dataesr/scientific-paragraphs-categorization huggingface dataset:
Synthesis: Understanding the Differences Between the Earth's and Other Planet's Interiors This ISSI Special Issue and book and Space Science Reviews Topical Collection discusses the synergistic use of gravity and magnetic field data and of the planet's rotation to explore the deep interior of the Earth. Historically, these data have been provided by networks of observatories on the Earth's surface. But in recent years observations from spacecraft in orbit around the Earth have significantly augmented the data set. Planetary scientists use the same techniques to explore the interiors of planets, satellites and small bodies in the solar system although a comparable coverage in space and time has been achieved only for a couple of objects, Moon and Mars. But why would anyone interested in the Earth's interior care about the interior of other planets? It is the differences and the commonalities in the interior structures and the workings of the planets that require explanation and offer opportunities for a better understanding of the "Bowels of the Earth"  (Elder 1978 ).
FCD-relevant genes DNA extracted from snap-frozen surgical brain tissue and matched blood samples of 22 patients were sent to five genetic laboratories. Each group performed an independent analysis with hybrid capture sequencing targeting their own set of FCD-relevant genes (Table  S1 ). Genetic results from four of the five laboratories were available for the final round of reviews. In Lab A (Daejeon), technical replication of deep sequencing targeting of 13 genes was performed (SoVarGen). Analysis for replicated data was performed in accordance with a previous study. 18 he RePlow variant caller was applied for somatic mutations. 30 After a filtering process, all candidate variants were validated using targeted amplicon sequencing (Miseq Dx sequencer; Illumina). Germline mutations were analyzed in a similar pipeline as Genome Analysis Toolkit (GATK)'s best practices.
For the MIP design, custom scripts incorporating the MipGen tool were generated that allowed for dense tiling of all exons and up to 60 bp of flanking intronic regions, and putative splicing regulators for all genes. All 33 183 unique MIPs were designed to include a custom backbone consisting of primer binding sites and a dual 8-nt unique molecular index (UMI). MIP were rebalanced in the pool based on the percent of GC content within the regions. MIP pool was amplified with low cycles (17 cycles), high-fidelity polymerase, and custom common primers, allowing for large quantities to be generated. Captured products were amplified using 15 cycles of PCR with dual 8-nt indexing primers and sequenced on the Illumina HiSeq platform with 1 × 150-bp paired end reads. All regions were sequenced to a minimum of ×1000 coverage, allowing for accurate assessment of somatic alleles down to.
5% alternate allele frequency. Raw sequencing data were analyzed using existing in-house pipelines that, briefly, include quality assessment, mapping using BWAmem, UMI-collapsing, additional trimming, and local realignment. Finally, variants were called using multiple calling algorithms including Mutect2 and CLC Genomics' Low-Frequency algorithm. Lab E (Amsterdam) carried out additional validation of somatic single nucleotide variants (SNVs) using a dedicated custom Ion AmpliSeq FCD next generation sequencing (NGS) panel and ddPCR for MTOR and AKT3 variants in Cases 3, 12, 14, 16, 21, and 22 (Table  3 ; results from individual centers are summarized in Tables  S2-S6 ).
A hyperactivated mTOR kinase due to somatic or germline mutations in FCD Type 2 is also a promising candidate for targeted drug treatment of mTOR inhibitor (ClinicalTrials. gov identifier NCT03198949). 43 Thus, genetic diagnosis will be helpful and add an objective measure for an integrated diagnosis of FCD, thereby better stratifying the patient cohort, advancing our knowledge about the underlying disease pathomechanism, and promoting personalized medicine in epileptology. MOGHE is a recently described new entity observed in young children with early onset and difficult-to-treat frontal lobe epilepsy, and histopathologically defined by oligodendroglial hyperplasia and heterotopic neurons in the shallow subcortical white matter. 22, 44 There was a majority vote from only 23% of reviewers in the first and second rounds for Cases 12 and 17.
The use of biorepository tissues and the study protocol were approved by the Cleveland Clinic Institutional Review Board (IRB#18-1134), the institutional review boards of Boston Children's Hospital, the Committee for the Protection of Persons Ile de France II (No. ID-RCB/ EUDRACT-2015-A00671-48) registered on ClinicalTrials. gov (No. NCT02890641), and the Korea Advanced Institute of Science and Technology Institutional Review Board and Committee on Human Research. T A B L E 1.
