dataesr/scientific-paragraphs-categorization huggingface dataset:
Neutron diffraction from rat and mouse CNS myelin Previous work suggested that CNS myelin had only a limited capacity to provide meaningful neutron scattering data  (Worcester, 1976). To determine the extent to which ND could be used to analyze CNS myelin, we examined rat optic nerve and spinal cord (2 mm in diameter; >15 mm in length), followed by mouse optic nerve and spinal cord. Because of their small size ($0. 5 mm in diameter; <10 mm in length), we expected rat optic nerves to diffract much more weakly than sciatic nerves. It also has been previously demonstrated using XRD  (Avila et al. , 2005  and subsequently by our own ND experiments) that diffraction from CNS myelin is generally of lower quality than that from PNS myelin because of the smaller coherent domain size (fewer layers of myelin) and increased disorder in membrane packing in CNS myelin (Fig.
The water-exchange rates determined for mouse sciatic nerves were consistent with the data from rat sciatic nerves: exchange from 100 to 20% D 2 O-saline followed a single exponential decay with a relaxation time of 1. 72 min (n = 1), while the reverse exchange (20!100% D 2 O-saline) showed a relaxation time of 2. 47 min (n = 1; Fig. 6c, Table 2 ). Exchange experiments were not performed on mouse optic nerves because of their weak diffracting power (Fig. 3 ). Instead, mouse spinal cords were examined. During exchange from 100 to 20% D 2 O-saline, these samples displayed a decrease in F 2 that consistently showed a double exponential decay, with a primary relaxation time of 5. 84 AE 1. 15 min and a secondary relaxation time of 0. 67 AE 0. 27 min (n = 6; Fig. 6d, Table 2 ). The reverse exchange (20!100% D 2 O-saline) was significantly slower, showing primary and secondary relaxation times of 7.
The effect of heavy water on myelin structure It has previously been reported that frog (Rana pipiens) PNS myelin in H 2 O-saline produces identical XRD patterns to nerves soaked in D 2 O-saline  (Akers & Parsons, 1970). However, throughout our ND experiments, we noticed that the samples exhibited a slight, but constant, tendency towards a lower period as the concentration of D 2 O increased. This difference was typically no greater than 4 A ˚between nerves in 100% H 2 O-saline versus nerves in 100% D 2 O-saline (data not shown). To test whether deuterium was causing unexpected structural changes, we soaked nerves in H 2 O-saline and D 2 Osaline and analyzed them using XRD, which does not distinguish between deuterium and hydrogen. We found that mouse sciatic nerves in D 2 O-saline displayed a 1.
This is in stark contrast to the condensed nature of the major dense line as observed in EM. It is commonly written that the major dense line is formed by the fusion of cytoplasmic leaflets of the oligodendrocyte/Schwann-cell membrane and is therefore devoid of cytoplasm; however, our measurements clearly demonstrate that the cytoplasmic apposition is similar to the extracellular apposition in terms of width (CNS) and water content (CNS and PNS), and could harbour small metabolites and other molecules in an aqueous environment. Our analysis of the ND data also revealed more subtle variations in membrane structure. In particular, we measured an apparent asymmetry in the bilayer, as shown by an increased neutron scattering density in the extracellular leaflet. The higher scattering density of the extracellular leaflet may represent an enrichment of cholesterol on this side of the membrane, as the steroid nucleus of cholesterol has a higher neutron scattering density than stiff-chain hydrocarbon: 0.
For example, mice lacking components of the axo-glial junctions or interlamellar tight junctions and animal models of multiple sclerosis, such as the experimental autoimmune encephalomyelitis (EAE) mouse, would be of particular interest. A forthcoming manuscript will focus on our use of ND and XRD to characterize myelin from mice lacking the CNS interlamellar tight junction protein claudin-11  (Gow et al. , 1999; Devaux & Gow, 2008). We thank Adrian Perkins and Didier Richard at the ILL and Dominique Dallery, Charlene Caloud and Helene Bernard at the ESRF for experimental support. We thank Dr Alexander Gow and Kathleen Maheras (Wayne State University Medical School, Detroit, Michigan, USA) for providing some of the animals used in this study. We thank Brian White and Perry Nuckle at NOVA Scientific Inc.
Simulation tools Network simulations were performed using the simulator NEST, interfaced with PyNest  [22, 23]. The differential equations were integrated using forth order Runga-Kutta with a time step of 0. 1 ms. Simulation data was analyzed using the Python scientific libraries: SciPy and NumPy. The visualization of the results was done using the library Matplotlib  [24]. The code to reproduce several results presented in this work (Figure  1b , Figure  3a , Figure  4a , Figure  5b  and Figure  S6a ) is available at https:// github. com/AlexBujan/ctr. Other results can be reproduced by modifying that code.
