dataesr/scientific-paragraphs-categorization huggingface dataset:
Inclusion and Exclusion Criteria Subjects were eligible to enroll if they had a confirmed diagnosis of retinitis pigmentosa (U. S. ) or outer retinal degeneration (Europe), bare or no light perception in both eyes, functional ganglion cells or optic nerve (confirmed by photoflash detection or measurable electrically evoked response), and a history of useful form vision. Age inclusion criterion was initially 50 years or older, and was later changed to 25 in the U. S. and Switzerland and 18 in France and the U. K. Exclusion criteria included diseases or conditions that affected retinal or optic nerve function, ocular structures or conditions that could prevent successful implantation, and any inability to tolerate the implant surgery or medical/study follow-up. Full inclusion and exclusion criteria are listed at ClinicalTrials.
Detailed methods were described previously  8. At the beginning of the study, assessments of patient-reported activities of daily living (ADL) and quality of life (QoL) were made with the VisQoL vision-related utility instrument  10  and the Mass of Activity Inventory. 11 These instruments were not fully validated in RP patients with minimal or no sight, and thus were used primarily for exploratory purposes in this study (data not shown). Patient reported outcomes (PROs) from this study will be reported elsewhere. In order to evaluate the impact of the Argus II System on subjects' everyday lives, the Functional Low-vision Observer Rated Assessment (FLORA) was developed at the request of and with input from the FDA and introduced partway through the trial. The FLORA was performed by independent visual rehabilitation experts to subjectively assess real-world benefit of the Argus II System.
This is supported by the results on the Find the Door and Follow the Line tasks (Table  2B ), which show essentially equal performance at years 1 and 3 on the same group of 28 subjects. Visual function results indicated that 89% of subjects performed significantly better with the System ON than OFF for Square Localization at 3 years post-implant; 56% for Direction of Motion; and 33% scored on the scale on Grating Visual Acuity with the System ON (no subjects scored with the System OFF). Similar proportions of System ON vs. OFF performance were reported from different datasets earlier in the clinical trial  8, 12, 13  ; these latest results indicate that visual function benefit from the Argus II System is sustained out to at least 3 years post-implant. For the 33%-48% of subjects who scored on the Grating Visual Acuity scale with their Systems ON, the mean visual acuity was 2.
Acknowledgments Financial Support  NIH  grant:  5R01EY012893-10 Greenberg (PI) 07/2000 -02/2011   NEI, Research/Development of Artificial Retinas for the Blind. NIH  grant:  1RC3EY020778-01  Greenberg (PI),  Development and Testing of Low Vision Assessment Tools for Retinal Prostheses. The clinical trial was sponsored by  Second Sight Medical Products, Inc. The sponsor participated in the design and conduct of the study; data management, analysis, and interpretation; and preparation and review of the manuscript. The authors would like to thank  Suber Huang, M. D. , who served as the  Independent Medical Safety Monitor for the Argus II Clinical Trial. Some funding was provided by grants from the  National Institutions of Health  ( R01EY012893 ,  RC3EY020778 ).
* This work was supported by grants from the  Fondation Recherche Médicale (Equipe FRM  to R. J. ), The  French National Research Agency (ANR) Recherches Partenariales et Innovation Biomedicale 2012  " MED-HET-REC-2 ,"  INSERM ,  CNRS , and the  Who am I? laboratory of excellence   ANR-11-LABX-0071  funded by the  French Government  through its " Investments for the Future" program  operated by the  ANR  under Grant  ANR-11-IDEX-0005-01.
Data were acquired through an AC-coupled amplifier (bandwidth: 70 -3 kHz) and a Digidata 1440A interface using the Clampex 10. 2 software (Molecular Devices). Evaluation of reciprocal inhibition. The protocol was adapted from previous reports  (Wang et al. , 2008; Talpalar et al. , 2011; Sonner and Ladle, 2013). Single pulses were delivered to the DR to evoke responses in the homonymous VR. We stimulated at two to three times the threshold (T) intensity that evoked an incoming volley in the DR. The current pulses (0. 3 ms duration) required to elicit the maximal response varied among preparations (from 0. 2 to 0. 6 V for mice; from 0. 6 to 1. 2 V for rats). Stimulations were delivered every 20 s to avoid fatigue and synaptic depression described previously  (Lev-Tov and Pinco, 1992). Test and conditioning stimulations were delivered to the L5 and L3 DRs, respectively.
