dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements This work was supported by the  Académie des Sciences -Grand Prix Lamonica de Neurologie  and by the  FRM 'Equipe 2015 ' to LN, and by  Sorbonne Universités ED3C  (PhD funding to CR). This work has been also supported by the program " Investissements d'avenir "  ANR-10-IAIHU-06  and the  ICM-OCIRP. TSM work was supported by fellowships of the  Israel Science Foundation   57/15 , and  Marie Skłodowska-Curie 702577. We would like to thank  Imen El Karoui  for her contribution to iEEG data analysis. We thank the patients for their collaboration. We thank the Editor and the two anonymous reviewers for their constructive suggestions.
FLUOVIEW FV1000 Confocal laser scanning microscope (Olympus) or Pannoramic MIDI automatic digital slide scanner (3D HISTECH) was used to capture images. BrdU immunostaining was in consistent with previous report. 27 dU (Sigma-Aldrich) was intraperitoneally injected every other day (50 mg/kg, IP, dissolved in saline). Brain slices of BrdU immunostaining were incubated with 1 N HCl at 45°C for 30 minutes and then neutralized with 0. 1 mol/L sodium borate buffer (pH 8. 0) before immunofluorescence staining. The positive cells of immunofluorescence staining were counted by Image J 1. 5 software (Wayne Rasband, NIH) and analyzed by a blind observer. The representative images used to count the number of positive cells were taken from six random microscope fields in the transplantation periphery of ipsilateral cortex, SGZ or SVZ, and repeated with at least 3 independent animals per group.
Fresh chromogenic substrate DAB was added to visualize the section staining. Digital microscope (Leica Microsystems) was used to obtain images. The positive cells of immunohistochemistry staining were counted by Image J 1. 5 software (Wayne Rasband, NIH) and analyzed by a blind observer. The representative images used to count the number of positive cells were taken from six random microscope fields in the transplantation periphery of ipsilateral cortex and repeated with at least 3 independent animals per group.
| Statistical analysis All data were shown as mean ± SEM. The line graphs were prepared in SigmaPlot 10. 0 software (Systat Software Inc); the histograms were prepared in GraphPad Prism 7. 0 statistical software (GraphPad Software, Inc). Statistical analyses were performed in the SPSS 11. 0 software (SPSS Inc). Two-tailed Student's t-test was used for comparison between two groups. ANOVA comparison followed by Bonferroni post hoc tests was used for comparison of mean value among groups. P <. 05 was considered statistically significant.
DAPI labels nuclei (blue). Scale bars: 50 μm. C-E, Quantitative analysis of neurogenesis by counting BrdU + /Nestin + , BrdU + /DCX + , and BrdU + /NeuN + cells in the transplantation periphery of ipsilateral cortex at 7, 14, 28, and 56 dpi. Immuno-stained positive cells were counted with six random microscope fields in the transplantation periphery of ipsilateral cortex, and repeated with at least three independent animals per group. All data were shown as mean ± SEM and analyzed by ANOVA with Bonferroni posthoc tests. *P <. 05, **P <. 01 vs TBI group; #P <. 05, ##P <. 01. N. S, not significant | 689 WANG et Al.
A, Representative images of in-vivo differentiated COs by immunostaining of human cytoplasmic marker (STEM121, green) and neural stem cells (Nestin, red), neurons (Tuj1, red), or astrocytes (GFAP, red) at 7, 14, 28, and 56 dpi in 55 d-CO transplantation group. The cells of STEM121 + /Tuj1 + and STEM121 + /GFAP + gradually increased but STEM121 + /Nestin + cells gradually decreased until they disappeared. DAPI labels nuclei (blue). Scale bar: 50 μm. B, Quantification of the percentage of STEM121 + /Nestin + and STEM121 + /Tuj1 + cells in the in-vivo differentiated COs. Immunostained positive cells were counted with six random microscope fields in the transplantation periphery of ipsilateral cortex and repeated with at least three independent animals per group. All data were shown as mean ± SEM and analyzed by ANOVA with Bonferroni posthoc tests.
