dataesr/scientific-paragraphs-categorization huggingface dataset:
Such hyperemic activity might be physiologically important as it was kept throughout evolution, despite its energy consumption. Moreover, a clear picture of global brain activity during REMS is still currently missing. In this study, we used functional ultrasound imaging to gather data on >250 brain regions in both coronal and sagittal planes, thus providing a very exhaustive characterization of global brain hemodynamics during rodent REMS. We demonstrate a clear dissociation between basal/midbrain structures and superficial ones, respectively activated in a tonic and phasic manner. We also disentangle the vascular structures involved in the irrigation of the brain during REMS episodes providing a detailed outlook of blood supply. Finally, one of the most noteworthy results of this work is the striking global dissociation of the amygdala activity from the rest of the brain during the REM episodes.
3  for further details. Electrode implantation verification. Electrodes sites' locations were verified post mortem via histology to reconstruct the tract of electrode bundles in the tissue. Each rat was euthanized and perfused with paraformaldehyde 4% to preserve the brains. Each brain was then cut using a vibratome to make 100µm-thick slices. The slices were then contrasted using hematoxyline/eosine coloration and scanned using a nanoscan. We then compared the slices with plates from Paxinos and defined the trajectory of implantation using the marks left by the electrode in the brain. Knowing the distances between the recording points, we could then define their position. Recording sessions. After a recovery week following the surgical procedure, the animals were fit to undergo data acquisition.
LFP acquisition. LFP, electromyogram (EMG) and accelerometer (ACC) signals and video were monitored continuously from video-EEG device for offline processing. Intracranial electrode signals were fed through a Blackrock Cereplex System using the Cereplex Direct Software Suite (version 7. 0. 6. 0) developed by Blackrock Microsystems (Salt Lake City, UT, USA), together with a synchronization signal from the ultrasound scanner. LFP signals were pre-amplified and digitized onto the animal's head which prevent artifacts originating from cable movement. A regular amplifier was used, and no additional electronic circuit for artifact suppression was necessary. A large bandwidth amplifier was used, which can record local field potentials in all physiological bands (LFP, 0. 1-2 kHz). The spatial resolution of LFPs ranges from 250 µm to a few mm radius.
As a result, the pulse repetition frequency of the plane wave transmissions was 4000 Hz. To discriminate blood signals from tissue clutter, the ultrafast compound Doppler frame stack was filtered, removing the 60 first components of the singular value decomposition, which optimally exploited the spatiotemporal dynamics of the full Doppler film for clutter rejection, largely outperforming conventional clutter rejection filters used in Doppler ultrasound. All these parameters taken together we obtain a Doppler movie with 100 ms order temporal resolution and 100 µm order spatial resolution. LFP analysis. All analysis was performed in MATLAB (version R2017b, Mathworks, USA). NPMK package (version 4. 5. 3. 0) developed by Blackrock Microsystems was used to import the raw LFP data into MATLAB. EEG was collected and low-pass filtered under 250 Hz.
Acknowledgements The authors would like to thank  F. Segura ,  M. Nouhoum ,  H. Serroune ,  A. Bertolo  for their help in the different steps of the research leading to these results. The research leading to these results has received funding from the  AXA Research Fund  under the chair "New hopes in medical imaging with ultrasound". The authors would also like to thank  Dr. Isabelle Arnulf  and  Dr. Karim Benchenane  for their fruitful scientific discussions and advice.
Interestingly, in the MRI scan performed one day after stroke, the patient's eye position revealed a significant deviation towards the contralateral side, supporting neglect diagnosis as described by Becker and Karnath  [29]  (Figure  1a ). To classify the neuroanatomical localization of the patient's lesion, we used images from a second control MRI which was performed ten weeks after stroke. First, the patient's individual cerebral lesion was manually delineated on individual structural MRI images using the open-source MRIcron software (https://www. nitrc. org/projects/mricron/, accessed on 17 February 2022). The borders of the lesion were manually delineated on every transverse slice of the individual MRI images. Then, images were normalized into MNI space with the Clinical Toolbox for SPM (  [31] ; https://www.
Interestingly, in the MRI scan performed one day after stroke, the patient's eye position revealed a significant deviation towards the contralateral side, supporting neglect diagnosis as described by Becker and Karnath  [29]  (Figure  1a ). To classify the neuroanatomical localization of the patient's lesion, we used images from a second control MRI which was performed ten weeks after stroke. First, the patient's individual cerebral lesion was manually delineated on individual structural MRI images using the open-source MRIcron software (https://www. nitrc. org/projects/mricron/, accessed on 18 February 2022). The borders of the lesion were manually delineated on every transverse slice of the individual MRI images. Then, images were normalized into MNI space with the Clinical Toolbox for SPM (  [31] ; https://www.