Delays between the two stimulations ranged from 0 to 40 ms. Each delay was tested at least three times in the following way: five controls (test only) followed by five paired (conditioning ϩ test) stimulations. The order in which delays were tested was randomized from series to series to prevent possible order-dependent effects. Data analysis was performed offline and consisted in measuring the peak-to-antipeak amplitude of the L5 monosynaptic reflex (Clampfit 10. 2 software). To consider only the monosynaptic component, we restricted measurements to the first 3 ms after the response onset  (Kudo and Yamada, 1987). We defined the duration of the inhibition as the intersection of the regression line calculated from data with the x-axis (GraphPad Prism 5. 01 software). Quantification of polysynaptic responses.
We rectified VR signals and measured the areas under the curve from 3 to 100 ms after response onset (Clampfit 10. 2 software). The effect of the drug was considered 30 -60 min following bath application. Quantification of rate-dependent depression. We delivered 15 stimulations at various frequencies (20 s between each series) and we normalized the amplitude of monosynaptic responses (the first three discarded) to the controls evoked at 20 s intervals (mean of 5 pulses). We took into account at least three series of stimulations before and 30 -60 min after the onset of drug application. Intracellular recordings. After removing the pia, we recorded lumbar MNs intracellularly using glass microelectrodes filled with 2 M K-acetate (70 -100 M⍀ resistance). We recorded intracellular potentials in the discontinuous current-clamp mode (Axoclamp 2B amplifier; Digidata 1200 interface; pClamp9 software; Molecular Devices).
We considered only neurons exhibiting a stable (Ͼ15 min) resting membrane potential (V rest ) for analysis. We identified MNs in the L4 or L5 segments by their antidromic response to VR stimulation. We used glass suction electrode to stimulate the ipsilateral ventral funiculus at the L2-L3 level. Such stimulations induced GABA A -and glycine-mediated IPSPs in the presence of DL-2-amino-5-phosphonovaleric acid (DL-APV; 50 M) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 M;  Boulenguez et al. , 2010; Bos et al. , 2013). We recorded IPSPs at various holding potentials (500-ms-long current pulses) and collected at least 20 values for each MN. We measured and plotted amplitudes of IPSPs against holding potentials and obtained E IPSP from the regression line (GraphPad Prism 5. 01 software).
Curves were obtained from seven animals with at least five observations at each delay. E, Histograms represent the strength of inhibition at short and long interstimulus intervals (10 and 30 ms, respectively). F, Linear regression analysis of the data reported in D (r ϭ 0. 67 and r ϭ 0. 75, respectively for SCI and ZnCl 2 conditions). Statistical differences between SCI and ZnCl 2 conditions are noted above delays in D, above histograms in E and near regression lines in F (Wilcoxon test and linear regression analysis; *p Ͻ 0. 05, **p Ͻ 0. 01). (Jean-Xavier et al. , 2007). Similarly, the duration of inhibition and E Cl are negatively correlated, in agreement with the present observations that the duration of inhibition is decreased after reducing KCC2 function/expression. A major conclusion of the simulations we made was that membrane potential changes spread electrotonically as inhibitory synapses are moved away from the soma, whereas the shunting is local  (Jean-Xavier et al.
Microscope Setup and Image Acquisition 1. Perform live imaging using a Plan Apo VC 20x DIC objective (NA: 0. 75) on a confocal laser scanning microscope system attached to an inverted thermostated chamber at 37 °C under 5% of CO 2 atmosphere. 2. Position the 96-well µ-Plate inside the pre-warmed and equilibrated thermostated chamber and replace the lid by a thermostated cover. 3. Open the NIS-Elements software and click in the menu bar on "Acquire/Acquisition controls/ND acquisition" to select the options of the timelapse (length, stage positions, confocal z-sections,…), "Acquire/Acquisition controls/Ti Pad" to select the objectives and "Acquire/Acquisition controls/A1plus Settings" to select the PMT level for each fluorescence in the menu bar. Select a folder to save the data files. 4. Using the ND acquisition window, set the center of each well as a stage position and select the large image option to 7 x 7 mm².
Acknowledgements We are indebted to  C Joubert ,  V Neuville ,  V Barroca ,  J Tilliet  and all the staff of animal facilities; to  J Baijer  and  N Dechamps  for cell sorting;  O. Etienne  for technical assistance, and  A. Gouret  for her administrative assistance. Flow cytometry and cell sorting were carried out at the iRCM Flow Cytometry Shared Resource, established by equipment grants from  DIM-Stem-Pôle, INSERM, Fondation ARC , and  CEA. This work was supported by grants of  Electricité de France  (EDF). M. D. has a fellowship from  La Ligue Contre le Cancer  and L. M. from  Région Ile-de-France (DIM Biothérapies). Marc-André Mouthon  and  François D. Boussin  share co-senior authorship.