More cell survival from transplanted 55 d-CO than 85 d-CO in rat TBI model. A, Representative images of COs survival by immunostaining of human cytoplasmic marker (STEM121, green) at 7, 14 and 28 dpi in the transplantation periphery of ipsilateral cortex of 55 d-CO transplantation and 85 d-CO transplantation groups. STEM121 + cells distributed throughout the lesioned cavity. DAPI labels nuclei (blue). Scale bar: 50 μm. B, Quantitative analysis of STEM121 + cells per field in 55 d-CO transplantation and 85 d-CO transplantation groups. Immunostained positive cells were counted with six random microscope fields in the transplantation periphery of ipsilateral cortex and repeated with at least three independent animals per group. All data were shown as mean ± SEM and analyzed by ANOVA with Bonferroni posthoc tests.
F I G U R E 3 3 More cell survival from transplanted 55 d-CO than 85 d-CO in rat TBI model. A, Representative images of COs survival by immunostaining of human cytoplasmic marker (STEM121, green) at 7, 14 and 28 dpi in the transplantation periphery of ipsilateral cortex of 55 d-CO transplantation and 85 d-CO transplantation groups. STEM121 + cells distributed throughout the lesioned cavity. DAPI labels nuclei (blue). Scale bar: 50 μm. B, Quantitative analysis of STEM121 + cells per field in 55 d-CO transplantation and 85 d-CO transplantation groups. Immunostained positive cells were counted with six random microscope fields in the transplantation periphery of ipsilateral cortex and repeated with at least three independent animals per group. All data were shown as mean ± SEM and analyzed by ANOVA with Bonferroni posthoc tests.
Conclusion The historic use of categorical diagnoses and classifications has failed NDDs in that the boundaries between disorders are not clear and comorbidity is common. The neurodevelopmental continuum underscores the need for new and flexible approaches to diagnosis and patient stratification, and the high degree of pleiotropy suggests that therapeutic approaches may be fruitful across diagnostic boundaries. The rate of disease gene identification has accelerated dramatically over the past decade and with whole-exome and genome sequencing becoming increasingly routine practice, the genotype-first approach will likely soon spread beyond autism and developmental delay to include genes and CNVs associated with other psychiatric disorders. This surge in technological development to generate large datasets has been accompanied by increasing sophistication in the statistical methods used for data analysis.
The observations that some member peptides, in particular CHH, are pleiotropic and often overlap with biological activities of other members probably reflect the evolutionary history of the CHH family  (29) (30) (31). Based on the structure of the genes and the hormone precursors, and the characteristics of the mature peptides, the CHH-family peptides were divided into two groups: Type I (CHH) and Type II (MIH/ GIH/MOIH)  (30, (32) (33) (34). Increasingly, the CHH-family peptides have been identified more through nucleotide sequencing of transcripts (cDNA cloning or transcriptomics) than by the conventional approach of biochemical purification and peptide sequencing. In a recent report, in silico mining of transcriptome datasets from 112 crustacean species (representing three Classes: Malacostraca, Branchiopoda, Copepoda) resulted in a collection of 413 genes encoding CHH-family peptides  (35).
PEPTIDE STRUCTURE, SIGNAL TRANSDUCTION PATHWAYS, AND RECEPTORS Peptide Structure The first structural model of the CHH superfamily peptide was that of MIH (Pej-MIH) from M. japonicus resolved by nuclear magnetic resonance (NMR) spectroscopy. It consists of a long Nterminal tail, followed by five alpha helices (a1-a5), and a Cterminal tail  (92). Subsequently, two more structures of the crustacean member peptides have been elucidated: Pej-SGP-I-Gly, the glycine-extended precursor of a M. japonicus CHH by X-ray crystallography  (91) , and Sco-CHH-L, the CHH-L from the pericardial organ of S. olivacea by NMR spectroscopy (Protein Data Bank: 5XS1). Although topologically equivalent helices-a2, a3, and a4 (p4 in Sco-CHH-L)-are present in the core of the three structures, Pej-MIH and Sco-CHH-L are more topologically resemble one another than Pej-SGP-I-Gly (Figure  3 ).
1 x 10 -8 M and 1. 3 x 10 -8 M, respectively) and BNGR-A24 to ITP-L (EC 50 : 2. 6 x 10 -8 M). Interaction between ITPs and BNGRs was evaluated by an in vitro assay that showed co-localization of the ligand and BNGR at the cell membrane of CHO cells heterologously expressing the receptor; the interaction occurred in a ligand-receptor-specific manner, consistent with the data for the distinct receptor responses to ligand activation observed using Ca 2+ imaging. Stimulation of B. mori ovaryderived (BmN) cells by either ITP or ITP-L significantly increased the intracellular cGMP levels. Coupling of the BNGRs to the ITPs-induced cGMP signaling was demonstrated by observations that simultaneous knockdown of bngr-A2 and -A34 significantly decreased the cGMP response to ITP in BmN cells, whereas knockdown of bngr-A24 led to decreased cGMP responses to ITP-L; transient expression of bngr-A24 potentiated the response of BmN cells to ITP-L.