Pattern Recognition Today, pattern recognition is widely used with the development of learning-based methods, whose performance is well established. However, such approaches cannot apply, as no databases exist about IC structures in our context of infrared viewing. This issue is mostly due to the trade secret policies, but also to the fact that, in characterization processes, the studied IC may be prototypes designed with new technologies. On the opposite, methods based on signal analysis (e. g. , cross-correlation  [39] ) are efficient for optimal recognition contexts where a template image exactly occurs in a target image, even though linear transforms can be tolerated (such as scale or rotation). In our study, a structure to locate in a target IC is subjected to linear transforms like scale, rotation and intensity variation: from one IC to the next, the material properties may imply less contrasts compared to the reference IC.
Location Method Validation As far as we know, there exists no database of infrared views of integrated circuits. Moreover, the trade secret context does not allow us to create one. For that reason, we validated our method on synthetic data. In  [68] , a data set is built from synthetic images that match the practical constraints encountered in our context, where noisy graphs occur. In line with the design of IC, electronic structures are simulated through combination of random but orthogonal white lines. These templates are noised with a random multiplicative noise to simulate thermal noise. Synthetic IC are built from the combination of several templates that are scaled and rotated in black images. The resulting database is then composed of synthetic IC, on which we test our location framework of synthetic templates.
The small number of highlighted matched nodes was a consequence of outliers between the schematic template and the target. This revealed a risk of lack of connectivity in the matching resolution. Both experiments were conducted successfully. Validation over a synthetic database and the experiments presented here may constitute sufficient evidence of the validity of our method and good reason to continue investigating it: the presented results, from the IC viewing system to the template location system, show that our framework achieved the purpose of this study. Figure  13. Projection of the template graph (left) located in the target graph (right). These graphs were created from the images shown in Figure  12. From the matching, only the largest connected sub-graph is kept (highlighted in pink in the target) and used to estimate the template projection.
5951, NS). As expected, PCP administration significantly increased locomotor activity (Figure  8A ). Mixed-design ANOVA with treatment as between-subject factor and time as repeated factor revealed that treatment affected PCP-induced hyperactivity during 0-120 min following PCP administration (time × treatment interaction: F(92,1150)=2. 184; p < 0. 05). Detailed analysis of the AUC activity data measured for the 0-60 and 65-120 min post-PCP treatment periods revealed that during the initial 0-60 min, treatment affected activity (F(4,50)=4. 063; p < 0. 01) and that FPPQ decreased PCPinduced hyperactivity at both doses (1 and 3 mg/kg) while clozapine at the same doses appeared to be ineffective (Figure  8C ). During the second hour following PCP administration, treatment also affected activity (F(4,50)=4.
Journal of Medicinal Chemistry Finally, we assessed the interaction between another 5-HT 6 R antagonist CPPQ (which behaves as a neutral antagonist) and ondansetron on hyperactivity evoked by PCP. The dose of ondansetron (0. 5 mg/kg) was the same as in the previous experiment while the doses of CPPQ (0. 3, 1, and 3 mg/kg) were based on the previous report. 29 nalysis of the AUC at times -25 to 0 min (i. e. , 30-60 min following CPPQ and ondansetron administration) revealed effects of treatment on spontaneous activity (F(6,49) = 3. 920, p = 0. 003) and its inhibition by CPPQ at 3 mg/kg, suggestive of sedative-like action of this dose (Figure  11A, B ). Thus, data of the 3 mg/kg CPPQ group were not taken for further analyses. Figure  11A  shows robust hyperactivity due to PCP administration.
Two-way ANOVA on 0-120 min AUC post-PCP activity data with CPPQ dose and ondansetron as between-subject factors revealed no effects of ondansetron (F(1,43)=2. 153; NS), CPPQ dose (F(2,43)=2. 864; p = 0. 068), nor their interaction (F(2,43)=0. 184; NS). However, as the a priori hypothesis was that the combined treatment with 5-HT 6 R and 5-HT 3 R antagonists would produce different effects than their individual actions and/or vehicle, we analyzed 0-120 min AUC activity data with contrast coefficients. These planned comparisons revealed that combined treatment with CPPQ (0. 3 mg/kg) and ondansetron (0. 5 mg/kg) inhibited PCP-induced hyperactivity compared with vehicle (Figure  11C ). Of note, CPPQ alone per se did not increase activity, in contrast to SB399885 (see Figure  10C ). A large body of evidence had indicated that cognitive impairment is a pervasive and core pathological component of schizophrenia.
