dataesr/scientific-paragraphs-categorization huggingface dataset:
C L I N I C O P A T H O L O G I C A L F E A T U R E S The main clinicopathological data are summarised in Table  1. Forty-five patients were included. The mean age was 52. 3 years (range: 13-88 years). No peak of incidence was observed. The male/female ratio was 0:8. None of the patients had a history of carcinoma. There was a predominance of the Kadish C (66. 7%) and Dulguerov T4 (42. 2%) stages. The Hyams grade distribution showed a predominance of grade II cases (42. 2%), followed by approximately the same proportion of grade III (26. 7%) and VI (22. 2%) cases, and a few grade I (8. 9%) cases. Surgery was performed in 84. 5% of the cases. Of these, 29% had received neoadjuvant chemotherapy and 69% had received adjuvant radiotherapy. Fifteen per cent of the patients were treated with surgery alone, and 11% were treated only with radiotherapy and/or chemotherapy, without surgery.
7). B cells (CD20+ cells) were also found predominantly in the stromal compartment of the tumour, and their number varied from 163 to 1308/mm 2 (median: 79/mm 2 ) (P < 0. 0001; Figure  3F ). We then assessed the association between the distribution of TILs and Hyams grade. Examples of TILs in low-grade and high-grade ONBs are shown in Figure  4A-D. The numbers of intratumoral CD8+ cells/mm 2 and CD4+ cells/mm 2 were greater in Hyams III-IV ONBs than in Hyams I-II ONBs (P = 0. 0015 and P = 0. 043, respectively) (Table  4 ; Figure  5A, B ). The survival data were used to further investigate the prognostic significance of TIL infiltration. The distribution of TILs did not follow a normal distribution (Figure  S2 ): the TIL variables were therefore classified according to the quartiles. Neither the numbers of T cells/mm 2 (CD4+ or CD8+) nor the number of B cells/mm 2 were associated with  survival, but a CD4/CD8 ratio of >2 was significantly associated with shorter survival (P = 0.
Allele-Specific Inactivation or Correction of the DNM2 Mutation Rescue of the Alterations in Endocytosis DNM2 is important for the fission of vesicles during clathrin-mediated endocytosis. 26 Contradictory data have been reported on the impact of DNM2-CNM mutations on endocytosis with either no effect or decreased endocytosis. 21, 23, 27 These data were obtained on transfected cells or on non-muscle cells. To assess the impact of the R465W mutation on the endocytic pathway in a muscular context expressing DNM2 endogenously, cyanine 3 (CY3)-labeled transferrin uptake was measured in mouse immortalized myoblasts by using ) and Dnm2 R465W/+ KI (KI1, KI2) mouse myoblasts and from Dnm2 R465W/+ KI myoblasts edited through out-of-frame or in-frame NHEJ or corrected through HDR. (G) Quantification from three independent experiments of DNM2 protein levels, related to GAPDH from WT (WT1, WT2) and Dnm2 R465W/+ KI (KI1, KI2) mouse myoblasts and from Dnm2 R465W/+ KI myoblasts edited through out-of-frame or in-frame NHEJ or corrected through HDR.
36 ± 0. 19-fold; WT2: 1. 25 ± 0. 49fold; KI1: 3. 46 ± 1. 04-fold; and KI2: 3. 3 ± 0. 5-fold) (Figures  4A  and 4B ). To define if this observation underlies a blockade or an increase in autophagy, BafA1-treated cells were analyzed. Under basal conditions, BafA1 treatment induced an increase of around 4-fold of LC3-II in WT myoblasts (Figures  4A  and 4C ). However, in KI myoblasts the effect of BafA1 was increased by only 1. 65-or 1. 86-fold, depending on the clones. Under the starved condition, the BafA1-induced increase in LC3-II was hampered in KI myoblasts, although the difference compared with WT myoblasts was not statistically significant (Figure  4C ). Altogether, these data suggest a decrease in autophagy dynamics in KI myoblasts. To assess whether the inactivation or the correction of the DNM2 R465W mutation could reverse the autophagy defects, the LC3-II expression level was quantified in edited myoblasts under the basal condition after BafA1 treatment.
DNM2 was detected with a homemade rabbit polyclonal antibody  38  and GAPDH with a mouse monoclonal anti-GAPDH (Sigma-Aldrich) antibody in TBST 0. 1% containing 0. 5% BSA at 4 C overnight. Membranes were then incubated with peroxidase-conjugated secondary antibodies in TBST 0. 1% and 0. 5% BSA at room temperature for 45 min. Membranes were revealed with an enhanced chemiluminescence (ECL) kit (Thermo Fisher Scientific) and Imager AI 600. Protein quantification was determined with ImageJ software.
