dataesr/scientific-paragraphs-categorization huggingface dataset:
A study by Ng and Raveendran et al. [68]  found an increase in the PSD of lower alpha and beta activity at the left motor cortex, whereas delta activity did not show any significant change. They concluded that beta activity is associated with motor control. Furthermore, Baumeister et al. [69]  reported a reduction in the lower and upper alpha activity in the frontal cortex of the brain during a knee joint reproduction task which might be an indication to the existence of physical fatigue. Physical fatigue has also been assessed by the ratio of EEG power. Aryal et al. [59]  reported an increase in the ratio of the power of (α+θ/β) under the condition of fatigue induced during a material handling task carried on a construction site. That study concluded that monitoring the individual physical state using brain data is a very promising method compared to subjective methods (i.
Transcriptome GEO-dataset GSE4170 allowed us to associate 125 of 249 of the aberrations that we detected in CML-iPSC with the CML progression genes already described during progression from chronic and AP to BC. Among these candidates, eleven of them have been described in CML and related to tyrosine kinase inhibitor resistance and genomic instability. Conclusions: These results demonstrated that we have generated, for the first time to our knowledge, an in vitro genetic instability model, reproducing genomic events described in patients with BC.
The occurrence of these genomic events is difficult to predict in individual patients. CML patient-derived iPSCs express BCR::ABL1  [22, 23] , allowing the possibility of enhancing global abnormalities by in vitro mutagenesis. In order to explore the possibility of generating such a model from an iPSC derived from a CP-CML patient, we have chosen an in vitro mutagenesis approach using N-ethyl-N-nitrosourea (ENU). Here, we show that CML patient-derived iPSCs can be used to generate an experimental model mimicking cytological and genomic instability patterns observed in primary blast crisis cells. Moreover, we show that abnormalities induced by this technology are representative of those described in large databases of genomic events described in primary CML patients in blast crisis.
Western Blots Cells were lysed in ice with RIPA buffer containing (NaCl (200 mM), Tris (pH 8; 50 mM), Nonidet P40 (1%), acid deoxycholate (0. 5%), SDS (0. 05%), EDTA (2 mM)) supplemented with 100 µM phenylmethylsulfonyl fluoride (PMSF), 1 mM sodium fluoride (NaF), 1 mM orthovanadate (Na 3 VO 4 ). Separation of proteins occurred by electrophoretic migration on a 3-8% polyacrylamide gel under denaturing conditions. The proteins were then transferred in a semi-liquid condition on PVDF membrane pre-activated in methanol. After saturation with TBS Tween 5% BSA for 1 h, membranes were hybridized with primary (Anti-phosphoHistoneH2A. X (Ser139) clone JBW Millipore Paris France) and secondary antibodies coupled to HRP. They were then revealed by chemiluminescence with SuperSignal West Dura or Femto reagents and data acquired using G:BOX iChemi Chemiluminescence Image Capture system.
Evaluation of Hematopoietic Cell Phenotypes On day 19 of cultures, the methylcellulose cultures were washed with PBS. Living cells were counted in trypan blue and stained with the following antibodies in PBS 4%BSA at 4 • C 45 min: CD45Pe-Vio770 (Miltenyi), CD34Vioblue (Miltenyi), CD41aPE (BD), CD43FITC (Miltenyi), CD31FITC (Beckman Coulter), CD235aAPC (BD), IL1-RAP APC (R&D), CD38PE (Miltenyi), CD71PE (BD), CD14FITC (Beckman Coulter), CD33APC (BD), CD133APC (BD), BB9PE (BD), SSEA1PE (BD). After 1 h, cells were washed and resuspended in PBS 4%BSA with viability staining reagent 1 µg/mL (7-AAD) 7-aminoactinomycin D (Sigma Aldrich). Stained cells were analyzed with a MACSQuant 10 (Miltenyi Biotec) flow cytometer and Flowjo analysis software.
Automatic scoring of MN was performed using MNScore software (version 3. 8. 101 MetaSystems, Althaussen, Germany) with a Metafer 4 image analyzer (MetaSystems, Althaussen, Germany) comprised of a Zeiss Axioplan 2 imager to detect MN. An operator validated and excluded the false MN in cells. For each sample, 1000 cells were scored.