Journal of Medicinal Chemistry Analyser (Hanau, Germany). All values are reported as percentages, and were within ±0. 4% of the calculated values. Compounds 1-4 were obtained according to the previously reported procedure and the analytical data are in accordance with the literature. 29 eneral Procedure for Preparation of Compounds 5a-5b. Compound 4 (0. 35 g, 1. 7 mmol, 1 equiv) was dissolved in acetonitrile followed by addition of amine (1. 26 g, 6. 8 mmol, 4 equiv). The reaction was heated in a microwave at 140 °C for 5h. The solvent was evaporated, and the crude product was purified by chromatography using silica gel with CH 2 Cl 2 /MeOH 9/1. 5 (v/v) as a developing solvent. In Silico Simulations. Preparation of the Proteins. The construction of the 5-HT 6 R homology models has been described in detail elsewhere.
Selected compounds were tested using an additional method. After establishment of the first 5-HT concentration-response curve, washing out of the tissue, and stabilization period, the same tissues were subsequently incubated with one of the concentrations of the tested compound for 15 min and the next cumulative concentration curve to 5-HT was obtained. Only one concentration of a studied compound was tested in each piece of tissue. Concentrationresponse curves were analyzed using GraphPad Prism 5. 0 (GraphPad Software Inc. , San Diego, CA) and the antagonistic properties were expressed as pD 2 ′ or pA 2. The Schild analysis was performed, and when the slope was not significantly different from unity, the pA 2 value was determined (pA 2 the negative log of molar concentration of the antagonist which reduces the effect of double dose of the agonist drug to that of a single dose).
Peak inward currents were measured in response to the serotonin additions in the presence of a single concentration of the compound. Obtained data have been normalized to the baseline peak current induced by the addition of EC 80 serotonin for 2 s, according to eq 1 = + I I normalized peak current compound ser ser (1)   Received data were analyzed using a four-parameter logistic equation in GraphPad Prism software. Experiment was performed Eurofins, France. Determination of 5-HT 6 R Constitutive Activity at Gs Signaling. cAMP measurement was performed in NG108-15 cells transiently expressing 5-HT 6 R using the Bioluminescence Resonance Energy Transfer (BRET) sensor for cAMP, CAMYEL (cAMP sensor using YFP-Epac-RLuc). 65 NG108-15 cells were co-transfected in suspension with 5-HT 6 R (or empty vector for Mock condition) and CAMYEL constructs, using Lipofectamine 2000, according to the manufacturer protocol, and plated in white 96-well plates (Greiner), at a density of 80 000 cells per well.
Cells were fixed in 4% paraformaldehyde (PFA) supplemented with 4% sucrose for 10 min. PFA fluorescence was quenched by incubating the cells in PBS containing 0. 1 M glycine, prior to mounting in ProLong Gold antifade reagent (Thermo Fisher Scientific). Cells were imaged using an AxioImager Z1 microscope equipped with epifluorescence (Zeiss), using a 20× objective for cultured cells, and neurite length (index of 5-HT 6 R constitutive activity as Cdk5 signaling) was assessed using the Neuron J plugin of the ImageJ software (NIH). Determination of Metabolic Stability in Rat and Human Liver Microsomes. Test compounds were prepared in phosphatebuffered saline (PBS) from 10 mM dimethyl sulfoxide (DMSO) solution so that the final incubation concentration was 1 μM. Pooled human (Invitrogen) or rat (Pharmidex Pharmaceutical Services Ltd) liver microsomes were diluted in PBS to allow for a 0.
The samples were analyzed by highresolution accurate mass UHPLC-TOF MS. The UPLC-MS system comprised an Agilent 1290 Infinity UHPLC pump with an Agilent 1290 Infinity HTS Autosampler, coupled with an Agilent 6550 iFunnel QToF mass spectrometer, equipped with a Waters Acquity BEH Phenyl UPLC column (50 × 2. 1 mm 2 ), 1. 7 μm particle size. The system was controlled by MassHunter software vB. 05. 01. Gradient elution was employed with mobile phase components A and B being water/formic acid (0. 1%, v/v) and acetonitrile/formic acid (0. 1%, v/ v), respectively. Initial conditions, from 0 to 0. 3 min, were 2% B. Between 1. 3 and 1. 35 min %B was decreased to 2%, and this was maintained until the end of the run at 1. 8 min. The flow rate was 0. 4 mL/min, the injection volume was 5 μL, and the column was maintained at 50 °C.
