dataesr/scientific-paragraphs-categorization huggingface dataset:
Binding affinities were estimated using five scoring functions (F-Score, PMF, D-Score, Chem-Score, G-Score) to obtain a final consensus score. 11 Compounds with high consensus scores and conserved interaction with both docking algorithms were further selected for experimental testing. 3D data were analyzed and generated by PyMOL and SYBYL. 5. 2. Chemistry. The synthesis and chemical characterization of the compounds is detailed in the Supporting Material. 5. 3. Biochemistry and Cell Biology. Compounds were experimentally tested using an enzyme-linked immunosorbent assay (ELISA)-based kinase assay as previously described. 8, 12 riefly, purified recombinant ALK kinase domain (aa 1073-1410), wild-type or L1196M mutant, was incubated with inhibitors and Mg ++ -ATP in an appropriate buffer and loaded onto peptide substrate-coated wells.
The reaction was run at 30 °C for 20 min. The phosphorylated peptide was then quantified by anti-phosphotyrosine antibody (clone PY20), after washing. Radiometric assays and selectivity profiling were run at ProQinase GmbH (Germany). Ba/F3 cells stably expressing NPM/ALK variants were generated by electroporation, selection with G418 (1 mg/mL), and second selection by IL3 withdrawal, as previously reported. 13 Cell proliferation was assayed by [ 3 H]-thymidine incorporation as described. 14 Doseresponse curve fitting was performed by GraphPad Prism software, using nonlinear regression of normalized data. Western blotting was performed as described previously  13  using phospho-ALK (Tyr1604; #3341) and total ALK (#3633) antibodies (Cell Signaling Technology). 5. 4. Crystallization and Structure Determination.
Crystallization and X-ray diffraction studies were carried out at Argenta Discovery 2009 Ltd. (Harlow, U. K. ). Briefly, the ALK kinase domain (aa 1093-1411 with N-terminal cleavable His6tag) was purified from Sf9 cells by nickel affinity chromatography and crystallized by the hanging drop vapor diffusion protocol as previously described. 15 The ALK:149 complex was obtained by soaking 2 mM compound into ALK-KD crystals. Diffraction data were collected at the Diamond synchrotron (U. K. ). The coordinates file will be deposited in the PDB database and is freely available upon request to the corresponding author.
coluzzii auditory system  (Pennetier et al. , 2010)  as a low-frequency background noise to the sound stimulus. Swarming arena. The swarming arena in the sound-proof chamber was designed to include the key environmental conditions and sensory cues known to control mating and swarming flight in the field. A large mosquito bed-net enclosure (NATURO, L x W x H = 1. 8 m x 1. 7 m x 2 m) filling most of a sound-proof chamber (Fig. 1 ) enabled mosquitoes to fly freely in a volume 100 times greater than that covered by the typical swarming space. Lighting was provided by an artificial-sunlight system to imitate natural daylight, sunrise and sunset (LEDs 5630, HMCO FLEXIBLE dimmer, and PLeD software, custom-built). Dimming the ambient light level at the appropriate circadian time elicits mosquitoes to take-off, followed by swarming behaviour in response to the presence of a visually conspicuous matt-black marker on the floor; both males and virgin females fly in loops above the marker, but this is rarely observed if males are present because males mate with females quickly and mated females cease swarming behaviour  (Poda et al.
Flight track recording. The 3D flight trajectories of male mosquitoes were recorded at a sampling rate of 50 Hz with Trackit software (SciTrackS GmbH, Switzerland  (Fry et al. , 2004) ). Two video cameras (Basler, ace A640-120gm) were fitted with wide-angle lenses (Computar, T3Z3510CS, 1/3" 3. 5-10. 5mm f1. 0 Varifocal, Manual Iris) to maximize 3D volume of video-tracking. IR lights (Raytec RM25-F-120 RAYMAX 25 FUSION) enabled the tracking system to detect flying mosquitoes as silhouettes against an IRilluminated white back-wall made of thin cotton cloth (Fig. 1 ). The 3D-flight trajectories were smoothed using a cubic spline interpolation at a sampling frequency of 200 Hz on Matlab (version R2017a) Temperature monitoring. Temperature was monitored by type-T thermocouples (IEC 584 Class 1, Omega) associated with a temperature logger (HH506RA, Omega) totalling a measurement accuracy error of ±0.