Statistical analyses Normality of distribution was analyzed with the Shapiro and Wilk test. Despite significant departures from normality, all biological variables except glucose levels were transformed to their logarithmic scores. A linear model (GLM procedure; SAS Institute Inc. , Cary, NC, USA) was used to study the fixed effects of batch and sex. Birth and weaning weights were also tested as covariates in two different models. In addition, the Pearson correlations were estimated between variables and both birth and weaning weights, after correction for batch and sex effects. Residual Pearson correlations among variables, after correction for batch effect and birth or weaning weight, were calculated. Correlations were estimated with the CORR procedure (SAS) and compared between males and females with the Fisher's z transformation.
Data are given as arithmetic means ± SD. Significance threshold was set at P < 0. 05. Genetic parameters were estimated using restricted maximum likelihood methodology applied to a multiple trait animal model, with the VCE6 software  (Neumaier and Groeneveld, 1998). The model of analysis included the effect of batch and sex, and animal additive effect as a random effect. Random effect of litter was estimated. The part of variance estimated for this effect was low thus litter effect was removed from the final analysis. Pedigree, up to six generations of ancestors for both sires and dams, included a total of 1556 animals. Owing to lack of precision for genetic parameter estimation, only results for cortisol and CBG are reported here.
Patch-clamp glass microelectrodes (4 -7 M⍀) were filled with the following solution (in mM): 120 K-gluconate, 20 KCl, 0. 1 MgCl 2 , 1 EGTA, 10 HEPES, 0. 1 CaCl 2 , 0. 1 GTP, 0. 2 cAMP, 0. 1 leupeptin, 77 D-mannitol, 3 Na 2 -ATP, pH 7. 3. Sharp glass microelectrodes (70 M⍀) were filled with 2 M K-acetate. Extracellular motor activities were recorded from various spinal cord ventral roots. For long ventral roots at the lumbar level, Vaseline-insulated stainless steel pin electrodes were used. For the short thoracic ventral roots, glass suction electrodes were used. Extracellular activities were amplified using custom-made amplifiers. Electrophysiological recordings were digitized using an analog-to-digital interface (Heka) driven by the Axograph software (Axograph). Extracellular raw signals were high-pass filtered (50 Hz), rectified, and integrated before analysis.
Locomotor parameters were computed using custom-made routines written in Matlab (Mathworks). The mean cycles were computed using one L2 ventral root as the reference because it invariably exhibited the best signal-to-noise ratio (Fig. 1 ). Wavelet transform analyses  (Mor and Lev-Tov, 2007)  were performed using the Matlab wavelet coherence package provided by Aslak Grinsted (http://noc. ac. uk/using-science/crosswavelet-wavelet-coherence). This methodology is more accurate than conventional manual or semiautomated burst detection methods, especially with low signal-to-noise ratio recordings  (Mor and Lev-Tov, 2007). Moreover, using this method allows access to the evolution of a signal's frequency content over time. Of particular interest is the possibility of extracting the common power, correlation, and phase relationship between two simultaneously acquired signals of the cross wavelet transform and wavelet coherence  (Torrence and Compo, 1998; Grinsted et al.
The skin was bonded with surgical glue and pups were progressively warmed up and checked during recovery from the anesthesia before being returned to their mother. One day after tracer injection, the pups were anesthetized using isoflurane and their spinal cords were dissected out and postfixed in 4% paraformalde-hyde in 0. 2 M phosphate buffer. After dehydration, the spinal cord was cut and prepared for ChAT immunochemistry. Statistical analysis. Statistical analyses were performed on the raw data with nonparametric t tests using Prism software (Graphpad). The Wilcoxon matched-pair test was used to compare two series of data. Oneway ANOVA was performed to test Ͼ2 groups. The level of significance was set at p Ͻ 0. 05. All data are expressed as the mean Ϯ SEM in the text and in the figures.
The asterisks in the figures indicate positive significance levels, and the numbers in or above the histogram bars refer to the number of neurons tested. Circular statistics were performed using the circular statistic toolbox in Matlab  (Berens, 2009)  and Oriana (Kovach Computing Services). (top)  and wavelet coherence between bilateral L2 activities revealed the common high-power frequencies and correlation between signals over time, respectively. The power and coherence of the frequencies between traces are color coded with warm and cool colors to indicate high and low values, respectively. Black contours delimit areas within the 5% significance level. Regions of interest (white dashed rectangles) were defined from the map obtained by mixing the results of the cross-wavelet and wavelet coherence (bottom map).
