dataesr/scientific-paragraphs-categorization huggingface dataset:
Identification of UGTs that might be responsible for HGL-DTG biosynthesis To identify UGTs, we performed a genome-wide survey of N. attenuata and detected 107 putative UGT sequences containing the PSPG motif at the C-terminus (Supplemental Figure  1 ). We phylogenetically characterized these UGTs (Supplemental Figure  2  and Table  1 ) and examined their amino acid sequences (Supplemental Figure  3 , Supplemental Table  2  and 3 and Supplemental Data Set 1). HGL-DTGs are specialized metabolites of N. attenuata, whose biosynthetic steps of glycosylation are regulated by the defense phytohormone jasmonic acid  (Heiling et al. , 2010). Genes involved in a shared biological process tend to be co-expressed in large-scale expression datasets because they are frequently under the control of a common regulatory network  (Saito et al.
NaUGT74P3 and its N. obtusifolia homologue NoUGT74P4 readily used UDPglucose as a donor, producing several novel products with a mass-to-charge ratio of m/z 491. 3003 [M + Na] + corresponding to a mono-glucosylated 17-HGL and two additional products with m/z 653. 3509 [M + Na] + corresponding to lyciumoside I and another di-glucosylated 17-HGL (Figure  4 ). Lyciumoside I was identified by comparing retention times and MS/MS fragmentation patterns to a purified authentic standard, and the novel compounds were annotated based on comparisons of their MS/MS fragmentation patterns to an in-house database of HGL-DTG spectra. Thus, NaUGT74P3 and NoUGT74P4 function as UDPglucosyltransferases for HGL-DTGs synthesis via their ability to catalyze glucosylation at C-3 and C-17 of the 17-HGL aglycone. Enzymatic assays conducted with NaUGT74P5 and NoUGT74P6 in the presence UDP-glucose as donor and 17-HGL as substrate also produced a mass signal at m/z 491.
Performance assays Freshly hatched neonates were fed leaf disk material taken from the between-vein laminal tissue of the four lowest stem leaves of 43-day-old flowering N. attenuata plants (WT, IRugt91t1, IRugt74p5, IRugt74p2/ugt74p5, IRggpps) in round plastic PE-packing cups. Leaf disk material was exchanged every 2 days until day 6 and then exchanged every day until day 12. Plant transformation and screening of stably silenced N. attenuata plants Transformation of N. attenuata was performed as described in  Krugel et al. (2002)  using the pRESC8 vector  (Gase and Baldwin, 2012)  containing the hygromycin phosphotransferase II gene (hptII) from pCAMBIA-1301 (GenBank AF234297) and a 306 bp long fragment for UGT91T1, a 310-bp long fragment for UGT74P3, or a 295bp long fragment for UGT74P5.
All primers are shown in Supplemental Data Set 13. Diploid plants were selected by flow cytometry of leaf material of elongated N. attenuata transformants performed on a CCA-II flow cytometer (Partec, http://www. partec. com) as described by  Bubner et al. (Bubner et al. , 2006). Afterward, seeds were collected and individuals with the T-DNA insertion were selected for hygromycin resistance by adding 35 mg L -1 hygromycin B to the germination medium. After 10 days, the ratio of seedlings surviving the antibiotic treatment was determined. Seedlings were chosen with a survival rate of 50-90%, and 12 T1 plants per line were checked for T-DNA insertion. To confirm the integrity of the T-DNA insertion, we performed a diagnostic PCR using the primer pairs PROM FOR/INT REV and INT FOR/TER REV  (Gase et al.
VIGS Vector construction, plant growth, and inoculation conditions for VIGS were as described by  Saedler and Baldwin (Saedler and Baldwin, 2004). Briefly, 200-to 300-bp fragments of N. attenuata and N. obtusifolia target genes were amplified by PCR using primer pairs as listed in Supplemental Data Set 13. Amplified fragments were cloned in the vector pTV00  (Ratcliff et al. , 2001). Agrobacterium tumefaciens strain GV3101 was transformed by electroporation with the resulting plasmids. We used the empty pTV00 vector as a negative control in all experiments. Four leaves of 24-to 27-day-old N. attenuata and 25-day-old N. obtusifolia plants were infiltrated with a 1:1 mixture of A. tumefaciens transformed with pBINTRA  (Ratcliff et al. , 2001)  and one pTV00 derivative carrying a fragment of a gene of interest.