The 10 stimuli were played sequentially, with a 10 s interval of silence to be played-back during the behavioural assays. To avoid an effect of the order in which stimuli were played, 10 different sequences were generated, each containing the 10 sounds in random order. All stimuli were sampled at 8 kHz / 24 bits and designed in Matlab (R2017a, The Mathworks Inc, Natick, USA). Fig. 2  gives the sound spectrum and amplitude along time of each type of stimulus. Table  S1  gives the filter/frequency parameters used to generate the stimuli. Table  1  gives the sound levels for each of them. Audios 5, 6 are the original 1-female and 30-female sound recordings, respectively. Audios 1, 2, 3, 4 are the 4 types of stimuli; 2-harmonic 1-female, 2-harmonic 30-female, 1-harmonic 1-female, 1-harmonic constant, respectively.
Control of distance between live mosquito and playback speaker. Swarming mosquitoes confine themselves to a limited area of the flight arena naturally, which enables us to estimate the incident SPL at the mosquito's location, because the distance between swarming mosquitoes and the sound stimulus source was limited to a known range. The speaker (Genelec 8010A) that reproduced the females' flight tones was placed 0. 9 m from the centre of the swarm marker. Their flight positions were recorded by 3D-tracking Trackit Software  (Fry et al. , 2004)   (Figs 4 A, 4 B ) which enabled us to determine the distance between a mosquito and the speaker emitting mosquito sound to be 0. 9±0. 2 m, 95%-CI (Fig. 4 C ). Estimate of SPL errors at mosquito's location. Two types of SPL errors were taken into account.
Extraction of traits used to quantify male responses Following the results of preliminary experiments, we used two components of male flight: 1) angular-speed, calculated from their 3D trajectories and 2) wingbeat frequency, extracted from sound recordings (see Fig. 4  B for example and statistics of wingbeat and flight dynamic characteristics before, during and after exposure to the loudest 1-female sound-stimuli (44±2 dB SVL)). The two components were synchronized using the same techniques as in a previously published study  (Feugère et al. , 2021c). Angular-speed refers to how much the mosquito flight direction changes per unit time. It was calculated from the linear-velocity components provided by the Trackit software as follows: avel=∆θ / ∆t, where ∆t = t n -t n+1 is the duration between two consecutive time indexes n and n+1, and ∆θ is the turn angle defined as: ∆θ ൌ ‫ݏܿܽ‬.
Statistics Wingbeat-frequency and angular-speed values for a given stimulus were averaged over the different responses of the same day to form a replicate. The wingbeat and angular-speed response-parameters were analysed using a Bayesian Linear Mixed-Effects Model (blmer function, lme4 package, R). Stimulus sound levels (continuous), number of females in the recording (1 or 30), number of harmonics (1 or 2) and sound type (recording or synthesis) and their interaction were considered as fixed effects. Days, for which replicates were performed, were considered random effects. The dataset was split into the 3 subsets A, B, C, as shown in Fig. 3. A total of 6 models were built (2 parameters x 3 subsets). Stepwise removal of terms was used for model selection, followed by likelihood ratio tests.
quinquefasciatus  (Warren et al. , 2009). However, the image channel resulting from the non-linear vibration of the antennae from the sound of the two sexes was shown to reinforce the hearing sensitivity of males close to/slightly above the frequency of the female's second harmonic in electrophysiological measurements in Cx. pipiens pipiens  (Lapshin, 2012)  and Ae. communis  (Lapshin and Vorontsov, 2021). The results of our behavioural assay suggest that this reinforcement is negligible in practice, at least in An. coluzzii. The limitation of our stimulus recording approach is to be found in the long distances between the microphone and the single female (0. 7±0. 2 m), which induced a low signalto-noise ratio of 1. 7, despite noise filtering below the first harmonic and above the second harmonic (against a ratio of ~48 for the 2-harmonic 1-female stimulus; if considering the noise level as the noise floor between the 2 harmonics, using the Matlab function snr).
Data Availability Raw response files (sound and tracked flight trajectories) are available at: https://doi. org/10. 5061/dryad. 9cnp5hqhj (Feugère et al. , 2021a). Sound stimuli (Audios 1, 2, 3, 4), as well as the original sound recordings (Audios 5, 6) are available as supplementary material. Custom audio-video code for parameter-extraction and audiovideo synchronization (modified Matlab files from https://doi. org/10. 17632/hn3nv7wxpk. 3  (Feugère, 2020) ), custom statistics code for data analysis and figure plot (R files) and dataset (Text files) are available at https://doi. org/10. 17632/6w5jttwkj8. 2  (Feugère, 2021).
