of 163 participants acquired at 7 Tesla by the Human Connectome Project Team  62   Preprocessing of Neurosynth data. Two researchers (V. R. K. and M. T. S. ) acted as judges, selecting terms that, in their view, were related to specific cognitive processes. The selection procedure consisted of two stages. During the first stage, the judges made their selection independently. Brain anatomical (e.
mcgill. ca/ ServicesAtlases/ICBM152NLin2009, using the Greedy symmetric diffeomorphic normalisation (GreedySyN) pipeline distributed with the Advanced Normalisation Tools (ANTs, http://stnava. github. io/ANTs/)  63. The symmetrical template was downsampled to a 2 mm voxel size to match the voxel dimensions of the standard template. The estimated transformation between non-symmetrical and symmetrical MNI spaces were then applied to all functional maps. The following steps were performed to obtain lateralisation indices for each functional map following their co-registration with the symmetrical template. Firstly, we split the functional maps into the left-and right hemisphere parts and smoothed the resulting maps using a 6 mm FWHM Gaussian filter. We then flipped the left hemisphere maps and subtracted them from unflipped right hemisphere maps in order to obtain laterality indices (LI) maps (see  24  for a similar approach).
The default HCP preprocessing pipeline (v3. 19. 0) was applied to the data  66, 67. In short, the susceptibility-induced off-resonance field was estimated from pairs of images with diffusion gradient applied with distortions going in opposite directions  68  and corrected for the whole diffusion-weighted dataset using TOPUP  69. Subsequently, motion and geometrical distortion were corrected using the EDDY tool as implemented in FSL. ExploreDTI toolbox for Matlab (http://www. exploredti. com  70, 71 ) has been used to extract estimates of axonal water fraction  28. Next, we discarded the volumes with a b-value of 1000 s mm -2 and whole-brain deterministic tractography was subsequently performed in the native DWI space using StarTrack software (https:// www. mr-startrack. com). A damped Richardson-Lucy algorithm was applied for spherical deconvolutions  72.
A fixed fibre response corresponding to a shape factor of α = 1. 5 × 10 -3 mm 2 s -1 was adopted, coupled with the geometric damping parameter of 8. Two hundred algorithm iterations were run. The absolute threshold was defined as three times the spherical fibre orientation distribution (FOD) of a grey matter isotropic voxel and the relative threshold as 8% of the maximum amplitude of the FOD  73. A modified Euler algorithm  74  was used to perform the whole-brain streamline tractography, with an angle threshold of 35°, a step size of 0. 5 mm and a minimum streamline length of 15 mm. We co-registered the structural connectome data to the standard MNI 2 mm space using the following steps: first, whole-brain streamline tractography was converted into streamline density volumes where the intensities corresponded to the number of streamlines crossing each voxel.
Second, a study-specific template of streamline density volumes was generated using the Greedy symmetric diffeomorphic normalisation (GreedySyN) pipeline distributed with ANTs. This provided an average template of the streamline density volumes for all subjects. The template was then co-registered with a standard 2 mm MNI152 template using flirt tool implemented in FSL. This step produced a streamline density template in the MNI152 space. Third, individual streamline density volumes were registered to the streamline density template in the MNI152 space template and the same transformation was applied to the individual whole-brain streamline tractography using the trackmath tool distributed with the software package Tract Querier  75  , and to the axonal water fraction maps, using ANTs GreedySyn.
This step produced a whole-brain streamline tractography and axonal water fraction maps in the standard MNI152 space. Determination of functionally lateralised regions. In these analyses, completed in two steps, we thought to identify the regions with significant functional lateralisation. See Supplementary Figure  5. In the first step, we addressed the redundancy while preserving the richness of the Neurosynth data. For instance, many selected terms were related as singular and plural forms of the same word (e. g, "visual form" and "visual forms") and therefore their maps are likely to be very similar. To this end, we reduced the dimensionality of the data using a data-driven varimax-rotated principal component (PC) analysis implemented in SPSS (SPSS, Chicago, IL) with the LI maps as inputs  [76] [77] [78].
Given that a partial spatial overlap between lateralised regions associated with different components is possible, in the analyses we picked the dominance values associated with components that rendered the largest z-score in a particular voxel. In order to obtain robust estimate for the relationship between hemispheric dominance and the strength of inter-hemispheric connectivity, the voxels were binned by the probabilities of connection such that the smallest bin width was of the size equal to 1/163 and increased with the probability of connection (given by logspace function in Matlab). This procedure was used to partially compensate for the fact that only a very limited number of voxels had a high probability of connection to the corpus callosum, whereas the majority were characterised by small values.
