dataesr/scientific-paragraphs-categorization huggingface dataset:
org/10. 1101/391961). The MSSD method processes structures using CE-Symm and SymD with a range of customized parameters and then, among other considerations, filters the results based on the position of the detected structural repeats with respect to the membrane. MSSD can report multiple symmetries within either a complex or a chain; the corresponding symmetry axes and transformations; the residue ranges and multiple alignment of the structural repeats; and the orientation of the repeats and the symmetry axes relative to the membrane. Finally, taking advantage of the networks of structural and sequence similarities described above, the database reports so-called inferred symmetries. These are obtained by assuming the presence of repeated or symmetric elements in a given chain based on their detection with the MSSD method in related protein chains.
DATABASE ACCESS The EncoMPASS web server is hosted at http://encompass. ninds. nih. gov and is equipped with a a simple PDB-code search as well as a more versatile search tool that allows the user to explore the many features of the database. The complete list of search criteria organized by category is reported in Supplementary Table  S1. Information is provided for each PDB entry on two levels: entire protein complexes (Figure  1 ) and individual transmembrane chains (Figure  2 ). The pages for each protein complex are divided into four sections, containing a general description of the protein, a summary of its transmembrane chains and their structure relationships, and descriptions of the symmetries obtained by the standard symmetry detection algorithms and by the MSSD procedure. The first section of each whole structure page reports general information about the complex and provides links to the corresponding entry in the PDB and OPM databases, as well as a graphical interface that allows real-time visualization of the structure from different perspectives.
This section also provides a button for downloading the coordinates of the protein. Note that the displayed structure is not identical to that in the PDB: for example, the biological assembly might differ, and the membrane boundaries are highlighted by two planes of pseudo-atoms. The second section contains a table summarizing the characteristics of each of the transmembrane chains in the complex. This includes: the number of transmembrane regions, the number of sequence and structural neighbors, and the symmetry order of any internal symmetry detected by either the MSSD, CE-Symm or inferred symmetry methods in that order of preference. By clicking on the transmembrane chain identifier, the user is redirected to the relevant page for that chain, while the sequence-, structure-and all-neighbors fields are linked to tables describing the corresponding structures.
The third and fourth sections of each complex page are dedicated to symmetry analyses. The third section summarizes the results of the two standard symmetry detection algorithms, CE-Symm and SymD. CE-Symm can detect multiple symmetries for the same structure, so the user can scroll through the different symmetries. Each symmetry is represented using different colors for each repeat and a black line for the symmetry axis. By comparison, SymD can detect only one symmetry axis in a structure and its output does not indicate the boundaries of each repeat. Hence, in the 3dmol visualization of the SymD results, all residues that are related by the detected symmetry axis are colored blue. The raw data and a PyMOL visualization script can be downloaded directly from this section. It is important to note that the output of the two symmetry recognition programs does not distinguish between quaternary and internal symmetries and, therefore, the results for complexes might include information on both.
On the other hand, the subsequent section (the fourth section) contains results from our MSSD procedure focused exclusively on quaternary symmetries. The layout of the MSSD results section mirrors that of the CE-Symm results, but the reported data also includes classification of the topology of the repeats with respect to the membrane (antiparallel or parallel), as well as the angle of each reported symmetry axis to the membrane normal. Finally, the user can download a PyMOL script that allows visualization of the superposition of all repeats. The web pages for individual chains are extended versions of the whole structure pages, with a total of five sections (Figure  2 ). The second section on each chain page is notable, in that it includes visual representations of the analysis of sequence and structure relationships.
Three graphs are presented. The first graph illustrates the structural similarity between the chain of interest and its close structural neighbors (TM-score ≥ 0. 6), where the distance between any two points is proportional to their similarity (i. e. , inversely proportional to the TM-score). Since large structural differences could be explained simply by a difference in size, each point on this plot is colored in shades from blue to red to show the (greater or fewer, respectively) number of transmembrane regions relative to that of the chain of interest. Hovering over the points with the cursor brings up their PDB identifiers, while clicking on a point navigates to the EncoMPASS page describing the corresponding protein chain. All the information provided in this first plot, however, is focused on structural similarity.
