dataesr/scientific-paragraphs-categorization huggingface dataset:
Workflow of the ensemble refinement using SAXS data 1) First, we collected the conformational pools of the apo TIM hexamer and the TIM9$10/ Ggc1 complex as large as possible by MD simulations with all-atom or coarse-grained models (see above). For the TIM9$10/Ggc1 complex, the atomistic structures were reconstructed from the C a coordinates of the coarse-grained trajectories using PULCHRA  (Rotkiewicz and Skolnick, 2008). 2) We back-calculated the SAXS curve of each frame using Crysol3  (Franke et al. , 2017). For a few frames we also compared with FoxS  (Schneidman-Duhovny et al. , 2013)  (like Crysol uses a fast but implicit description of the hydration layer) and WAXSiS  (Knight and Hub, 2015)  (slower but with an explicit model for both the hydration layer and the excluded solvent), and found that the SAXS calculation by Crysol3 matched rather closely those from WAXSiS (data not shown), but with the computational cost as low as FoxS.
e. , a large deviation from the molecular dynamics ensemble). The software to perform the ensemble refinement is available from https://github. com/sbottaro/bme, and we used the back-calculated scattering data for apo TIM (q = 729) and the TIM9$10/Ggc1 complex (q = 1369) (Figures  S6F-S6I ). The comparison of the final results with experimental scattering data is shown in Figures  S6A-S6D. 4) Lastly, to provide a simpler way for visualizing the ensembles, we reconstructed a sub-ensemble by randomly picking 1,000 frames with individual probabilities proportional to their reweighting weights in the conformational pool. These conformations were then clustered  (Daura et al. , 1999)  with an RMSD cut-off of 0. 8 nm after aligning the structure by the position of two TIM hexamers. We repeated the reconstruction process three times, and all resulted in similar sub-ensembles.
QUANTIFICATION AND STATISTICAL ANALYSIS General considerations about quantitative analysis of NMR data Quantitative NMR data, such as HETSOFAST data, CPMG relaxation dispersion or relaxation data have been based on analyses of peak integrals, determined in CCPNMR  (Vranken et al. , 2005) , and subsequent analyses in in-house written python scripts, unless stated otherwise. Generally, error margins on peak integrals have been determined from the spectral noise (generally 3 times the standard deviation of spectral noise was used), and Monte Carlo analysis of the fit data. Diffusion ordered NMR spectroscopy Diffusion coefficients were obtained from a series of methyl-detected DOSY NMR experiments. The integrated intensity as a function of the gradient strength was used to fit the diffusion coefficient (D) using the following equation: I = I 0 $exp À À D,g 2 H ,g 2 ,d 2 ,ðD À d=3 À t=2Þ Á ; where I is the peak integral, g H is the gyromagnetic ratio of protons, g is the gradient strength in Gauss/cm, and D, d and t are delays in the pulse sequence as described in  Didenko et al.
HH The physical constants are g H = 2. 67522. 10 8 s -1. T -1 , r HH = 1. 813 A ˚, q axis,HH = 90 degrees, m 0 = 4p. 10 À7 H. m -1 and P 2 denotes the second-order Legendre polynomial. Error margins of the fitted parameters were obtained using a standard Monte Carlo procedure. Hereby, 1000 synthetic datasets were generated, by adding random noise (within the experimentally determined noise levels) onto the data points that were back predicted from the best-fit parameters. These 1000 datasets were fitted analogously to the experimental data, to extract the standard deviation over these fitted parameters. The raw data and analysis scripts have been deposited in the Mendeley data repository (see Key Resources Table ).
CPMG experiments CPMG profiles, R 2eff as a function of n CPMG , were fitted with a numerical approach, using the program ChemEx (version 0. 6. 0, available at https://github. com/gbouvignies/chemex/releases), in order to obtain a global exchange rate constant, k ex , and site-specific chemical-shift differences jDuj. The two-state exchange model was used as an approximation, and the populations of the two exchanging states were set to 50%. The CPMG RD profiles of ALV TIM in its apo state and bound to Ggc1 and Aac3 have been deposited in the Mendeley data repository.