The mass spectrometer was operated in full scan mode, with positive ion electrospray data acquired over the m/z mass range 100-1000. Pharmacological and Safety Profile of FPPQ. The binding and safety profile of FPPQ was investigated using the SafetyScreen TM Panel (Eurofins) including enzymatic (n = 13) and binding assays (n = 74), (h t t p s : / / w w w. Determination of Agonist Effect of FPPQ for 5-HT 2B Receptors. Agonistic effect of compound FPPQ was determined as inhibition of 10 -6 M serotonin using the HTRF technique. Experiment was performed in duplicate at Eurofins, France. Determination of Mutagenic Potential of FPPQ. Sodium azide (SA), 4-nitro-o-phenylenediamine (NPD, magnesium sulfate, sodium ammonium phosphate, D-glucose, D-biotin, sodium chloride, L-histidine HCl, L-tryptophane, dimethyl sulfoxide (DMSO), sodium phosphate-dibasic, citric acid monohydrate, potassium phosphatedibasic, and sodium phosphate-monobasic were purchased from Sigma-Aldrich.
The system was controlled by MassHunter software vB. 01. 04. Sample analysis of FPPQ was carried out in positive ion electrospray mode for the following reaction monitoring transitions, precursor ion (m/z) = 411. 1 and fragment ion (m/z) = 184. 3. Chromatographic separations were achieved using a Kinetex C18 column (5 μm, 50 × 2. 1 mm 2 , Phenomenex, U. K. ) maintained at 50°C. The mobile phase consisted of water + 0. 1% formic acid (solvent A) and acetonitrile + 0. 1% formic acid (solvent B) programmed to linearly increase the proportion of solvent B as detailed: time after injection -0 min (5% B), 0. 3 (5% B), 1. 9 min (95% B), 2. 3 (95% B), 2. 4 (5% B), 3. 4 (5% B). On the day of analysis, plasma samples were thawed and vortex mixed. Control plasma was spiked with SP14040 to create calibration standards.
Data Analysis. The activity data collected every 5 min are presented as a raw readout as well as an Area Under Curve (AUC) of the distance traveled, in centimeters. The measurements (30 min) preceding PCP administration indicate drug-induced effects on spontaneous locomotor activity. The second period (measured in the same animals at 0-120 min following PCP administration) indicates drug-induced alteration of PCP-induced hyperactivity. Mixed-design two-way ANOVA with treatment(s) as betweensubject factor and time as repeated measures factor on raw distance data, and separate one-way or two-way ANOVAs (on AUC data) followed by Dunnett's multiple comparison, LSD or Tukey's post hoc tests as well as analyses of contrast coefficients (Statistica 12 for Windows, IBM SPSS ver 26 for Mac) were used to assess the effects of compounds on activity.
C910 inhibits CNF1-mediated invasion of cells by UPEC Invasion of epithelial and endothelial cells by UPEC leads to severe and recurrent forms of infections  (32). Here, we investigated whether C910-induced resistance of cells to CNF1 cytotoxicity could decrease the susceptibility of host cells to bacterial invasion. The protective action of C910 was assessed in gentamicin-protection experiments, upon infecting cells with a cnf1-deleted strain of UPEC in the control condition versus complementation with exogenously added CNF1 at 1 nM. This setting allowed to measure reproducible rates of cell invasion  (33). Remarkably, cells treated with C910 at 15 μM were protected against CNF1-mediated invasion by UPEC without affecting bacterial adhesion to the cells (Figure  2A  and 2B ). C910 had no impact on bacterial viability (data not shown).
We also recorded an absence of effect of C910 on the cellular binding of the B-subunit of Shiga toxin (STxB) (Sup. Figure  2B ). Furthermore, C910 had no detectable effect on the internalization of CNF1-Cy3 and STxB (Figure  4B ). Taken collectively, these data indicate that C910 operates neither at initial steps of host cell receptor binding and endocytosis of CNF1 and STxB nor at a later stage of CNF1 enzymatic activity. These exploratory results prompted us to examine a broader impact of C910 on the intracellular transport to lysosomes, by using a protease-dependent dequenching of selfquenched red fluorescent DQ TM Red BSA (DQ-BSA). At a late timing of the chase of 18 h, we observed an accumulation of cleaved DQ-BSA with no detectable effect of C910 (data not shown). When the chase was carried out during a shorter period of 4 h, we observed a strong reduction of cleaved DQ-BSA in C910-treated cells, as compared to control conditions (Figure  4C ).
Therefore, host-targeted therapy targeting host vesicular trafficking represents an alternative strategy in the event of diversion of such a deadly pathogen. Previous studies have shown that host-targeted prophylactic strategy endows the antitoxin inhibitors an expanded efficacy against viruses  (2, 4, 62, 63). Nevertheless, this is the first time to our knowledge that an anti-toxin inhibitor exhibits prophylactic potential against influenza A virus H1N1. In pilot experiments, we recorded a protective response induced by C910 in the group of male mice contrary to females (data not shown). This bias likely relates to the reported exacerbation of IAV-associated pathogenesis in female mice  (64). Moreover, differences of C910 efficacy between male and female mice may reflect differences of pharmacokinetics.