Transcriptome Dataset Rosetta/Merck Human 25k v2. 2. 1 microarray Array data matrix of normalized log ratios from GSE4170 was downloaded on Gene Expression Omnibus website: (http:// www. ncbi. nlm. nih. gov/geo/query/acc. cgi?acc=GSE4170 (accessed on 27 March 2017) and annotated with GPL2029 (http://www. ncbi. nlm. nih. gov/geo/query/acc. cgi?acc=GPL2 029 (accessed on 27 March 2017) In this dataset, CD34+ cell samples belonging to the 3 experimental groups corresponding to the different evolution phases of chronic myeloid leukemia were analyzed: chronic phase, accelerated phase and blastic crisis  [26].
Bioinformatics Boxplot and two-sided Student's t-test with Welch correction were performed in R Software version 3. 2. 3. Heatplot was generated with made4 package  [27]. Functional enrichment was performed with Go-Elite Standalone software version 1. 2 on the Gene Ontology Biological Process, KEGG and CommonsPathway databases included in Homo sapiens EnsMart77Plus (Ensembl-Biomart) update  [28]. Functional interaction networks were performed with Cytoscape software version 3. 2. 1  [29]. Unsupervised principal component analysis was performed on gene expression profile with R package FactoMiner; p-value was calculated by group discrimination on first principal component axis. Pubmed gene prioritization was realized with gene valorization web application  [30]. Circosplot on contingency table of Pubmed gene prioritization was realized with Circlize R package  [31].
Circosplot of genomic aberrations with HG19 coordinates were performed with OmicCircos R package  [32]. ROC curves were performed with ROCR R package. Genomic aberration gene candidates were also matched with important databases such as: database PLURINET for genes implicated in pluripotency  [33] , cancer genes COSMIC database: Catalogue of somatic mutations in Cancer (http://cancer. sanger. ac. uk/census (accessed on 27 April 2023))  [34]  and transcription factors  [35].
CGH Array Analysis of PB32-ENU-Derived Hematopoietic Cells Figure  5  shows the experimental strategy to perform this analysis. As can be seen in this figure, DNA from either PB32-ENU Embryoid body-derived hematopoietic colonyforming cells (CFC) or from blast-colonies (Bl-CFC) were hybridized with non-mutated iPSC PB32 DNA (Figure  5 ). Cytogenomics software from Agilent technologies with mosaic workflow allowed us to detect 20 quantitative genomics aberrations: copy number variations (CNVs), which comprised 313 gene loci. After filtration on the European Caucasian genomic polymorphism database, still, 295 gene loci were comprised in these genomic aberrations (Figure  6A  and Supplementary Table  S1 ). The majority of the gene loci events were affected by a gain of genomic DNA (69%) versus a loss (31%) (Figure  6B  and Supplementary Table  S1 ).
Matching these genomic aberrations with the transcription factor database, cancer gene database and pluripotency gene database allowed us to observe that these important deregulated actors are principally affected genes from chromosomes 5, 7, 21, 22, and X (Figure  6B ). The majority of these genomic events have been found to be transcription factors such as zinc finger ZNF and IRX (Figure  6B ). Some pluripotency genes were also identified, as well as cancer genes, such as TET1, ALK, EP300, ERG, MKL1 and PHF6, already described as being involved in leukemia. Functional enrichment of genomic alterations of EB-derived CFCs allowed us to highlight perturbations in megakaryocytic development with HBD, HBE1, HBG1 and HBB molecules and HDAC enzymes, including EP300 and SIRT1 (Figure  6C, D ). Functional enrichment on the Gene Ontology database allowed us to identify SIRT1, EP300 and CDH13 as key genes, especially SIRT1, which is implicated in p53-dependent DNA damage in response to hydrogen peroxide and cellular response to hypoxia.
SIRT1 is also involved in the negative regulation of NF-kappaB (Figure  6E, F ). When the same analysis was performed using DNA of Bl-CFC, 22 quantitative genomics aberrations were detected. These included copy number variations (CNVs), which comprised 332 gene loci. After filtration on the European Caucasian genomic polymorphism database, still, 255 gene loci were found to be comprised in these genomic aberrations (Figure  7A  and Supplementary Table  S2 ). The majority of these events represented a loss of genomic DNA (71%) with a loss of heterozygosity (23%), and 6% of them represented gains of DNA (Figure  7B  and Supplementary Table  S2 ). Matching these genomic aberrations with the transcription factor database, cancer gene database and pluripotency gene database allowed us to demonstrate that these important deregulated actors were principally involved on chromosomes 7, 8, 15, Y and X (Figure  7B ).