The user may also be interested in the sequence similarity between protein chains that have related structures, or conversely, the structural variability among entries with similar sequences. Thus, in the second graph, the structural similarity according to the TM-score is plotted against the sequence identity from the MUSCLE pair-wise sequence alignment, for every compared chain. The contour lines on the graph illustrate the abundance of pairs of compared structures across the entire database. Finally, to illustrate how different regions of the protein chain compare, the third graph provides the structural similarity (i. e. distance between C␣ atoms) as a function of residue number for each structure alignment. All similarity measures and structure alignment outputs for the protein chain of interest are also downloadable.
Sections three and four of the individual chain pages follow the same layout as those on the complex page, but obviously only report symmetries within the given chain. In the fifth section, each chain page includes results from an additional procedure that relies on the structural and sequence neighbors to infer symmetry. That is, if the chain has a neighbor, for which the MSSD analysis detected a more extensive symmetric relationship, the symmetry of that neighbor is used as a template for mapping out the repeats in the current chain. The symmetry axis and structural similarity between these repeats are reported in a similar fashion as in the MSSD results section. The EncoMPASS dataset is created and updated automatically using a set of python libraries available at https://www. github. com/EncoMPASS-code/EncoMPASS.
All data entries and processed PDB files can be downloaded as a single file from http://encompass. ninds. nih. gov/downloads. The online database for EncomPASS is designed using the Oracle Relational Database System, and utilizes the Java 2 Enterprise Edition platform, the Spring Framework, and JavaScript libraries. Representative page for the whole structure of PDB entry 3M75 (a TehA homologue), including a brief summary of the characteristics of each of its transmembrane subunits (left) and analysis of the symmetries within the complex (right) using two standard symmetry detection algorithms as well as the multi-step symmetry detection (MSSD) method. Note that on these pages the MSSD section contains results only if quaternary symmetries (i. e. , involving multiple chains) have been detected.
CASE STUDY: INVESTIGATING SODIUM-DEPENDENT TRANSPORT As an illustration of how EncoMPASS can be used to generate function-related hypotheses about membrane proteins, we consider the example of the sodium-coupled betaine symporter BetP. BetP uses the translocation of two sodium ions to energize the transport of each betaine molecule  (25). The available structural data for BetP, however, only indicate the location of one of the two required sodium ions, at the so-called Na2 site, for example in PDB identifier 4AIN, chain B)  (26). Unfortunately, no evidence has been found for the other sodium ion (Na1) in the six available structures of BetP. Interestingly, however, EncoMPASS reports the presence of two inverted-topology structural repeats in the BetP protomer (Figure  3A, 4AIN B ). Hence, examining the region of the protein that is structurally related to the Na2 binding site may reveal residues contributing to the Na1 site.
Us-Figure  2. Example EncoMPASS online database chain page. Representative page for chain A of PDB entry 3M75. These pages follow the same outline as for the complex in Figure  1 , but contain analysis specific to each chain, including sequence and structural relationships, and any detected internal symmetries. Chain A of 3M75 has 39 sequence and structure neighbors. (Visualization of the polar or scatter plots, shown here as clickable icons, reveals that these structures are all closely related, both structurally and by sequence. ) In terms of the internal symmetry, all methods agree that chain A contains a five-fold circular pseudo-symmetry (C5), although there are some differences in the details. As in the pages for complexes, the MSSD section reports the relationship of the symmetry axis to the membrane plane.
CONCLUSION The online EncoMPASS database curates a wide variety of membrane protein structural data, which we expect will appeal to diverse communities. For example, users interested in finding template structures for homology modeling should find particularly useful the visual analysis of structure similarity networks; the analysis of symmetric regions provides complementary information to infer functionality; the complete set of accurate pairwise structure alignments and their corresponding structure-based sequence alignments constitutes a robust benchmark for membrane pro- tein sequence alignment programs; and symmetric region classification could be used to trace evolutionary sequencestructure relationships. For this reason, the website has been designed to be easily searchable by different criteria, to provide intuitive interfaces to access the results of our analyses, and to allow access to all data for postprocessing.
