dataesr/scientific-paragraphs-categorization huggingface dataset:
g. , Iberian Peninsula, France, Mid-Europe, Mediterranean, Eastern Europe) with a spread in the frequency of high-intensity heat waves of 20 times or more. The predominance of the energy-limited evaporative regime in Scandinavia and Northern Europe leads to a weaker land-atmosphere coupling, and thus to a relatively low impact of groundwater coupling on the frequency of simulated heat waves of high intensity. We studied the impact of groundwater on summer heat events in a new dataset from a coupled regional climate system, the Terrestrial Systems Modelling Platform (TSMP), with an explicit representation of three-dimensional groundwater hydrodynamics, compared to an ensemble of EURO-CORDEX climate change scenario RCM control runs. In particular, we investigated the impact of groundwater coupling on the frequency of hot days, the occurrence of heat events of different duration, and the frequency of high-intensity heat waves in Europe between 1976 and 2005 with respect to the reference period 1961-1990.
We estimate the cumulative number of hot days, TG90p index, for each summer season during 1976-2005. The results from two regional climate models, the  Terrestrial Systems Modelling Platform  (TSMP) and CCLM (COSMO model in CLimate Mode; e. g. , Rockel et al. , 2008;Steger and Bucchignani, 2020), for several years are shown in Fig. 3 as an example. Both RCMs, TSMP and CCLM, are driven by the same forcing data from the  Max-Plank Institute 's MPI-ESM-LR r1i1p1 GCM experiment Acknowledgements. This work was funded by the  Helmholtz Association of German Research Centres (HGF)  under the  HI-CAM  project ( Helmholtz Initiative Climate Adaptation and Mitigation ). We thank the  EURO-CORDEX climate modelling groups  for producing and making available their model output. We are grateful to the  Max-Plank Institute  for performing  MPI - ESM-LR r1i1p1  GCM experiment and the  German Climate Computing Centre (DKRZ)  for providing the MPI-ESM-LR dataset.
Code and data availability. The TSMP v1. 2. 2 used in this work is available at the master GIT repository, https://github. com/HPSCTerrSys/ TSMP. The dataset from the regional Terrestrial Systems Modeling Platform (TSMP) driven by MPI-ESM-LR r1i1p1 is currently available at https://datapub. fz-juelich. de/slts/regional_climate_tsmp_hi-cam/. Author contributions. The study was designed by S. K. and K. G. with contributions by L. P-S. and N. W. L. P. -S. conducted the model simulations and performed the data processing, N. W. provided technical and programming support. The analysis was conducted by L. P. -S. with further inputs from S. K. and K. G. L. P. -S. wrote the paper. All co-authors contributed to the interpretation of the results, active discussions, and revisions of the paper. The work was done under the supervision of S.
The Political Ethnography series is an outlet for ethnographic research into politics and administration and builds an interdisciplinary platform for a readership interested in qualitative research in this area. Such work cuts across traditional scholarly boundaries of political science, public administration, anthropology, social policy studies and development studies and facilitates a conversation across disciplines. It will provoke a re-thinking of how researchers can understand politics and administration. www. man ches teru nive rsit ypress. co. uk British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Annika Lindberg's inaugural dissertation was submitted in the fulfilment of the requirements for the degree of Doctor rerum socialum at the Faculty of Business, Economics and Social Sciences at the University of Bern.
, , 2015;; Knepper et al. , 2019; Shalhout et al. , 2021; Stachyra et al. , 2021; Starrett et al. , 2020; Wong et al. , 2015; Zehir et al. , 2017). To the best of our knowledge, the only publication that focused on PARPi in MCCs described mutations of DNA damage repair genes in 64% of cases  (Ferrarotto et al. , 2018). Sensitivity to olaparib was observed in one MCC cell line, suggesting a potential use for conducting clinical trials using PARPis. However, data on pathogenic and targetable alterations of the BRCA1/2 genes are scarce and remain to be established. The main issue is to distinguish, among published variants, those that are definitively or likely pathogenic and may therefore be efficiently targeted by PARPi from variants of unknown significance (VUSs) or benign. The individual classification of a variant implies a time-consuming task of database and literature screening.
