dataesr/scientific-paragraphs-categorization huggingface dataset:
Isothermal titration calorimetry The binding affinity of Spy H96L for Im7 6-26 peptides was determined by isothermal titration calorimetry (ITC) using a MicroCal iTC200 instrument (Malvern). The thermodynamic parameters upon the titration of Spy H96L (1. 25 mM) with the Im7 6-26 peptides (0. 11 mM for the wild type, 0. 055 mM for the Im7 6-26 peptides L18pI-Phe, L19pI-Phe and K20pI-Phe) were measured at 10 C in a buffer consisting of 40 mM HEPES-NaOH pH 7. 5, 100 mM NaCl. For each experiment, an injection volume of 2 ml was used at intervals of 180 s. The ITC thermograms were fitted to a one-site model using the Origin software provided with the instrument. The Im7 6-26 peptide binds to Spy H96L with a dissociation constant of 7. 8 AE 0. 6 mM, which is similar to the dissociation constant of a partially folded variant of Im7 and wild-type Spy.
For example, in the L19pI-Phe data collection, which showed several lowoccupancy anomalous signals, the ANODE anomalous peaks were analyzed with a cutoff at 6 to ensure confidence in assigning the anomalous signals beyond the noise level (Supplementary Fig. S5 ). It is generally accepted that the rate of radiation damage in protein crystals is proportional to the dose. Here, the effect of radiation damage on crystals has been investigated by monitoring a number of parameters as a function of the absorbed dose (Supplementary Table  S1 ). For each data set, the absorbed dose was estimated using knowledge of the incidentbeam characteristics (energy, flux and size) and the crystal characteristics (volume, morphology, unit-cell size, protein atomic content, number of amino acids and solvent composition), as well as the exposure time per image and the total number of images.
87 and 2. 75 keV phased anomalous difference Fourier maps of the best L19pI-Phe Spy-Im7 crystal (labeled according to PDB entry 6owz). At 2. 87 keV, f 00 for Cl is 3. 98 and f 00 for Zn is 4. 0. At 2. 75 keV, f 00 for Cl is 0. 43 and f 00 for Zn is 4. 4 (Supplementary Fig. S2  additional data collections from the same crystal. The phased anomalous difference Fourier maps from this additional data collection showed that three of the anomalous positions from the first data collection are preserved in the data collected at the different angle (Fig. 1a ). Finally, to test whether these anomalous positions are reproducible in other L19pI-Phe crystals, we collected additional 5. 2 keV data sets from three other L19pI-Phe crystals. These crystals diffracted to resolutions of 2. 2, 2. 9 and 3. 2 A ˚, respectively.
In the phased anomalous difference Fourier map of the crystal that diffracted to 2. 2 A ˚resolution, we were able to identify three different iodine signals that overlap with the signals detected in the highest resolution crystal (Fig. 1c ). These signals were also present in other data collections ( = À40 ) from the crystal that diffracted to 2. 2 A ˚resolution (Fig. 1c ). In the crystals that diffracted to 2. 9 and 3. 2 A ˚resolution, we only detected one iodine signal in each, but these overlapped well with the strongest anomalous signal from the highest resolution crystal. It is therefore clear that the ability to detect low-intensity signals is highly dependent on the crystal quality, as the best diffracting crystals showed the most highquality anomalous signals. To further examine the anomalous peaks detected here, we also compared these iodine positions with those identified in our previous Spy-Im7 crystallographic study, in which we used the same L19pI-Phe peptide with Spy H96L.
Other Im7 peptides suggest additional Im7 binding sites in the crook of the Spy cradle The Im7 peptides L18pI-Phe and K20pI-Phe crystallized in complex with Spy show a very different pattern compared with the multiple signals observed for L19pI-Phe. The 5. 2 keV phased anomalous difference Fourier maps of L18pI-Phe and L20pI-Phe each show only one distinct anomalous signal attributable to iodine. In both cases the peak heights in the phased anomalous difference Fourier maps were very strong: the iodine signals were detected at 26. 4 and 32. 5 for L18pI-Phe and K20pI-Phe, respectively (Figs. 3  and 4,  and Table 4 ). Both peaks are in the interior of the cradle of Spy, near the flexible loop region. For K20pI-Phe, a second data set was collected below the iodine edge at 4. 5 keV. The large decrease in the anomalous signal in this data set confirmed that the position ascribed to iodine was indeed iodine (Fig.