Circosplot analysis also allowed us to show that the majority of these events involved transcription factors, such as MESP, implicated in mesodermal cell migration and IKZF1 (Figure  7B, F ). Several genes that we identified included IDH2, NCOA2, IKZF1 and BLM described as being involved in leukemia (Figure  7B, F ). Functional enrichment of genomic alterations of PB32 iPSC on the KEGG database allowed us to highlight perturbations in hematopoietic lineage and cytokine-receptor interaction, affecting TPO, CSF2RA, ILRA, PIK3RA and CRFL2 involved in the JAK-STAT signaling pathway (Figure  7C, D ). Functional enrichment on the Gene Ontology database allowed us to uncover gene implications (Figure  7E ,F) such as IKZF1 and MESP1.
Several transcription factor genes were also involved, such as ZNF or the ERG family of transcription factors (Figure  6 ). Functional enrichment on the Gene Ontology database showed the implication of SIRT1, EP300, CDH13 and SIRT1 being involved in TP53-dependent DNA damage. The analysis performed using comparative hybridization of Bl-CFC DNA yielded additional information with losses (71%) and gains (6%), and matching these genomic aberrations with the transcription factor database, cancer gene database and pluripotency gene database allowed us to confirm that these essentially affect chromosomes 7, 8, 15, Y and X (Figure  7B ). Circosplot analysis showed that the majority of these abnormalities implicate transcription factors such as MESP (implicated in mesodermal cell migration) and IKZF1 (Figure  7B, F ).
Amongst pluripotency genes, we have identified cancer genes (IDH2, NCOA2, IKZF1, BLM) which are already described as being involved in leukemia. Functional enrichment of genomic alterations of PB32 iPSC on the KEGG database highlights perturbations in hematopoietic lineage and cytokine-receptor interaction, affecting TPO, CSF2RA, ILRA, PIK3RA, CRFL2, cytokines and receptors, allowing activation of the JAK-STAT pathway (Figure  7C, D ). Differences observed between genomic abnormalities in hematopoietic progenitor (CFC)-derived DNA and blast-cell colony (Bl-CFC)-derived DNA could be due to the occurrence of random genetic abnormalities induced by ENU throughout the genome. We then asked whether the abnormalities identified using CGH arrays could be matched with genomic aberrations described in primary leukemic cells from blast crisis patients.
At an isothermal crystallization temperature of 133 °C, a shear pulse of 1 s at rates of 10, 50, and 90 s -1 is applied and the structure formation is followed for 30 min. For all X-ray scattering/diffraction measurements, the acquired patterns are normalized to the incident beam intensity and background-subtracted. Data integration is done using the FIT2D open-source software developed by the ESRF. [73] [74] [75]  The crystallinity is determined by fitting an amorphous halo obtained from an atactic polypropylene sample to the noncrystalline regions of the diffraction pattern, i. e. , the region at low and high q where no diffraction peaks are visible. The area A total beneath the diffraction pattern and A amorph below the fitted amorphous halo, as indicated in Figure  1 , are used to calculate the weight fraction crystallinity A A A total amorph total = (5) Subsequently, the crystalline diffraction peaks are deconvoluted using Voigt functions to obtain the respective intensities from which the phase composition is then calculated.
Because of significant overlap between the diffraction peaks of the αand γ-phases of polypropylene, the integrated intensity below (130) α , (300) β , and (117) γ is used to calculate the relative fraction of phase i = α, β, γ according to 60,76 A A A A i i (130) (300) (117) = + + (6) The average lamellar thickness of these crystals is calculated from the 1D Lorenz-corrected SAXS data. First, the 2D scattering data is azimuthally integrated, i. e. , integrated over the angle ϕ as schematically depicted in the left panel of Figure  2a , and plotting the obtained intensity versus the scattering vector q q 4 sin( ) = (7)   in which λ is the wavelength of the incident light (X-rays in this case) and θ is half of the scattering angle. For an isotropic scattering system, the long period is determined from the Iq 2 versus q plot, as indicated in Figure  2b , according to L q 2 p max = ( 8 ) where q max is the absolute value of the scattering vector at the point where Iq 2 is maximum.
Noteworthy, these data are in full agreement with the experimental literature available for URB597  [122] , JNJ42165279  [74] , PF-04457845  [109] , and V158866  [90]. As far as the MGL and FAAH/MGL inhibitors are concerned, only three of them were predicted as able to induce hERG-related cardiotoxicity, namely JZL184, ABX-1431, and JZL195. Importantly, these data are again in agreement with the available literature as Grice et al. recently showed that ABX1431 is responsible for a significant hERG activity (IC 50 = 7 µM) in vitro  [105]  while McAllister et al. provided experimental evidence that PF-06795071 is not a hERG blocker  [109]. To the best of our knowledge, no data are instead available for JZL184 and JZL195. In summary, this preliminary investigation focused on the prediction of hERG-mediated cardiotoxicity indicates that it would be wise not to consider it an ideal candidate for repurposing JZL184, ABX-1431, and JZL195.