Molecular features in our series Next-generation sequencing (NGS) analysis failed in five cases (Figure  1  and Supplementary Table  S1 ). Comparative genomic hybridization on array (aCGH)/SNP on array (aSNP) analyses failed in one case (case number #12) and could not be performed in case numbers #9 and #25 because of an insufficient amount of genomic DNA (Figure  1  and Supplementary Table  S1 ). The frequency of pathogenic BRCA1/2 variants in our series was 3% (Supplementary Tables  S1  and S2 ). We only found one BRCA2 pathogenic variant: a nonsense mutation of BRCA2 in case number #34, with a variant allele frequency of 10% classified as pathogenic, according to all databases (class 5 variant) (Figure  2  and Table  2 ). In case number #4, we detected a missense mutation of BRCA2, with a variant allele frequency of 45% classified as VUS because this variant was not yet reviewed in BRCA Exchange and BRCAshare databases and unknown in the ClinVar and gnomAD databases (class 3 variant) (Figure  2  and Table  2 ).
, 2021; Wong et al. , 2015). In three published series  (Carter et al. , 2018; Goh et al. , 2016; Knepper et al. , 2019) , BRCA1/2 variants were not annotated; authors only mentioned BRCA1/2 mutations as missense, nonsense, or frameshift. This did not make it possible to classify them according to their pathogenicity. In the remaining cases of MCC with available genomic and/or protein data, we were able to determine a class of pathogenicity, with concordant classes most of the time according to the four public databases. We only identified 10 pathogenic (class 5) BRCA1/2 nonsense or frameshift mutations (Table  2 ). We also found two missense mutations subject to conflicting interpretations of pathogenicity (at least one interpretation as pathogenic). In fact, the numerous remaining BRCA1/2 variants reported in the literature were VUS as well as benign variants and mainly corresponded to missense mutations.
The pathogenicity of germline BRCA1/2 variants is notably based on criteria established by the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium (https://enigmaconsortium. org/). These criteria include clinical data (cosegregation with disease, cooccurrence with a pathogenic variant in the same gene, reported family history, breast tumor histology) as well as in silico prediction of pathogenicity. For somatic mutations, the pathogenicity is determined by querying public databases: BRCAExchange and BRCAShare, which are specific to BRCA1/2 variants, and other databases such as ClinVar and gnomAD. The type of mutations is also important because many pathogenic variants are nonsense or frameshift mutations, leading to premature protein truncation, whereas most of the missense and intronic variants of BRCA1/2 (except in splice sites) are benign variants or VUS (in 90% of cases according to  Parsons et al.
Base calling, barcode sorting and trimming, alignment to the human reference genome (hg19, Genome Reference Consortium Human Build 37), and variant calling were achieved using the Torrent Suite, version 5. 16, and the Torrent Variant Caller plugin with the Somatic-Low stringency default parameters. Mutations were annotated using Ion Reporter, version 5. 16 (Thermo Fisher Scientific). Classification of pathogenicity of BRCA1/2 variants Every BRCA1 and BRCA2 variant was classified according to their pathogenicity using public databases such as BRCAExchange (https://brcaexchange. org), ClinVar (https://www. ncbi. nlm. nih. gov/ clinvar), GnomAD (https://gnomad. broadinstitute. org), and BRCA-Share (formerly known as the UMD-BRCA mutations database) (Figure  1 ). Only BRCA1/2 variants of class 5 (pathogenic), class 4 (likely pathogenic), and class 3 (VUS or not yet reviewed) were listed in the Results section, Supplementary Table  S2 , and Figure  2.
aCGH and aSNP We performed aCGH/aSNP on 80 ng DNA/sample to detect wholegenome CNAs and losses of heterozygosity using the OncoScan CNV Assay (Thermo Fisher Scientific) according to the manufacturer's instructions. Data were analyzed using the Chromosome Analysis Suite (ChAS 3. 3) software (Thermo Fisher Scientific). Annotations were based on the human reference hg19 (Genome Reference Consortium Human Build 37). Raw data have been submitted to the Gene Expression Omnibus database with the accession number GSE210602.
Meta-analysis of BCRA1 and BRCA2 variants reported in the literature The PubMed database was searched for studies published in English from January 2000 to November 2022, using the following terms: BRCA1 AND Merkel cell carcinoma, BRCA2 AND Merkel cell carcinoma, sequencing AND Merkel cell carcinoma, molecular AND Merkel cell carcinoma, and gene AND Merkel cell carcinoma. We have also interrogated large-scale molecular, pan-cancer cohorts available in the cbioportal database (https://www. cbioportal. org) to identify molecular analyses in MCC. We collected data when BRCA1 and/or BRCA2 variants were found (Figure  1 ). We used the same procedure previously described to classify these variants according to their pathogenicity.