This work was supported by  FACETS-ITN  ( PITN-GA-2009-237955 ),  CNRS ,  BrainScales  ( FP7-2010-IST-FETPI 269921 ),  ANR Complex-V1 , the  German Federal Ministry of Education and Research  ( BMBF 01GQ0420  to  BCCN Freiburg  and  01GQ0830  to  BFNT Freiburg/Tu ¨bingen ) and the  BrainLinks-BrainTools Cluster of Excellence  funded by the  German Research Foundation  (DFG # EXC 1086 ). AK and AA acknowledge  INTERREG IV Rhin superieur program  and  European Funds for Regional Development (FEDER)  through the project  TIGER A31. We also acknowledge the use of the computing resources provided by the  Black Forest Grid Initiative  and the bwGRiD (http://www. bw-grid. de),member of the  German D-Grid initiative , funded by the  Ministry for Education and Research (Bundesministerium fu ¨r Bildung und Forschung)  and the  Ministry for Science, Research and Arts Baden-Wuerttemberg (Ministerium fu ¨r Wissenschaft, Forschung und Kunst Baden-Wu ¨rttemberg).
Cognitive Study. The cognitive assessment included 4 tests systematically taken in 30 minutes in the following order (in both ON and OFF periods): verbal fluency test, Stroop test, Wisconsin sorting card test, and FAB (frontal assessment battery) test. In the verbal fluency test, patients were asked to name in one minute as many items as they could from one semantic category (animals) and then as many words as they could beginning with the letter M (one minute); category switching (boys' names and fruits) was then assessed (one minute). In an alternative form  [23] , the last one of these verbal fluency tests was used for evaluation of mental flexibility  [24]. The Stroop test was used for evaluation of inhibitory control  [25]. With the Wisconsin card sorting test (WCST), we collected data ("number of series, " "number of mistakes, " and "perseveration percentage") in order to evaluate mental flexibility  [26].
5 Hz; low-pass filter: 15 Hz). The horizontal and vertical bipolar electrooculogram (EOG) was recorded during the task to monitor artefacts. Trials with artefacts were automatically excluded from the averages: if any data point (beyond the first 2. 5 ms of the sweep) was greater than 96% full scale, the entire sweep was rejected and was not added to the memory block. Two consecutive averages of artefact-free trials were obtained. Subjects were tested seated in a sound-attenuating chamber. All of them reported normal hearing function. The prerecorded stimulus sequence was presented without instructions (passive condition). After this first run, all subjects were able to distinguish high-pitched from low-pitched tones and were then instructed to keep a mental record of the rare tones and to report their number at the end of the run (active condition).
The software we used for data capture and analysis was Statview 5. 0 (from SAS Institute © ). Periods). The apathy score was correlated, during OFF periods, with a decrease of P300 amplitude in Cz and Pz locations and with average P300 amplitude in Cz and Fz locations (see Table  1  and Figure  1 ). During ON periods, there was a significant decrease of the amplitude of P300a wave (in Fz) in apathetic subjects (see Table  1  and Figure  2 ). During OFF periods, there was a tendency towards decrease of P300a amplitude in Fz (statistically insignificant:  = 0. 0707). The apathy score was positively correlated, on the one hand with alteration of mental flexibility (WCST and verbal fluency test) and on the other hand with severity of executive dysfunctions (FAB) during ON and OFF periods, whereas there was no correlation with disturbed inhibitory control (explored by the Stroop test) (Table  1 ).
Statistical analysis All data are expressed as the mean ± SEM. Behavioral and biochemical data were statistically analyzed using comparisons between saline and LPS-treated mice at PND14 using an unpaired Student's t-tests. A P value <0. 05 was considered as significant. Data obtained after a second LPS stimulus were analyzed using a two-way ANOVA test with treatment at PND14 (saline versus LPS) and treatment at adulthood (saline versus LPS) as between factors, followed by Bonferroni post-hoc comparisons when appropriate.
Lipopolysaccharide treatment at postnatal day 14 alters emotional behavior of adolescent and adult mice Anxiety-like behavior of LPS-treated PND14 mice was measured in NSFT at adolescence (PND30) and adulthood (PND90). At PND30, the time for saline-treated mice to reach and start eating the food pellet in the center of the arena was significantly shorter as compared to the LPS-treated mice (P <0. 05, t = 2. 404) (Figure  3 , top left panel). No significant difference in the latency to reach and eat the food pellet was measured in saline and LPS-treated mice at PND90 (Figure  3 , top right panel). Even if neonatal LPS-treated mice slightly gained more weight than controls throughout life, no significant difference in weight loss was measured after fasting (data not shown), suggesting that the longer latency to eat the pellet is not related to a change in hunger in the LPStreated animals.