Few exceptions are represented by one FAAH inhibitor (PF-04457845), three MGL inhibitors (JZL184, KML29, and ABX-1431), and one dual FAAH/MGL inhibitor (JZL195). Noteworthy, all the compounds already predicted as hERG blockers returned low (< 0. 6) QED values, thus supporting the idea whereby these inhibitors are not the best candidates as antipsychotics. Table  2. Drug-likeness and ADME properties were computed for the compounds under investigation. Notice that the QED values were obtained by using an in-house script based on the paper by Bickerton et al. [126] , while the software program QikProp, available from the Schrodinger suite 2022-4  [127] , was employed to compute all the other relevant ADME properties. QED values > 0. 6 are highlighted in bold. Obviously, to have an antipsychotic activity, a given drug must be able to act in the CNS.
Furthermore, oral administration is highly desirable. Keeping this in mind, we also computed several descriptors related to the CNS activity as well as oral adsorption in humans using QikProp  [125]  as a software program, namely: (i) CNS, able to provide an estimation of the CNS activity on a -2 (inactive) to +2 (active) scale; (ii) QPPCaco, providing an estimation of the Caco-2 cell permeability in nm/sec (i. e. , ability to cross the gut-blood barrier; <25 poor, >500 great); (iii) QPlogBB, providing an estimation of the brain/blood partition coefficient; (iv) HumanOralAbsorption, providing a score indicating a low (1), medium (2) and high (3) qualitative human oral absorption; (v) PercentHumanOralAbsorption, providing a score based on multiple linear regression on 0 to 100% scale (>80% is high; <25% is poor) and (vi) RuleOfThree; which is the number of violations of the so-called Jorgensen's rule of three  [128].
Compound Finally, we predicted whether the compounds object of the present investigation reacts with one (or more) cytochrome P450 isoforms (among the most important ones, namely CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). The prediction was performed using as software program CypReact, recently published by Tian et al. [129]  and available in the recently published web platform for de novo design DeLA-Drug  [130]. The obtained results are shown in Table  3. All FAAH and MGL selective inhibitors should be substrates of several cytochrome P450 isoforms and thus possibly act as metabolic auto-/heteroinducers. Possible adverse events due to drug-drug metabolic interactions should be considered. Interestingly, both FAAH/MGL inhibitors 19 and 20 were predicted as poor substrates of all cytochrome P450 isoforms, thus performing as the best candidate for repositioning when metabolic liability is concerned.
Funding: This research was supported by the  National Research Council of Italy  (G. F. M. , P. D. , G. L. ( Giuseppe Lamanna ), M. C. L. , M. S. ),  University of Bari Aldo Moro  (M. M. C. ,  G. La ,  G. L. (Giovanni Lentini )),  FCT-Fundação para a Ciência e a Tecnologia (Base Fund   UIDB/00674/2020  and  Programmatic Fund   UIDP/00674/2020 ,  Portuguese Government Funds)  and  ARDITI-Agência Regional para o Desenvolvimento da Investigação Tecnologia e Inovação  through the project  M1420-01-0145-FEDER-000005-CQM + (Madeira 14-20  Program) (S. M. ), and the  University of Urbino Carlo Bo  (A. D. ). The Ph. D. fellowship of  Dr. Giuseppe Lamanna  was co-funded by  Chiesi Farmaceutici S. p. A. under the program " Dottorato Industriale CNR XXXVI ciclo. "Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable. Funding: This research was supported by the  National Research Council of Italy  (G. F. M. , P. D. , G. L. ( Giuseppe Lamanna ), M. C. L. , M. S. ),  University of Bari Aldo Moro  (M. M. C. ,  G. La ,  G. L. (Giovanni Lentini )),  FCT-Fundação para a Ciência e a Tecnologia (Base Fund   UIDB/00674/2020  and  Programmatic Fund   UIDP/00674/2020 ,  Portuguese Government Funds)  and  ARDITI-Agência Regional para o Desenvolvimento da Investigação Tecnologia e Inovação  through the project  M1420-01-0145-FEDER-000005-CQM + (Madeira 14-20  Program) (S. M. ), and the  University of Urbino Carlo Bo  (A. D. ). The Ph. D. fellowship of  Dr. Giuseppe Lamanna  was co-funded by  Chiesi Farmaceutici S. p. A. under the program " Dottorato Industriale CNR XXXVI ciclo.