3b ). To further validate this observation, we collected a third data set at an additional goniometer angle ( = À20 ) above the iodine edge. This data set again showed strong anomalous signal (16. 1 in the phased anomalous difference Fourier map) at the same position (Fig. 3a ), with the peak height reduced by radiation damage (Supplementary Table  S1 ). Finally, we collected data sets at 5. 2 keV from three additional crystals that showed strong anomalous signals in the same position (26. 7, 26. 0 and 6. 5 in phased anomalous difference Fourier maps), demonstrating good reproducibility for this signal (Fig. 3c ). Consistent with the L19pI-Phe data collections, the strength of the iodine anomalous signal detected is highly dependent on the crystal quality. This combination of measurements confirmed that K20pI-Phe produced detectable anomalous scattering from a single position in the crystal, providing an ideal case for determining the position of a partially occupied anomalous scatterer.
Unfortunately, for L18pI-Phe the single crystal that showed diffraction adequate for anomalous analysis degraded during the second 5. 2 keV data-set collection (Fig. 4  and Table  5 ). This data set, collected at = À40 , confirmed the presence of the anomalous signal (Fig. 4 ), but the 4. 5 keV data set could not be analyzed further owing to radiation damage. However, other indicators strongly suggest that this ANODE anomalous peak also arises from iodine. (i) The height of the ANODE anomalous peak is the second largest observed in this study and, at 26. 4 in the phased anomalous difference Fourier map, is substantially larger than the signals observed from zinc, Figure  2  2D histogram showing occupancy refinement of the iodine positions in the three structures, L18pI-Phe (PDB entry 6owx), L19pI-Phe (PDB entry 6owz) and K20pI-Phe (PDB entry 6owy), after 50 rounds of refinement from 10 000 randomly assigned ADP/occupancy starting values (shown in Supplementary Fig.
6 ). To further investigate the coherence of the two data sets, we tested how an ensemble determined using either the old or the new L19pI-Phe data set could predict the value from the other corresponding data set. Using all of the old data  (Horowitz et al. , 2016) , the four new L19pI-Phe signals presented here could be predicted with an average deviation of 0. 85 A ˚. Replacing the old L19pI-Phe signals with the new signals, the old L19pI-Phe signals were back-predicted with an associated error of 0. 89 A ˚on average (only one signal was reproduced with an error of 3. 9 A ˚, while the other six could be predicted within 0. 41 A ˚on average). This cross-validation procedure shows that selections run using either the new or the old L19pI-Phe signals can reproduce all of the signals in the other data set, with the exception of one point of the old data set, underlying the internal coherence of the data.
To further investigate the binding of Im7 onto the surface of Spy, we additionally attempted selections using the L18pI-Phe and K20pI-Phe signals. In the case of L18pI-Phe, the molecular-dynamics simulation used to generate the conformational pool was found to not sample positions encompassing the iodine position in the crystal, preventing any fitting and further analysis of this signal (Supplementary Fig. S10 ). In this case, improvement of the conformational sampling in the molecular-dynamics simulation will be required to fit this ensemble, while the L18pI-Phe and K20pI-Phe data will require more advanced conformational sampling to properly assess their coherence with the determined ensemble.
Discussion Our new, optimized data-collection strategy provides an improved method to obtain high-quality anomalous signals with less noise contamination; it also verifies the presence of several of the iodine anomalous signals identified in our previous data sets. Combined, the experiments demonstrate that the Im7 peptide binds to Spy in multiple different binding poses, which are detectable using anomalous scattering. Refining the occupancies of the iodines suggests that we are able to detect iodine anomalous signals at as low as $12% occupancy, even with a high temperature factor of 80 A ˚2. These low-occupancy states were confirmed via reproducibility through independent data collections at multiple angles and using separate crystals. The iodine positions are plausible, and on average are located around 3.
25 A ˚from the closest atom (Supplementary Table  S2 ). READ selections demonstrated that the new L19pI-Phe data produced a consistent ensemble with previous efforts, while the consistency of the L18pI-Phe and K20pI-Phe data could not be assessed properly with our initial sampling. Spy-Im7 binding has recently received attention as a model system for understanding chaperone-client interactions. NMR spectroscopy, molecular-dynamics simulations, chemical kinetics and X-ray crystallography have all concluded that client binding to Spy is dynamic and that Im7 can bind to Spy in an array of conformations and poses  (He & Hiller, 2018; He et al. , 2016; Stull et al. , 2016; Horowitz et al. , 2016; Salmon et al. , 2016). These studies showed that Im7 binding occurs at various sites on the concave surface of the Spy cradle.
