dataesr/scientific-paragraphs-categorization huggingface dataset:
Conclusion and Future Work Data in the agronomic domain are highly heterogeneous and dispersed. For plant scientists to make informed decisions in their daily work it is critical to integrate information at different scales. Semantic Web technologies play a pivotal role in data integration and knowledge management. The biomedical domain provides a good example to follow by capitalizing on previous experience and addressing lessons learned. To build on this line of research in the agronomy field, we have developed the AgroLD KG. The knowledge base exploits the power of seamless data integration offered by RDF. It contains more than 900 Millions triples resulting of the integration of roughly 100 datasets gathered in 33 named graphs. However, it coverage with respect to the species and the data sources are expected to grow with the subsequent releases.
To our knowledge, AgroLD is one of the first initiatives taken to bring Semantic Web practices to the agronomic domain, playing a complimentary role in the integrative approaches adopted by the community. AgroLD is being actively developed based on feedback from domain experts. It also benefits from the support of the SouthGreen Bioinformatics Platform since its beginning in 2015 by providing IT support and infrastructure to host data and web applications. SouthGreen is one of the core platforms of the French Elixir-EU node, thus will provide a long lasting support for AgroLD. AgroLD is strongly linked to several use-cases of the D2KAB project 23 (National Research Agency funded project) to demonstrate the benefits of linked data to discover gene-phenotype interactions. With the achievement of the second phase, user feedback reveals some limitations and challenges on the current version.
Study Design and Cohort Population The cohort was selected with ConSoRe, a new data analysis solution aggregating diverse forms of structured and unstructured data extracted from digital medical files at a number of French cancer centers. ConSoRe uses natural language processing to search aggregated data and perform advanced data mining  [18]. This data mining tool was used to find all over the age of 18 years with inoperable locally advanced or metastatic solid tumors who received immunotherapy in metastatic setting between January 2017 and 30 June 2020 at the Centre Leon Berard (Lyon, France). We excluded patients treated with immunotherapies other than pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or ipilimumab in monotherapy or with combinations of ipilimumab with nivolumab or durvalumab with tremelimumab.
Patients receiving adjuvant or neoadjuvant immunotherapy and patients receiving immunotherapy in combination with other antitumor therapies (i. e. , chemotherapy or targeted therapy) were also excluded from the cohort. Data collection was approved in September 2020, by the local data protection officer, on behalf of French regulatory authorities (Commission Nationale de l'Informatique et des Libertés, CNIL) in accordance with MR004 methodology. All patients were informed of the possibility of their health data being used for research purposes and expressed no opposition to this possibility. Clinical data and tumor characteristics were extracted from digital medical files, including hospitalization and consultation notes. The clinical variables extracted included sex, age, weight at diagnosis and before starting immunotherapy, and height.
Two-component systems (TCS) are widespread signaling systems present in all domains of life. TCS typically consist of a signal receptor/transducer and a response regulator. The receptors (histidine kinases, chemoreceptors and photoreceptors) are often embedded in the membrane and have a similar modular structure. Chemoreceptors were shown to function in highly ordered arrays, with trimers of dimers being the smallest functional unit. However, much less is known about photoreceptors. Here, we use small-angle scattering (SAS) to show that detergent-solubilized sensory rhodopsin II in complex with its cognate transducer forms dimers at low salt concentration, which associate into trimers of dimers at higher buffer molarities. We then fit an atomistic model of the whole complex into the SAS data.
An important advantage of SAS is that structural data can be collected for solubilized protein complexes in conditions close to their native environment. NpSRII/NpHtrII mediates negative phototaxis in halobacterial N. pharaonis and represents a model TCS sensor and, similarly to chemoreceptors  30  , the NpSRII/NpHtrII complex forms trimers of dimers in the N. pharaonis membrane  31. N. pharaonis grows optimally at 3. 5 M NaCl  32. It has been shown that structure and oligomerization state of the NpSRII/NpHtrII strongly depend on salt concentration  33. Here, we describe the full-length structure of a sensory rhodopsin II/transducer complex (NpSRII/NpHtrII) by integrating published high-resolution structural data with SAS measurements. Structural information was gained for NpSRII in complex with the transmembrane domain of NpHtrII, which show a dimeric organization in different activated states  24, 34, 35.
