dataesr/scientific-paragraphs-categorization huggingface dataset:
14 AE 0. 50 with a median value of 0. 01. Human subpopulations included both male and female genders, different age groups, individuals with a range of diets, geographical origin and likely a range of CYP2D6 genotypes and phenotypes. Overall, human variability in CYP2D6 was substantial, as also indicated by the SD reported in each study, generally higher than the mean value itself. Therefore, although data variability could be expected to be averaged out by the mean (or median) value, reported in each paper, this is not the case for CYP2D6. The fact that mean and median value differ by more than one order of magnitude indicates that the distribution of values is asymmetrical, with a distribution shifting to lower values. Data on human variability in kinetics for CYP2D6 including inter-phenotypic differences have been described elsewhere  (Darney et al.
, 1999; El Desoky et al. , 2005). Grouping of the datasets while considering urinary 6β-hydroxycortisol/cortisol MR (collected in the morning the day after dosing), the MR distribution was 11. 24 AE 17. 25 (median value = 6. 5). Conversely, when selecting CYP3A4/A5 activity data from urinary DEX/3-MM ratio (25À30 mg DEX collected between 0À8 hours after oral dosing), variability in MR was lower with mean/SD values of 3. 27 AE 2. 86 and a median value of 2. 95. Some authors suggested that there are no 'ideal' markers to predict CYP3A4 enzymatic activity with high accuracy, since none of them are uniquely metabolised by the isoform  (Benet, 2005)  and the possibility that multiple substrates are simultaneously bound to the isoform cannot be excluded  (Ekroos and Sjogren, 2006). As expected, a data gap emerged regarding the in vivo activity data for CYP3A7; only few in vitro were data collected from the screened literature, that were exceptionally entered into the inventory file.
While considering the impact of these isoform-specific genetic polymorphisms on CYP1A2, 2A6, 2D6 and 3A4/3A5/3A7 activities, the available peer-reviewed literature was large (n = 418)  and included a range of populations of different geographical ancestry. Data collection was performed using reviews and meta-analyses. Relevant and informative reviews include  Gaedigk et al. (2017)  and  Zhou et al. (2017)  to whom the reader is referred for full details. The latter reported a global distribution map of CYP alleles with clinical relevance and integrated wholegenome and exome sequencing data from 56,945 unrelated individuals for five major human world populations to potentially develop population-adjusted pharmacological dosing  (Zhou et al. , 2017). Tables  5 6 7 8 illustrates the frequencies of polymorphisms for CYP 1A2, 2A6, 2D6 and 3A4/3A5/3A7 in healthy adults from different geographical ancestry.
Conclusions and future perspectives The manuscript presents the results of large extensive literature searches from the peer-reviewed scientific literature and the creation of the OpenCYP database which will be public (DOI: 10. 5281/zenodo. 5031737) (Supplementary material A and B): an open source database providing data for human variability in the baseline activities and frequencies of polymophisms for CYP1A2, CYP2A6, CYP2D6, CYP3A4/3A5 and CYP3A7 across world populations. This database presents a collection of quantitative data on CYP enzymatic activities extracted from in vivo studies conducted on ethnically heterogeneous populations. This peculiarity represents its added value with respect to what is currently avaialble, given that the majority of search engines that are freely accessible generally provide only qualitative information on enzymatic activities for specific substrates or, in most cases, indicate only the coherent reference literature.
As relevant examples, reliable and high quality databases addressing data collection of human genotypes and phenotypes are already available, as the central repositories PharmGKB (http:// www. pharmgkb. org) and PharmVar Consortium (https://www. pharmvar. org/). They both represent an important open-access source of information, especially directed to clinical applications, considering different responses to drugs based on genetic variability. The former, structured around four specific entities: variants, genes, drugs and diseases, provides clinical information, including dosing guidelines and drug labels, potentially clinically relevant gene-drug association, and also information on how genetic variants can be involved in the PK or PD pathways of a specific therapeutic drug. Analogously the Pharmacogene Variation (PharmVar) Consortium reports pharmacogene (PGx) variation with a focus on haplotype structure and allelic variation, supporting the interpretation of pharmacogenetic test results to guide precision medicine.
Besides clinical applications, having available data on human variability on the activity of phase I, phase II enzymes and transporters involved in ADME processes, represents critical data needs to move towards the development of PBK and in silico tools that provide reliable estimates when used in the risk assessment process. Having information on the isoform-specific biotransformation of a chemical obtained in vitro, the possibility to integrate data on human variability of the active enzyme (as the ones included in the OpenCYP database) could allow for improvement and testing the prediction power of PBK generic models. The OpenCYP database, as an open source database, aims to provide CYP-specific enzymatic activity for healthy adults and their genetic polymorphism frequencies across world populations.