Neutron capture cross section measurements of isotopes close to s-process branching-points are of fundamental importance for the understanding of this nucleosynthesis mechanism through which about 50% of the elements heavier than iron are produced. We present in this contribution the results corresponding to the high resolution measurement, for first time ever, of the 80 Se(n, γ) cross section, in which 98 resonances never measured before have been reported. As a consequence, ten times more precise values for the MACS have been obtained compared to previous accepted value adopted in the astrophysical KADoNiS data base.
Fig. 2  shows the neutron capture yield of 80 Se obtained in this work and analyzed with the SAMMY code  [22]. The latter employs the R-Matrix theory to fit the capture yield resonances using the properties of the nuclear levels of the compound nucleus, such as the energy, E 0 , partial widths, Γ γ and Γ n , and the spin-parity, J π. In this work, a total of 113 resonances have been characterized, 98 of them for the first time and 15 previously known from transmission measurements  [23]. No resonance data were known from the previous ToF neutron capture measurement  [13].
4. The MACS values obtained in this work are between 20% and 40% lower compared to the previous ToF measurement  [13]. This disagreement is slightly reduced but still present when comparing the new data with those available in the KADoNiS v1. 0 database  [27]. The high energy resolution of our n_TOF-EAR1 and the low neutron sensitivity of the setup compared to the previous experimental data set have allowed us, among others, to carry out a very precise background subtraction. Moreover, the careful application of the PHWT has enabled an accurate assessment of the detection efficiency. These factors may be responsible for the differences with the previous work. Finally, Tab. 3 displays the numerical values of the 80 Se(n, γ) MACS for three different kT values, which are close to relevant points of the s-process, and where our data can be compared to the rest of calculations.
Acknowledgement We acknowledge support from from the  European Research Council (ERC)  under the  European Union 's  Horizon 2020 research and innovation program  (grant agreement No. 681740 ), and the  Spanish Science Ministry  for funding projects  FPA2017-83946-C2-1-P  and  PID2019-104714GB-C21. This work is part of the PhD Thesis of  V. Babiano-Suarez.
| Outcomes and definitions The primary outcomes which were explored in our cohort were determined by the predictive models in each of the studies (i. e. PROTECT, PIBD-ahead study and Schechter et al. ). These included SFR at 3 and 12 months (defined in our cohort as clinical remission without steroids), SSFR (i. e. SFR at the 3-and 12-month visits) and treatment escalation to biologics, colectomy and ASC rate [i. e. admission requiring intravenous corticosteroids (IVCS)]. For prediction, we included only outcomes occurring at least 1 month from diagnosis. Clinical remission was defined as PUCAI <10, mild disease as PUCAI 10-30, moderate disease as PUCAI 35-60 and severe disease as PUCAI ≥65. 11 ea under the curve (AUC) was used to validate models when feasible. Additionally, in order to assess data in a clinically applicable manner, per patient, patients were classified categorically as positive or negative for each model.
2. 5. 3. Intrinsic Activity toward H 3 R. To identify the lead compounds' functional profile, their intrinsic activity was tested in a 3′,5′-cyclic adenosine monophosphate (cAMP) accumulation assay in HEK cells expressing human recombinant H 3 R. 34  All tested compounds reversed the R-αmethylhistamine inhibition of cAMP production in forskolinstimulated cells and were therefore classified as H 3 R antagonists/inverse agonists. The IC 50 values obtained in the H 3 R functional assay are assembled in Table  3. 2. 6. In Silico Studies. Molecular Modeling: Docking Studies and Molecular Dynamics Simulations. In addition to experimental studies, the protonation states of compounds were also evaluated in silico using two software packages: InstantJChem and Epik (Figure  8 ). Although there are slight differences in the numerical values of predicted pK a , the overall tendencies observed for the performed experiments are preserved: nitrogen atoms belonging to the piperidine moieties are characterized by higher pK a values than those of piperazine, and therefore, they are less likely to protonate at physiological pH.
To confirm the validity of the docking poses discussed above, the molecular dynamics (MD) simulations were carried out. The obtained data were analyzed both in terms of the variation in the ligand-protein contacts as well as via the examination of ligands' RMSDs. Both approaches confirmed the stability of the obtained docking poses: the compounds occupied the same region of the binding pocket during the whole simulation process, and the patterns of ligand-protein interactions in general remain the same (Figures  S27  and S28 ). We are aware of the H 3 R crystal structure, which was released in late October 2022 in the PDB repository (PDB ID: 7F61). 47  The crystalized complex contains an antagonist in the binding pocket, PF03654746, as well as the unexpected cholesterol binding at the allosteric site.