During the same period, in HCV KTR, interferon based regimens were contraindicated due to the high risk of transplant rejection. KDIGO recommendations were to treat patients on hemodialysis  24  , but interferon-based regimens were associated with a low efficacy  25  and poor tolerance in ESRD patients  [25] [26] [27] [28]. Since 2017, the updated KDIGO and international guidelines recommend extensive use of the new direct anti-viral agents (DAAs) because of their good efficacy and safety)  29, 30. The aims of the present study were to update on the influence of HBV and HCV on patient and graft survival and to assess the prognostic influence of viral replication in a large prospective French database of KTR.
Study Conduct Both scientific Committees from the ANRS (in charge of the research on viral hepatitis) and the ABM (Agence de Biomédecine in charge of graft allocation), two French governmental agencies, approved the study. The CNIL (Commission Nationale de l'Informatique et des Libertés), the French government agency in charge of the authorization for the use of database, allowed the CRHU of Lille to analyze these data on December, 28 th 2012 (authorization number: 912384).
Data collection and variables From January 1993 to December 2010 data were extracted from CRISTAL, a national database begun in 1993 and administered by the ABM that prospectively collects data on all organ transplant recipients in France along with their outcomes and donor characteristics. Recipient and donor data are entered into the CRISTAL registry by transplant and procurement centers, respectively. Recipient deaths are reported prospectively. The study was performed in accordance with the French law indicating that research studies based on the national registry CRISTAL are part of transplant assessment activity and do not require institutional review board approval. Data are entered into the register by each center. Data collection is mandatory. Variables potentially associated with outcomes were analyzed.
Random checking of viral replication in infected HBV and HCV recipients We randomly selected 191 HBV and 511 HCV KTR cases to assess the control of viral replication among the centers with high yearly transplant activities from the CRISTAL database. This numbers were calculated on the basis of the following assumptions: a) for HBV cases, we expected 70% of patients with control viral replication, a relative precision of 20% in the estimation of this rate (corresponding to a width of 95% confidence interval) and 25% with unavailable virological data. b) for HCV KTR cases, we expected 20% of patients with control viral replication, a relative precision of 40% in the estimation of this rate and 25% with unavailable virological data. Between 2014 and 2015, research assistants visited the centers of selected recipients to analyze recipients' medical records and recorded in case report forms the following information: results of quantification of HBV DNA viral and/or HCV RNA, antiviral therapy ("yes" or "no"), the type of regimen in treated patients, data for diagnosis of cirrhosis such as histological data and/or results of Fibrotest® and Fibroscan®.
For each candidate predictor, the proportional hazards assumption was assessed by examining Schoenfeld residuals plots. The log-linearity assumption for continuous predictors was assessed by examining Martingale residual plots. Since the log-linearity assumption for the age of recipients and donors was satisfied after including both linear and quadratic terms, the effect of both ages was modelled using a polynomial function. All candidate predictors associated with survival at a level of significance of p<0•10 were included in the multivariate Cox regression models. We derived hazard ratios (HRs) from Cox regression models as effect size measures with the 95% confidence intervals (CIs). The percentage of patients treated by antiviral therapy and the percentage of responders to antiviral therapy were compared from random samples of available viral data from HBV and HCV KTR between HBV patients with viral replication and HCV patients with detectable RNA using the Chi-square test.
Finally, comparisons of overall and graft-survivals between HCV KTR and their matched non-infected controls were performed separately based on detectable HCV RNA using Cox regression models with the robust sandwich variable estimate to take into account the matched sets. Statistical testing was performed at the 2-tailed α-level of 0. 05. Data were analyzed using SAS software (version 9. 4, SAS Institute Inc. , Cary, NC, USA).
RESULTS Between January 1993 and December 2010, 32,249 KTR were entered into the Cristal database, and 816 who were < 18 years old were excluded from the study (figure  1 ). A total of 31,433 adult KTR (19,580 men and 11,853 women) were included with a median age, duration of dialysis, and cold ischemia of 49. 4 years, 28. 1 months, and 18. 8 hours, respectively. Patients were grouped according to virological status (table 1): 575 HBV KTR (HBs antigen positive) (1. 83%), 1,060 HCV KTR (anti-HCV positive) (3. 37%), and 29,798 non-infected patients (without anti-HCV antibodies or HBs antigen) (94. 8%). The 3 groups differed significantly for sex ratio, age, duration of dialysis and cold ischemia, year of transplantation, and causes of underlying nephropathy (table  1 ). The prevalence of HBV decreased after 2003 (the median year of transplantation) from 2.