For the rest of the NpHtrII, homologues were chosen including the HAMP domains of Aer2 cytoplasmic sensor  23  and for the hypothetical transmembrane receptor AF1503  36  , sensor histidine kinase NarQ  [18] [19] [20] 37  , kinase control modules including the methyl-accepting chemotaxis protein I (Tsr) from E. coli  22  and the chemotaxis protein from Thermatoga maritima  38, 39. Ou  work both confirms the dependence of oligomeric state on ionic strength and provides molecular models of the dimeric and "trimer of dimers" forms of the full-length complex. In our manuscript, we used the term "molecular model" meaning a model, which is constructed by molecular modeling with the high-resolution structures of the fragments of full-length protein (transmembrane domain, HAMP1 and HAMP2 domains and Kinase control module) under low resolution SAS constraints and verified with available biochemical and biophysical literature data.
Discussion In present study, the combination of SAS and molecular modeling has allowed us to propose a molecular model of the full-length phototaxis complex from the halophilic archaeon N. pharaonis and to reveal the effect of salt concentration on its oligomeric state and dynamics. We verified our molecular model with available biochemical and biophysical literature data. The monomer-monomer interactions between transducers are in accordance with the following high-resolution structural data. The dimer of the transmembrane domain is based on its available structure (PDB code 1h2s  24  ). Dimers of HAMP1 and HAMP2 domains are constructed according to homology with HAMP domain of NarQ from E. coli (PDB code 5jeq  18  ). The cytoplasmic domain (kinase control module) is presented by the coiled-coil of two antiparallel helices connected by a "U-turn", as it was shown for cytoplasmic domains of TsrQ from E.
coli (PDB code 1qu7  22  ), MCP from Termatoga maritima (PDB code 2ch7  38  ), etc. In these cases, coiled-coil structure stabilized by interactions between the extended interfaces consisting of hydrophobic amino acids, mainly leucines. Dimer-dimer interactions (Fig. 4D ) are mediated by a number of inter-residue contacts involving amino acids conserved across homologs of NpHtrII (see logo plot, Fig. 4G ). Positions of highly conservative residues 345-355 in the cytoplasmic tip domain of NpHtrII in our molecular model of the NpSRII/NpHtrII trimer of dimers are in a good agreement with the EPR studies by Orban-Glaß et al. 43. In that work, the dynamic and structural properties of the cytoplasmic tip domain of NpHtrII were investigated using site-directed spin labeling electron paramagnetic resonance spectroscopy.
4B ) trimers of dimers (brown line) and the "transmembrane-bound" conformation of trimer of dimers of the NpSRII/NpHtrII (Fig. 4A ) (black line). For greater clarity, distance distribution functions were normalized to obtain maximum values of 1. 0 for the experimental and 0. 6 for the theoretical curves. a trimer of dimers is formed with I347 facing inside the resulting structure (see Fig. 4F , Fig. S6A ), playing an important role in the formation of inter-dimer contact due to hydrophobic interaction. At low ionic strength (150 mM NaCl), our SAS data are most compatible with a dimeric conformation for both the truncated NpSRII/NpHtrII 137 and for full-length NpSRII/NpHtrII. In the latter, the very long cytoplasmic domain of the dimeric NpHtrII transducer appear to be highly flexible, corroborating the intrinsically dynamic nature of chemo-and photoreceptors described in some recent publications (e.
g. 10, 40, 44 ). Coupled with the conclusions of a previous study that the cytoplasmic domain of NpHtrII's (pHtrII-cyt) does not form dimers at low ionic strength  33  , our results imply that only the transmembrane region is required for dimerization of NpSRII/NpHtrII. However, this observation is in contrast to that obtained for a similar construct (NpSRII/NpHtrII 157 containing HAMP1 and inter-HAMP (137-156 a. a. ) domains). This might be due to a lower detergent concentration used in the current experiments. While the minimum construct required for NpSRII/NpHtrII to form dimers may still be a matter for debate, our SAS data obtained at low ionic strength clearly suggest that full-length NpSRII/NpHtrII forms dimers under such conditions (see Fig. 2A ). In order to improve the agreement between theoretical and experimental scattering curves data, we generated models of different possible conformations of the NpSRII/NpHtrII dimers which, while maintaining an elongated shape for the NpHtrII dimers, considered both bending at its flexible hinges  11  and partial unfolding  33, 40  of this domain at low salt conditions.