Studies selection A search of the PUBMED database was performed on May the 17th of 2021. The query included the following terms: ("elderly" OR "frail elderly" OR "risk factors" OR "MCI" OR "alzheimer") AND ("PET" OR "brain imaging" OR "MRI" OR "structural MRI" OR "functional MRI") AND ("training" OR "nutrition" OR "diet" OR "physical activity" OR "cognitive training" OR "cognitive stimulation" OR "exercise"). The full search strategy is provided in the Supplementary material. We selected preventive studies involving older adults susceptible to convert to AD and evaluated the effect of CT, nutrition/diet, PE or MD interventions on brain imaging outcomes. The description of the aim of this review, using the PICO framework  (Huang et al. , 2006) , is available in Supplementary Table  1. As our goal was to examine the effect of interventions on brain regions, including areas located in subcortical structure, we did not select studies using electrophysiological techniques such as electroencephalography (EEG), which have a relatively low spatial resolution  (Krishnaswamy et al.
e. , for two studies evaluating the effect of PE, control condition could either be resistance or balance training). When multiple brain imaging outcomes were evaluated in a study, they were all reported and equally considered. The distinct types of brain imaging data are referred to as imaging "modalities. " Article's abstract screening was performed by LP and fulltext review was performed by GB and LP independently and validated by AG and ELB. Any discrepancy was resolved through discussion until a consensus was obtained. The inclusion of the studies was described by a PRISMA flowchart generated by the PRISMA 2020 Shiny application (https://estech. shinyapps. io/prisma_flowdiagram/;  Haddaway et al. , 2022).
Quality control procedures are implemented Additional quality criteria specific to neuroimaging studies were assessed: (1) imaging protocol and analyses had to be adequately described and (2) appropriate correction for multiple testing had to be implemented (e. g. , voxel-wise analysis). An additional point was attributed to studies performing extra quality controls for raw imaging data or analyses' outputs. All criteria were assessed independently by GB and LP, differences in notation were discussed until a consensus was met. Studies were attributed a percentage of validated criteria and classified into limited, good and high quality if they respectively had <50%, between 50 and 80% and more than 80% of validated items.
We did not clarify whether the positive results reported for an intervention and a modality described concurrent or opposite effects (e. g. , if for instance brain FC was decreased or increased). It is important to point out that we focused for this review on the PUBMED database which is public and easily accessible. However, we may have missed studies in other databases that could have been relevant to this review. Finally, the nosographic entity of AD has varied over time, and we may have missed studies relevant to our review when screening abstracts. Several points should be emphasized in this review. Structural imaging of gray matter was the most studied modality, probably because it is very commonly acquired and presents homogenous acquisition and analysis methods. It seemed however less responsive to interventions.
Statistical Analysis Every group consisted of 13-16 rat pups. All results were expressed as arithmetic means ± SEM. Oneway analysis of variance (ANOVA) followed by the post-hoc test of Tukey was performed to study data between groups. Statistical analyses were performed using GraphPad Prism Software Version 6. 0 (GraphPad Software, Inc. , La Jolla, CA, USA). Significance was set at p < 0. 05.
Whole Exome and Whole Genome Sequencing Family 360. WES was first performed in five individuals at IntegraGen S. A (OncoDNA group). Four affected individuals (IV-24, III-14, IV-28 and IV-40) and one spouse (III-15, father of IV-24) were selected for sequencing (Fig 1A). Genomic DNA was captured using Agilent insolution enrichment methodology (SureSelect Human All Exon Kits Version 5, Agilent) with their biotinylated oligonucleotides probe library (Human All Exon v5-50 Mb, Agilent), followed by paired-end 75 bases massively parallel sequencing on Illumina HiSEQ 2000. The bioinfomatics analysis of sequencing data was based on the Illumina pipeline (CASAVA1. 8. 2). Variant annotation was performed through an IntegraGen in-house pipeline. Sequencing results were filtered for a depth ≥10Â and for July 2022 123 heterozygous variants shared between these four affected relatives and not present in the unaffected father of one of them.