Experimental data acquisition Data were collected over two experimental sessions. The first session consisted of two consecutive scanning sequences of the participant's dominant leg: a T1-weighted MRI scan to determine muscle volume, and a DTI scan to determine muscle fascicle lengths. For the second session, participants walked on a treadmill (Nautilus Trimline T345, TX, USA) at their preferred walking speed (1. 1 ± 0. 1 m⋅s -1 ), which was determined at the beginning of the protocol  (Dal et al. , 2010). During walking, we recorded surface EMG and B-mode ultrasound of the GM and GL of the dominant leg to measure muscle activation and fascicle behavior, respectively. Foot position was measured using motion capture to identify phases of the gait cycle. Participants walked under two conditions presented in a randomized order: (i) 0% treadmill grade (level walking) and (ii) 10% treadmill grade (incline walking).
They performed two trials at each walking condition and repeated each condition a second time, first to record EMG and second to measure fascicle behavior. The EMG and the ultrasound recordings were conducted in separate trials to ensure that the measures were taken on the same mid-region of the muscle belly. Participants also performed three isometric plantar flexion maximal voluntary contractions (MVCs), with 120 s rest between contractions, to determine maximal GM and GL EMG amplitude for EMG normalization. The EMG and ultrasound data have been published elsewhere  (Hamard et al. , 2021).
MRI Participants were placed in a 3T MRI scanner (Magnetom Prisma, Siemens, Germany) in a supine position. The dominant foot was secured into a custom-built MRI-compatible foot plate with the hip extended and the ankle positioned at a 90 • angle. The dominant knee was positioned in slight flexion (<5 • ) by using a foam wedge under the knee. Details on the MRI parameters have been described elsewhere  (Pinel et al. , 2021). The T1-weighted MRI images were analyzed using a combination of semi-automated (Sashimi V1. 1; Bolsterlee, 2020) and manual segmentation software (ITK-SNAP v3. 8. 0, NIH, USA). We calculated total muscle volume for the GM and GL as the sum of the volume of all voxels in each muscle (ITK-SNAP v3. 8. 0, NIH, USA). These muscle volumes were included in the Hill-type model (see 2.
DTI DTI scans were performed with the same scanner as for the MRI. Detailed information on the DTI parameters, processing and data analyses has been described elsewhere  (Aeles et al. , 2021). Briefly, the muscle was divided into smaller muscle regions in the local muscle frontal plane. Then, fascicles were assigned to the muscle region that contained the fascicle midpoint and the median muscle fascicle length was calculated for each region. Finally, the mean of all muscle regions was calculated and used as an input for optimal fiber length.
3D motion capture 3D motion capture (Flex 13, OptiTrack, Corvallis, OR, USA) was used to record a static calibration trial with 8 marker clusters and 16 individual markers placed bilaterally on the lower limbs and pelvis to scale a musculoskeletal model  (Rajagopal et al. , 2016)  for each participant (OpenSim v3. 3). Then, during the walking protocol, we used the markers attached bilaterally to the calcaneus and the fifth metatarsophalangeal joint to determine the timing of the heel-strike and toeoff events using custom-written scripts based on foot vertical velocity  (O'Connor et al. , 2007). Motion capture data were collected at 120 Hz (Motive, OptiTrack, Corvallis, OR, USA) and raw marker positions were filtered using a second-order low-pass Butterworth filter with a cut-off frequency of 10 Hz.
B-mode ultrasound To image the GM and GL during walking, we placed two linear ultrasound probes (5-8 MHz, 60 mm field-of-view, LV8-5L60N-2, ArtUS, Telemed, Vilnius, Lithuania) on the same location as used for the EMG electrodes. The probe orientation was optimized to be aligned in the fascicle plane and secured with elastic bandages. Ultrasound data were recorded at 120 Hz for 15 s of walking. Post data collection, we analyzed five gait cycles of ultrasound data per trial using a validated  (Cronin et al. , 2011; Gillett et al. , 2013)  semi-automated tracking algorithm (UltraTrack;  Farris and Lichtwark, 2016) , combined with manual corrections (for details, see  Hamard et al. , 2021). Ultrasound data were lowpass filtered at 12 Hz and fascicle velocity was calculated as the first time derivative of fascicle length.