DATA AND SOFTWARE AVAILABILITY NMR resonance assignments have been deposited in the BioMagResBank. The accession number for the resonance assignment is BioMagResBank: 27052. The accession number for SAXS data are SASBDB: SASDEF2 (TIM910) and SASBDB: SASDEG2 (TIM910/Ggc1). CPMG relaxation dispersion data have been deposited in Mendeley data. Accession numbers can be found in the Key Resources Table. residue number in Tim9/Tim10 (aligned order) residue number in Tim9/Tim10 (aligned order) (legend on next page).
ACKNOWLEDGMENTS We thank  Nikolaus Pfanner ,  Vilius Kurauskas ,  Sebastian Hiller , and  Sandro Bottaro  for discussions and  Aline Le Roy  and  Christine Ebel  for AUC experiments. This work was supported by the  European Research Council  ( StG 311318 and CoG 648235 ), the  Sonderforschungsbereich 1140 , the  Excellence initiative  of the German federal and state governments (EXC 294 BIOSS and  GSC-4 Spemann Graduate School) , the  BRAINSTRUC  initiative from the  Lundbeck Foundation , and the  Deutsche Forschungsgemeinschaft  ( RA1028/8-1  to D. R. ). We thank the  ESRF  for beamtime at BM29. This work used the high-field NMR and EM facilities at the  Grenoble Instruct-ERIC Center (ISBG ;  UMS 3518 CNRS CEA-UJF-EMBL ) with support from  FRISBI  ( ANR-10-INSB-05-02 ) and  GRAL  ( ANR-10-LABX-49-01 ) within the  Grenoble Partnership for Structural Biology.
In the dataset shown in (I), residue L36 is not graphically shown due to its large error margin; its value is 0. 097 ± 0. 5. All error margins shown in this figure were determined from 3 times the spectral noise level. (J and K) The observed PRE effects are plotted onto the structure of TIM9$10 in (MTSL at C222 in J) and (MTSL label at C8 in K). (D) 1 H-15 N NMR spectra of deuterated carrier precursor proteins bound to unlabeled TIM9$10. Left: 1 H-15 N BEST-TROSY  (Favier and Brutscher, 2011)  spectrum of Aac3(2TM) bound to TIM9$10. Middle: 1 H-15 N CRINEPT-TROSY  (Riek et al. , 1999)  of Ggc1 bound to TIM9$10 recorded in an overnight experiment at 35 C. The sensitivity of an INEPT-based TROSY experiment was significantly lower without providing additional cross-peaks (data not shown). Right: Overlay of 1 H-15 N correlation spectra of Ggc1 solubilized in 8 M urea (blue), where it is unfolded, approx.
However, most studies were characterized by a small sample size and many had conflicting results. It is thus a matter of concern that drugs approved for the treatment of PAH are commonly used in patients with PH-LHD despite insufficient data supporting their safety and efficacy  [13]. We therefore systematically assessed the efficacy and safety of PH-targeted therapies for patients with HFpEF/HFrEF. The aim of the present systematic review and meta-analysis was to assess the effect of PH-targeted therapies for patient with HFpEF/HFrEF on clinically relevant outcomes including exercise capacity, hospitalisation and death compared to conventional therapies.
Data extraction and analysis The whole process of data extraction was independently made by two reviewers (CAG/LVMT) with tested and validated data collection forms. Retained information included study design, patient characteristics and mean treatment effect on exercise capacity, mortality (all-cause and cardiac-related), hospitalisation (all-cause and cardiac-related), NT-proBNP levels, echocardiographic and hemodynamic parameters and discontinuation rate. 2x2 tables were constructed based on treatment received and available data for the primary and secondary dichotomous outcomes. Forest plots were created for each outcome. Data were analysed using the Mantel-Haenszel method based on a random-effects model, which accounts for within-study and betweenstudy variability  [18]. For continuous outcomes, when multiple scales were used (e.