According to the authors, the H 3 R orthosteric binding pocket is shallow, and PF03654746 occupies an extended part of it (EBD). To evaluate the quality of our homology model, we docked PF03654746 to the model, and we obtained a similar pose to that observed in the crystal structure (Figure  S29 ). The RMSD (root-mean-square deviation) of ligands was 1. 48 Å, and it is less than the crystal resolution (2. 6 Å), which indicated that our model was coherent with the crystal structure. It is worth to stress that the proposed binding mode of KSK ligands engaged the same protein helices (especially TM7) and crucial amino acids. 47  For this reason, we decided not to perform in silico calculations once again using an experimental H 3 R structure. 2. 7. Determination of Selected ADMET Parameters. 2.
48  By using UPLC-MS with an internal standard, the exact quantity of molecules that penetrated from donor to acceptor wells through the phospholipid membrane was measured. The results were expressed as permeability coefficient P e calculated according to the formulas described in the literature. 49  Taking into account the collected data and comparing them with two standards: well-permeable caffeine (P e = 10. 49 × 10 -6 cm/s) and lowpermeable sulpiride (P e = 0. 05 × 10 -6 cm/s), it seems justified to consider the tested molecules as substances with highly passive transport through biological membranes (Table  5 ). In general, compounds with a P e value above 4 × 10 -6 cm/s are considered permeable, whereas those with a lower value are considered impermeable. All tested ligands showed P e values greater than the threshold value.
Chemical shifts were expressed in parts per million (ppm) using the solvent signal as an internal standard. Data are reported in the following order: multiplicity (s, singlet; d, doublet; dd, double of doublets; t, triplet; tt, triplet of triplets; quin, quintet; qd, quartet of doublets; m, multiplet; br, broad), approximate coupling constants J expressed in hertz (Hz), and number of protons. 13  C NMR spectra were recorded on a Varian-Mercury-VX 300 MHz PFG or Bruker 400 MHz spectrometer at 75 MHz in DMSO-d 6. Elemental analyses (C, H, N) were performed on a Vario El III elemental analyzer (Hanau, Germany). For CC purification (column chromatography using silica gel 60 (0. 063-0. 20 mm); Merck), the following solvent systems were used: I: petroleum ether/EtOAc (9:1); II: CH 2 Cl 2 /MeOH (9:1).
The analytical procedure was a follows: volume V 0 = 4. 5 mL of titrant D was titrated with 0. 1 M titrant T using the CerkoLab System equipped with a 5 mL syringe pump. Titrant T was added to titrant D in 0. 005 mL increments with 10 s intervals. pK a values were calculated from the experimental data points {(Vj,pHj)/j = 1,. , N} according to the Kostrowicki and Liwo algorithm. 29, 30  4. 4. NMR Spectroscopy Measurements in the pH-Controlled Environment. NMR spectra were measured on a JEOL JNM-ECZR 600 MHz spectrometer equipped with a Royal HFX probe. All measurements were carried out at stable 303 K. DMSO-d 6 of purity 99. 8% was purchased from Eurisotop and stored over A3 molecular sieves for a few days. Proton spectra were collected from 16 scans and 32,768 points with an acquisition time of 2.
The bound radioactivity was determined using a liquid scintillation counter (Beckman LS 6500). 64  The K i values were calculated with the program GraphPad Prism 7. 0 (GraphPad Software, San Diego, CA, USA). The K i values are given as mean value ± CI from at least two independent experiments performed in duplicate. 4. 5. 2. Affinity at Histamine Receptors. Compounds (as oxalate salts) were tested in H 3 R in vitro binding studies using the methods described previously. [21] [22] [23]  Ligands were tested at 5 to 11 appropriate concentrations in a [ 3 H]N α -methylhistamine (K D = 3. 08 nM) radioligand depletion assay to determine the affinity at human recombinant histamine H 3 R stably expressed in HEK-293 cells. Radioligand binding experiments at the H 1 R, H 2 R, and H 4 R were performed as previously described in Rosier et al.