Lipopolysaccharide treatment at adulthood impairs spatial memory performance in lipopolysaccharide-treated postnatal day 14 mice We then evaluated the effect of a second LPS administration at adulthood on spatial memory (Figure  5 ). At adulthood, NaCl or LPS-treated mice at PND14 received an i. p. administration of NaCl (NaCl-NaCl and LPS-NaCl) or LPS (NaCl-LPS and LPS-LPS) and spatial memory was assessed using a Y-maze test 24 h later. Spatial memory differed across the treatments since only mice subjected to a double-hit of LPS spent the same time exploring the familiar arm and the novel arm (NaCl-NaCl, P <0. 05, NaCl-LPS, P <0. 05, LPS-NaCl, P <0. 01, LPS-LPS, P = 0. 166) (Figure  5 ). Total locomotion was not affected by the LPS treatment (data not shown).
These differences could not be attributed to altered locomotor activity since the mice showed no difference in locomotion (data not shown). We also evaluated depressive-like behavior at both periods (PND30 and PND90), and we reported an increased occurrence of immobility in the FST only in adult LPS-treated PND14 mice, showing a higher level of depressive-like behaviors. We reported here for the first time a dichotomic pattern between anxiety-like and depressive-like symptoms induced by postnatal inflammation. Previous studies demonstrated an aversive effect of endotoxin exposure in early life on anxiety during adulthood  [57]  but not during adolescence  [58]  and on depressive-like behaviors  [59]. But, these results were obtained with a neonatal inflammatory event occurring between PND3 and PND5, which could account for the discrepancy since it has been shown that the period of postnatal exposure to LPS impacts the perinatal programming of adult behavior.
The action potentials waveform and the corresponding TTL pulses generated by the discriminator were digitized (50 kHz sampling rate, Superscope, GW Instruments), visualized on-line and stored for off-line analyses. The pulses were sent to the acquisition board (PClab, PCL 720) of a laboratory microcomputer, which registered them with a 50 μs resolution and provided online displays of the neuronal responses. For each animal, the signal from each electrode was tested daily and the data collection only started when, under 1-3 electrodes, action potential waveforms can be unambiguously attributed to a single neuron.
AUDIOMETRY AND EXPOSURE TO THE TRAUMATIC SOUND Auditory brainstem responses (ABRs) were recorded as previously described  (Gourévitch et al. , 2009; Gourévitch and Edeline, 2011). Briefly, ABR were recorded via subcutaneous electrodes (SC25, Neuro-Services); using a Centor-USB interface and software (DeltaMed, France). The signal was filtered (0. 2-3. 2 kHz, sampling rate 100 kHz), waveforms were averaged (500-1000 waveforms depending on the stimulus intensity) and stored for off-line analyses on a computer. An artifact rejection procedure was used during averaging, the rejection criterion being ±40 μV. The stored waveforms were examined and the threshold was defined as the lowest level (dB re:20 μPa) at which a clear waveform could be observed. Intensity levels were always below 90 dB in order to avoid inducing additional hearing loss on traumatized animals.
The whole sound delivery system (HP 8903B, attenuators, and speaker) was calibrated from 0. 1 to 35 kHz and could deliver tones of 80 dB up to 20 kHz and of 70 dB up to 35 kHz. Harmonic distortion products were measured to be down about 50 dB from the fundamental. The EEG (bandpass 1-90 Hz) was displayed on a polygraph (Grass, model 79D) to make sure that the animal was awake during the entire recording session (the data collection was stopped when large voltage EEG signals characteristic of slow-wave sleep were present). When the recordings were stable enough and the animal quiet enough after completion of the tuning curve determination, three typical guinea pig vocalizations  (Berryman, 1976; Harper, 1976)  used in our previous studies  (Philibert et al. , 2005; Huetz et al. , 2009)  were presented in their natural and time-reversed versions.
These vocalizations were collected from five adult male guinea pigs recorded either in pairs or individually in a sound attenuated room. Calls were recorded using a Sennheiser MD46 microphone connected to a microcomputer and digitized using SoundEdit software (44 kHz sampling rate). The relationships between these calls and the animal behavioral repertoire have been previously described  (Berryman, 1976; Harper, 1976). A "chirp" is a brief call (0. 7-15 kHz, <100 ms) that is believed to be a low-intensity distress call or a warning signal. A "chutter" consists of a chain of five components (0. 5-3. 5 kHz, 150-250 ms separated from each other by 140-175 ms) emitted during discomfort. A "whistle" is a two-part call (250-400 ms, with the first part from 1-3 kHz and the second part rising steeply to 8-20 kHz) emitted when animals are isolated or in response to stimuli associated with caretaking.