Only variants with a minor allele frequency <0. 01% in public variant databases and absent from an in-house Integragen whole-exome data set of 176 additional exomes were retained. Nonsense, missense, insertion/deletion, and splice variants were selected before applying selection filters. Whole genome sequencing (WGS) was performed in the mother-daughter pair III-14 and IV-24 from family 360 by the deCODE Genetics Company. Briefly, Illumina's HiSeqX platform was used by generating sequencing libraries using the so-called PCR-free sample preparation method. Mean depth was at least 30x. The candidate variant in polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1; NM_033109. WGS was performed on individual IV-2 at AGRF Melbourne on four lanes of an Illumina HiSeq 2,500 in rapid-run mode, producing 150 bp paired-end reads with a target depth of 48x.
WGS was also performed for II-3 and III-2 on the Illumina HiSeq X Ten producing 151 bp paired-end reads with target depth of 60x at the Kinghorn Centre for Clinical Genomics, Darlinghurst, Australia. FastQ data was aligned with Bowtie2 (version 2. 2. 5) and reads were sorted and merged by Novosort v1. 03. 07. Variant calling was performed with the HaplotypeCaller in GATK. Variants were filtered that did not fit the following criteria: within 1 Mb of the linkage regions (as given by the SNP chip linkage analysis below), alternative allele frequency equal to or less than 0. 01 in the 1,000 Genomes Project 2 (ANNOVAR 1000g2012feb), NHLBI 6500 exomes and ExAC (release 0. 3) databases, less than 10 observed alleles in 132 in-house control samples, in an ORF or within 5 bp of a splice site, and not a synonymous change.
SNP Chip Linkage Analysis All available DNA samples from the Australian family were hybridized to the Illumina HumanCytoSNP-12 v2. 1 SNP chip. SNP genotypes were called in Illumina BeadStudio. Relatedness was verified with XIBD 3 (Supplementary Materials and Methods, which are available online). Inbreeding coefficients were estimated with FEstim 4 and LINKDATAGEN  5  selected 11,995 SNP markers for linkage analysis performed essentially as described previously. 6 he obligate carrier II-1 was modeled as unknown. As SCAs may be a late-onset disorder, the two unaffected samples with data were modelled with unknown affectedness status.
Repeat Expansion Analysis In the French family 360, WGS data from affected individuals III-14 and IV-24 was analyzed with Expansion hunter (v. 3. 0)  8  to exclude known repeat expansion loci. BAM files were also visually inspected with the Integrative Genome Viewer (IGV) software to check for unexpected variation in read depths and to detect possible new pathogenic expansions in the SCA25 locus. In the Australian family, a search for putative repeat expansions in the linkage interval was performed using ExpansionHunter Denovo. 9 STR loci with a p-value of less than 0. 1 were further characterized using Expansion Hunter (v. 3. 2. 0, with inclusion of off-target reads, read depth of 30, and minimum anchor-read mapping quality score of 20) and exSTRa 10 (default parameters).
RNA and Protein Analyses in the Australian Family Lymphoblast cell lines were established for IV-2 and three unrelated control individuals. Total RNA was isolated (RNeasy, Qiagen) and libraries prepared using the TruSeq RNA V2 kit (Illumina) and sequenced to a depth of $90 million reads. Paired end fastq files were aligned to the ENSEMBL human genome (Homo_sapiens. GRCh38. 99) using STAR  11  (version 2. 7. 3a). Bam files were generated using samtools  12  (1. 9). Read counts per gene were generated using featureCounts,  13  with a quality score cutoff of 10. Differential gene expression of IV-2 compared to the controls was determined using limma and edgeR, as described in Law et al. 14  Western blot analysis was performed as previously described. 15 Primary antibodies (rabbit anti-PNPase (Abcam, ab96176, 1:500) and mouse anti-β-Actin (Sigma, A5441, 1:10,000) were used and images were captured with ImageQuant AI680 and quantified using Imag-eQuantTL software (GE Healthcare).
, and treated with DNase (TURBO DNA-free, Invitrogen). Reverse transcription (RT) was achieved with the SuperScript First-Strand Synthesis System kit using Oligo(dT) (Invitrogen). Primers were designed to detect abnormal splicing between exons close to the variants, or to detect intron-retention. RT-PCR products were then sequenced by standard Sanger sequencing. Proteins were extracted after lysis of cells. Immunoblot analysis was performed with proteins from the individuals' cells using antibodies directed against N-terminal parts of PNPase (sc-365,049 from Santa Cruz Biotechnology) and rabbit anti-Alpha-Tubulin (Ab18251). Proteins were visualized with fluorescent antibodies or by enhanced chemiluminescence (Pierce) and fluorescence/chemiluminescence signals were captured with the Odyssey Imaging System (Li-COR), or with the Chemidoc Touch Imaging System (Bio-Rad) and quantified with Li-COR Image Studio (Li-COR) or Image Lab Software (Bio-Rad).