4B ). This is in agreement with previous EPR studies suggesting that NpSRII/NpHtrII dimers may form oligomers of higher order (e. g. , trimers of dimers) due to interactions between the transducer tips alone  43. In our model, inter-dimer separations in the regions containing putative sites (Fig. 4C ) of methylation/demethylation (determined by homology with HsHtrII of Halobacterium salinarum  7  , see alignment in Text document S2) vary between 30 and 40 Å (Fig. S8 ). Thus, they are all potentially accessible to modifications by the chemotaxis methyltransferase CheR and methylesterase CheB (the radii of gyration calculated for CheR and CheB from Salmonella typhimurium (PDB IDs 1AF7 and 1A2O) being approximately 21 Å and 20 Å, respectively). To the date, there is very little structural information available for full-length E.
They are manifested by a change of the diffusion coefficient (and, consequently, of the Stokes radius) of the protein complex and can be explained by unfolding of HAMP domains during signal transfer  52, 53. The changes in the Stokes radius, as well as in the radius of gyration, could be easily detected and characterized using SAS (direct measurements by SAXS). Furthermore, small-angle scattering experiments could provide detailed information about the shape of the molecule, including those arising from changes in tertiary and quaternary structure and/or conformational rearrangements. These changes could, for example, be monitored/characterized via standard SAS experiments with a continuously light-irradiated sample  54  , or using time-resolved SAXS technique  55, 56  applied for the protein solution after the short flash of light.
For the full-length NpSRII/NpHtrII and for the truncated complex NpSRII/NpHtrII 137 , SAXS profiles were obtained for the samples with protein concentrations of 0. 57 and 0. 78 mg/ml, correspondingly; exposure time was Small-angle neutron scattering measurements. SANS measurements were performed on the YuMO spectrometer (IBR-2, Dubna, Russia) with two-detector system  69, 70. Raw data were processed with program SAS  71. For SANS measurements, NpSRII/NpHtrII sample was divided after gel filtration into two parts (sample A and B). For each part, gel-filtration was used to replace H 2 O with D 2 O (Fig. S9A ). The buffer for sample A contained 150 mM NaCl, 25 mM Na/Na-Pi (pD + = 8. 0)  72  , 1 mM EDTA, 0. 05% DDM. Sample B was dissolved in 4. 0 M NaCl, 100 mM Na/Na-Pi (pD + = 8. 0), 1 mM EDTA, 0.
Molecular modeling. Initial model of the full-length NpSRII/NpHtrII dimer was generated from the existing high resolution crystal structures of T. maritima MCP, PDB code 2ch7  38  , E. coli NarQ receptor, PDB code 5jeq  18  and truncated N. pharaonis NpSRII/NpHtrII complex, PDB code 1h2s  24  for the cytoplasmic domain, HAMP domains and transmembrane region, respectively, using template-based homology modeling in SWISS-MODEL  73. The missing fragments (primarily, the inter-HAMP region, which was predicted to be an α-helix  74  ) were modeled ab initio as ideal helices. The obtained all-atom model of the full-length NpSRII/NpHtrII dimer was a subject for further optimization by MD simulation during 100 ns with a number of constraints applied. The regions homological to those resolved by X-ray crystallography were guided towards the initial coordinates by means of harmonic steering forces (k constr = 150 kcal/mol/Å 2 ).
This model was further optimized using a 100 ns long MD simulation with the transmembrane region restrained at its initial coordinates and the cytoplasmic domain steered (k steer = 200 kcal/mol/Å 2 ) to the homology model of the highly conserved trimeric interface of E. coli Tsr receptor resolved by X-ray crystallography, PDB code 1qu7  22. Finally, in order to obtain the "tripod"-shaped conformation of the trimer-of-dimer we run another round of steered MD, in which the cytoplasmic tip of the complex was constrained to the crystallographic contacts similar to the previous simulation while the transmembrane regions of individual dimers were gradually repulsed from their joint center-of-masses using the colvar feature of NAMD (k spring = 200 kcal/mol/Å 2 ). The simulation time of this run was also 100 ns.
All all-atom MD simulations were carried out using NAMD 2. 9  76  and CHARMM27 force field  77. The simulations were run in NVT ensemble (maintained by the Langevin thermostat, T = 303. 15 K) using Generalized Born implicit solvent model (GBIS). The ionic strength in the simulations were set to 4. 0 M. The timestep of 2 fs was used. The production simulations were prefaced by energy minimization using the steepest descent (5000 steps). In all simulations of the trimer-of-dimers, the three-fold symmetry was maintained by the symmetry constraint as realized in NAMD 2. 9. SAS data processing. SAXS and SANS profiles I(q) were processed using ATSAS  78  and BioXTAS RAW  79  software suites. The protein concentrations were small, consequently the structural factor influence to scattering curves was negligible  80, 81.