For human myoblasts, the protocol described above was used with minor modifications. Cells (100,000) were seeded in 24-well plates containing coverslips. After 3 h, cells were starved with DMEM containing 0. 5% BSA for 30 min. Cells were then incubated with the same medium containing fluorescently labeled CY3-transferrin (20 mg/mL) for 10 min on ice, and endocytosis was started by incubating the cells at 37 C. The cells were acid washed to remove the remaining bound transferrin at the cell surface, then fixed with PFA 4%. Cells were visualized using a Leica SP8 confocal microscope, and single Z-images were taken at the equatorial plane of the cells. CY3 intensity per cell was measured using ImageJ software after the subtraction of the CY3 intensity of the cells that were not incubated with CY3transferrin.
Non-specific sites were blocked using TBST 0. 1% and 3% BSA for 1 hour. LC3-I and -II were detected with a rabbit polyclonal anti-LC3 antibody (Novus) and GAPDH with a mouse monoclonal anti-GAPDH (Sigma-Aldrich) antibody in TBST 0. 1% containing 0. 5% BSA at 4 C overnight. The membranes were then incubated with peroxidase-conjugated secondary antibodies in TBST 0. 1% and 0. 5% BSA at room temperature for 45 min. The membranes were revealed with an ECL kit (Thermo Fisher Scientific) and Imager AI 600. Protein quantification was determined with ImageJ software.
ACKNOWLEDGMENTS We thank  Marc Bitoun  for providing the Dnm2 R465W/+ mouse;  Leigh Waddell  for providing patient cells;  Christine Kretz ,  Claudine Ebel , and  Muriel Philipps  for excellent technical assistance; the animal house, cell culture, flow cytometry platforms, and imaging center of IGBMC for support; and the  Institut de Myologie  for the human cell immortalization platform. This work was supported by  INSERM ,  CNRS , the  University of Strasbourg , the  Agence Nationale de la Recherche  ( ANR14-CE12-0009 ), and grant  ANR-10-LABX-0030-INRT  from a  French State  fund managed by the  ANR  under the  frame program Investissements d'Avenir  ( 10-IDEX-0002 ). A. R. is a recipient of a doctoral fellowship from  Strasbourg University.
Retinal Organoid Immunostaining-Clearing and Imaging. Retinal organoids were fixed with 4% PAF in PBS for 30 to 60 min before immunostaining with a PBS solution containing 0. 2% gelatin, 0. 5% Triton X-100, and 0. 01% thimerosal (Sigma-Aldrich) as previously described  [11]. Samples were next submitted to the 3D imaging of solventcleared organ (3DISCO) clearing procedure  [19]. 3D imaging was performed with an inverted confocal microscope (Olympus FV1200) with numerical objectives for high-resolution imaging. Images, 3D volume, and movies were generated with Imaris x64 software (version 7. 6. 1, Bitplane) using the "snapshot" and "animation" tools. 2. 7. RNA Extraction and TaqMan Assay. Total RNAs were extracted using the NucleoSpin RNA II kit (Macherey-Nagel) and cDNA synthesized using the QuantiTect reverse transcription kit (Qiagen) following the manufacturer's recommendations.
Acknowledgments The authors would like to thank  Professor José-Alain Sahel  ( Director of the "Institut de la Vision" ) for administrative and financial support and  K. Marazova  for comments and advice on the manuscript. We thank  V. Fradot  for valuable advice in Müller glial cell cultures,  N. Oudrhiri  and  A. Bennaceur  ( GHU Paris-Sud APHP ) for the conventional cytogenetic analysis, and  Dr. C. Craft  ( Mary D. Allen Laboratory for Vision Research, USC ROSKI Eye Institute ) for Cone arrestin antibody. This work was supported by grants from the  "Agence Nationale de la Recherche " ( ANR-15-RHUS-001 ,  ANR-16-CE17-0008-02 , and  ANR-17-CE18-0004-01 ), the  Labex Revive  ( ANR-10-LABX-73 ), the  Labex LifeSenses  ( ANR-10-LABX-65 ), the  Technology Transfer company SATT Lutech , and  Retina France Association.