Acknowledgements We particularly thank  Nathalie Tzourio-Mazoyer  and her team (GIN) for useful discussion and for providing us with fMRI maps of left and right hands finger tapping. This project has received funding from the  European Research Council (ERC)  under the European Union's  Horizon 2020 research and innovation programme  (grant agreement No. 818521 ). We also thank  Lauren Sakuma  for useful discussion and edits to the manuscript. The research leading to these results received funding from the  "Agence Nationale de la Recherche " [grant number  ANR-13-JSV4-0001-01 ]. Additional financial support comes from the program " Investissements d'avenir "  ANR-10-IAIHU-06  and the  Fondation pour la Recherche Medicale  [grant number  DEQ20150331725 ]. M. C. was supported by  NIH   R01NS095741 , and a strategic grant from the  University of Padua.
ASOs bind to the mRNA by Watson-Crick base pairing, so one method of lowering SOD1 is to target the SOD1 mRNA using ASOs (that activate RNase H1 that destroys the targeted RNA)  [121]. After first demonstrations of the utility of ASOs in animal models, a first human clinical trial began in 2013 (IONIS Pharmaceuticals ("ISIS Pharmaceuticals" until December 2015): it consisted in the intrathecal delivery of ASO against SOD1 (ISIS333611) for patients with SOD1 FALS, showing that it should be a feasible treatment for neurological disorders (ISIS333611 has no dose-limiting toxic effects or other safety and tolerability concerns; the CSF and plasma drug concentrations were consistent with those predicted in preclinical studies). [123]. Based on these results, a second generation SOD1-targeting ASOs, BIIB067 (IONIS-SOD1RX) is currently being tested in an ongoing phase I randomized, placebo-controlled escalating dose trial (NCT02623699), as well as the long-term extension study of the effects of BIIB067 (NCT03070119) in SOD1 FALS patients  [124].
[33]. The high spin heme a 3 was ligated by a water molecule, and Cu B with a hydroxide and with the catalytic tyrosine (Y245) in its anionic state  [34]. Standard protonation states were used for all other amino acids, except subunit I residues E243, K319, and D364, which were patched neutral. CHARMM NTER and CTER patches were used, respectively, for all the N-and C-terminals and, CHARMM force fields were used for the protein, membrane, water, and ions  [35, 36]. An energy minimisation procedure was used for the constructed systems (2 × 50,000 steps with maximum force < 1000 kJ mol -1 nm -1 ) before running a short equilibration run (0. 2 ns). Berendsen barostat  [37]  and Nosé-Hoover thermostat  [38, 39]  were used during the equilibration. GROMACS software  [40]  was used for all the MD simulations.
By constraining bonds associated with hydrogen (using LINCS  [41] ) a time step of 2 fs was used. During production runs, Parrinello-Rahman barostat  [42]  and Nosé-Hoover thermostat were utilized. The simulation lengths are given in Table  1. Simulation trajectory analysis and visualization was performed with VMD software  [43]. pK a calculations were performed on simulation snapshots using PROPKA software  [44]. To complement and consolidate our homology model-based MD simulations (Table  1 ), we performed additional simulations on a two subunit (I and II) model system constructed from the recently solved yeast CcO structure  [17]  with redox centres modelled in fully oxidised and in fully reduced states (see Table  S1  for model systems and their simulation lengths). The oxygenous ligands of metal centers in the fully oxidised state were modelled as described above, whereas in the fully reduced state high spin heme a 3 and Cu B were modelled without oxygenous ligands and catalytic Y245 in its neutral form.
Acknowledgements VS acknowledges research funding from the  Academy of Finland  ( 294652 ), the  University of Helsinki  and the  Sigrid Jusélius Foundation. PRR was funded by  BBSRC  grants  BB/K001094/1  and  BB/L020165/1  and much of the redox potentiometry was performed by student  Antonios Poulitsidis. VS is thankful to  Center for Scientific Computing -IT Center for Science, Finland  for computational support.
Alternatively, the corneal rim samples were cryo-embedded in optimal cutting temperature (OCT) compound (Tissue-Tek, VWR, Singapore) and sectioned (6 µm thick). Immunostaining was performed as before, followed by fluorescence-conjugated secondary antibody. Serial z-stack images (1 µm thickness) were collected by laser-scanning confocal microscopy (TCP SP8, Leica, Wetzlar, Germany; AxioImager II, Carl Zeiss) and 3D-reconstructed montaged images were obtained using LAS X software (Leica, Wetzlar, Germany). The staining intensity profiles were analyzed using ImageJ software (Fiji version, National Institute of Health, Bethesda, USA) after the antibody-specific channel was grey-scaled and thresholded to background level. A total of 3 samples with a minimum of 6 fields for each antibody-stained image were analyzed.
information, Table S3: Expression primers, Video S1: Serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction of human transition zone/peripheral endothelium (TZ/PE) junction, Video S2: Serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction of human transition zone/peripheral endothelium (TZ/PE) junction. Available online at https://zenodo. org/record/3477657#. XaFjz-cvPeQ).
