dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements We thank  Prof. F. Azorin  and  Prof. F. Posas  for helpful discussion. We are also indebted to  P. M. Martínez  and the  IRB Biostatistics/Bioinformatics Unit  for their technical advice and the  Functional Genomics Facility  for support with RNA microarrays. This work was supported by the  Spanish Ministry of Science and Innovation  ( BIO2012-32868 ),  Instituto de Salud Carlos III (INB)  and the  European Research Council  ( SimDNA  project). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Structural and functional studies of the ESR1 mutation The identified R394H mutation was introduced within the human ER (hER) a ligand-binding domain (Protein Data Bank identification code 1GWR; www. rcsb. org/pdb) using PyMOL software (www. rcsb. org/pdb) (10). The orientation of the histidine side chain was adjusted using the PyMOL rotamer function. The mutation was inserted by means of site-directed mutagenesis using the QuickChange XLII Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA) into a nonmutated ESR1 clone, VP16-ERa (Addgene, Cambridge, MA). Human embryonic kidney 293T (HEK293T) cells were transiently transfected with wildtype (WT) or mutant ESR1 plasmids and a luciferase reporter construct containing 3 estrogen-response elements (EREs), 3xERE-TATA-luc (Addgene). Transfection efficiency was adjusted by cotransfection with a plasmid encoding b-galactosidase regulated by a cytomegalovirus promoter.
1181G. A), leading to the substitution of histidine for arginine at residue 394 of the ligand-binding domain of ERa (p. Arg394His), a pivotal residue completely conserved among species (Fig. 1D ). Three unaffected related subjects, the proband's parents (III-5 and III-7) and 1 sister (IV-4), were heterozygous for this mutation. The R394H mutation was absent in Exome Variant Server and ExAC databases and predicted to be deleterious according to the SIFT score and PolyPhen-2. Western blot analysis revealed that both WT and mutant ERa were expressed at similar protein levels in transfected HEK293T cells (Fig. 2A ). Transactivation of an ERE-dependent luciferase reporter gene in transiently transfected HEK293T cells showed a highly reduced sensitivity of R394H ERa mutant to 17b-estradiol stimulation (Fig.
The arrow shows the homozygous mutant genotype resulting in a nucleotide change from G to A at complementary DNA nucleotide 1181 (GenBank accession number, NM_000125. 3). Below, the 8 coding exons of the ESR1 gene and the corresponding domains of ERa protein are schematically represented. Arrows indicate the nucleotide (c. 1181G. A) and residue (p. Arg394His) changes in affected patients. (D) Alignment of the Arg (R) 394 residue in ERa protein of other species, indicating complete conservation among species. DBD, DNA binding domain; LBD, ligand binding domain; NTD, N-terminal domain.
Results are mean 6 standard error of the mean of 3 independent ERE-luciferase reporter assays performed in sextuplicate. Dotted line represents the 100% maximal transcriptional activity of WT ERa. Statistical comparison between WT and R394H ERa mutant reveals significant difference for each experimental condition. (D) Estradiol within the ligand-binding cavity of the WT (upper panel) and the R394H mutant hERa (lower panel). From the N-to the C-terminus of the domain, the secondary structure elements are represented as ribbons with a blue-green-yellow color gradient. Only residues involved in estradiol anchoring are shown. Red dashed lines indicate hydrogen bonds between estradiol and the hERa residues. The figures were generated using PyMOL software (www. rcsb. org/pdb).
Acknowledgments We thank  Dr Sylvie Brailly-Tabard  for her help in determining inhibin and AMH measurements and  Dr Franck Giton  for measuring estrone. We thank the patients and all of the members of the family described in this article. Address all correspondence and requests for reprints to:  Sophie Christin-Maitre, MD, PhD ,  Service d'Endocrinologie et des Maladies de la Reproduction, Centre de maladies endocriniennes rares de la croissance, H ôpital Saint-Antoine, Assistance Publique-H ôpitaux de Paris, Universit é Pierre et Marie Curie , 184 rue du Faubourg Saint-Antoine, F-75011, Paris, France. E-mail: sophie. christin-maitre@aphp. fr. This work was supported by grants from  INSERM and Universit é Paris Sud. V. B. was a recipient of a fellowship (Poste d'accueil-Plan Cancer 2014-2019) from  INSERM.