Statistics We conducted the statistical analyses in Statistica v8. 0 (Statsoft, Tulsa, OK, USA). All data passed the Kolmogorov-Smirnov test for normality. First, we compared the muscle volume, fascicle length and F max between the two methods and the two muscles using 2-way repeated-measures ANOVAs (factor: method [scaling, experimental], muscle  [GM, GL] ). Additionally, the GM/(GM + GL) ratios of muscle volume, fascicle length and F max were calculated and we used paired ttests to determine whether these ratios differed between the two methods. We also assessed the relationship between the two estimation methods for muscle volume, fascicle length and F max using Pearson's correlation coefficient. Finally, we used the root mean square error (RMSE) to determine the discrepancy between methods for muscle volume, fascicle length and F max.
Force output When considering the peak force, which occurred during the stance phase (Fig. 2 ), there was a main effect of muscle (P < 0. 001) and condition (P = 0. 001), with no main effect of method (P = 0. 513), nor any interaction (all P ≥ 0. 303) (Table  1 ). Similarly, when considering the force integral calculated over the whole gait cycle, we observed a main effect of muscle (P < 0. 001) and condition (P = 0. 003), with no main effect of method (P = 0. 557), nor any interaction (all P ≥ 0. 333). Overall, the GM produced more force compared to the GL during Fig. 1. Individual data for muscle volume (A), fascicle length (B) and maximal force-generating capacity (F max ; C) determined using the scaling and experimental methods. Data are depicted for both the gastrocnemius medialis (GM) and gastrocnemius lateralis (GL).
OASIS SCOR working group #162 and TTs Membership of the OASIS Scientific Committee for Ocean Research (SCOR) Working Group (WG) #162 covers multiple disciplines and methodologies, and spans data cre-ators to information users (i. e. "end-to-end"). OASIS includes representatives from all Global Ocean Observing System (GOOS) panels (physics and climate, biogeochemistry, and biology/ecosystem). The WG spans the globe and is diverse in terms of gender and career level. Nearly all members were involved in OceanObs'19 either as lead or contributing authors with significant ties to user communities in their respective nations and regions. One of the WG's first activities was to get OASIS endorsed as a UN Decade of Ocean Science for Sustainable Development Programme. OASIS will work with community members across five TT (Figure  3 ): The "Observing Network Design & Model Development" TT will harmonize OceanObs'19 and other community rec- ommendations into a coherent strategy and will define process studies and transformational actions needed to reach our 2030 goals of a predicted, healthy, resilient, productive, clean, and safe ocean.
Methods and results Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1. 9%) patients had a first diagnosis of VTE during the 9. 6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.
Mendelian randomization studies 2. 2. 1 One-sample Mendelian randomization We used the UK Biobank data, which is a large prospective cohort study that included 502 602 participants aged 40-69 years, recruited between 2006 and 2010 from 22 assessment centres across the UK. Details of the UK Biobank design have been published elsewhere. 23, 24 UK Biobank genotype data were imputed with IMPUTE4 using the Haplotype Reference Consortium and the UK10K + 1000 Genomes panel  25  to identify ∼96 million variants for 487 381 participants. We excluded 55 208 individuals who were not white British, had a variant call rate <98%, and were outliers based on heterozygosity. Finally, we included 432 173 participants in the Mendelian randomization study. We built a weighted polygenic risk score as an instrumental variable for systolic BP using independent genetic variants (linkage disequilibrium r 2 < 0.
37 We also assessed the probable directional pleiotropy using a funnel plot similar to that being used to determine publication bias in meta-analysis. 37  Statistical analyses were performed using Stata Statistical Software, release 14 (StataCorp LP) and R, version 3. 3 (R Foundation for Statistical Computing, Vienna, Austria). The 'MendelianRandomization' and 'TwoSampleMR' packages for R were used to implement the Mendelian randomization analyses. 38, 39  The study protocol was approved by the UK Biobank scientific committee (project number 42447). UK Bi bank study obtained informed consent from the study participants and approval from its institutional review board. This study conforms to the principles outlined in the Declaration of Helsinki.