Heterologous expression of UDPglucosyltransferases and enzymatic activity assays The four UGT cDNAs coding for NaUGT74P3, NoUGT74P4, NaUGT74P5, and NoUGT74P6 were cloned into a Gateway V R pDEST17 expression vector (ThermoFisherScientific, http:// www. thermofisher. com) using pET28a EV as a control. Integrity of the sequence was checked by Sanger-sequencing using an ABI PRISM 3130 Genetic analyzer (Applied Biosystems, http://www. thermofisher. com) and the appropriate gene-specific primers (Supplemental Data Set 13). The resulting plasmid was transformed into BL21 (DE3) E. coli, which is optimized for the expression of eukaryotic genes; 50 mL LB medium containing 50 mg mL -1 carbenicillin was inoculated with 500 mL of an overnight culture corresponding to each candidate gene. Cultures were grown at 37 C until the OD 600 reached 0.
ESI conditions for the maXis UHR-Q-TOF-MS system were capillary voltage 4,500 V, end plate offset 500 V, nebulizer 1. 8 bar, dry temperature 200 C and a dry gas flow of 8 L min -1. MS data were collected over a range of m/z from 100 to 1,600. Mass calibration was performed using sodium formate (50 mL isopropanol, 200 mL formic acid, 1 mL 1 M NaOH in water). Data files were calibrated using the Bruker high-precision calibration algorithm. Lock mass calibration was performed for the profiling of the stable lines using signal m/z 622. 0289 (molecular formula C 12 H 19 F 12 N 3 O 6 P 3 ) from the ESI Tuning Mix (Agilent Technologies, http://www. agilent. com). MS/MS experiments were performed using AutoMS/MS runs at various CID voltages from 12. 5 to 22. 5 eV for ammonium adducts. Instrument control, data acquisition, and reprocessing were performed using HyStar 3.
1 (Bruker Daltonics). Molecular formulae were determined using SmartFormula 3D. SmartFormula calculates the elemental compositions from accurate mass as well as the isotopic pattern information using MS (SmartFormula) and MS + MS/MS information (SmartFormula 3D;  Krebs and Yates, 2008; Kind and Fiehn, 2010). The mass tolerance was set to 4 mDa, and the filter H/C element ratio was set between 1 and 3. Isotope peaks were assigned using the Simulate Pattern Tool of DataAnalysis software version 4. 2 (Bruker Daltonics). We used QuantAnalysis (Bruker Daltonics) to integrate the peak areas.
Dereplication of HGL-DTGs The dereplication workflow relies on a comprehensive MS and MS/MS database constructed by our group for HGL-DTGs of several solanaceous species  (Heiling et al. , 2016)  and a detailed rule-set for the annotation of fragmentation patterns of the different moieties decorating the 17-HGL aglycone. The MS and MS/MS database is based on the retention time and mass spectrometric data of purified HGL-DTGs, which are used as authentic standards. Novel HGL-DTGs are annotated based on their spectral similarity to the MS and MS/MS in-house database. For the visualization and identification of HGL-DTG profiles, we computed the extracted ion chromatogram (EIC) m/z 271. 2420. This m/z fragment corresponds to the 17-HGL aglycone lacking both hydroxyl-groups and is produced by in-source fragmentation during ionization for all HGL-DTGs independently of the type and degree of metabolic decorations.
Acknowledgments We thank the gardening staff at the  Max Planck Institute for Chemical Ecology. We thank  Thomas Hahn ,  Nicolas Heinzel ,  Alexander Weinhold ,  Mario Kallenbach , and  Matthias Schoettner  for the analytical and technical support as well as  Dapeng Li  and  Felipe Yon  for the fruitful discussions. We thank  Raimund Nagel  for his help with the terpene quantification. Additionally, we thank  Eric McGale  and  Jyotasana Gulati  for their statistical wisdom and  Michael Court  for assistance naming UGTs.
3 4 5 6 7 8 and Table  1 ). Particularly high-level expression of EGFP was observed in the liver, whereas heart, kidneys, lung, and the brain showed a more moderate EGFP staining (Table  1 ). Considering that targeting the central nervous system (CNS) with AAVs remains one of important goals in generation of transgenic animals, our analysis of GENISYST expression in the brain extended into cerebral cortex, thalamus and the cerebellum. While the cerebral cortex and the thalamus showed detectable EGFP immunofluorescence (Figs. 7  and 8 ) we failed to detect significant EGFP expression in the cerebellum (data not shown). High expression of AAV-derived transgene in the liver is likely a reflection of a high affinity of AA9 serotype for hepatocytes  (Sands, 2011). Most organs exhibited near-uniform expression of EGFP throughout the tissues indicating that almost cell types were successfully transduced by the virus.