Thus, analysis of transcriptome data derived from P. clarkii tissues has uncovered GPCRs, Procambarus GPCRs A52, A53 and A63, that clustered with BNGR-A34, and Procambarus GPCR A9 with BNGR-A24, with A52 and A63 being abundantly expressed in the hepatopancreas, implying these GPCRs could be the crayfish CHH, MIH, or CHH-L receptor  (97). In addition, analysis of the data derived from the spiny lobster Sagmariasus verreauxi revealed 2 annotated GPCRs (Sv-GPCRA11 and 12) that are phylogenetically clustered with BNGR-A34 (96). In the blackback land crab G. lateralis Y organ transcriptome 3 GPCRs (Gl-GPCRA9, Gl-GPCRA10, Gl-GPCRA12) were similarly identified using phylogenetic analysis as potential CHH-like receptors, as these sequences clustered into the putative CHH receptors clade  (95). Expression of one of the GPCRs, Gl-GPCRA12, decreased in late pre-molt and post-molt stages, suggesting that it may be the MIH receptor  (95).
ACKNOWLEDGMENTS The authors thank  Ceĺine Ollivaux  ( Sorbonne Universite, France ) for providing the images used in Figure 2, and  Yun-Ru Chen  ( Academia Sinica Protein Clinic ) and  Syuan-Huai Shih  ( National Changhua University of Education ) for preparing Figures 3 and4, respectively. Special thanks are due to  Kurt Liittschwager  for editing an early version of the manuscript. Financial support from the  Ministry of Science and Technology  ( 107-2311-B-018-001 ,  108-2311-B-018-001 ) to C-YL and from  Ministry of Education through National Penghu University of Science and Technology  ( 107G0049 ,  108G0038 ) to H-YC is acknowledged.
Purpose: Iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ( 123 I-FP-CIT) SPECT can be performed to distinguish degenerative forms of movement disorders/parkinsonism/tremor from other entities such as idiopathic tremor or drug-induced parkinsonism. For equivocal cases, semi-quantification and comparison to reference values are a necessary addition to visual interpretation of 123 I-FP-CIT scans. To overcome the challenges of multi-center recruitment and scanning of healthy volunteers, we generated 123 I-FP-CIT reference values from individuals with various neurological conditions but without dopaminergic degeneration, scanned at a single center on the same SPECT-CT system following the same protocol, and compared them to references from a multi-center database built using healthy volunteers' data.
Overall, the reduction rate per decade in SBR was between 3. 80 and 5. 70%. Women had greater SBRs than men, but this gender difference was only statistically significant for the Flash3D database. Linear regression was used to correct for age-dependency of SBRs and to allow comparisons to age-matched reference values and "normality" limits. Generated regression parameters and their 95% confidence intervals (CIs) were comparable to corresponding European Normal Control Database of DaTscan (ENC-DAT) results. For example, 95% CI mean slope for the striatum in women is -0. 015 ([-0. 019, -0. 011]) for the Flash3D database versus -0. 015 ([-0. 021, -0. 009]) for ENC-DAT. Caudate-toputamen ratios and asymmetries were not influenced by age or gender.
2017 ). These semi-quantification methods use either manually drawn or predefined regions of interest. However, quantitative measures have little clinical value without reference ranges, especially in cases when diagnostic decisions cannot be drawn from quantification as the scans cannot be interpreted visually as abnormal  (Albert et al. 2016 ). In addition, as 123 I-FP-CIT uptake depends on normal ageing, quantitative values are only of value if age effect on DAT availability is accounted for  (Nicastro et al. 2016). A few years ago, a 123 I-FP-CIT database was generated from healthy volunteers in a multi-center European study  (Varrone et al. 2013 ). This study included 139 healthy individuals (74 men, 65 women; age range 20-83 years, mean 53 ± 19 years) scanned at 13 different centers on 17 different SPECT systems of 11 different models.