The authors received no specific funding for this work. SB holds a Canadian Research Chair in translational research in pulmonary vascular diseases at UniversiteLaval. JCL has received lecture fees from  Actelion Pharmaceuticals. SP is clinician-scientist of the received research grants from  Actelion Pharmaceuticals, Bayer  and  GlaxoSmithKline , and has received speaker fees from  Actelion Pharmaceuticals. The  Pulmonary Hypertension Research Group  is also supported by the " Reseau en SanteRespiratoire " of the FRSQ". The other authors have no competing interests to declare.
This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.
Ethics and dissemination The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public. trial registration number NCT02866526; Pre-results. mainly males (annual incidence: 1/5000 male births). 1  It is characterised by bleeding due to a lack of clotting factors (factor VIII (FVIII) for haemophilia A or factor IX (FIX) for haemophilia B). Bleeding often starts in early life, due to psychomotor skills acquisition. Seriousness of the symptoms depends on the severity of the lack of FVIII/FIX.
MEthods/dEsIgn study design This study is designed as a multicentric (29 HTC from FranceCoag), observational, cross-sectional study, based on an explanatory sequential mixed methods design,  [41] [42] [43] [44] [45] [46] [47]  with two complementary and consecutive phases: ► The quantitative phase focuses on the determinants of adherence to healthcare (considered as a marker of the success of transition), and compares data from a group of adolescents with those from a group of YA, in order to provide a general understanding of the issue of adherence in young PWH. ► The qualitative phase explores participants' views in more depth (few patients selected from the quantitative phase) to explain and refine the general understanding from the quantitative phase. Interpretation and discussion of the global results will be done by integrating the results of both phases of the study.
Explanatory collected data Psychosocial and behavioural data ► Quality of life will be assessed using the validated French version of the SF-12 generic scale. 52 Two sub-scores, mental health and physical health, will be calculated. The SF-12 allows assessing the quality of life of adults as well as adolescents (14+ years). -Quality of life of adolescents will also be assessed by the validated French version of the 10-items Kidscreen Index, which explores the following domains: physical well-being, psychological well-being, autonomy and relations with parents and home life, peers and social support and school environment. 53 -Haemophilia-specific quality of life will be assessed in all participants using the validated French short version of the Haemo-QoL questionnaire. 54  55 ► Time perspective will be assessed using the past negative (PN) and future (F) subscales of the French validated version of the Zimbardo time perspective inventory.
Data collection procedure Main medical data will be extracted from the FranceCoag database, and completed by a short questionnaire filled in by the referent physician from each HTC. Organisational data will be completed by a medical representative from each HTC. Eligible participants will be identified and approached by the HTC team by which they are followed (approach either during a medical consultation, or by phone call, or by a personalised mail sent at their home). Survey documents (information sheet, informed consent form, booklet, and prepaid envelope) will then be sent by post to eligible young PWH. Participants' self-reported data will be collected through a standardised booklet including several questionnaires (an adolescent version and a YA version). Consent will be collected through the signature of the informed consent form by the parents or the legal representatives for adolescents, and by the signature of the YA directly for YA.
Sample size justification According to the exhaustive FranceCoag database and considering the specific inclusion criteria of the TRAN-SHEMO study (severe A or B haemophilia, patients aged 14-17 or 20-29 years, followed in one of the 29 participating HTC), 154 adolescents and 389 YA are eligible for this study. We hypothesised a difference of 20% between adolescents and YA regarding the main evaluation criterion (90% of adherence to healthcare in adolescents vs 70% in YA). Then, under the hypothesis of a non-response rate of 30%, and considering a bilateral alpha risk of 5%, the power of this study would reach 99%. 62 63 ta management A specific database will be created using EpiData software, and merged with the FranceCoag database. A process will be used to assign to each participant a unique anonymous number.
Descriptive analysis A descriptive analysis will first be performed. Qualitative variables will be presented as numbers and percentages, quantitative variables as means and SD, or as medians and IQRs. Subjective data will be described by their overall scores and their subscores. Reasons for non-inclusion will be listed. Included patients will be compared with non-included eligible patients using basic sociodemographic and clinical data, available in the FranceCoag database.