Strikingly, in the kidney and lung, specialised substructures such as proximal tubules and bronchioles, showed EGFP protein enrichment (Figs. 5 and 6 respectively; Table  1 ). Localised EGFP expression in the kidney and lung likely reflects virus distribution due to blood flow through these organs, as comparable staining pattern with enrichment in proximal tubules was observed after intravenous injection of a soluble cell-penetrating fluorochrome  (Sandoval, Kennedy, Low, & Molitoris, 2004). Thus, GENISYST achieved efficient targeting of vital organs already at 14 days after administration. Encouraged by our data with fluorescent anti-EGFP protein detection in multiple tissues at 14 days post-injection (Figs. 3 4 5 6 7 8 ) we next aimed to corroborate our findings in animals harvested 70 days after GENISYST administration.
We focused on the heart and the kidney due to the high unmet need for disease models involving those organs. As previously described, we detected strong mRNA EGFP expression levels at 70 days post injection in the liver (Fig. 2 ). We next stained deparaffinised tissue sections for EGFP, with haematoxylin/eosin counterstaining to visualise tissue ultrastructure (Fig. 9 ). This approach demonstrated prominent EGFP staining throughout the cardiac epicardium (top part of the image in Fig. 9B ) but also in the myocardium (bottom part of the image in   9B ). In the kidney, in agreement with previously obtained data (Fig. 5 ), an enrichment of EGFP signal was observed in proximal tubules and in the glomeruli (Fig. 9A ). In conclusion our experiments with GENISYST EGFP-expressing rAAVs resulted in a systemic delivery of EGFP protein to most tissues achieving both early and persistent expression -therefore demonstrating the potential utility of this approach for human gain-or loss-of-function disease modelling in minipigs.
Such criteria should include confirmation of consistency for transgene expression and of the phenotype establishment as well as definition of essential downstream functional assays. It is anticipated that many of QC criteria will be specific to modelled disease. Progression of disease should also be assessed by harvesting animals at different timepoints to define the best timeframe for further studies. Although a multitude of approaches had been developed to model gain-of-function traits in minipigs, most of them incur both long   generation times and a significant cost  (Uchida et al. , 2001). In stark contrast to those methods, GENISYST technology described here is fast, cost-effective and efficient. In summary, our data demonstrated a feasibility of using recombinant AAVs for rapid generation of transgenic Göttingen Minipigs with the aim of human disease modelling for drug discovery and development.
qPCRs At sacrifice, a sample of the liver lobe was snap frozen in liquid nitrogen. Expression of the EGFP gene was evaluated by RT-PCR according to the following protocol: Small liver tissue biopsies were homogenised (MP Homogeniser FastPrep) in RLT buffer and total RNA was extracted with RNAeasy kit (Qiagen). Total RNA was converted to cDNA with the use of oligo-dTprimed EcoDry cDNA synthesis kit (TaKaRa). QPCR reactions were run with SybrGreen-containing premix (Applied Biosystems) and run on StepOnePlus qPCR machine (Applied Biosystems). Raw data was exported Excel (Microsoft) and gene expression changes were calculated by a delta/delta Ct method. Expression of EGFP was normalized to housekeeping gene levels (HPRT). Statistical analysis was performed with an unpaired 2-tailed t-test in Prism (GraphPad software).
Images were carefully sampled to be representative of the respective tissue with similar tissue density and tissue region chosen for comparison. For each animal/tissue five representative sections were used for quantification. EGFP immunofluorescence signal was quantified with ImageJ software (NIH, USA). The statistical significance by 2-tailed unpaired t-test was assessed in Prism (GraphPad software). For grading tissue EGFP signal intensity (Table  1 ) mean fluorescence intensity signal from uninjected animals (background staining) was subtracted from signal measured in GENISYST injected animals to obtain normalized mean fluorescent intensity. EGFP signal was graded "++++" for normalized mean fluorescent intensity values above 30, "+++" for values between 30 and 20, "++" for values below 20 and above 10 and "+" for values below 10.