DATA ANALYSIS For each cell, the frequency tuning was quantified from threshold up to 80 or 70 dB by 10 dB steps. At each intensity, the best frequency was determined as the frequency eliciting the largest evoked responses. The breadth of tuning was quantified by the Q 20 dB (but the Q 10 dB and the Q 40 dB were computed as well). The latency of the tone-evoked responses was computed at each intensity used to test the frequency tuning curve. At a given intensity, the responses obtained for all the tested frequencies were considered, and the latency of the first spike after tone onset was computed (1-ms precision). For each cell, at each intensity, the variability of the latency was quantified by the standard deviation of the mean latency value. For each cell, the responses to the vocalizations were analyzed in terms of evoked firing rate and spike timing reliability.
EVALUATION OF THE HEARING DEFICIT BY ABR Since we did not record the ABRs of our animals (n = 10) before and after the acoustic trauma, hearing loss evaluation is only based on ABRs obtained a few weeks (between 4 and 8 weeks) after the last recording session. We compared the ABRs obtained from our hearing impaired animals with a large database of ABRs obtained (with exactly the same equipment) in control guinea pigs (n = 46) of the same age (4. 7 ± 0. 6 months) and weight (585 ± 113 g) than the ones used here. The control animals had typical ABR audiograms similar to those previously published  (Gourévitch et al. , 2009; Gourévitch and Edeline, 2011). Compared to control animals, the animals used in the present experiment had a consistent hearing deficit (15-20 dB on average) in the 4-8 kHz range (Figure  1 ).
METHODOLOGICAL CONSIDERATIONS An obvious pitfall of our experiment is that the ABRs were only recorded at the end of the experiment. Therefore, the hearing loss was assessed by comparing the post-trauma ABRs with a large database of ABR obtained from control animals of the same age and weight. Another consequence was that we could not follow the time course of the ABRs changes in parallel with the changes in cortical responses. However, testing the ABR daily would have required to anesthetize the animals daily (or every other days), which was a risk we did not want to take given that (i) the animals were implanted with chronic micro-electrodes and (ii) they were already adapted to restrained conditions. Despite these limitations, there is clear evidence for hearing loss within one octave at, and above, the trauma frequency.
ACKNOWLEDGMENTS This work was supported by grants from the  National Research Agency (ANR program Neuro2006 ,  ANR-11-BSH2-004-01 HEARFIN ) and from the  Fédération pour la Recherche sur le Cerveau (FRC)  to  Jean-Marc Edeline. Special thanks to  Nathalie Samson  and  Pascale Leblanc-Veyrac  for taking care of the guinea-pig colony.
Samples were micro-centrifuged twice at 17,000×g (Eppendorf Centrifuge 5415 R) for 5 min at 4°C and the supernatant measured as above. Tyrosine, l-DOPA and DA absolute values were calculated by calibration curve regression using XCMS/MZMatchR program  (Tautenhahn et al. , 2008). Arithmetic mean and standard deviation were calculated over three independent samples. For flies fed a standard diet, values were expressed as picogram of l-DOPA or DA per fly (fly weights showed no statistically significant difference [p = 0. 85564545, D. melanogaster vs D. sechellia, Student's t test]). To compare flies fed different diets, values were expressed as picogram of l-DOPA per milligram of body tissue.
Louis, MO] or anti-α-tubulin [mouse, Sigma, St. Louis, MO]) diluted in 2. 5% non-fat milk in TBS tween ON at 4°C. Membranes were further washed in TBS-tween at RT and re-blocked in 10% non-fat milk TBS-tween for 10 min at RT before being incubated with 1:10000 dilution of corresponding secondary HRP-conjugated anti-mouse or anti-rabbit (BioRad, Germany). Proteins were detected using an enhanced chemiluminescence detection kit (Thermo scientific pierce, Germany). The densitometry of bands was performed using ImageJ package (http://imagej. nih. gov/ij/). Relative densities of TH-PLE and CATSUP were scaled using the relative densities of the loading-controls (α-Tubulin).