Qualitative phase Data collection procedure Few subjects (adolescents on one hand and YA on the other hand) who will have participated in the quantitative phase will be selected for this phase according to the following characteristics (assessed from the quantitative phase): adherent or not, and under prophylaxis or not. If they agree, they will be contacted to participate in research interviews conducted by a psychologist, at any place at their convenience (eg, at home and at the HTC). The interviews will be individual, confidential, semi-structured, and tape-recorded. The psychologist will be blind to the responses in the questionnaires of the participant, and to his/her status adherent/non-adherent as defined according to the main evaluation criterion of the quantitative phase. The psychologist will start with a general question, then he/she will adopt a non-directive attitude and will allow the participant to spontaneously and freely broach the answers which they consider relevant.
Patient and public involvement The development of the research question, study design and outcome measures involved interpretation of literature, professional experience reported through the clinicians, nurses and psychologists working in the various HTCs participating in the French national registry FranceCoag, and patients' priorities and experience reported through the AFH that is member of the steering committee of the study. Patients will not be directly involved in the recruitment, but the AFH will regularly communicate about the study (internet, newsletters, social networks, magazine, etc) to inform eligible participants in order to maximise the recruitment. Results will be popularised to be communicated via the AFH to participants and to the general public. dIsCussIon And lIMItAtIons strengths and limitations of the database As the issues concerning transition into adulthood may intrinsically depend on features of the healthcare system, we intend to explore the specific perceptions of young PWH in France, whose healthcare system model is specific.
The support of the FranceCoag registry to this study is therefore an important strength. While the exhaustivity of inclusions in this registry might have been an issue for patients with moderate or minor haemophilia, the exhaustivity concerning patients with severe haemophilia is guaranteed since 2000. Even if 5 HTCs over the 34 active ones (ie, 15%) did not accept to participate in the TRANSHEMO study, the loss of eligible patients was small (only 4% of the eligible young PWH). The comparison of basic sociodemographic and medical data, available in the FranceCoag database, between included patients and non-included eligible patients will allow to discuss the representativeness of the included sample. Moreover, the implication of clinicians, nurses, psychologists and clinical research associates in both the clinical follow-up of patients and this study via their participation in the FranceCoag registry will help to maximise the recruitment and limit the risk of dropouts for this study.
Adherence is a concept which might be defined by the agreement between the behaviour of a patient and the received recommendations or prescriptions. 77 We chose to assess adherence to prophylactic treatment, which is the commonly used evaluation criterion when assessing adherence in haemophilia  29 35  but which would have been valid only for young PWH under prophylactic treatment. We therefore also chose to assess adherence to clinical follow-up, which is valid for all young PWH (even if the rhythm of visits might be different depending on their personal situation). Moreover, we chose to collect data on adherence through three sources of information: (i) data from the FranceCoag database (follow-up visits, injections of prophylactic treatment, haemorrhagic events), (ii) referent physician-reported data and (iii) patient-reported data.
For adolescents, consent will be obtained from their two parents or from their legal representatives, in line with the French laws and regulations. All data will be analysed confidentially and anonymously. The study was designed according to Good Clinical Practices, and all procedures will be in accordance with the Declaration of Helsinki. The study approval was in line with the General Data Protection Regulation principles. The protocol was registered in ClinicalTrials. gov (NCT02866526). dIssEMInAtIon This study will allow to comprehend what the potential impact of transition from adolescence to adulthood could be in young PWH in France, which is of particular interest in the global approach whose goal is to take care of all aspects of life in patients with chronic diseases. This study will also allow to identify determinants of adherence, considered as a marker of a successful transition in young PWH.