Aims: To evaluate all epidemiological evidence in the literature linking the metabolic syndrome (MetS) and migraine in adults. Methods: Database (Medline, Embase; published reports up to November 2017) and manual searches were performed. Information on data collection, sample characteristics, study design, MetS and migraine assessment, and results was extracted from each relevant publication. The methodological quality of each study was also assessed. Results: A total of 15 observational epidemiological studies in adults, published between 2009 and 2017, were retrieved. Of these, one employed a prospective design, while the rest had a cross-sectional (13 studies) or case-control (one study) design. Five studies assessed the presence of migraine in individuals with MetS, whereas 10 studies assessed the presence or risk of MetS in migraineurs.
Methods Our intention was to synthesize data from all observational epidemiological studies with a bearing on the link between MetS and migraine in adults. An extensive search was therefore performed of Embase and Medline/PubMed (all available reports from the beginning of database indexing up to November 2017), supplemented by a manual search through the reference lists of retrieved articles. Published conference proceeding abstracts were also considered. No language restrictions were applied. MeSH indexing terms 'metabolic syndrome X' and 'abdominal obesity metabolic syndrome' were associated with 'migraine disorders', 'migraine without aura', 'migraine with aura', 'headache', 'headache disorders, primary' and 'headache disorders'. A total of 253 and 17 articles were identified from database and manual searches, respectively.
From the pool of non-duplicated hits, all review articles (with no original data) and research reporting on individual MetS components, but not MetS itself, were excluded. Ultimately, a total of 15 studies met the selection criteria (Fig. 1 ) and were subjected to detailed reviews performed independently by two investigators (V. A. A. and E. K. -G. ). From each study, the following information was extracted: place and year of data collection; type and size of sample; study design; MetS and migraine assessment criteria; migraine treatment; and results [prevalence, incidence, odds ratio (OR) or other estimates of association, statistical adjustment]. In our summary of findings, the term 'presence' was employed when referring to estimates obtained from cross-sectional and casecontrol (retrospective) studies, and the term 'risk' was used when referring to estimates obtained from prospective studies.
For example, with MC1 (aa7-9 and aa313-322), conformational epitope specific reactivity is observed in Braak stages I and II in AD  [348]. In addition, MC1 immuno-purified soluble tau species readily assembled into paired helical filaments in vitro  [348]. Therefore, antibodies against these unique species of tau are also being investigated in preclinical studies to attenuate tau pathogenesis. MC1 therapy slightly reduced insoluble tau and number of tangles in the brain of experimental mice  [54, 56, 72]. Currently, only a handful of humanised tau antibodies are being investigated at various stages of clinical development (Clinicaltrials. gov). Humanized versions of N-terminal specific antibodies 8E12  [374, 375] , and BIIB092 (also known as BMS-986168 or IPN007)  [43]  are being currently investigated at various phases of trials for treatment of PSP and AD.
Antisense therapies This is an exciting juncture in the hunt for therapies against neurodegenerative disorders by directly targeting those causative genes. The efficacy and safety of ASO therapy has been demonstrated in clinical trials for nusinersen (Spin-raza®; ClinicalTrials. gov Identifier: NCT02193074) for the treatment of spinal muscular atrophy (SMA) and eteplirsen (Exondys51®; NCT00844597, NCT01396239/NCT01540409, NCT02255552) to treat Duchenne muscular dystrophy (DMD). More recently, IONIS-HTT Rx (RG6042; NCT02519036) was tested for the treatment of Huntington's disease (HD)  [317]. This specifically targets the mutant, expanded huntingtin gene (HTT) mRNA and supresses its expression. A recent Phase 1/2a clinical trial with intrathecal delivery of the ASO has had no adverse drug-related incidents and showed promising reduction of mutant HTT mRNA levels in CSF  [317].
These can in part be overcome by chemical modifications of the DNA or RNA phosphodiester backbone or ribose sugar  [190]  and the use of the likes of viral vectors, liposomes, polyplexes, or cell-penetrating peptides to enhance delivery  [96, 222, 367]. Based on the striking success and safety profile of recent ASO-based clinical trials and, and the recent in vivo ASO-based tau reduction work by de Vos and colleagues  [80] , a clinical trial of IONIS-MAPT Rx (BIIB080, ISIS 814907), the first ASO targeting tau in mild AD patients, is currently under way [ClinicalTrials. gov Identifier: NCT03186989]. Via repeated intrathecal delivery, it appears that this ASO can overcome the BBB in non-human primates with about 75% reduction of MAPT mRNA in both hippocampus and cortex and no dose-limiting side-effects  [227].