On the other hand, this study has some limitations worth mentioning. Our cohort study was based on routinely collected data from linked electronic health records, which may be prone to measurement errors. With regards to our exposure variable, this issue was addressed by using the repeated measurement of systolic BP before the VTE event, and their correction for regression dilution bias. The outcome was defined using an externally validated algorithm. 20 However, we acknowledge a degree of misclassification because outcome definition relied mainly on data retrieved from linked electronic health records with no data available for sub-classification of cases as provoked or unprovoked VTE. However, the previous IPD meta-analysis that also reported a negative association between systolic BP and VTE found no evidence of interaction between provoked and unprovoked cases of VTE.
Highlights We assembled a highly phenotyped and characterised cohort of patients with NAFLD across the full spectrum of NAFLD. Lipidomic and metabolomic interrogation of this dataset reveals crucial metabolic tipping point of NAFLD at fibrosis stage F2-F3. NAFLD processes of fibrosis, steatosis, and NASH progression parallel distinct changes in metabolomic profiles. Oxidative stress-buffering potential of the liver via ether lipids appears 1 of the key changes en route to late-stage NASH.
Study participants Samples came from a cohort of 627 histologically characterised patients recruited from clinics at a number of leading international tertiary liver centres (UK, France, Germany, Brazil, and Italy) participating in the 'European NAFLD Registry' project (Clinicaltrials. gov NCT04442334). This cohort includes the full spectrum of disease, from histologically normal liver tissue through NAFL to NASH-F4 (cirrhosis). The protocol and detailed description of the Registry has recently been published. 15 Briefly, patients with alternate diagnoses and aetiologies were excluded, including excessive alcohol intake (>30 g per day for males and >20 g for females), viral hepatitis, autoimmune liver diseases, and steatogenic medication use. Collection and use of samples and clinical data for this study was approved by the relevant local and/or national ethical review committee covering each participating centre, with all patients providing informed consent for participation.
Liver histology Liver biopsy specimens (at least 1. 6-cm length and 1-mm diameter) were formalin-fixed and paraffin-embedded. Tissue sections (3-4 lm thick) were stained with H&E and trichrome stain for visualising collagen. All cases were recruited at tertiary centres where liver biopsies were routinely assessed according to accepted criteria by experienced liver pathologists and scored using the well-validated National Institute of Digestive Diseases and Kidney NASH Clinical Research Network (NIDDK NASH-CRN) system. 16 To ensure optimum data quality, biopsies were retrieved from archival storage where possible and scored centrally by a central expert liver pathologist, as previously described. 15 Where archival samples were unavailable for central reading, the local liver pathologist's scores were used.
Metabolomics Analyses of molecular lipids and polar metabolites are described in detail in the Supplementary information. In brief, for lipidomics, lipids from serum samples were extracted in randomised sample order using a modified version of the previously published Folch procedure, as applied recently,  18  and analysed by ultrahigh-performance liquid chromatography (UHPLC) coupled to quadrupole-time-of-flight mass spectrometry (QTOFMS). MS data processing was performed using MZmine version 2. 18. 19 For the analysis of polar metabolites, serum samples were randomised, and sample preparation was carried out as described previously, using gas chromatography (GC) coupled to QTOFMS. 20.
Statistical analysis All analyses were carried out in the R statistical programming language environment (R Foundation for Statistical Computing, Vienna, Austria). 21 Missing values in the lipidomic/polar metabolite data were replaced with imputed half-minimums for their respective feature, log 2 -transformed, and scaled to zero mean and unit variance. The sample intersection between the lipidomic, polar metabolomic, and clinical information datasets was retained. A detailed description of the statistical analysis methodology in provided in the Supplementary information.
Results Study setting and data survey Following integration of the metabolomics and clinical data, the study comprised 627 histologically characterised individuals across the full spectrum of NAFLD severity (Table  1 ), with a metabolomics dataset comprising 176 identified lipids and 36 quantified metabolites. To obtain a global overview of differences in metabolite levels across stages of NAFLD, we first applied model-based clustering to the metabolomics data. Clustering revealed 9 lipid clusters (LCs), in which clear groups of lipid classes are visible (Table  2 ). The polar metabolites data were found to not contain clusters, and as such was left unclustered as individual data features. Both lipidomics and polar metabolomics data were verified to not cluster by study site, as assessed by principal component analysis (PCA).