Detector and dataset The LHCb detector  [76, 77]  is a single-arm forward spectrometer covering the pseudorapidity range 2 < η < 5, designed for the study of particles containing b or c quarks. The detector includes a high-precision tracking system consisting of a silicon-strip vertex detector (VELO) surrounding the interaction region  [78] , a large-area silicon-strip detector located upstream of a dipole magnet with a bending power of about 4 Tm, and three stations of silicon-strip detectors and straw drift tubes  [79]  placed downstream of the magnet. The tracking system provides a measurement of the momentum, p, of charged particles with a relative uncertainty that varies from 0. 5% at low momentum to 1. 0% at 200 GeV. The minimum distance of a track to a primary collision vertex (PV), the impact parameter, is measured with a resolution of (15 + 29/ p T ) µm, where p T is the component of the momentum transverse to the beam, in GeV.
Different types of charged hadrons are distinguished using information from two ring-imaging Cherenkov detectors  [80]. Photons, electrons and hadrons are identified by a calorimeter system consisting of scintillating-pad and preshower detectors, an electromagnetic and a hadronic calorimeter. Muons are identified by a system composed of alternating layers of iron and multiwire proportional chambers  [81]. The trigger  [82]  consists of a hardware stage, based on information from the calorimeter and muon systems, followed by a software stage, which applies a full event reconstruction. In the present analysis, a dataset of minimum-bias triggered events collected in pPb collisions recorded in 2013 at a nucleon-nucleon centre-of-mass energy √ s NN = 5. 02 TeV is used, with 4 and 1. 58 TeV beam energies, respectively.
Two collision modes were used in this data-taking period with the beam directions reversed, which permits the study of pPb collisions both in the forward and backward rapidity regions. The recorded pPb and Pbp samples correspond to integrated luminosities of 1. 06 nb -1 and 0. 52 nb -1 , respectively. As only a fraction of ∼ 10 -5 of the collisions corresponds to multiple interactions, a dedicated selection requirement is applied to accept only the events with a single primary vertex. The data samples available in the current study after selection described in Sec. 4 corresponds to ∼ 6. 3 × 10 7 (5. 7 × 10 7 ) events for the pPb (Pbp) collisions. Simulation samples corresponding to the 2013 pPb data-taking conditions are produced using the EPOS-LHC  [83]  generator, with a specific LHCb configuration  [84].
Decays of hadronic particles are described by EvtGen  [85] , in which final-state radiation is generated using Photos  [86]. The interaction of the generated particles with the detector and its response are implemented using the Geant4 toolkit  [87, 88] , as described in  [89]. The BEC effect is not activated in the simulation. Each of the pPb and Pbp simulated dataset contains ∼ 1. 2 × 10 7 events after selection, with the number of interactions per bunch crossing fixed to unity. The simulation samples are used mainly for the event-selection optimization, while the background modelling is performed with a purely data-driven approach.
The width σ bkg and amplitude A bkg are multiplicity-dependent values that characterize the cluster contribution and are parametrized as  [46, 56]   [GeV] Q  σ bkg (N VELO ) = σ 0 + σ 1 exp - N VELO N 0 , (10) 6 - 4 - 2 - 0 2 4 6 pull 1 C 2 (Q) 1 C 2 (Q) Q [GeV] A bkg (N VELO ) = A 0 (N VELO ) n A. (11) The fits to the correlation functions for OS pairs are performed simultaneously in all multiplicity bins available in the given sample (separately for the pPb and Pbp datasets). In this procedure, the parameters from Eqs. 10 and 11 are common for all bins, while the N and δ values (Eqs. 7 and 9 respectively) are left free for each correlation function. A negative log-likelihood function (see Eq. 8) is constructed for all the N VELO bins in the given dataset and minimized globally to obtain the best description of the data.
The lower Q fit range for the OS pairs is limited with respect to the SS ones, due to a significant contribution of multibody resonance decays in the very low Q region  [46, 59]. The global fits are performed for Q > 0. 25 GeV. Also, as it is found that the best stability of the global fits is obtained with a fixed value of the N 0 parameter from Eq. 10, its value is set to 15 based on the fit results for the entire pPb dataset obtained with this parameter left free. Results of the global fits to the OS correlation functions for the pPb and Pbp data are shown in Fig. 1  and summarized in Table  2. The quality of the fits is evaluated through the normalized Baker-Cousin likelihood ratio  [91]  corresponding to the final value of the function minimized in the fitting procedure (see Eq. 8), divided by the number of degrees of freedom in the fit (∼2 for both pPb and Pbp).