65  and Bartole et al. 66  The following radioligands and concentrations were used:   68  at HEK293T-SP-FLAG-hH x R (x = 1, 2, or 4) expressing the respective hHR. Data represent mean values ± CI from three independent experiments, each performed in triplicate. The normalized competition binding curves were then fitted with a four-parameter logistic fit yielding IC 50 values using the Prism 8. 4. 3 software (GraphPad, San Diego, CA). The K i values were estimated from the Cheng-Prusoff equation. 69  4. 5. 3. Cyclic Adenosine Monophosphate (cAMP) Accumulation Assay. The LANCE Ultra cAMP assay (Perkin Elmer), a homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay, is designed to measure cAMP produced upon modulation of adenylyl cyclase activity by GPCRs. The assay is based on the competition between the europium (Eu) chelate-labeled cAMP tracer and sample cAMP for binding sites on cAMP-specific monoclonal antibodies labeled with the ULight dye.
Experiments were conducted twice in triplicates, and IC 50 values were determined using the Prism 8. 4. 3 software. 4. 6. In Silico Studies. Molecular Modeling: Docking Studies and Molecular Dynamics Simulations. 4. 6. 1. Structures of the Receptors. The histamine H 3 receptor homology model was built using the AlphaFold server,  70, 71  and we chose the model with the highest values of the predicted local-distance difference test (pLDDT). The structures of σ 1 R were retrieved from the Protein Data Bank  72, 73  (PDB ID: 5HK1, 74 5HK2, 74 6DJZ, 75 6DK0, 75 6DK1 75 ); however, on the basis of the similarity of crystalized ligand and preliminary research, we choose the crystal structure of σ 1 R in complex with the antagonist haloperidol  17  (PDB ID: 6DJZ). 4. 6. 2. Induced Fit Docking (IFD).
Ligand-protein contacts occurring during MD simulations were analyzed with the use of the Simulation Interaction Diagram (Schrodinger Suite). 4. 6. 7. Protonation Studies. The protonation studies were carried out in two software packages: InstantJChem and Epik. 77  In the latter case, water was selected as a solvent. 4. 7. Determination of Selected ADMET Parameters. 4. 7. 1. Permeability across Lipid Membranes. The precoated PAMPA Plate System Gentest was obtained from Corning (Tewksbury, MA, USA). It consists of a 96-well receiver filter plate that has been precoated with structured layers of phospholipids and a matched donor microplate. The stock solutions of tested compounds and reference drugs were diluted in the PBS buffer (pH 7. 4) to the final concentration of 100 μM according to the method described previously.
The responsiveness to thermally induced pain was determined by a tail flick analgesic meter (Tail-Flick Unit; Ugo Basile) as previously described. 95  Tail flick latency was measured on the dorsal part of the tail at two-thirds of its length by applying a focused beam of light (thermal stimulus). The time interval between onset of the thermal stimulus and withdrawal of the tail from the beam was recorded; the cutoff latency was 9 s to prevent tissue damage. 4. 8. 7. 2. Data and Statistical Analysis. The behavioral data in Figure  14  are presented as a percentage of the maximal possible effect [% MPE = 100% × (measured responsebasal)(cutoff valuebasal)] of drug action. In the Supporting Information, the results from the von Frey test are expressed as pressure (g) applied with the filament.
The behavioral data are presented as mean ± SEM. The oneway ANOVA was performed, and the differences between the groups were further analyzed with Bonferroni's post hoc test. Significant differences between group are indicated when *p < 0. 05, **p < 0. 01, and ***p < 0. 001. The analysis and charts were prepared using GraphPad Prism v. 9. 1. 2 (GraphPad Software, La Jolla, CA, USA).
Funding We are pleased to acknowledge the generous support of the  National Science Center, Poland , granted based on decisions  2020/36/C/NZ7/00284 ,  2019/35/D/NZ7/01042 , and  2020/ 04/X/NZ7/01338. This study was partly supported by statutory funds from the  Faculty of Pharmacy Jagiellonian University Medical College, Krakow, Poland  ( N42/DBS/ 000242 ). Support by  ERNEST COST Action   18133  is also acknowledged. We also acknowledge funding from the  University of Catania , PIA. CE. RI. 2020-2022  Linea di intervento 3   Starting Grant  project  CARETO  (grant  57722172136  to E. Amata). S. Poc. was supported by the  Fonds der Chemischen Industrie  (grant  661688 ). L. J. H. was funded by the  Deutsche Forschungsgemeinschaft (DFG ,  Research Training Group   GRK 1910 ). The crystal structure analysis was performed on the equipment purchased thanks to the financial support of the  Ministry of Science and Higher Education, Warsaw, Poland  (grant  6903/IA/SP/2018 ).