On examination she showed head tremor and diplopia and scored 4/40 on the SARA. Clinical features are presented in Tables  1  and 2. Analysis of the WES data identified a single heterozygous variant on chromosome 2 (chr2:g. 55643155T>C, GRCh38/hg38) that satisfied the criteria of selection and transmission, and was absent from the gnomAD database v. 2. 1. 1 or v. 3 (https://gnomad. broadinstitute. org/). Notably, this variant lies in the region of significant linkage identified previously as SCA25 on chromosome 2 in the same family. 1 This intronic substitution is located near the canonical exon 25 splice donor site of PNPT1 (NM_033109. 5:c. 2069 + 3 A>G), a gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPase). WGS was then performed in the affected mother-daughter pair who had previously undergone WES to search for non-sequenced variants that could have been missed using WES, and also to test for known expansion loci repeat length (Fig  1A ).
We did not detect pathogenic expanded repeats in any of the known loci responsible for repeat expansion diseases tested. After filtering, 32 ultra-rare variants, absent from population databases and predicted to be deleterious (Combined Annotation Dependent Depletion CADD phred score 20 >20), were shared between the two affected individuals. The c. 2069 + 3 A>G substitution in PNPT1 was the only variant that mapped to the SCA25 locus. In parallel, a combined strategy including linkage, WES, WGS, and RNA-Seq analysis was performed in a four-generation Australian family (family A1) with ataxia and sensory neuropathy in most affected individuals (Fig  1B ). Six individuals presented with an autosomaldominant progressive ataxia. Variable age at onset (ranging from 5 to 56 years of age) and presence of sensory neuropathy were noted (Table  3 ), as observed in the French family.
A previous study showed that two diseaselinked missense variants located before the S1-domain caused dimer formations, while truncated PNPase lacking the S1-domain formed trimer, with different altered function. 32 herefore, it is possible that mutations removing or altering the S1-domain (as observed in patients who developed ataxia) lead to different PNPase enzymatic structures compared to missense variants located upstream the S1-domain. Altered sensing of certain mtRNA may be the molecular basis of the apparent correlation between ataxia and variants affecting the S1-domain. Such correlations often highlight specific mechanisms that partly explain the clinical variability among carriers of pathogenic variants in the same gene in mendelian disorders. Analysis of the GTEx database (https://gtexportal.
Acknowledgments Part of this work was carried out on the iGenSeq sequencing and the Data Analysis Core bioinformatic facilities of the  ICM. The authors would like to thank  Michael Wilson ,  Greta Gillies , and  Kate Pope  ( Murdoch Children's Research Institute ) for their technical assistance. We thank the patients and their families for participation in this study. The research leading to these results has received funding from the program " Investissements d'avenir "  ANR-10-IAIHU-06  and  ANR-11-INBS-0011 -Neu-rATRIS:  Translational Research Infrastructure for Biotherapies in Neurosciences. European funding: 6th PCRD (EUROSCA, to A. B. ), 7th PCRD (Neuromics, to A. B. ) et H2020 (SOLVE-RD, to G. S. );  Agence Nationale de la Recherche  ( ANR SPATAX-QUEST , to G. S. ),  Association Connaitre les Syndromes Cérébelleux  (to G.
S. ) and  Fondation Maladies Rares  (to G. S. ). This work was supported in part by  NHMRC   GNT2001513  to PJL and MBD. Additional funding was provided by the  Independent Research Institute Infrastructure Support Scheme  and the  Victorian State Government Operational Infrastructure Program. Whole Genome Sequencing  for the Australian family was funded through the  Austin Health Adult Undiagnosed Diseases Program , which is supported by  Austin Health  and the  Victorian Medical Research Acceleration Fund. Me. B. was supported by an  Australian National Health and Medical Research Council (NHMRC)   Senior Research Fellowship  ( 1102971 ). K. C. D. was supported by an  Australian Research Training Program Scholarship. R. M. T. was supported by an  Australian Postgraduate Award  and funding from the  Edith Moffat fund.