1A ). In the remaining 16 of 79 preparations, the locomotor activity recorded at the lumbar level did not spread up to the thoracic segments, where only a tonic activity was observed (data not shown). In the 63 preparations from which thoracic motor bursts were evoked, we computed the level of tonic activity from the baseline, which is shown by the gray area below each rectified and smoothed recording from the ventral roots in the left panel of Figure  1B. The ratio between the amplitudes of the burst and tonic components of the recorded activities was smaller in the thoracic segments than in the lumbar segments. On average, the mean ratio obtained from the L2 ventral roots in all experiments (n ϭ 63 preparations, 1. 75 Ϯ 0. 08) was significantly greater than the mean ratio obtained from pooled thoracic recordings (1.
, 2012; Sharott et al. , 2012; Nakamura et al. , 2014). Briefly, after 1-2 h of incubation in "Triton PBS" (PBS with 0. 3% v/v Triton X-100 and 0. 02% w/v sodium azide; Sigma) containing 10% v/v normal donkey serum (Jackson ImmunoResearch Laboratories), sections were incubated overnight at room temperature in Triton PBS containing 1% v/v normal donkey serum and a mixture of between two and four of the following primary antibodies: goat anti-choline acetyltransferase (ChAT; 1:500 dilution; Millipore, AB144P)  (Stacy et al. , 2005) ; mouse anti-ChAT (1:1000; gift from C. Cozzari)  (von Engelhardt et al. , 2007) ; rabbit anti-ER81 (also known as ETS variant gene 1 protein; 1:5000; gift from S. Arber)  (Arber et al. , 2000) ; goat anti-forkhead box protein P2 (FoxP2; 1:500; Santa Cruz Biotechnology, sc-21069); rabbit anti-FoxP2 (1:1000; Sigma, HPA000382)  (Reimers-Kipping et al.
Each immunofluorescence protocol was repeated (and thus, each neuronal expression profile was quantified) at the three levels along the rostrocaudal axis of GPe in a minimum of three adult rats. Data from rostral, central, and caudal GPe of both hemispheres were exported to Excel (Microsoft) and, unless stated otherwise, were pooled for further analyses. In the bar graphs shown in figures, gray bars represent grand averages from all rats tested, with each superimposed black dot representing the average from an individual rat to give an indication of cohort variance. Viral vector-mediated retrograde tract-tracing. To elucidate the axonal projections of populations of GPe neurons, we performed retrograde tracttracing using a recombinant, pseudotyped lentiviral vector (RV-G-MND-EGFP-WPRE) injected into either the STN or dorsal striatum.
Analyses of in vivo electrophysiological data. Data from the recording session were visually inspected, and epochs of robust cortical SWA or cortical activation were selected according to the previously described characteristics of these brain states  (Magill et al. , 2006; Mallet et al. , 2008a, b; Sharott et al. , 2012). ECoGs were assumed to be realizations of stationary, zero-mean time series; their power spectra during SWA were calculated with a frequency resolution of 0. 25 Hz using the MATLAB (MathWorks) toolbox Neurospec 2. 0 for multivariate Fourier analyses (www. neurospec. org). A portion of the spike train recorded during each defined brain state was isolated and used for statistical analyses (average epoch duration of 119 Ϯ 7 s, mean Ϯ SEM). We assumed spike trains to be realizations of stationary, stochastic point processes.
Putative singleunit activity was isolated with standard "spike sorting" procedures  (Mallet et al. , 2008a) , including template matching, principal component analysis, and supervised clustering (Spike2). Isolation of a single unit was verified by the presence of a distinct refractory period in the interspike interval (ISI) histogram. Only neurons in which Ͻ1% of all ISIs were Ͻ2 ms were analyzed in this study. For further analysis, single-unit activity was converted so that each spike was represented by a single digital event (Spike2). Mean firing rate (spikes per second; spk/s) was calculated from the total number of spikes per data epoch. The coefficient of variation of the ISIs (CV ISI ), a value used widely as an indicator of regularity in point processes  (Johnson, 1996) , and the SD of the ISIs (SD ISI ) were also calculated.
To be included in the CV ISI and SD ISI analyses, a GPe neuron had to fire at least eight spikes during the in vivo recording. To investigate how the spike firing of individual GPe neurons varied in time with respect to ongoing cortical slow oscillations during SWA, we used the Hilbert transform to analyze the instantaneous phase relationships between GPe spike times and cortical oscillations in a frequency band of 0. 4 -1. 6 Hz  (Sharott et al. , 2012; Nakamura et al. , 2014). Signal conditioning and analyses were performed using MATLAB (version 7. 3; MathWorks). ECoG signals containing robust SWA were first filtered at 0. 4 -1. 6 Hz using a second-order Butterworth filter. Subsequently, the instantaneous phase and power of the ECoG were calculated from the analytic signal obtained via the Hilbert transform  (Lachaux et al.