In clinical trials, MTC was introduced under the name Rember™ (TauRx Therapeutics) as a potential anti-AD drug candidate. Some improvements in AD-related symptoms have been reported, but the drug failed phase II trials due to undesirable side effects, including diarrhoea, urgency, painful urination, dizziness and others (Clinical Trial Identifier, NCT00515333 and NCT00684944). Results of these studies prompted researchers to develop a new generation of MTC derivatives. These new compounds (LMTX) include leuco-methylthionium bis (hydro-methanesulfonate (LMTM) and leuco-methylthionium dihydrobromide (LMTB)stable, reduced forms that permit direct absorption of LMT without the need for the aforementioned conversion step (Fig. 3 ). LMTM (TRx0237) has reached phase III trials, and was better absorbed, with improved safety and tolerability compared to methylene blue (Rember™).
Nevertheless, results of Phase III clinical trials involving LMTM in the treatment of AD were disappointing as they did not yield unambiguously positive data. The first phase III trial (NCT01689246) included 891 participants with mild to moderate AD, who received 125 mg of LMTM twice a day, or 75 mg twice a day while the control group received 4 mg twice a day. No significant difference in cognitive faculties or the ability to perform daily activities was observed between the treatment and control groups  [110]. Due to the low number of participants  (79)  in this study, these results require further confirmation. Currently, TauRx has begun a new clinical trial (LUCIDUTY, NCT03446001) using FDG-PET imaging to examine the potential of LMTX in delaying the progression of pathological changes in the brain in AD patients who do not receive cholinesterase inhibitors or memantine.
Acknowledgements We would like to especially acknowledge the pioneering work of professors  Heiko Braak  and  Constantin Bouras. Without their outstanding contribution to the field, the current progress in the development of tau therapy would not have been possible. The Eurotau2018 meeting was sponsored by  UCB BioPharma, Janssen Pharmaceutical Companies, Sanofi, Axon Neuroscience, Servier, Quanterix, Proteome Sciences and Proteintech. It was also supported by  French  and Spanish academic funds from  University of Lille ,  SFR DN2M ,  LabEx DISTALZ, LiCEND , and Ciberned.
Preprocessing. First, the quality of each electrode signal was checked, and spherical interpolation was used when necessary. Data were down-sampled at 2048 Hz, filtered (High-pass 0. 5-1Hz; Low-pass 46-48Hz) and set to average reference. First, artifacts (movement-induced perturbations including especially eye movements, ballistocardiac noise, electrode displacements and other electrical noises) were rejected by means of independent component analysis (ICA) / blind source separation (BSS) (UWSOBI, 300 times delays;  (Yeredor 2000)  and the EEGLAB toolbox  (Delorme and Makeig 2004). Second, data were partitioned into epochs of 2 seconds with an overlap of 50% and an automatic rejection procedure for outlier epochs was applied. The Frobenius norm between the covariance matrix of each epoch and the covariance matrix of the mean dataset was calculated.
Basically, after a set of matrices of SOS between electrodes has been estimated and made symmetric -time delayed covariance is not symmetric-, a linear transformation that enhances spectral diversity between sources is searched -the mixing matrix is calculated by approximate joint diagonalization of the whole set-. Importantly, the output of the separation provides components that are statistically independent regarding the parameters used for separation (whole spectrum signature). This does not mean that independent components cannot be functionally connected and part of the same neural network, i. e. , cannot provide similar or interrelated activation patterns in response to specific events or conditions within specific frequency bands. For each epoch, 300 lagged-covariance matrices (time delays: 0/2048s to 300/2048s) were calculated, averaged across dataset epochs, and finally across subjects.
Independent components source localization. To identify the neuronal generators of the electrical patterns recorded on the scalp, standardized low resolution electromagnetic tomography was performed with the sLoreta software  (Pascual-Marqui 2002). The cortical distribution of the electric neuronal activity generating each IC on the basis of its topography was estimated (solving the inverse problem). sLoreta uses the current density estimate obtained from the minimum norm estimate, and standardizes it by means of its variance. Here, standardized current source density was calculated at each of the 6239 voxels (resolution: 5mm) of a head model built on the basis of the boundary element method -BEM-and the MNI152 template  (Mazziotta et al. 2001 ). The 3D solution space was constrained to gray matter, and sLoreta solutions were calculated with an amount of Tikhonov regularization optimized for an estimated Signal/Noise Ratio of 100.