The results shown were additionally filtered by the term 'Chain A' and sorted by TM-score to reveal the least similar structures. (F) Structure-based sequence alignments of representative structural homologues relative to BetP allow interrogation of putative sodium binding sites or sodium-independent mechanisms. Alignments were extracted from pairwise structure alignments provided in EncoMPASS, and combined using pyali (https://github. com/christang/pyali). The positions of Na1 and Na2 site residues in BetP are indicated by arrows colored by repeat.
D320Figure 3. 3 Figure 3. Examining structure-function relationships in the sodium-coupled betaine transporter BetP and its homologues using EncoMPASS. (A) Structural symmetry reported by MSSD for BetP (PDB identifier 4AIN chain B), in which residues 135-326 (repeat 1, orange) are pseudo-C2-symmetric to residues 360-542 (repeat 2, blue), and related by an axis (black line) that lies in the plane of the membrane. The protein is viewed from the extracellular side of the membrane. The protein is shown in cartoon helices; elements of the structure not related by symmetry are colored gray. Note that ligands are not included in this representation. (B) Sequence alignment between repeats extracted from the structural alignment in the regions contributing residues to the Na2 binding site. The Na1 site residues are Ala147, Met150 from repeat 1 (orange arrows) and Phe464, Thr467 and Ser468 from repeat 2 (blue arrows).
Genescan and CDR3 analysis Complementary DNA (cDNA) from sorted Tet2-deficient abnormal B cells (B220 low CD19 1 ) and wild-type (WT) B cells (B220 1 CD19 1 ) was polymerase chain reaction (PCR) amplified using VH family primers (VH1, VH2, VH3, VH5, VH6, and VH7, as indicated) and a common JH fluorescein amidite-conjugated primer to assess immunoglobulin H (IgH) CDR3 diversity. 22 PCR products were run on a 3130xl sequencer (Applied Biosystems), and data were analyzed using Peakscanner software (Applied Biosystems). PCR fragments were sequenced using the same VH family primer used for amplification. Sequences were analyzed using IgBlast  23  and International ImMunoGeneTics (IMGT) V-Quest,  [24] [25] [26]  and IgH V, D, and J genes with highest significance in both analyses are shown in Table  1.
5 J2 C TR EYLG STTVP TIL DY W 16 1 4,44 Sequence analysis of PCR products obtained from GeneScan analysis was down using the JH primer. Results obtained were subject to analysis using IMGT/Vquest and IgBlast software to define all V, D, and J genes, as well as the CDR3 sequence. Columns show the identified IgH-V, -D, and -J genes; the resulting CDR3 sequence, the CDR3 length; the D genes reading frame, and the isoelectric point (IP) of the CDR3. The background of the mice that developed the abnormal B-cell population is indicated. 2 abnormal populations heterozygous for Tet2 gene-trap model (Tet2LacZ ANO) are shown, as well as 4 heterozygous Tet2 floxed alleles (Tet2 2/1 ) and 6 homozygous inactivated Tet2 (Tet2 2/2 ) in CD19-Cre Tet2 background. The last 3 lines represent analysis of 3 abnormal Tet2 populations that have emerged in 3 secondary recipients engrafted from the same primary Tet2CD19-Cre 1 mice.
Acknowledgments The authors thank the members of the  Gustave Roussy Platforms , including  Patrick Gonin  for excellent mouse care,  Yann Lecluse  and  Philippe Rameau  for flow cytometry, and  Olivia Bawa  for histopathological analysis. This work was supported by grants from  INSERM , the  Institut National du Cancer  ( 2013-PLBIO-09 ,  2016-PLBIO-068 ,  INCa-DGOS-INSERM 6043 , and  SIRIC-SOCRATE 2. 0 ), the  Fondation pour la Recherche M édicale , and the  Association Laurette Fugain. This work was also supported by grants from  Region Ile de France and Fondation de France  (H. G. ),  Canc éropole Ile de France et Fondation pour la Recherche M édicale  (C. K. L. ), and the  Dutch Cancer Society "KWF Kankerbestrijding " and the  Daniel den Hoed Cancer Foundation  (I. P. T. ).