In addition, additional efforts have supported the generation of human variability distributions for a range of Phase I, Phase II and transporters using human in vivo kinetic parameters and bayesian meta-analyses (e. g. CYP3A4 and paraoxonoase-1, carboxylesterases, CYP2D6)  (Darney et al. , 2019 (Darney et al. , , 2020a (Darney et al. , ,b, 2021submitted)submitted). For these enzymes, pathway-related uncertainty factors were derived for populations of different geographical ancestry (CYP3A4, CYP2D6, paraoxonoase-1 and carboxyl esterases) and inter-phenotypic differences (paraoxonoase-1) associated with genetic polymorphisms  (Darney et al. , 2019 (Darney et al. , , 2020a (Darney et al. , ,b, 2021;; Di Consiglio et al. , 2021). While compiling the OpenCYP EFSA database, we conclude that, despite the high number of collected papers, discrepancies in the reporting of the age and demographic characteristics of enrolled individuals were noted across the datasets and constituted a challenge to perform a full statistical analysis of CYP-specific activities and variabilities in relation to geographical origin.
In addition, when the same probe substrate was used, the lack of standardisation in the experimental conditions (dosing, time of sampling, matrix collected) hampered the possibility to perform a full statistical analysis. Data investigating age groups other than adults such as the elderly, children and neonates were very limited and fragmented constituting an additional important data gap. Moreover, few papers reported both phenotyping and genotyping results. These considerations highlight the need to use standardised methodologies in the experimental design and reporting, whenever data on enzymatic activity in humans are investigated within a specific population. The use of MR measured in urine or plasma was considered an adequate metrics for possible comparison and allowed to derive variability of CYP enzymatic activities within healthy individuals.
When data were sub-divided according to similar testing conditions, our analysis indicates that variability was quite limited for CYP1A2 (assessed with caffeine as a probe substrate) and a symmetrical distribution of metabolic activities values was observed. CYP3A4 activity showed also a limited variability, when assessed by using the urinary DEX/3-MM ratio. Conversely, when the urinary 6β-hydroxycortisol to cortisol ratio was used as index of CYP3A4 activity, large interindividual/interethnical differences were shown. This could be the result of the overall variability due to both CYP3A4 and to the genetic polymorphism of transporters responsible for the renal excretion (clearance) of cortisol. Genetic variants in kidney membrane carriers can cause considerable interindividual variation in physiological processes as well as in pharmacotherapy  (Tracy et al.
It is proposed to extend the database for other CYP isoforms and phase I enzymes (CYP2C9, CYP2C19, ADH, paraoxonases, esterases) as well as phase II enzymes (UGTs, GSTs, sulphotransferases, methyltransferases, glycine conjugation etc) and transporters (P-glycoprotein, OATPs, OATs etc), while including absolute expression levels of the isoforms using proteomic analyses. It is foreseen that the integration of databases such as OpenCYP with the available large databases on human in vivo variability in markers of acute and chronic exposure, as well as absolute expression levels of the isoforms from recent proteomic experiments, would support the further development of QIVIVE and PBK models to be applied in chemical assessment  (Darney et al. , 2019 (Darney et al. , , 2020a (Darney et al. , ,b, 2021;; Kasteel et al.
55 Å and a defocus range of -1 to -3. 2 µm. Six datasets were collected with a dose rate of 6-8 e -/pixel/s (1. 1 Å pixel size at the specimen) on the detector. Images were recorded with a total dose of 50 electrons/Å 2 , exposure time between 7-10 and 0. 2-0. 25 s subframes (35-50 total frames). Data processing. Processing of each data set was done separately following the same procedure until the 3D refinements where particles were merged. The gain reference for the super-resolution dose-fractionated subframes was generated of each dataset with 'relion_estimate_gain' subprogram in RELION 3. 1  49. The subframes were then gain-corrected, twice, drift-corrected and dose-weighted using RELION 3. 1 MotionCor2 own implementation yielding summed images with 1. 1 Å pixel size. The contrast transfer function of the corrected micrographs was estimated using GCTF v1.