K. B. H. was suppported by an  NHMRC   Early Career Fellowship , and a  Melbourne Children's Clinician Scientist Fellowship. B. R. E. A. was supported by an  NHMRC   Early Career Fellowship  ( 1157776 ). P. J. L. was funded by the  Vincent Chiodo Foundation. Italian Ministry for Education, University and Research (Ministero dell'Istruzione, dell'Università e della Ricerca-MIUR)  under the programme " Dipartimenti di Eccellenza 2018-2022 " Project code  D15D18000410001  to  Alfredo Brusco. H. R. was supported by an  NHMRC   EL1 Investigator Grant  ( 1194364 ).
We compared the changes in LRET induced by the full agonist LY379268 on VFT closure in both variants, and found strikingly similar results with regard to LY379168 potency, while only slight differences in the low and high average LRET efficiencies were observed (Figure  2d ). Such heterodimers allowing to monitor the VFT closure from a single FRET pair within one protomer are suitable for our confocal single molecule experiments and further rule out contributions arising from intersubunit FRET. Labeling of only one subunit was achieved using the previously described GABAB quality control system, which allows only heterodimers of PrF248-PrF358-C1 and WT-C2 C-terminal tails to be transported to the cell surface. Data in e-g represent the mean of 3-12 measurements +/-SD.
PIE-MFD smFRET setup Single-molecule FRET experiments with pulsed inter-leaved excitation (PIE)multiparameter fluorescence detection (MFD) were performed on a homebuilt confocal microscope 37 using the SPCM 9. 85 software (B&H) as described previously  17. Modifications are described in the following. A combination of 530/20 (530AF20, Omega Optical, Brattleboro, VT, USA) and 530/10 nm (FLH532-10, Thorlabs, Maisons-Laffitte, France) bandpass filters was used for Cy3B and Alexa546 excitation. A 488/10 (Z488/10 X, Chroma, Bellows Falls, VT, USA) bandpass filters was used for Alexa488 excitation. A 635/10 (FLH635-10, Thorlabs, Maisons-Laffitte, France) bandpass filter was used for "red" and Alexa647 excitation. The excitation power was 30 µW (prompt at 535 nm), 12 µW (delayed at 635 nm) for Cy3B / "red"; 50 µM (prompt at 535 nm), 15 µW (delayed at 635 nm) for Alexa546 / Alexa647; 25 µW (prompt at 488 nm), 12 µW (delayed at 635 nm) for Alexa488 / Alexa647 at the entrance into the microscope.
22, δ = 0. 09 (SNAPα = 0. 1, δ = 0. 13, γ = 0. 7, β = 0. 95 (248-Alexa546/647), α = 0. 08, δ = 0. 12, γ = 0. 9, β = 1. 2 (358-Alexa546/647) and α = 0. 02, δ = 0. 05, γ = 1. 2, β = 0. 75 (248+358-Alexa488/647). To display FRET histograms, doubly-labeled molecules with an S = 0. 3-0. 7 (S = 0. 35-0. 75 for SNAP-Cy3B/red) were selected and normalized for the same number of molecules based on the macrotime of the experiment for individual biological replicates. In this way, average histograms with the mean FRET efficiency +/-SEM were obtained. Fitting was performed using Origin 6 (Microcal Software, Inc. ) on average FRET histograms and for each individual data set separately to derive data shown in scatter plots. Histograms and plots were displayed using GraphPad PRISM 7. 05.
Acknowledgments Our research is supported by grants from the  Agence Nationale pour la Recherche  ( ANR-09-PIRI-0011  to  PR ,  ANR 17-CE09-0026-02  to EM and  ANR 18-CE11-0004-02  to EM and JPP) ; the  Fondation Recherche Médicale  ( DEQ20170336747  to JPP). P. R. and J. -P. P. were by supported by the  Institut National de la Santé et de la Recherche Médicale  (INSERM ;  International Research Program « Brain Signal » ) and the  Franco-Chinese Joint Scientific and Technological Commission (CoMix)  from the  French Embassy in China. H. L. was supported by  Sino-French Cai Yuanpei program. J. L. was supported by the  National Natural Science Foundation of China (NSFC)  (grant numbers  31130028  and  31225011  to J. L) ; the  Ministry of Science and Technology  (grant number  2012CB518000  to J.
L. ) ; the  Program for Introducing Talents of Discipline  to the  Universities of the Ministry of Education  (grant number  B08029  to J. L. ). X. R. by a  FEBS long term fellowship  and by a  Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) BP  post-doctoral fellowship. The CBS belongs to the  France-BioImaging  national infrastructure supported by the  French National Research Agency  ( ANR-10-INBS-04 ,.