The putative mutation frequency was searched in the National Heart, Lung, and Blood Institute Exome Sequencing Project database (Exome Variant Server 2012, National Heart, Lung, and Blood Institute GO Exome Sequencing Project, Seattle, WA; http://evs. gs. washington. edu/EVS/, accessed February 2013) and in the new Exome Aggregation Consortium (ExAC) Browser Database (http://exac. broadinstitute. org), which includes more than 120,000 alleles. To assess the possible functional effect of ERa amino acid variant, PolyPhen-2 v. 2. 2. 5 (http://genetics. bwh. harvard. edu/pph2/) and Sorting Intolerant From Tolerant (SIFT; http://sift. jcvi. org/) software were used.
Computerized Solution: iGrafter To facilitate the application of the previously described principles, avoid complex calculations, save time, and guarantee surgical technique precision, we developed a free web app based on JavaScript (Oracle Corp, Santa Clara, CA, USA) to iPad (Apple Corp, Palo Alto, CA, USA), named iGrafter. It is freely available at http://www. igrafter. net. In the surgical field, the iPad should be inserted inside a transparent and sterile plastic bag. The values corresponding to the corpora cavernosa longitudinal size on each cardinal point (dorsal, ventral, right, and left), between the beginning and end of the curvature, as well as the penile circumference should be inserted into the app (Figure  5A ). If hourglass deformity is present, click on the "hourglass" button and another screen will appear with new fields to be filled with the values of normal circumference (C1), narrowest circumference (C2), and longitudinal distance from the narrowest central part of the defect to distal (h1) and proximal (h2) normal circumference (Figure  3 ).
ACKNOWLEDGMENTS We would like to thank  Pedro Estarque  for transforming our mathematical equations, logic, and workflow into the iPad app. Corresponding Author:  Alexandre F. Miranda , MD, PhD, Urogenital Research Unit, State  University of Rio de Janeiro ,  Av 28 de Setembro , 87, Fundos,  Vila Isabel , Rio de Janeiro,  RJ  20551-030, Brazil. Tel:  þ55 21 98330-7007 ; Fax:  þ55-21-2868-8527 ; E-mail: contato@alexandremiranda. com. br.
Thermomechanical Tests All tests were performed by TMA in triplicate under the following conditions. The hardening reaction of the resin was evaluated by TMA by the study of the rigidity of the wood-resin joint as a function of temperature. The samples were prepared by applying 22 mg of resin system between two beech wood plies in a layer of 350 µm, for total sample dimensions of 21 × 6 × 1. 1 mm 3 (moisture content = 12%). These beech-resin-beech specimens were tested in non-isothermal mode between 40 and 220 • C (heating rate 10 • C/min). The thermomechanical analyzer was a TMA40 instrument from Mettler Toledo (Columbus, OH, USA). The software used for data treatment was STARe (Mettler Toledo, Columbus, OH, USA). Deflection curves, which permitted the determination of the modulus of elasticity (MOE), were obtained in a three-point flexion mode.
Satisfactory lignin yields were obtained from L4 to L8 (>15%) with a lignin purity (Klason lignin) higher than 95% (data not shown). The molecular mass of the lignin fractions, estimated by Size Exclusion Chromatography, are in accordance with previous results  [9]. From Table  1  (L1-L8), it can be seen that the molecular mass decreased with the severity: the higher weight (M w > 10,000) were isolated at low severity (CS = 1-1. 5) and at low temperature (T ≈ 160 • C). This observation confirms previous works showing that the organosolv pulping extensively cleaved aryl-ether linkages in lignin network and that this degradation is a function of the pulping conditions  [8, 9]. It also can be seen that, at a constant temperature of 185 • C (L3 to L5), an increase in sulfuric acid concentration from 0% to 1.
The sulfuric acid catalyzed organosolv lignins were also analyzed with a 31 P NMR quantitative method (after phosphitylation) in order to determine the concentration of hydroxyl functional groups. The concentrations of aliphatic and aromatic OH groups of L1 to L9 were 2. 5 mmol/g (±1 mmol/g) and 2. 1 mmol/g (±0. 5 mmol/g), respectively (data not shown). Whatever the severity of the organosolv process, the amount of OH groups in alfa lignin appeared to be comparable to herbaceous organosolv lignin previously described in the literature including wheat straw, switchgrass  [24] , and miscanthus  [8, 9]. The characterization of series of alfa lignin oligomers were successfully performed by MALDI TOF. The Figure  2  gives the scan range of m/z 300-1800 Da for L9. As previously observed for wheat straw lignin  [12] , the most abundant ion over the mass range of m/z 100-1000 Da was detected at m/z = 331.