The output is a map of current density power (arbitrary units) whose maximum value corresponds to the exact generating dipole location in noise-free conditions. 2. 3. 4 Blind spectral analysis. We performed analysis of resting state spectral activity without a priori knowledge about anatomical sources or frequency bands. The ICs obtained with group BSS were used as a filter to go back to subject level for spectral analysis (deconcatenation). For each dataset of each PD patient, and each one of the 10 ICs accounting at least for 1% of explained variance (group effect), relative power was estimated. The power spectral density was calculated with the Welch's method for each epoch (with segments of 2048 samples, windowed with a Hamming window, and an overlap of 2000 samples between segments), and averaged across epochs for each dataset.
Acknowledgments This work was supported by a grant  PALSE 2016  to CS and a grant ANR to PB. The authors are thankful to  Francesca Natuzzi ,  Francesco Turco  and  Chiara Siri  ( Parkinson Institute in Milan ) who helped to collect neuropsychological data, and are also thankful to  Mauro Schiavella  and  Matteo Pelagatti  from the  University of Milan-Bicocca  who substantially contributed to the build-up of local capacity.
Patients According to the local Institutional Ethics Boards approval, the data were collected until the end of December 2018, from the AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group cohort of ASSD. The inclusion criteria were a clinical diagnosis of ASSD, being confirmed by ARS positivity, along with at least one triad finding. All of the patients should have been evaluated at least once in the local referral center between April 2014 (date of AENEAS collaborative group institution) and December 2018, with a follow-up of at least six months in order to be included in the study. ASSD was defined complete (all triad findings) or incomplete (one/two triad findings) and the onset identified with the first pulmonary, muscle, or joint symptom/sign. Features's onsets were defined as concomitant when they occurred less than three months apart.
Acknowledgments The authors thank  Richard Bastier ,  Henri  and  Jean-Frédéric Chibret ,  Arnaud Danse ,  Janel Hooven ,  Armel Jaunasse ,  Julien Lacaux ,  Eric Leplat ,  Bernard Stoloff  for their advice, proofreading, and technical support. Disclosure:  T. Bourcier , None;  J. Chammas , None;  D. Gaucher , None;  P. Liverneaux , None;  J. Marescaux , None;  C. Speeg-Schatz , None;  D. Mutter , None;  A. Sauer , None.
Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic literature review was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs-fMRI. We included studies investigating connectivity in presymptomatic (pre-HD) and manifest HD gene carriers compared to healthy controls, implementing seed-based connectivity, independent component analysis, regional property, and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre-HD, showing disease stage-dependent changes.
| Study selection A systematic literature search of rs-fMRI studies was conducted according to The PRISMA Statement, a checklist of items and guidelines to collect, check, and critically appraise data for reporting systematic review and meta-analysis  (Liberati et al. , 2009). We searched PubMed, EMBASE, and Web of Science databases for rs-fMRI articles using different combinations of keywords (Huntington AND "resting state"; Huntington AND "functional connectivity"; Huntington AND "functional network"). Further studies were identified through tracing of the retrieved articles and relevant reviews. Figure  1.
| Data extraction From the full articles of the eligible studies, the following variables were recorded: population characteristics (sample size, age, gender, education years, mean age disease, unified Huntington's disease rating scale [UHDRS], and mini-mental state examination scores), resting state networks investigated, methods for network analysis, acquisition characteristics (scanner field strength, acquisition time), and correlations with disease burden or CAG repeats and cognitive/motor outcomes. Studies reporting overlapping samples or a subset of rs-fMRI data  (Espinoza et al. , 2018; Harrington et al. , 2015; Koenig et al. , 2014; Wolf, Sambataro, Vasic, Baldas, et al. , 2014; Wolf, Sambataro, Vasic, Depping, et al. , 2014; Wolf et al. , 2015)  were included.
| RESULTS Database searching identified 263 articles, which yielded 80 citations after duplicates were removed. Fifty-four articles were excluded because reporting analysis in animals (n = 4), reviews (n = 14), or no rs-fMRI studies (task fMRI, n = 17; positron emission tomography, n = 2; arterial spin labeling, n = 2; structural MRI, n = 6; electroencephalography, n = 5; behavioral task, n = 2; genetic/biological studies n = 2). Twenty-six full-text articles were assessed for eligibility. Three of these articles were further excluded because not reporting connectivity contrasts between HD versus healthy controls (HC) or correlation with genetic load. The 23 articles included in the final review encompassed 648 HC (sample range 10-94), 266 manifest HD (sample range 10-34) and 641 pre-HD (sample range 10-183) individuals (Table  1 ).