4 ). The cryo-EM maps of the DNA-binding/cleavage domain in State 1 and State 2 state as well as the entire complex in the two same conformations have been deposited in the EMDataBank under accession numbers EMD-11550, EMD-11551, EMD-11553, EMD-11554, respectively. The EM map with well-resolved N-gate/DNA-gate linkers have also been deposited in the EMDataBank under accession number EMD-11552. Model building and refinement of the DNA-binding/cleavage domain. The two reconstructions of the DNA-binding/cleavage domain in State 1 and State 2 at 3. 6 and 4. 1 Å, respectively, were used to refine a crystal structure of the hTopo IIα DNA-binding/cleavage domain in complex with DNA and etoposide  27. PDB 5GWK was stripped of all ions and water molecules, with all occupancies set to 1 and B-factors set to 50.
6 ). Refinement followed the same procedure as for the masked DNA-binding/cleavage domain except that the local real-space fitting was replaced by a rigid-body refinement. Resolution limit for refinements was set according to the gold standard FSC-0. 143 criterion. Refinement parameters, model statistics, and validation scores are summarized in Supplementary Table  1. The atomic models of the full-length hTopo IIα in State 1 and State 2 conformations have been deposited in the Protein Data Bank under accession numbers 6ZY7, 6ZY8, respectively. Expression and purification of hTopo IIα mutants. The modified pVote0GW vector used for wild-type hTopo IIα overexpression was mutated by site-directed mutagenesis using the QuikChange XL Site-Directed Mutagenesis kit (Agilent) in order to generate the plasmids harboring K 418 A, K 425 A, W 414 A-F 417 S, K 425 G-K 426 G-C 427 P mutations and Δ1193 or Δ1217 truncations.
5, 150 mM potassium acetate, 8 mM magnesium acetate, 7 mM BME, 100 μg/mg of BSA, 4U/5U of PK/LDH mixture, 2 mM PEP, and 0. 2 mM NADH and 4 mM ATP. Phylogenetic and structure prediction analysis of the TOP2. 33 TOP2 genes, from unicellular eukaryotes to Human (Supplementary Table  4 ), were aligned with ClustalW 63 using the BLOSUM weight matrix. The subsequent alignment was injected into the ConSurf server  64  to analyze the conservation of the primary sequence. Secondary structure prediction of the hTopo IIα was performed using the PSIPRED server  65. Protein domain graphs (Figs. 4  and 5 ) were generated using domainsGraph. py (archived at https://github. com/elifesciences-publications/ domainsGraph)  66. hTopo IIα CTD production and purification. The sequence coding for the human Topo IIα CTD (1191-1531) was inserted into a modified pAX vector containing an N-terminal 10 His-tag and a C-terminal twin-strep tag.
After the ion exchange chromatography, fractions containing the intact CTD were pooled and loaded on a Superdex S200 16/60 sizeexclusion chromatography column (GE Healthcare) using 25 mM Hepes, 100 mM NaCl, 100 mM KCl, 1 mM EDTA, 2. 5% v/v glycerol, 5 mM DTT, pH 7. 5. After the purification process, 4 mg of the hTopo IIα CTD were obtained per liter of cell culture (Supplementary Fig. 9a ). Uncropped gel is provided in Source Data. SAXS experiments. SAXS data of the hTopo IIα CTD (1191-1531) at 10 or 20 mg/ml was collected on an in-house Rigaku BioSAXS-1000 (Rigaku) apparatus, equipped with a Rigaku MicroMaxTM-007HF generator and a Pilatus 100k detector. The sample was maintained at 10 °C and exposed to the X-ray beam for 2 h. A total of eight images were recorded every 15 min. All the data processing steps were performed using the program package PRIMUS  67.
Refinement parameters, model statistics and validation scores are summarized in Supplementary Table 1. The atomic models of the DNA-binding/cleavage domain in State 1 and State 2 conformations have been ARTICLE NATURE COMMUNICATIONS | https://doi. org/10. 1038/s41467-021-23136-6 10 NATURE COMMUNICATIONS | (2021) 12:2962 | https://doi. org/10. 1038/s41467-021-23136-6 | www. nature. com/naturecommunications deposited in the Protein Data Bank under accession numbers 6ZY5, 6ZY6, respectively.
Acknowledgements We thank  Julio Ortiz  and  Gabor Papai  for their help with EM data collection, as well as  Marlène Vayssières  for technical assistance with protein preparation. Computational resources were provided by the  Méso-centre de Calcul (University of Strasbourg ). We are also grateful to  Albert Weixlbaumer  and  Sebastian Klinge  for sharing computational resources. This work was supported by the  Fondation ARC , the  Association Alsace contre le Cancer  and the grant  ANR-10-LABX-0030-INRT  (managed by the  Agence Nationale de la Recherche  under the  frame program Investissements d'Avenir   ANR-10-IDEX-0002-02 ). The authors acknowledge the support and the use of resources of the  French Infrastructure for Integrated Structural Biology FRISBI   ANR-10-INBS-05  and of Instruct-ERIC.