For calculation of values of ε, molecular mass, ν and SLD from sequence, programs ProtParam 82 , Peptide Property Calculator  83  and SLD calculator web (https:// sld-calcu lator. appsp ot. com/) were used (see Tables  S1, S2 ). Distance distribution functions P(r) and regularized I(q) were obtained using GNOM program, which realizes the method of Indirect-Fourier Transform (IFT)  84. Values of R G and I(0) (Tables  S1, S2 ) were calculated from P(r) and using Guinier approximations (see Fig. S11 ). CRYSOL and CRYSON programs were used for evaluating the solution scattering from macromolecules and fitting it to experimental small-angle scattering curves  85, 86. OLIGOMER program  87  from ATSAS software suite was used for a set of curves calculated for dimers and trimers of dimers using CRYSON to fit an experimental scattering curve from a two-component mixture of dimers and trimers of dimers of the NpSRII/NpHtrII to validate different variants of their molecular models and to find the volume fractions of each component in the mixture.
MEMPROT software  88  was used to generate pseudo-atomic model of the detergent belt of the transmembrane part of the protein and to fit experimental SAXS curves using a model combined from the detergent belt pseudo-atomic model and protein atomic model. Before MEMPROT running, the center of the transmembrane part of the protein was placed at the origin (zero) and direction of the normal vector to the membrane plane was set along the z-axis using PPM web server  89. The MEMPROT settings included CRYSOL3 option and protein surface algorithm 2. See Supplementary Information (Tables  S1, S2 ) for other details of SAS data treatment  90. Pseudo-atomic model of the detergent belt. Pseudo-atoms CH 3 и NH 3 generated by MEMPROT software simulate 9/97 of the X-ray scattering length of hydrophobic tail (C 12 H 25 ) and 10/181 of the X-ray scattering length of hydrophilic head (C 12 H 21 O 11 ) of DDM molecule correspondingly, proportionally to their numbers of electrons.
92 × 10 -6 Å -2 for the hydrophobic core and hydrophilic face of the detergent belt, respectively. Fitting of the SAXS profile of the full-length complex using the model of the flexible hinges. Firstly, SAXS data for the full-length complex NpSRII/NpHtrII (Fig. 2A , top) were approximated with the solution scattering evaluated from the atomistic model of the "straight" NpSRII/NpHtrII dimer with pseudo-atomic model of the detergent belt generated by MEMPROT software  88  , and χ 2 of the fit was 5. 1. Secondly, we generated modified atomic models of the NpSRII/NpHtrII dimer with the bends at the HAMP1-, HAMP2-and Gly-hinges from -90° to 90° each (with the step of 30°), and add pseudo-atoms imitating detergent belt obtained on previous step to them. Thirdly, we evaluated theoretical SAXS profiles from the modified NpSRII/NpHtrII dimer models with the detergent belt using CRYSOL3 software  78.
Fourthly, we approximated experimental SAXS profile for the full-length NpSRII/NpHtrII as a combination of the scattering profiles from the modified NpSRII/NpHtrII dimer models with the detergent belt using Tikhonov regularization method (see Text document S1 for the details). For fitting of this data, Wolfram Mathematica software  91  was used. Analogous analysis of the protein polydispersity based on SAS data was realized in works  92, 93. SAXS could be used in studying of highly polydisperse macromolecules, making it possible to obtain data that are in good agreement with other structural methods such as electron microscopy  94. UV-VIS spectroscopy. Absorption spectra for the protein solutions were acquired by using a UV-2450 UV-VIS Spectrophotometer (Shimadzu, Kyoto, Japan). Protein solutions were placed in a 1 mm quartz cell (Weiju, Lianyungang, China).
Acknowledgements We acknowledge  European Synchrotron Radiation Facility at Grenoble (France)  for granting access to the synchrotron  BM29  Bio-SAXS beamline. We acknowledge  Frank Laboratory of Neutron Physics (FLNP) ,  JINR at Dubna (Russia)  for granting access to the small-angle neutron scattering spectrometer YuMO (IBR-2). We acknowledge  DESY (Hamburg, Germany) , a member of the  Helmholtz Association HGF , for the provision of experimental facilities. Parts of this research were carried out at the  EMBL PETRA III P12 BioSAXS beamline. We thank  Anatoly Mikhailov  and  Pavel Kuzmichev  for their help in measuring CD spectroscopy. We acknowledge  Ivan Okhrimenko ,  Vitaliy Shevchenko ,  Taras Balandin ,  Andrii Ishchenko  and  Dmitriy Bratanov  for fruitful discussions. We thank  Alexander Kazantsev  for the help with fitting of the SAXS experimental data and  Dmitry Verteletskiy  for the help with preparing the figures.