Evaluating efficacy of C910 against intoxication Protein synthesis inhibition was measured as described  (22). Briefly, cells were plated overnight in 96-well Cytostar-T microplates with scintillator incorporated into the polystyrene. Cells were then challenged with increasing doses of toxins for the indicated periods of time (DT: 6 h; Stx1, Stx2, PE: 18 h) in presence of vehicle or various concentrations of C910. The medium was replaced with DMEM supplemented with L-[ 14 C(U)]-leucine at 0. 5 μCi/ml for an additional 3 h (Stx1, Stx2, PE) or 15 h (DT). Protein synthesis was determined using a Wallac 1450 MicroBeta scintillation counter (PerkinElmer). All values are expressed as means of duplicates ± s. e. m. , data were fitted using the nonlinear regression dose-response and the goodness-of-fit for toxin alone (carrier) or with drugs was assessed by r 2 values and confidence intervals with Prism ver.
Western blot analysis Samples were size-separated via SDS-PAGE, transferred to Immobilon-P PVDF membranes (Millipore) and labelled by primary antibodies. Signals were revealed using horseradish peroxidase-conjugated goat anti-mouse or swine anti-rabbit secondary antibodies (DAKO) followed by chemiluminescence using Immobilon® Western (Millipore). The chemiluminescent signals were recorded on a Syngene PXi imager (OZYME), and the data were quantified using Fiji software (NIH).
Binding of CNF1 to cells analyzed by FACS Recombinant CNF1 toxin was fluorescently labeled with Cy3 (Cy®3 Mono 5-pack, GE healthcare, PA23001) according to the vendor's recommendations. Briefly, purified toxin preparations (1 mg/ml) were incubated with the Cy3 dye in 100 mM bicarbonate buffer for 18 h at 4°C and applied to dialysis to separate the toxin from the free dye. CNF1-Cy3 (  16 nM) was absorbed to the cells at 4°C for 30 min and cells processed for FACS analysis using a BD LSRFortessa™ flow cytometer. Data were analyzed with FlowJo (BD Bioscience).
In vivo IAV infection model All mice were housed under specific-pathogen-free conditions at Seattle Children's Research Institute and all animal experiments performed at Seattle Children's Research Institute were approved by the Institutional Animal Care and Use Committee (IACUC00580). A pilot experiment showed a protective effect of C910 in male animals therefore we used male mice for further experiments (data not shown). Viral challenges were carried out on groups of 9~10 week-old C57BL/6 male mice (Charles River Laboratories). Animals were treated by intraperitoneal injection with either 20 mg/kg of C910 or vehicle control DMSO as described in the figures. Anesthetized mice were infected intranasally with the IAV H1N1 PR/8 strain (Charles River Laboratories) diluted in 25  L PBS, at a high dose (1.
0  254. 9 (identity confirmation). Data Analysis software (Bruker Daltonics) was used for qualitative and quantitative processing of raw MS and MS/MS data. The ion chromatograms of MS/MS transitions of C910 as well as of the internal MS standard were extracted (EIC). These EIC peaks were integrated and the ratio C910/IS of the corresponding MS transitions enabled to plot calibration curves of C910 in plasma or lung homogenates and further quantity C910 in any of these biological matrices from mice treated with C910. In vivo pharmacokinetics (PK), biodistribution and plasmatic diagnostic Animal care and surgical procedures were performed according to the Directive Isle, France). Mice were injected intraperitoneally with 10 mg/kg, i. e. 29,716 nmol/kg, of C910. Blood samples were collected at 5 min, 15 min, 30 min, 45 min, 1 hr, 6 h and 24 h after injection, on three distinct mice at each time.
Quantification of C910 concentration contained in plasma at each time was performed by LC-MS/MS. PK parameters were calculated from these data with the non-compartmental analysis Linear up/Log down method, using the PKSolver add-in program. Plasmatic diagnostic was performed at 24 hrs after injection using the Piccolo® AmLyte 13 and the Piccolo Xpress® chemistry analyzer (Abaxis, USA). Levels of glucose, blood urea nitrogen, creatinine, total bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, creatine kinase, amylase, sodium, potassium, and calcium were determined in heparinized plasma of five mice injected with vehicle or C910. Quantitative data are shown as means, with error bars indicating the standard error of the mean (SEM).