The assessment of social, psychosocial and behavioural data will allow to describe the sociocognitive processes, which may facilitate or complicate adherence, while taking into account other factors, that is, medical, organisational and socio-demographic factors. The results obtained from the quantitative phase of the study will be enlightened by the analysis of the interviews conducted in the qualitative phase. This analysis will bring supplementary and complementary data which would not have been accessible via the analysis of the questionnaires, especially concerning expectations and fears about health, and about personal and professional life. Singular results from this qualitative phase could be used to better design a future quantitative study on the issue of transition, by assessing complementary outcomes to those assessed in the present quantitative phase.
Acknowledgements The authors would like to thank all collaborators who participate in the study:  Tafat Ait Chekdhidh  ( Hospital of Montmorency, France ),  Kahéna Amichi  ( APHM, France ),  Claire Arce  (AFH),  Marie Augagneur  ( University Hospital of Brest, France ),  Thérèse Auriol-Vigne (APHM, France) ,  Lynda Bendjemar  ( Hospital of Montmorency, France ),  Linda Bodet  ( University Hospital of Lyon, Hospital Edouard Herriot, France), Aurélie Cadet (University Hospital of Reunion, Reunion Island, France ),  Amandine Celli  ( University Hospital of Nantes, France ), Carine on April 15, 2022 by guest. Protected by copyright. http://bmjopen. bmj. com /BMJ Open : first published as 10. 1136/bmjopen-2018-022409 on 25 July 2018. Downloaded from.
Binding of LpoB alters the structure of UB2H To investigate possible structural changes to the UB2H domain resulting from LpoB binding we expressed and purified the UB2H domain of E. coli PBP1B (residues 108 to 200) and determined its structure by NMR spectroscopy. All NMR data recorded pointed towards the presence of a stable fold for the isolated UB2H domain in solution and were used to calculate a high-resolution structure (see Table  S1 ). Superimposition of the 20 lowest energy structures derived from NMR (PDB 6FZK) with the UB2H domain from the X-ray crystal structure of fulllength PBP1B (PDB 5FGZ) shows a similar secondary structure organisation with a backbone rmsd of 1. 1 Å for residues involved in secondary structures (Fig. 1A ). As described for the X-ray structure  (Sung et al.
, 2009; King et al. , 2016) , the domain architecture is formed by one α-helix followed by four long β-strands (β2 to β5), which are linked by mostly short turns to form an anti-parallel β-sheet. Only the turn between stands β3 and β4 forms a larger loop (Loop 1: residues 157 to 168). This loop shows a lower resolution in our NMR structure, which is correlated to an increase in flexibility in solution in this region, as evidenced by 15 N-NMR relaxation measurements (R 2 /R 1 and 1 H-15 N heteronuclear NOE are shown in Fig. S1A ). The N-and C-terminal extremities of the UB2H domain interact through two extended anti-parallel β segments (residues  109-115 and 193-200 ) that are Superimposition of the 20 lowest energy structures derived from NMR of (A) the isolated UB2H domain (in pale blue, PDB 6FZK) or (B) the UB2H domain in complex with LpoB (in blue, PDB 6G5R) and of the X-ray structure of the UB2H domain in full-length PBP1B (PDB code 5FGZ, in purple).
Consistent with its dominant negative effect on in vivo function, the presence of the R109G substitution decreased the basal GTase and TPase activities of PBP1B. TPase products were reduced to 42. 3 ± 1. 3%, and the GTase rate of PBP1B R109G was ~ half (0. 55-fold) of WT (Fig. 3A-C ). Furthermore, while the R109G substitution did not prevent activation of the synthase by LpoB (Fig. 3D ), the overall GTase and TPase activities did not reach WT levels. A similar activity profile was observed for R157A and E341A, decreasing TPase products to 39. 0 ± 3. 4% and A. H-bond network connecting points of structural change in UB2H domain with the other domains of PBP1B (green dashed lines between residues) (PDB code 5FGZ). This network involves residues (coloured in red) mainly located in the N-and C-terminal segments and in Loop 1 (residues  109-114, 196-200 and 157-168, respectively)  ultimately connecting the UB2H domain with residue D443 of the TPase domain, and residue E341 of the GTase domain.