Data availability The SAS data were deposited with SASBDB (http:// sasbdb. org). SAXS data deposited with accession codes SASDKZ6 and SASDK27 for the NpSRII/NpHtrII 137 and the full-length NpSRII/NpHtrII at 150 mM NaCl, correspondingly. SANS data deposited with accession codes SASDK37, SASDK47, SASDK57, and SASDK67 for the full-length NpSRII/NpHtrII at 0. 15 M, 1. 4 M, 2. 8 M and 4. 0 M, respectively. Detailed data validation metrics related to SASBDB depositions are placed in the Table  S3. PBD files for molecular models of NpSRII/NpHtrII 137 dimer and full-length NpSRII/NpHtrII dimer and trimer of dimers are available in the SASBDB depositions SASDKZ6, SASDK27, and SASDK67, respectively. Other data supporting the findings of this manuscript are available from the corresponding author upon reasonable request.
PET/CT acquisition and image reconstruction All patients underwent PET/CT on an analog 3-dimensional (3D) PET scanner (Philips Gemini Dual-slice EXP scanner-PET Allegro TM system with Brilliance CT scanner-Philips Medical Systems, Cleveland, OH). In accordance with the procedural guidelines for PET imaging  [36] [37] [38] , the injected tracer activity was 145. 1 ± 25. 3 MBq of 68 Ga-DOTA-TOC (range, 100-212 MBq). After 60 min of uptake and following freebreathing CT acquisition for attenuation correction from the vertex of the skull to the mid-thighs (5 mm slice, 40 mAs, and 120 kVp), PET data were acquired in 3dimensional (3D) mode, covering the same anatomical region of the CT, with 2. 5 min per bed position and 6-8 bed positions per patient. The PET scans were reconstructed by ordered subset expectation maximization (OSEM) algorithm (3D-RAMLA), with the following settings: 4 iterations, 8 subsets, and field of view (FOV) of 576 mm.
Lesion segmentation For each lesion, a three-dimensional volume of interest (VOI) was manually delineated (VOI m ), slice-by-slice, in the OSEM PET images by four independent observers, all nuclear medicine physicians (FC, VL, GP, and BD with 10, 7, 5, and 3 years of expertise, respectively), by using the software LifeX v. 4. 81 (IMIV/CEA, Orsay, France-www. lifexsoft. org) [39]. In additional, each lesion was also contoured using a semi-automatic edge-based (SAEB) algorithm (VOI SAEB ), homemade implemented in MATLAB (MathWorks) code, based on the active contour model proposed by Chan and Vese  [40]. The algorithm is semi-automatic since the operator intervention was required in order to insert the central point of the lesion (Fig. 1a ). The developed MATLAB graphical user interface allowed the operator to view both the PET and the CT images separately.
) Fig. 1  Semi-automatic edge-based (SAEB) algorithm workflow. The algorithm requires the intervention of an operator to insert the central point of the lesion (a) through an interface created in MATLAB, the operator can view both the PET and the CT images separately. As a second step, edge-preserving filters are applied to the image to emphasize the edge of the lesion (b) and, after that, and a level-set is used which is a shape that evolves iteratively over the image (c). The level-set acts both on the original image of the lesion and on the filtered image in which the contours are highlighted. The iteration 0 of the level set, which would be the initialization, is the center of the lesion indicated by the operator. The final outline of the lesion is achieved at the end of the process space; (d) three features from neighborhood gray-level different matrix (NGLD M): describing the difference between a voxel and its connected neighbors.
However, its ICC value was furtherly decreased from Lifex software due to an assigned artificial feature value equal to zero for VOIs smaller than 64 voxels rather than a Not A Number (NAN) as other RFs. This occurred also for SHAPE_Compacity for a total of 7 lesions and only for some operator, leading to a high inter-operator variability. After removing these lesions, the ICC increased for both SHAPE_Sphericity (from ICC = 0. 27 to ICC = 0. 59) and SHAPE_Compacity (from ICC = 0. 88 to ICC = 0. 95). In line with previous studies  [52, 53] , GLZLM (also called GLSZM) features and in particular the ones measuring zones with low gray-level (SZLGE and LZLGE) resulted to have a moderate robustness (ICC from 0. 5 to 0. 8) to segmentation (Fig. 5a ). This is likely related to the lower uptake in lesions edges, where operators and SAEB segmentation showed a higher variability (Fig.