1 IgM 1. C D UP DOWN Tet2-/- SpB1a Tet2-/- SpB1a 57 4 67 85 0 19 (13. 6%) (1%) (16%) (32. 8%) (0%) (7. 3%) 21 17 8 (5%) 129 7 (6. 6%) 39 (1. 9%) (30. 7%) (2. 7%) (15. 1%) 134 92 (31. 9%) (35. 5%) PCB1a PCB1a Gene Set Name p-value FDR q-value Gene Set Name p-value FDR q-value LEE_BMP2_TARGETS_DN 4,22E-09 7,50E-05 WONG_ADULT_TISSUE_STEM_MODULE 3. 37E-12 1. 6E-8 GSE15930_NAIVE_VS_24H_IN_VITRO_STIM_CD8_TCELL_DN 2,50E-08 0,000126 GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP 1. 37E-8 2. 45E-5 GSE33425_CD161_HIGH_VS_NEG_CD8_TCELL_DN 2,50E-08 1,26E-04 ZHANG_TLX_TARGETS_UP 1. 56E-8 2. 45E-5 WEI_MYCN_TARGETS_WITH_E_BOX 2,83E-08 1,26E-04 ZHANG_TLX_TARGETS_36HR_UP 4. 53E-8 5. 36E-5 VANOVA_HEMATOPOIESIS_STEM_CELL_AND_PROGENITOR 7. 41E-8 7. 01E-5 LEE_BMP2_TARGETS_UP 1. 7E-7 1. 13E-4 KUMAR_TARGETS_OF_MLL_AF9_FUSION 1.
14 The included patients had no macular edema, intravitreal hemorrhage, tractional retinal detachment, or lens opacity and had been treated with panretinal photocoagulation (PRP). Casual observation of patients in our tertiary referral center suggested that such patients often have variable VA despite having no apparent macular complications. We build on this observation by systematically analyzing the FAZ and the vessel density of the retinal capillary plexuses using OCTA data and correlating these results with VA.
Eyes with an OCTA signal strength index less than 50/100 were excluded. Visual acuity was measured on a Snellen chart and expressed as the logMAR. Based on VA levels, eyes were divided into 2 groups: eyes with a normal VA (logMAR, 0; Snellen equivalent, 20/20) and eyes with a decreased VA (logMAR, >0; Snellen equivalent, <20/20). Visual acuity and OCTA data were compared with those measured in healthy age-matched control participants (volunteer caregivers) (logMAR, 0; Snellen equivalent, 20/20). The fundus was imaged using an ultrawide field imaging system (Optos PLC) and OCTA (RTVue XR Avanti; Optovue). The OCTA findings from a single visit were analyzed. A 3 × 3-mm macular cube centered on the fovea, composed of 320 horizontal B-scans separated by 9 μm and containing 320 A-scans, was acquired.
Images were analyzed using the AngioVue OCTA system available on the RTVue XR Avanti device. Automated vessel density was calculated using the AngioAnalytic software, beta version 2016 200 037, including the projection artifact removal. We used the terminology proposed by Campbell et al  18  to name the different retinal vascular plexuses. The superficial vascular plexus (SVP), the deep capillary complex (DCC), and the DCP were automatically segmented using the default settings of the software, but the intermediate capillary plexus (ICP) was manually segmented. The location of the segmentation lines that determine each plexus are detailed in Figure  1. The accuracy of the automatic segmentation was verified visually by scrolling the 320 B-scans. Errors were found in 4 of the 22 eyes (18%), and manual correction was required.
by a 3 × 3-mm square centered on the fovea (whole en face image). The vessel density was measured at 4 different levels: SVP, DCC, ICP, and DCP. The FAZ area was measured using the nonflow function on the OCTA software and manually corrected in case of segmentation errors. Projection artifact removal software allows measurement of the FAZ, which is delimited by an anastomotic perifoveal ring identical in the SVP and the DCC. The central 1-mm subfield thickness was also studied using the AngioVue software as well as the inner retinal thickness (internal limiting membrane-inner plexiform layer distance) and outer retinal thickness (inner plexiform layer-retinal pigment epithelium distance).
Without any doubt, this project offers a solid base from which to analyze shifts in labor relations over time within societies, and which allows for interregional and worldwide comparisons. One drawback seems to be the strong role of demographical data as a starting point for examining each geographical unit and cross-section, given the fact that for continent such as Africa, this data is very sketchy and unreliable until right into the twentieth century. Moreover, the taxonomy does not really allow the capturing of overlaps and "grey zones" in individual labor relations. The Africa-related publications emerging from this project so far provide interesting new insights, but also refer to the limits of the database-driven approach for the history of African labor and its global connections, especially for the periods before 1900.