Gene cloning and sequencing For each species, we prepared total RNA (Trizol, Invitrogen, Life Technologies GmbH, Germany) and synthesized cDNA (SuperScript III First-Strand Synthesis System, Invitrogen, Life Technologies GmbH, Germany) that was used to amplify Catsup transcript by PCR (Advantage HD Polymerase, Clontech) with specific primers (forward 5′-ATGGCCAAACAAGTGGCTGA-3′ and reverse 5′-TTACTCGAACTTGGCGATAAC-3′). Each PCR product was cloned in pCRII vector (Invitrogen, Life Technologies GmbH, Germany) and at least 10 colonies were picked for plasmid DNA purification and sequencing. These sequences were aligned using MegAlign (DNASTAR) and a consensus sequence was obtained for each species. The sequence of Catsup In270Del was obtained from the Drosophila Polymorphism Database (DPDB)  (Casillas et al.
Acknowledgements We wish to thank  Regina Stieber ,  Sandra Scholz  and  Céline Callens  for expert technical support; and  Emily Wheeler, Boston , for editorial assistance. Stocks obtained from the  Bloomington Drosophila Stock Center  ( NIH P40OD018537 ) were used in this study. This work was supported by the  Max Planck Society  (SL-LL, AS, MK, MCS and BSH) and by grants from the  ESPCI ParisTech  and the  Fondation de France  to SB (TR and SB).
The prion protein (PrP) when misfolded into the pathogenic conformer PrP Sc is the major causative agent of several lethal transmissible spongiform encephalopathies in mammals. Studies of evolutionary pressure on the corresponding gene using different datasets have yielded conflicting results. In addition, putative PrP or PrP interacting partners with strong similarity to PrP such as the doppel protein have not been examined to determine if the same evolutionary mechanisms apply to prion paralogs or if there are coselected sites that might indicate how and where the proteins interact. We examined several taxonomic groups that contain model organisms of prion diseases focusing on primates, bovids, and an expanded dataset of rodents for selection pressure on the prion gene (PRNP) and doppel gene (PRND) individually and for coevolving sites within.
2003) , purifying  (Seabury et al. 2004) , and positive selection  (Premzl and Gamulin 2009)  depending on the dataset. A recent study including representatives of multiple taxa suggested that positive selection was acting on PrP in various domains and intradomains  (Premzl and Gamulin 2009). However, the selection analysis to date has been done on either, relatively small datasets, species specific or order specific data sets and only on the PRNP gene itself and not its paralogs. To investigate the interspecific evolution of PRNP and PRND, we examined lagomorph, eulipotyph, primate, and bovid sequences from GenBank along with 19 PRNP and 21 PRND sequences from 10 rodent genera and 21 rodent species produced in this study. The bovids, primates, and rodents in particular include animals susceptible to prion diseases, model organisms in prion research or both.
The existence of heterozygotes was examined by inspecting the traces for multiple peaks at a single position. For the species Bandicota savilei, and Rattus argentiventer several (up to three) individual rodents from different populations were available to be sequenced and identical sequences obtained and, though not conclusive for all species, suggested that intraspecific polymorphism did not affect the results. Sequence Alignment, Phylogenetic, and Selection Analyses PRNP and PRND GenBank accession codes were as follows: Mus cervicolor (KF466919, KF466939), Mus cookii (KF466920, KF466940), Mus caroli (KF466921, KF46 6941), Mus fragilicauda (KF466956, KF466957), Rattus losea (KF466924, KF466954) Rattus argentiventer (KF466 955, KF466925), Rattus nitidus (KF466938, KF466952), Apodemus sylvaticus (KF466922), Apodemus fulvipectus (KF466923, KF466953), Apodemus mystacinus (KF466 942, KF466935), Leopoldamys sabanus (KF466928, KF4 66943), Leopoldamys edwardsi (KF466944, KF466929), Bandicota indica (KF466930, KF466950), Bandicota savilei (KF466951, KF466931), Saxatilomys paulinae (KF466937, KF466958), Chiropodomys gliroides (KF466 945, KF466932), Berylmys berdmorei (KF466936, KF46 6946), Maxomys surifer (KF466947, KF466933), Myodes glareolus (KF466934).
2012). FUBAR is more robust to model mis-specification and also orders of magnitude faster in terms of algorithmic implementation  (Murrell et al. 2013). Furthermore, we employed the mechanistic empirical model (MEC) (Doron-Faigenboim and Pupko 2007) that accounts for the different amino acid replacement probabilities based on the JTT empirical substitution matrix  (Jones et al. 1992) , while estimating the codon rate matrix, thus allowing for positions undergoing radical amino acid exchanges to acquire higher dN rates than those with less radical exchanges. The codon-wise x estimates were mapped onto predicted protein tertiary structures deposited in PDB (http:// www. pdb. org; human prion protein (PrP), PDB ID: 1QLZ; human Doppel protein (Dpl), PDB ID: 1LG4) using the Selecton-3D web server (http://selecton.