Acknowledgments: We thank the  Lion Eye Institute for Transplant and Research (Tampa, FL, USA) ,  Lyon Cornea Eye Bank  ( Celine Auxenfans ,  Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France ) and  Singapore Eye Bank (Singapore)  for assisting with the procurement of donor corneas. We acknowledge  E Benson  and  G Kidd  from  Renovo Neural Inc. (Cleveland, OH, USA)  for  SBF-SEM, S Chai from BitPlane (Singapore)  for Imaris 3D reconstruction. We also thank the  Experimental Microscopy Platform ,  Singapore Eye Research Institute; Electron Microscopy Unit, National University of Singapore  and  SingHealth Advanced Bioimaging Core Facilities (Singapore)  for confocal and electron microscopies.
Patient selection We reviewed the charts of all consecutive MSA-C patients of the longitudinal cohort of 414 MSA patients (MSA-C = 128, MSA-P = 286) who were recruited at the French Reference Centre for MSA in Bordeaux or Toulouse between 2007 and June 2016. The clinical diagnosis of MSA was made following current consensus criteria  [2]. These criteria were also applied in patients who were diagnosed before 2008. Postmortem confirmation was obtained in 3 MSA-C patients who donated their brain after death. For the purpose of this study, we referred to the data that were collected at the visit prior or at the time of DAT-SPECT, including main clinical and imaging features of the second consensus statement: clinical signs of cerebellar impairment (gait ataxia, limb ataxia, dysarthria, oculomotor dysfunction), parkinsonism (bradykinesia, rigidity, tremor, postural instability), autonomic dysfunction (orthostatic hypotension and urinary dysfunction), pyramidal signs, stridor and features of MSA-C on brain magnetic resonance imaging (MRI; atrophy of putamen, middle cerebellar peduncles, or pons).
MRI was available for all but one patient. MRI was performed before in 36, at the same time in 30, and after DAT-SPECT in two patients. In patients without DAT-SPECT, data of the first visit at the French Reference Center for MSA were used for the analysis. All patients gave written informed consent to personal data processing for research purposes and all necessary regulatory approvals were obtained (CNIL 1338780 v1).
DAT-SPECT The main objective was to evaluate the proportion of patients for whom the diagnosis of "possible" MSA-C was made because of a positive DAT-SPECT, as the only additional feature of current consensus diagnosis criteria  [2]. A specialist in nuclear medicine (FH), who was blinded with regard to the clinical diagnosis, performed a visual analysis as well as a semi-quantitative assessment of all exams with the DaTsoft3D software (Toulouse, France, http://www. en. datsoft3d. com). According to current recommendations  [4] , the visual analysis was used as the primary criterion and the semi-quantitative assessment as the secondary criterion. DaTsoft3D software quantification provides an estimation of spatial resolution (FWHM) directly on striatal images before quantification and an automatic registration of a 3D MRIbased template of caudate and putamen (right and left).
SPECT may be due to the patient referral to tertiary centers only in more advanced disease, which is corroborated by the long mean interval between symptom onset and first visit. In conclusion, our results suggest that DAT-SPECT contributes significantly to the diagnosis of "possible" MSA-C. DAT-SPECT seems especially useful in patients with shorter disease duration, while a negative result does not exclude a diagnosis of MSA. Additional studies are warranted to confirm our main result in larger cohorts. Fabienne Ory-Magne  has received grants from  Orkyn ,  Medtronic , Abbvie, Aguettant; travel grants from  Orkyn ,  Medtronic ,  Abbvie  and teaching honoraria from  UCB, Aguettant, Orkyn, Abbvie, Zambon. Olivier Rascol  has received grants from  Agence Nationale de la Recherche (ANR) ,  CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJ Fox Foundation ,  Programme Hospitalier de Recherche Clinique, European Commission  ( FP7 ,  H2020 ) and has served as scientific consultant for  AbbVie, Adamas ,  Acorda ,  Addex, AlzProtect, Apopharma, Astra Zeneca, Bial, Biogen, Britannia, Clevexel, Cynapsus, INC Reasearch, Lundbeck, Merck, MundiPharma, Neuroderm ,  Novartis ,  Oxford Biomedica ,  Parexel ,  Pfizer ,  Prexton Therapeutics ,  Quintiles ,  Sanofi ,  Servier ,  Teva ,  UCB , XenoPort,  Zambon.