The concentrations of aliphatic and aromatic OH groups of L1 to L9 were 2. 5 mmol/g (±1 mmol/g) and 2. 1 mmol/g (±0. 5 mmol/g), respectively (data not shown). Whatever the severity of the organosolv process, the amount of OH groups in alfa lignin appeared to be comparable to herbaceous organosolv lignin previously described in the literature including wheat straw, switchgrass  [24] , and miscanthus  [8, 9]. The characterization of series of alfa lignin oligomers were successfully performed by MALDI TOF. The Figure  2  gives the scan range of m/z 300-1800 Da for L9. As previously observed for wheat straw lignin  [12] , the most abundant ion over the mass range of m/z 100-1000 Da was detected at m/z = 331. 11, assigned to a phenylcoumaran derivative 1. Further structural information regarding this ion was obtained by ASAP-MS/MS analyses.
Ions 1 and 7 (m/z 331 and 509 in positive mode and m/z 329 and 507 in negative mode, respectively) were detected in all the fractions. ASAP-MS/MS analyses were also performed from these ions (ion 1 from L5 in positive (Figure  S3 ) and negative (Figure  S4 ) mode, ion 7 from L5 in negative (Figure  S5 ) and positive (Figure  S6 ) mode). The collected data attested the presence of polyphenylcoumaran linkages in all the lignin fractions studied. For lignin L5, detected ions at m/z 1175, 1337, 1499, and 1823 attested the presence of polyhexose oligosaccharides (SP1) as previously reported  [25]. Thermomechanical analysis is an accurate technique to evaluate the hardening reaction of glue mixes by studying the rigidity of a wood-resin joint as a function of temperature  [26]. Adhesive formulations based on a mixture of glyoxalated organosolv lignins/Aleppo pine tannins were prepared and examined by TMA according to a technique already described.
The collected data attested the presence of polyphenylcoumaran linkages in all the lignin fractions studied. For lignin L5, detected ions at m/z 1175, 1337, 1499, and 1823 attested the presence of polyhexose oligosaccharides (SP1) as previously reported  [25]. Thermomechanical analysis is an accurate technique to evaluate the hardening reaction of glue mixes by studying the rigidity of a wood-resin joint as a function of temperature  [26]. Adhesive formulations based on a mixture of glyoxalated organosolv lignins/Aleppo pine tannins were prepared and examined by TMA according to a technique already described. The curves of the modulus of elasticity (MOE) as a function of the temperature for L9, L10, and L11 are given in the Figure  5a-c  respectively. The influence of the lignin content (from 0% to 50%) in the tannin-based formulation was examined.
Author contributions. Juliane Filser wrote the article, prepared Figs. 1 and 3 and the tables and compiled the contributions from all co-authors, who are listed according to their quantitative and qualitative impact on the manuscript, except for Juan José Jiménez, who was placed last as he is the chair of COST Action ES 1406 (KEYSOM). Lijbert Brussaard suggested including Fig. 2. Acknowledgements. The two anonymous referees and O. Schmitz are acknowledged for their critical comments, which significantly contributed to the revision of the original manuscript. We thank Antje Mathews for compiling the references and editing the manuscript. Many thanks to Karin Nitsch for linguistic proofreading. Oxford University Press and Wiley and Sons are acknowledged for the permission to include Fig. 2. This paper is a contribution to the COST Action ES1406 (KEYSOM) lead by the first and last author.
Due to the high absorption of Au NPs at the wavelength used, a very low excitation power was employed. The power used for this step, on one hand, must be high enough so that the fluorescence signal of Au NPs can be distinguished from that of SU8, hence precisely identifying the single Au NP within the diffraction limit (z250 nm for l ¼ 532 nm). On the other hand, the laser power must be sufficiently weak in order to prevent the polymerization in the working SU8 region, or in other words, ensure that no structure is formed during the mapping process. We obtained fluorescent images of individual Au NPs with a lateral resolution of about 243 nm and an axial resolution of 730 nm, which correspond to the diffraction limit of the objective lens. The extracted scanning data revealed a precision of <20 nm in the NP position.