Acknowledgements The publication of this book could not have been realized without the generous support of  Marti Huetink , publishing director at Brill. We are grateful to  Henk Wals , General Director of the iish, and  Leo Lucassen  its Research Director for their unconditional support for this volume. Richard Bowles  and  Anne Lee  perceptively edited the English-language contributions of the non-native speakers;  Joppe Schaaper  meticulously corrected the author's references and made the bibliography and index. 43  Arquivo Edgard Leuenroth , unicamp, processo criminal ( 1865-6 ),  Tribunal da Relação do Rio de Janeiro , reel  84. 0. ACR. 163 (microfilm copy of original belonging to the Arquivo Nacional). I have analyzed this document before in  Sidney Chalhoub , "The  Precariousness of Freedom ,"  427-429.
Finite element numerical modeling Numerical analysis was performed using finite element software (COMSOL Multiphysics). The scattering from a 100 nm spherical gold nanoparticle (for which the permittivity data were taken from ref. 18  was studied in the scattering-field formulation, with the simulation domain surrounded by a perfectly matched layer in order to guarantee the absence of back-reflection from the outer domain boundaries. The symmetry of the simulation setup (both the incident field and the object) was used to decrease the computational complexity. The simulation domain, which initially had a spherical form, was cut by two perpendicular planes intersecting along the beam axis. In the case of the plane wave illumination, these planes were the plane of the linear polarization and the wave vector plane perpendicular to it.
Acknowledgements This work was supported in part by  EPSRC (UK)  and  ERC  (project  789340 ). P. G. acknowledges the support by a  TAU Rector Grant  and the  German-Israeli Foundation  (GIF, grant number  2399 ). A. Z. acknowledges support from the  Royal Society  and the  Wolfson Foundation. A. K. and R. D. thank  Mr. Alexander E. Ageyskiy  for help with the microwave experiments.
Acknowledgements We thank  Alice Balmer ,  Benjamin Kellenberger  and  Anja Wettstein  for their help in data collection,  Rayko Jonas  and  Markus Meierhofer  for plant care and  Tanja Christoffel  for insect rearing. Franz Huber  helped with the volatile collection and analysis and  Kelsey Byers  provided helpful comments on earlier versions of this manuscript. We would also like to thank  Ted Turlings  for providing us access to the olfactometers in his laboratory. The seeds of the B. rapa IMB 211 line were kindly provided by  Dr. Federico Iñiguez-Luy. This study was funded by the  university research priority program (URPP) "Evolution in Action " of the  University of Zurich.
Product characteristics Of the 30 CMA drugs approved by the EMA until June 2016, 27 were included in the final analysis. Two drugs were excluded because the CMA was withdrawn by the marketing authorization holder and one product was excluded because it was not assessed by any HTA organization. Nine CMAs (33%) were granted for drugs based on solely uncontrolled studies. For the remaining 18 drugs, at least one controlled trial was available. Two of those had trials with active controls, whereas the rest had a placebo as comparator. Indications for the 27 CMAs included 17 oncology drugs, 6 infectious disease drugs, 3 Central Nervous System drugs, and 1 ophthalmologic drug. Thirteen drugs had their CMA converted to standard Marketing Authorization at the cutoff period for data collection. Twelve CMAs were for orphan drugs.
Limitations This study has several limitations. All data was extracted manually from HTA reports from different organizations and interpretation of data may have resulted in wrong categorization of HTA recommendations. However, we have validated our data extraction, found a high inter-rater agreement, and have performed a sensitivity analysis to minimize this limitation. Substantial differences in processes, methods, and procedures for HTA between jurisdictions exist and not all countries assessed all CMA drugs included in this study, which might have influenced the results. For example, in the Netherlands (ZIN) only one product with solely uncontrolled trials was assessed but ZIN recommendations were relatively more often positive for the CMA drugs they assessed. Our selection criteria excluded many HTA institutions in Europe, which differ vastly from the included institutes.