François Tison  received a travel grant from  ORKYN , and research grants from  French Health Ministry (PHRC) , outside the presented work. Anne Pavy-Le Traon  has received research grants from the  French Health Ministry , and the  European Community. Wassilios G. Meissner  has received fees for editorial activities with Springer, for consultancy activities from  Affiris, Biohaven ,  Lundbeck  and  Sanofi , teaching honoraria from  UCB  and  MDS , as well as research support from the  Michael J Fox Foundation , the  University Hospital Bordeaux , the  French Health Ministry , the  European Community ,  ANR ,  ARAMISE ,  PSP-France ,  MSA Coalition ,  ARAMISE, LABEX Excellence Initiative.
2. 1. Participants Twelve recreationally active males of 24±4 years (range 20 -33 yr, 182±6 cm, 76±8 kg) and fifteen active very old men of 82±1 years (range 80 -83 yr, 168±6 cm, 71±9 kg) volunteered to participate in the experiment and gave their written consent. Very old participants were selected from the PROgnostic indicator OF cardiovascular and cerebrovascular events (PROOF) cohort, which is a prospective longitudinal cohort of old adults started in 2001  [23]. Individual physical activity of the participants from this cohort is regularly assessed using a wrist wearable accelerometer (wGT3X-BT, ActiGraph, Pensacola, USA) and analyzed using ActiLife software (v6. 13. 4, ActiGraph, Pensacola, USA). Considering those data, all the very old men were considered as physically active (8840±1972 steps.
day -  ,  [24] ). All participants were free from musculoskeletal or neurological disorders. Before the experimental session, participants were asked to avoid strenuous exercises for at least 24 hours. All the experimental procedures were approved by the Comité de Protection des Personnes Sud-Est 1 (France), and the Agence Nationale Sanitaire et du Médicament (ANSM-France) and was performed in accordance with the Declaration of Helsinki (ClinicalTrials. gov, Identifier: NCT02675192).
2. 2. Mechanical recording and electromyography Participants were seated upright on a custom-built chair with hip angle set at 120° (180° corresponds to full extension) and knee angles set at 90° of flexion (Figure  1A ). Knee extensors force of the right leg was assessed using a calibrated force transducer (Omega Engineering Inc. , Stamford, CT, USA). Extraneous movements of the upper body were minimized by three belts across the thorax and waist. The force transducer was firmly attached above the malleoli. Force was sampled at 2 kHz and recorded without analogical or digital filter using a Power-Lab data acquisition system (16/30-ML880/P, ADInstruments, Bella Vista, Australia). Passive resting force was subtracted from the signal so that the baseline was set at 0 N. Electromyographic (EMG) activity was recorded from the vastus lateralis (VL) muscle of the right leg using pairs of self-adhesive Ag/AgCl surface electrodes (recording diameter = 10 mm, Kendall MediTrace foam electrode, MA) placed in bipolar configuration over the muscle belly with an interelectrode (center to center) distance of 30 mm.
Electrodes were placed following the SENIAM project recommendations. A reference electrode was placed on the right patella. Prior to electrode placement, the skin was shaved, abraded and cleaned with alcohol swab to lower the impedance (<5 kΩ, 87v, Fluke Corp. , Everett, WA, USA). EMG and force signals were digitized simultaneously at the same sampling rate (2 kHz) by PowerLab System (16/30-ML880/P, AD Instruments, Bella Vista, Australia). Force and EMG data were analyzed offline using Labchart 8 software (ADInstruments). EMG signals were amplified (gain = 500) using an octal bio-amplifier (ML138, AD Instruments) with a bandwidth frequency range of 10-500 Hz obtained through a band-pass filter. Prior to analysis, data were rectified and smoothed using a moving rootmean-square (RMS) with a time constant interval of 50 ms  [8].
2. 4. Data analysis All data were analyzed offline using Labchart 8 Software (ADInstruments). The Fmax and associated RMS-EMG signal (EMGmax) were defined as the average of the highest 0. 5-s window among the best MVC. Repeatability of MVC was tested using a bivariate correlation. The maximal rate of force development (RFDmax) was determined as the maximal value of the force-time derivative curve for each RFD contraction. Absolute RFDmax was used to identify the best five impulsive contractions retained and then averaged for further analysis, while the others were discarded (Figure  1B ). To assess the influence of within-subject variability among young and very old adults, the coefficient of variation (CV) was calculated for each participant and compared between groups. Time to RFDmax (tRFDmax) and force level at 25, 50, 100 and 200 ms from the onset of the force (see below) were identified.