Acknowledgments This work was supported by the  National Foundation for Science and Technology Development of Vietnam  under Grant  103. 03-2015. 78 ,and by a public grant overseen by the  French National Research Agency (ANR)  as part of the  "Investissements d'Avenir" program  (reference:  ANR-10-LABX-0035 ,  Labex NanoSaclay). We also acknowledge the International cooperation project under code  VAST. HTQT. PHAP. 02/14-15. Q. C. Tong  and  H. M. Ngo  acknowledge the fellowship from the  Vietnam International Education Development (911 project ).
Nuclear staining was performed using Prolong Gold antifade reagent with DAPI (Invitrogen). Fluorescence was imaged on a Zeiss LSM-510 multitracking laser scanning confocal microscope with a Helium/Neon laser at 543 nm and using AxioVision software (Carl Zeiss). No staining was observed when omitting the primary antibody. F4/80-and HO-1-positive cells from 10 fields/conditions were quantified. Results are expressed as percent of HO-1-positive cells per field. The number of SQSTM1/p62 or LC3-positive dots per F4/80-positive cell was quantified from 3-10 fields/condition. RNA preparation and real time polymerase chain reaction. Total RNA was extracted using RNeasy Mini kit (QIAGEN). cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kit (Life Technologies). Quantitative real time-PCR was performed using QuantiTect SYBRR Green PCR kit (Qiagen) on a Light Cycler 480 (Roche Diagnostics).
Acknowledgements This work was supported by the  INSERM  and the  Université Paris-Est Créteil  and by grants of the  Agence Nationale de la Recherche. The authors thank  Noburu Mizushima  for providing ATG5 flox/flox mice,  Aïda Habib  for the HO-1 antibody,  Patrice Codogno  for the RFP-GFP-LC3 plasmid and  JingHong Wan ,  Sophia Balustre ,  Marjorie Collery  and  Damien Fois  for their help during in vivo experiments.
METHODS Study design and participants AURA was conducted in eight countries (Canada, France, Germany, Ireland, Italy, the Netherlands, the UK and Venezuela)  15  from January 2009 to October 2012 (end of data collection). The primary objective of AURA was to monitor the changes in visual acuity during the first year (until day 360) and second year (until day 720) after the start of ranibizumab treatment in real-life, clinical practice settings. Patients who were diagnosed with nAMD and given ranibizumab by their physician from 1 January 2009 to 31 August 2009 were eligible, and those who had >1 postbaseline assessment of visual acuity were analysed (efficacy analysis set). Patients with follow-up data for at least 1 and 2 years after the first injection (first-year and second-year completers) were also documented.
Patients who switched to bevacizumab or pegaptanib also remained in the study. The mean change in visual acuity was measured using Early Treatment Diabetic Retinopathy Study letters or Snellen, and was converted to a standardised visual acuity score (letter count). The conversion chart used is provided in the online supplementary table S1 for the primary manuscript. 15 To account for missing data, mean change in visual acuity was evaluated using a last observation carried forward approach (unadjusted observational data were also recorded for comparison), and the statistical analysis was descriptive. Approval from the relevant independent ethics committees or institutional review boards was received, and written consent was obtained from each patient.
Analyses Regression analyses were performed using StataCorp LP 2007 (Stata Statistical Software: Release V. 10, StataCorp LP, College Station, Texas, USA) with the dataset and patient records from the AURA study, which provided information on demography, medical history, injections and visits. Continuous variables (listed in online supplementary table  S1 ) were reported with mean and SD, 95% CIs and p values. CIs were estimated based on the assumption that data were normally distributed. Categorical variables (listed in online supplementary table  S1 ) were reported as actual values or dummies (eg, for the variable 'sex', the values were 1 for male and 2 for female). The association between the mean change in visual acuity score (letter count) at years 1 and 2 and the AURA dataset variables was analysed using univariate regression analysis (data not shown).
It was unclear whether the better outcomes in patient receiving more injections was due to increased injection frequency or other factors that were also significantly different among the groups, such as baseline visual acuity score and age. Regression analysis methods (based on observational data) are also associated with a number of limitations. The models use a number of assumptions, including no adjustment for change in factors such as OCT usage since AURA was undertaken. The data were recorded from 2009 to 2012, when the risks of underdosing were not as well understood as they are today, and this may affect the extrapolation of the results. They are still relevant for countries and practices that still have limited resources for regular monitoring and injections; however, some countries may employ better regimens due to increased awareness of the risk of undertreatment, including the wider use of treat-and-extend regimens aimed at reducing the number of visits, which may improve adherence and, thus, outcomes.