Besides, based on the measurement of sideband asymmetry with the 3 single-tone schemes, a simple and precise method to quantify the ratio between microwave internal losses and the external coupling is proposed. Research and Innovation Programme, under grant agreement No. 824109, the European Microkelvin Platform (EMP). cryogenic setups). The gain of the HEMT chain used for the noise generator (NG) has been measured in the same conditions. The first step of the calibration procedure is then to characterize the microwave cavity. This is performed with a standard linear response procedure, applying a small probe tone (at frequency ω/2π, and fixed power P probe ) and measuring the output signal at the same frequency. Their ratio leads to the definition of the parameter S 11 [ω], the reflection component of the scattering matrix.
Acknoledgements I. G. and E. C. wish to thank  B. Pigeau  and  J-P. Poizat  for useful discussions. We acknowledge support from the  ERC CoG  grant  ULT-NEMS No. 647917  (E. C. ), and  StG grant  UNIGLASS No. 714692  (A. F. ). M. S. was supported by the  Academy of Finland  (contracts  308290 ,  307757 ,  312057 ), by the  European Research Council  ( 615755-CAVITYQPD ), and by the  Aalto Centre for Quantum Engineering. The work was performed as part of the  Academy of Finland Centre of Excellence program  (project  312057 ). We acknowledge funding from the  European Union 's  Horizon 2020 research and innovation program  under grant agreement No. 732894  ( FETPRO HOT ). The research leading to these results has received funding from the  European Union's Horizon 2020.
Since 2004, organ procurement is organized by the Biomedicine Agency, which is in charge of ensuring equity and safety of organ allocation and collecting donor characteristics, recipient characteristics, and follow-up through the French national database called CRISTAL. The national allocation system for deceased donors is made on the basis of a scoring system from the local and national levels and also, some national allocation priorities (Figure  1 ). Kidney transplantation is currently performed in 47 centers, mostly public university hospitals, of which 14 perform 60% of the transplants (3).
Acknowledgments The authors thank the  French Biomedicine Agency  for the completeness of data contained in its annual reports, which was very valuable for the realization of this work. The content of this article reflects the personal experience and views of the author and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the  American Society of Nephrology  (ASN) or Kidney360. Responsibility for the information and views expressed herein lies entirely with the author(s).
Study design, participants, data and setting We developed a population-based multilevel cohort study of adult patients diagnosed with DLBCL or FL between 1 st January 2005 and 31 st December 2013 in England. Patients were followed up until death or the end of the study at the 31 st December 2015, whichever occurred rst. Information on patients with DLBCL and FL was collected from the linkage of English cancer registry data, the Cancer Analysis System 21 (CAS) and Hospital Episode Statistics  22  (HES) datasets within the national cancer registry and analysis service (NCRAS). These datasets contained information on the patient's cancer, subtype (morphology), diagnosis date, comorbidity, admissions, accident and emergency presentations, and outpatient appointments at an NHS hospital. DLBCL and FL were de ned according to the 10 th revision of the International Statistical Classi cation of Diseases and Related Problems (ICD-10 codes C82.
29 The algorithm seeks for the presence of comorbidities retrospectively and de nes a time window of 6 to 24 months prior to cancer diagnosis where comorbidities are not recorded to avoid bias due to the presence of comorbidities related to cancer (i. e. , cardiological comorbidities due to DLBCL or FL cancer treatment). Patient's comorbidity status was adapted from the original Charlson comorbidity index  30  (CCI). We used the Royal College of Surgeons (RCS) modi ed Charlson Score (Supplementary Table  S1 ). 31 The score removes patients with a previous malignancy to avoid bias, does not weight differently comorbidities, and categorises comorbidities as: no comorbidities, one comorbidity and two or more comorbidities (multimorbidity). Socio-demographic and economic characteristics were collected from the HES dataset.
Missing data analysis We explored the missing data mechanism for each of the three variables with missing data. Due to clustered data and partially observed categorical variables, we used the latent normal joint modelling multiple imputation approach, under a missing at random assumption (MAR). The imputation model included all fully-and partially-observed variables, vital status indicator, the Nelson-Aalen estimate of the cumulative hazard, and accounted for clustering of patients within lower-super output areas. We generated 10 imputed datasets. The multilevel EHM was tted to each of these datasets, and results combined using Rubin's rules. 37, 38 Overall tests for the effects of age after multiple imputation were done using the F-based procedure for the test of multiple parameters after multiple imputation.