To address inter-center variability, quantitative values for each SPECT system were corrected using camera-specific calibration factors generated through phantom experiments  (Koch et al. 2006; Tossici-Bolt et al. 2011; Dickson et al. 2012). Despite the efforts to minimize inter-site variability, there remained significant variability in specific binding ratio (SBR) which could not be explained by age and other considered covariates and which might be related to SPECT equipment, including hardware and reconstruction software, used in the European Normal Control Database of DaTscan (ENC-DAT) study as was noted in  (Buchert et al. 2016a ). This led to some inconsistencies when comparing data and may have resulted in higher variability in the estimation of the regression lines, modelling the uptake decline as a function of age, and that of the percentage declines per decade as was noted by the authors.
(Nicastro et al. 2016)  proposed an approach to calculate sitespecific reference values using scans from individuals with non-degenerative conditions scanned following the same protocol. A normal scan was defined as a grade 0 123 I-FP-CIT SPECT  (Catafau and Tolosa 2004). This study included a cohort of 182 subjects with an older age range compared to the ENC-DAT database (73 men and 109 women (60%); age range 40-93 years, mean 69. 1 ± 11. 2 years). Most of the included subjects had drug-induced parkinsonism (DIP) (44%), while the remaining subjects had essential tremor (ET) (21%), psychogenic parkinsonism (17%), or other non-parkinsonian conditions. Not all included subjects were followed over time, and final neuropathological assessment was unavailable for the majority of them. Therefore, it may be possible that this study included cases with pre-clinical degenerative conditions affecting the nigrostriatal system.
In order to address some of the limitations mentioned above, we propose to build a database of reference values for 123 I-FP-CIT using a large cohort of subjects across a wide age range and with a well-balanced gender representation. Each included subject had both a normal 123 I-FP-CIT SPECT scan, based on semi-quantification and on visual interpretation by two trained nuclear medicine physicians, as well as a clinical diagnosis of non-degenerative parkinsonism or other non-parkinsonian entities at baseline and confirmed after a follow-up period ranging from 3. 5 to 10 years by experienced neurologists. Imaging data were all acquired at the same center on the same SPECT-CT imaging system and following the same imaging protocol. We have established reference values and limits for the striatum, caudate nucleus, putamen, anterior putamen, and posterior putamen while accounting for the age effect on DAT availability.
Materials and methods The selection of our cohort was performed in two different stages as illustrated on the diagram shown in Fig. 1. In the first stage, selection was based on visual reads combined with semi-quantification with an in-house software, and assessment of clinical diagnoses. This stage was performed at Lyon University Neurological Hospital nuclear medicine department where data were collected (CS and ABS, Lyon, France). The second stage consisted of additional and rigorous quality control of both anatomical and functional imaging data, combined with visual reads and semi-quantification of the SPECT data with syngo. via® software. Patients' clinical information was also taken into consideration when making a decision to include or reject a patient at this second selection stage.
Scan "normality" was mainly determined by visual interpretation and confirmed by semi-quantification using a fully automated in-house analysis program (CS). This program was implemented based on routines from the statistical parametric mapping (SPM) toolbox 1  , with CT-based attenuation correction (CTAC) and correction for age effect on DAT availability. Note that this analysis program is independent of the software application implemented in syngo. via®, which was used to generate the reference values. Once a scan was classified as normal, a second NM physician (ABS) was asked to visually confirm its normality. Then, we assessed the integrity of corresponding imaging and clinical data and the availability of final diagnosis based on a follow-up of at least 3 years after the 123 I-FP-CIT SPECT scan was acquired.
Patient selection-stage 2 The anonymized clinical and imaging data of the 256 subjects selected in stage 1 were further quality-checked (GP) looking for any large patient motion in the SPECT projections and/or any reconstruction or imaging artifacts, as well as any anatomical abnormalities (e. g. , major hydrocephalus or atrophies) in the CT images. Additional visual and semi-quantitative assessments of the SPECT data were performed (RF and GP) using a striatal analysis methodology implemented in syngo. via® software looking for any uptake abnormalities, such as large asymmetries. This software application generates quantifiable measures as well as a parametric "slab" view of the patient's image for improved visual assessment  (Buchert et al. 2016b ). The final clinical diagnoses as well as the clinical reads, performed at stage 1, of all SPECT images were considered when selecting which subjects to include in the database.