Data availability The data that support this study are available from the corresponding author upon reasonable request. All structural data and corresponding cryo-EM maps that support the findings of this study have been deposited to PDB and EMDB under the accession codes 6ZY5 and EMD-11550 for the hTopo IIα DNA-binding/cleavage domain in closed state; 6ZY6 and EMD-11551 for the hTopo IIα DNA-binding/cleavage domain in pre-open state; 6ZY7 and EMD-11553 for the entire hTopo IIα in closed state; 6ZY8 and EMD-11554 for the entire hTopo IIα in pre-open state; and EMD-11552 for the N-gate/DNAgate linkers. Source data are provided with this paper.
Acknowledgements This research was supported by the  National Natural Science Foundation of China  (Grant Nos. 21772088  and  91961116 ), the  Fundamental Research Funds for the Central Universities  ( 14380216 ), Programs for high-level entrepreneurial and innovative talents introduction of  Jiangsu Province  (individual and group programs). LM is member of the  Institute Universitaire de France. Humboldt Foundation and Chinese Academy of Science  are acknowledged for support. CalMip is also gratefully acknowledged for a generous grant of computing time.
The trials included the most prevalent peripheral NeP conditions: peripheral NeP after herpes zoster, HIV, or nerve injury (STRIDE), and PDPN (PACE). Taken together, the data collected in these trials cover treatment of mononeuropathies (e. g. , PHN and post-traumatic/ post-surgical nerve injury [PNI]) and polyneuropathies (e. g. , HIV-AN and PDPN). The data also cover peripheral NeP with a range of etiologies: PDPN is the prototype of a peripheral NeP caused by a continuous insult, whereas PNI is the prototype of a peripheral NeP caused by a noncontinuous nerve lesion. In both trials, repeat treatment was well tolerated, with little deterioration in sensory function  [13, 14]. Furthermore, average pain intensity continued to fall throughout follow-up (Figure  1 ), which suggests a potentially progressive response to long-term therapy.
Trial Design and Procedures This was a post hoc, exploratory analysis of data from two prospective, multinational, open-label trials of repeat treatment with the capsaicin 179 mg cutaneous patch over 52 weeks. STRIDE (NCT01252160) was a phase 4, single-arm, observational, safety trial in patients with nondiabetic peripheral NeP; all study subjects were treated with the capsaicin 179 mg cutaneous patch with repeated applications at 9-to 12-week intervals  [13]. PACE (NCT01478607) was a phase 3, randomized, controlled, safety trial in patients with PDPN; participants were randomized 1:1:1 to treatment of the feet with the capsaicin 179 mg cutaneous patch (30-or 60-minute applications) combined with standard of care (SOC) or to SOC alone, and repeated applications were given at 8-week intervals  [14, 15].
Characterization of the silylated castor oil 1 H, 13 C and 29 Si NMR analyses (Bruker Avance III 500 and 600 MHz equipped with cryoprobes) were performed on ICOm in order to determine its structure. The methodology was as follows: the NMR spectra were recorded at 298 K on a Bruker Avance III 600 MHz NMR spectrometer, using TCI Cryoprobe Prodigy ®. Chemical shift data were given in δ ppm calibrated with residual protic solvent (e. g. CDCl3: 7. 26 ppm -1 H / 77. 16 ppm -13 C). 2D heteronuclear spectra 1 H-13 C g-edited HSQC (Heteronuclear Single Quantum Coherence) and 1 H-13 C g-HMBC (Heteronuclear Multiple Bond Correlation) were acquired to assign the compound (8 -16 scans, 512 real (t1) × 2048 (t2) complex data points). 2D heteronuclear spectra 1 H-29 Si g-HMBC (16 scans, 512 real (t1) × 2048 (t2) complex data points) was obtained on a Bruker Avance III 500 MHz NMR spectrometer, using BroadBand Observable helium cryoprobe in order to establish presence of transesterification on silicium positions.