Secondly, on the other hand, patients referred through the TWW pathway have more severe symptoms and expected to have a higher excess hazard. Our results show no difference in the excess mortality indicating that TWW pathway prevents patients with more severe symptoms from having a higher excess hazard: suggesting the performance of TWW pathway is at least as bene cial to a patient's survival as GP referral. However, further factors associated with the interactions between comorbidities and health care systems leading to poorer survival among DLBCL and FL cancer patients need to be studied. The strengths of this study are that, rstly, we used a large population-based sample size obtained from cancer registry databases linked to HES, which encompasses all patients in England with a diagnosis of DLBCL and FL between 2005 and 2013.
, 2010) , and freshwater and nutrientrich discharges from rivers  (Dai and Trenberth, 2002). The open-boundary conditions of biogeochemical tracers are prescribed from the World Ocean Atlas observation database  (Garcia et al. , 2010)  for NO 3 , O 2 , Si, and PO 4 and from the global configuration ORCA2  (Aumont and Bopp, 2006)  for dissolved inorganic carbon (DIC), dissolved organic carbon (DOC), Alkalinity, and Fe. The other state variables are forced with very small constant values. The analysis has been performed using 5 d averaged outputs for a period of 5 years from 2002 to 2007. We refer the reader to  Damien et al. (2018)  for extended model and numerical setup descriptions. In this previous study, an extensive validation of the modeled properties were carried out, focusing on physical properties that are known to influence primary production and chlorophyll concentration: the mixed layer depth and the depth and slope of the nutricline.
Observational data set used Satellite observations are used to evaluate the ability of GOLFO12-PISCES to reproduce the dynamical and biological signatures associated with LCEs. Surface geostrophic velocities are derived from a 1/4 • multi-satellite merged product of absolute dynamic topography (ADT) provided by AVISO+ (http://marine. copernicus. eu, last access: 10 April 2021). Surface chlorophyll concentrations are from the Aqua-MODIS 4 km product  (Sathyendranath et al. , 2012;  http://marine. copernicus. eu, last access: 10 April 2021) and consist of 8 d composites from 2003 to 2015.
Acknowledgements. We acknowledge PEMEX's specific request to the hydrocarbon fund to address the environmental effects of oil spills in the  Gulf of Mexico. We acknowledge the provision of supercomputing facilities by  CICESE. Financial support. This research has been supported by the  National Council of Science and Technology of Mexico (CONA-CYT) -Mexican Ministry of Energy (SENER) Hydrocarbon Trust  (project no. 201441 ) and a contribution of the  Gulf of Mexico Research Consortium (CIGoM). Review statement. This paper was edited by  Kenneth Rose  and reviewed by  Z. George Xue  and one anonymous referee.
Code availability. The NEMO ocean engine code  (Madec et al. , 2019)  used in this study is accessible at a public repository: https://doi. org/10. 5281/zenodo. 1464816 (last access: 14 July 2021). The PISCES-v2 code is described in Aumont et al. (2015). Data availability. Data from the model simulation used in this study are available upon request to the corresponding author. Supplement. The supplement related to this article is available online at: https://doi. org/10. 5194/bg-18-4281-2021-supplement.
Cosmological observations in the microwave sky Confidence in inflationary ΛCDM relies on its spectacular consistency with observations of the CMB anisotropy, and with other cosmological probes [Ref. 4 , and references therein]. The primary CMB  1 gives an image of structures and velocity flows in a thin shell at z 1100, and hence also at a specific time. Cosmic variance 2  precludes stringent statistical tests of the global cosmological paradigm on the largest scales using primary CMB data alone. The CMB is a bath of radiation that permeates the entire Universe and interacts with everything in it. Every process that exchanges energy with the cosmic microwave photons leaves an imprint. We propose to exploit these imprints to extract answers to the key open questions in astrophysics by making measurements at microwave and submillimeter wavelengths of four sets of related phenomena: 1.
The photon noise to first order is the same for all channels; it depends on the integrated optical load over the total passband and scales linearly with the synthesized channel width. A broad-band FTS based on the PIXIE design  [81]  would achieve the science goals outlined above. PIXIE uses a single FTS with 15-GHz channels extending from 15 GHz to 6 THz. If foregrounds were negligible, PIXIE could detect the µ-distortion from Silk damping of primordial density perturbations at 2-3 σ and detect recombination lines at comparable levels. Astrophysical foregrounds degrade the ideal performance and require additional sensitivity at both low and high frequencies  [176]. Such sensitivity could be obtained using several nearly-identical FTS modules, each with different optical passbands and synthesized frequency channels, optimized for either the CMB distortion signals or for the measuring the competing foreground emission.