, 1999; Le Van Quyen et al. , 2001). In this formalism, peaks in the ECoG oscillations correspond to a phase of 0°and troughs to a phase of 180°. Linear phase histograms, circular phase plots, and circular statistical measures were calculated using the instantaneous phase values for each spike. Descriptive and inferential circular statistics were then calculated using the CircStat toolbox  (Berens, 2009)  for MATLAB. For the calculation of vector lengths and statistical comparisons, we included only those GPe neurons that fired Ն40 spikes during the entire recording during SWA. These neurons were then tested for significantly phase-locked firing (defined as having p Ͻ 0. 05 in Rayleigh's Uniformity Test). The null hypothesis for Rayleigh's Uniformity Test was that the spike data were distributed in a uniform manner.
We and others have previously remarked that the nonsinusoidal nature of some field potential oscillations, such as the cortical slow oscillation, can confound standard circular statistics, especially Rayleigh's Uniformity Test  (Siapas et al. , 2005; Mallet et al. , 2008a; Sharott et al. , 2012; Nakamura et al. , 2014). Thus, for analysis of GPe neuron firing relationships with cortical slow oscillations, Rayleigh's Uniformity Tests were only performed after any phase nonuniformities of the slow oscillations were corrected with the empirical cumulative distribution function of MATLAB  (Siapas et al. , 2005; Nakamura et al. , 2014). For each of the neurons that were significantly phaselocked, the mean phase angle was calculated. Differences in the mean phase angles of groups of neurons were tested by the Watson-Williams F test ( p Ͻ 0.
, 2005). The recorded membrane potential was therefore ϳ4 mV more depolarized than the true membrane potential and was corrected off-line. Somatic patch-clamp recordings were obtained using a Multiclamp 700B amplifier and Digitdata 1320A digitizer controlled by Clampex 9. 0 software (Molecular Devices). Electrode signals were low-pass filtered at 4 kHz and sampled at 20 kHz. Following electrophysiological recording in either a cell-attached or perforatedpatch configuration, the electrode was carefully withdrawn and the soma of the same neuron was repatched  (Oren et al. , 2009)  using new glass pipettes filled with a solution containing 1. 5% w/v biocytin (Sigma) and (in mM): 110 KMeSO 4 , 25 KCl, 3. 6 NaCl, 1 MgCl 2 ⅐ 6H 2 O, 10 HEPES, 0. 1 Na 4 EGTA, 0. 4 Na 3 GTP, and 2 Mg 1. 5 ATP. The pH and osmolarity of this pipette solution were 7.
After binding of primary and secondary antibodies, and final washing in PBS, sections were mounted in Vectashield and imaged on a confocal fluorescence microscope (TCS SP8; Leica Microsystems) equipped of a white light laser 2 with freely tunable excitation from 470 to 670 nm. Analyses of in vitro electrophysiological data. Data were analyzed using Origin 7. 0 (Microcal Software). Mean firing rates, CV ISI , and SD ISI were calculated as for recordings of GPe neurons in vivo. To quantify the autonomous firing of neurons recorded in the perforated-patch configuration, contiguous 60 s epochs of activity with zero current injection were analyzed. The input resistance of each neuron was calculated from the difference between the minimum membrane voltage reached during injection of a Ϫ100 pA, 500 ms current pulse, and the average subthreshold membrane potential during the 10 s preceding the current injection  (Deister et al.
"Rebound" burst firing was defined as spikes occurring at an instantaneous rate in excess of mean spontaneous firing ϩ 3 SDs in response to the injection of a 500 ms current pulse of Ϫ150 pA. In voltage-clamp recordings, persistent sodium channel currents were transformed into conductance (G) using Ohm's law in the form: G ϭ I/(V Ϫ E Na ), where V is the test potential and E Na is the sodium equilibrium potential calculated using the Nernst equation. Conductance was normalized, plotted against V, and fitted with a Boltzmann function of the form: G/G max ϭ 1/(1 ϩ exp[(V Ϫ V 1/2 )/k]) , where V 1/2 is the halfactivation voltage and k is the slope factor. Further statistical testing. The Shapiro-Wilk test was used to judge whether noncircular datasets were normally distributed ( p Յ 0. 05 to reject).