Spectra were processed and visualized with Topspin 3. 6. 2 (Bruker Biospin) on a Linux station. CDCl3 was purchased from Aldrich. For the quantitative determination of x, y, and z substituent ratios (explained in the result section), the various "CH" were identified by 2D NMR g-edited HSQC 13 C and g-HMBC 13 C and then integrated on 1D 1 H NMR. The ICOm was synthesized and analyzed in triplicate for the purpose. Furthermore, the viscosity of ICOm was measured with a rotative rheometer  (RM 200  Rheomat, Lamy Rheology) equipped with a DIN33 measuring system.
Transactivation experiments The cells were seeded at a density of 25000 cells per well in 96-well white opaque tissue culture plates (Greiner CellStar) in the aforementioned medium and conditions. The extracts were diluted in the culture medium according to defined concentrations of estradiol (10 -5 to 10 -12 M) and added to the cells. After 16 h of co-incubation, the diluted extracts were replaced with test medium containing 0. 3 mM luciferin. Luciferase activity was measured for 2 s in intact living cells using a MicroBeta Wallac luminometer (PerkinElmer). Tests were performed in quadruplicate in at least three independent experiments. Data were expressed as a percentage of the theoretical maximal activity of pure estradiol and were given as the mean ± SD. Agonistic activity of the ERα was tested in presence of increasing concentrations of extracted estradiol.
Pharmacokinetic (PK) parameter estimation is a critical and complex step in the model-informed precision dosing (MIPD) approach. The mapbayr package was developed to perform maximum a posteriori Bayesian estimation (MAP-BE) in R from any population PK model coded in mrgsolve. The performances of mapbayr were assessed using two approaches. First, "test" models with different features were coded, for example, first-order and zero-order absorption, lag time, timevarying covariates, Michaelis-Menten elimination, combined and exponential residual error, parent drug and metabolite, and small or large inter-individual variability (IIV). A total of 4000 PK profiles (combining single/multiple dosing and rich/sparse sampling) were simulated from each test model, and MAP-BE of parameters was performed in both mapbayr and NONMEM.
Second, a similar procedure was conducted with seven "real" previously published models to compare mapbayr and NONMEM on a PK outcome used in MIPD. For the test models, 98% of mapbayr estimations were identical to those given by NONMEM. Some discordances could be observed when dose-related parameters were estimated or when models with large IIV were used. The exploration of objective function values suggested that mapbayr might outdo NONMEM in specific cases. For the real models, a concordance close to 100% on PK outcomes was observed. The mapbayr package provides a reliable solution to perform MAP-BE of PK parameters in R. It also includes functions dedicated to data formatting and reporting and enables the creation of standalone Shiny web applications dedicated to MIPD, whatever the model or the clinical protocol and without additional software other than R.
MAP-BE relies on this a priori parameter distribution provided by the population PK model to estimate the most likely PK parameters for one individual given a set of patient-related data (i. e. , observed concentrations and covariates). An individualized dose can then be calculated based on the patient's a posteriori parameters. This approach was conceptualized nearly 50 years ago by Sheiner et al. 8  and led to the development of the NONMEM software, which is currently the gold standard to build population PK models and, among other applications, to perform MAP-BE. 9 1] [12]  Although these may be satisfactory in many situations, drawbacks limit their use: libraries limited to specific drugs, no possibility to define specific protocols, and cost. 13 Although the benefit of a model-based TDM approach is expected in areas other than antibiotics, such as antiepileptics  14  or anticancer drugs,  15  these are often missing from MIPD software.
Hospital pharmacists or biologists could perform MAP-BE with in-house models and data directly inputted within NONMEM, but this is not convenient nor safe for routine use. One approach could be to use R through in-house Shiny web applications. R is a free software and a programming language  16  increasingly used in the pharmacometrics community for a broad variety of tasks such as statistical analysis, data visualization, and reporting. With the Shiny package, it is possible to code a web interface to execute R tasks in the background using R code only  17  without prior knowledge of a web language (such as HTML, CSS, or Javascript). Shiny is well documented online and broadly used in the field of pharmacometrics and beyond,  18, 19  which makes it possible for anyone with basic R coding skills to build his/her own Shiny application and, for example, safely perform TDM.
A remarkable example of such an application is TDMx 20 ; however, its use is limited to antibiotics, and the source code is not published, preventing its generalization to other drugs. Existing R packages nlmixr  21  and saemix  22  are dedicated to population PK/pharmacodynamics (PD) modeling from a data set of concentrations of several patients. Others, such as RxODE  23  and mrgsolve,  24, 25   The objective of this study is to introduce mapbayr package features and to validate its performance in terms of parameter estimation compared with NONMEM.