Acknowledgements Medical writing assistance was provided by  S Phillips, PhD , from PAREXEL. Contributors FGH, RT, SB, AB, MGC, PH, GS and SS are members of the  Global Steering/Publication Committee  for the AURA study and were involved in provision of patient/data acquisition, data analysis, data review and interpretation. AA was involved in the design of the AURA study and protocol, and participated in discussions on the interpretation of the data. KW-J, JN and KK were involved in the design, data collection, analysis and interpretation of the regression analyses of AURA. All authors provided critical review of the manuscript and approved the final version for publication.
Mission Analysis The orbit selection was driven by minimizing three factors: passage through the South Atlantic Anomaly (SAA), radiation at higher altitudes, and atmospheric drag. Based on the ESA M3 study, 1 an orbital inclination of < 5 • was required. To avoid higher radiation exposures, the altitude must be no greater than 600 km. Stationkeeping requirements, driven mostly by atmospheric drag, determined the minimum altitude. The NASA Debris Assessment Software 10 (DAS) v2. 0. 2 was used to estimate the orbital altitude decay rate. Imposing a limit of 10 km degradation in altitude before raising the orbit back to the initial value resulted in a minimum recommended initial altitude of 550 km. Lower altitudes are possible, but station-keeping requirements increase substantially below 500 km, and do not offer any increase in payload mass capability to the launch vehicle.
Communications System An X-band system with a fixed omnidirectional antenna is used for the downlink data system. A fixed antenna is more reliable and reduces mission risk as compared to a gimballed antenna. A ground link analysis based on link times and daily accesses was performed to determine the best selection and number of required ground stations at 0, 5, and 10 degree inclinations. South Point Hawaii, Kourou, Guam, and Malindi were considered. South Point had no capability for a 0 • orbit. Downlink averages were 3. 8-5. 6, 3. 3-5. 7, and 4. 5-5. 3 Gbits/orbit for 0, 5, and 10 degree, respectively, assuming a maximum X-band downlink rate of 10 Mbps, indicating that no single ground station gave sufficient time to download the required 6. 7 Gbits/orbit of science data, and that 3-4 ground stations were required for the desired goal of 14 Gbits/orbit of science data.
Avionics and GN&C Two fully redundant Proton2x-Box flight computers from Space Micro are the core of the avionics system. These computers combine a commercial product set of building blocks, including a Proton400k processor, a power supply, DIO flash, up to 250 Gbit data storage, and 150 Mbs data rate transmission. Attitude knowledge is achieved using a redundant pair of Ball Aerospace star trackers and Northrop Grumman inertial measurement units (IMUs). The star trackers provide 4" of accuracy, meeting the 5" mission requirement. Both the star trackers and IMUs are at or above TRL 8. Pointing requirements for this spacecraft are modest, with a required pointing accuracy of 1 arcmin (3 σ) on 3-axis. Pointing stability is frequency dependent. The spacecraft will be normally inertially pointed, with uninterrupted observation times of about 1 ks to 100 ks (hours to days).
Preliminary Cost Estimate Costs for the LOFT-P mission were estimated using the following parametric models PCEC (Project Cost Estimating Capability), SEER-H, NICM (NASA Instrument Cost Model), and MOCET (Mission Operations Cost Estimating Tool) for ground data systems/mission operations systems costs. Two cost estimates were performed during the study. The first was based on the ESA M3 study of LOFT. 1  The second was based on the MSFC Advanced Concepts Office study of LOFT-P. Both were assumed to be NASA-led for cost assumptions. The NASA Standard Level WBS for space flight projects was assumed, based on NPR 71020. 5E: NASA Space Flight Program and Project Management Requirements, Appendix H. Costs were estimated in FY2016 dollars, with a fee of 12. 5%, and cost reserves at 35%. Launch vehicle costs were excluded from both estimates.
Mass with contingencies was used. MOCET was used to calculate all phase E costs, based on the Fermi mission, The costs for both concepts assumed the following for the LAD: 125 detector modules, 5 Panel Back end Electronics, 2 ICUs. Costs were based on one development and production of 125 modules. For the WFM, the model assumed 10 cameras, 2 WFM ICUs. Costs were based on one development and production of 10 cameras. Average modification on the electronic components of both instruments was assumed, given the considerable development that has already taken place in Europe. For both concepts, major modification for the spacecraft structure, average modification for the C&DH system, and minor modification for the electrical, thermal, propulsion, and communication systems were assumed. The same phase A-D schedules taken from 1 were used.