SPECT imaging: data acquisition and reconstruction Patients were scanned on the same Symbia™ T2 system equipped with low-energy highresolution collimators. Scans started 3 h post-intravenous injection of ~185 MBq of 123 I-FP-CIT which occurred 1 h following thyroid blockade with perchlorate when needed. In every case, the patient's head was constrained with a head holder to minimize motion, and acquisition was performed with the following parameters: rotational radius kept between 13 and 15 cm; matrix 128 × 128; 120 projection angles over 360°; and a hardware zoom of 1. 23 × 1. 23 to achieve an in-plane pixel size of 3. 9 × 3. 9 mm 2. In addition to the photopeak imaging window (159 keV ± 8%, 147-171 keV), two additional scatter energy windows were acquired. For each patient, a diagnostic CT was acquired (with a CT dose index of 35 mGy, and a dose length product of 940 mGy*cm) and was used for attenuation correction (AC).
We generated two databases of reference values corresponding to two image reconstructions methods: (1) Flash3D (OSEM3D with resolution recovery) with 10 iterations and 8 subsets, CTAC (as recommended for OSEM reconstructions), a triple energy window method for scatter correction, and 8mm FWHM Gaussian post-reconstruction smoothing; and (2) filtered back projection (FBP) reconstruction with Chang attenuation correction (linear correction coefficient: μ = 0. 11 cm -1 ), and Butterworth filter of order 5 and a cut-off frequency of 0. 45 cycles/ pixel.
Image quantification and analyses We used syngo. via® software to calculate 2  reference values on twelve striatal volumesof-interest (VOIs), including the left and the right sides of the caudate, striatum, putamen, anterior putamen, and posterior putamen. For each VOI, left and right specific binding ratios (SBRs) and asymmetry values as well as C/P ratios 2 were generated as follows: first, each 123 I-FP-CIT image was automatically registered to a SPECT template in the Montreal Neurological Institute (MNI) space using an affine transformation, followed by (automatic) positioning of predefined striatal and background (occipital lobe) VOIs. To ensure accurate positioning of these VOIs on the spatially normalized SPECT images, manual adjustments (translations and rotations) of the automatically placed VOIs, in three planes, were performed whenever needed.
Comparison of new subjects to reconstructed databases In order to test the robustness of the generated reference values, we have compared a set of subjects with different diagnoses against the generated databases. A total of 22 subjects (9 normal and 13 with confirmed degenerative forms of parkinsonism) were used for this purpose. For a test subject of a given age and for each striatal VOI, the patient's left and right SBRs were separately compared to the corresponding predicted and age-matched reference SBR. The latter is calculated by substituting the subject's age in the corresponding regression line equation. Using the equation of the lower bounding line of the predictive interval (-95% PI), the patient's age-matched normality threshold is also calculated and used to classify the subject.
2014 ): z ¼ z 1 -z 2 ð Þ ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 1 n 1 -3 ð Þ þ 1 n 2 -3 ð Þ r ð3Þ where z 1 and z 2 refer to the Fisher's r to z transformation of the coefficients r 1 and r 2 and n 1 and n 2 denote the corresponding sample sizes. Significance was set at p = 0. 05. Statistical analyses were mainly performed using the Statistics Toolbox of Matlab R2014a (MathWorks, Natick, MA).
8%). The young patient sub-group (8. 5%) with ADHD was included to have references at young ages. Table  1  summarizes final clinical diagnoses for all included subjects. Differences in specific binding ratio between hemispheres No statistical differences were found between left and right SBR values for any striatal VOI irrespective of gender, nor between left and right SBRs from men and women considered separately. Hence, for each striatal VOI, the left and the right SBRs were averaged to estimate a single reference value. Left and right SBR values for the Flash3D database are presented in Table  2. Corresponding results for the FBP database are not shown. Averaged left and right SBRs are shown in Table  4  for both databases and genders. A one-way ANOVA test comparing the averaged right and left SBR values for different diagnostic subgroups (see Table  1 ) resulted in no significant differences for caudate, putamen, and striatum (p > 0.
Gender and age effects on specific binding ratio We found that women had slightly higher SBRs with greater variances compared to men in all striatal regions regardless of the reconstruction method. Figures  3  and 4  show SBRs measured within the striatum according to gender for the Flash3D and the FBP databases, respectively, as a function of age. This difference tends to decrease with ageing. The differences in SBR between genders were only statistically significant for the Flash3D database as shown in Table  4. Hence, we have established SBR reference values identical for men and women for both reconstructions. Conversely, the effect of age was statistically significant for both databases and all SBRs as shown on Table  4. We observed a consistent decrease of SBR values with age for men and women in all striatal VOIs (e.