Random checking of viral replication in infected HBV and HCV recipients Virological data were available in 167 out of 191 medical records from HBV KTR patients (87. 4%). Viral replication was controlled in 157 out of 167 HBV KTR (94%), including 21 inactive carriers and 136 treated with NAs. In the ten HBV KTR with viral replication, three were not treated and seven insufficiently controlled by antiviral therapy. Virological data were available in 441 out of 511 medical records from HCV KTR patients (86. 3%) (figure  1 ). HCV RNA was undetectable in 155 out of 441 HCV KTR (35%), including 75 with spontaneous HCV clearance and 80 with a SVR after antiviral therapy. HCV RNA was detectable in 286 out of 441 HCV KTR (64. 9%), including 140 untreated patients and 146 non-responders to antiviral therapy.
An European initiative for HCV elimination (European Hepatology -EASL-and Nephrology association -ERA/EDTA) proposed a program for "micro-elimination" of HCV in CKD patients. The limit of this study was the absence of data concerning the anti-viral treatment and its efficacy on the viral replication in all patients collected in the Cristal database. We try to overcome this limit by performing a case-control study in which virological data and antiviral therapies were collected, by research assistance who analyze recipients' medical records. In conclusion, HBV and HCV KTR without viral replication have similar patient and graft survivals than non-infected patients. Recent access to DAA regimens in HCV patients with renal dysfunction provides exciting perspectives. and in their matching non-infected controls were estimated using the Kaplan-Meier method.
Acknowledgement to french kidney transplantation network (for adult patients):  Dr Gabriel Choukroun  and  Dr Fabien Saint  (Amiens),  Dr Thibault Culty  et  Dr Jean-François Subra  (Angers),  Dr Didier Ducloux  et  Dr François Kleinclauss  (Besançon),  Dr Jean-Marie Ferrière ,  Dr Pierre Merville ,  Dr Eric Dobremez (Bordeaux ),  Dr Georges Fournier ,  Dr Yannick Le Meur  (Brest),  Dr Xavier Tillou ,  Dr Thierry Lobbedez  (Caen),  Dr Jean-Paul Boiteux ,  Dr Anne-Elisabeth Heng  ( Clermont-Ferrand ),  Dr Philippe Grimbert ,  Dr Alaexandre de la Taille  (Créteil),  Dr Luc Cormier ,  Dr Christiane Mousson  (Dijon),  Dr Bénédicte Janbon ,  Dr Jean-Jacques Rambeaud  (Grenoble),  Dr Antoine Durbach ,  Dr Jacques Irani  ( Le Kremlin-Bicêtre ),  Dr Sébastien Bouye ,  Dr Christian Noël  (Lille),  Dr Aurélien Descazeaud ,  Dr Marie Essig  (Limoges),  Dr Lionel Badet ,  Dr Emmanuel Morelon  (Lyon),  Dr Yvon Berland ,  Dr Valérie Moal ,  Dr Eric Lechevallier  ( Marseille) ,  Dr Georges Mourad ,  Dr Rodolphe Thuret.
Patients The OPTiMiSE study was conducted in 27 general hospitals and clinics in 14 European countries, Israel and Australia (Clinicaltrials. gov identifier is NCT01248195). FEP patients based on the EUFEST (European First Episode Schizophrenia Trial) study definition  25  were recruited between May 2011 and April 2016 at the participating centers from nearby healthcare facilities. Eligible patients were aged 18-40 years and met criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th edition) for schizophrenia, schizophreniform disorder or schizoaffective disorder. A total of 479 patients signed informed consent. Diagnoses were confirmed by the Mini International Neuropsychiatric Interview plus. Patients were excluded if more than 2 years had passed since the start of the FEP; if any antipsychotic drug had been used for more than 2 weeks in the previous year and/or for a total of 6-week lifetime; if patients had a known intolerance to one of the study drugs; if patients met any of the contraindications for any of the study drugs; if patients were coercively treated and/or represented by a legal guardian or under legal custody; or if patients were pregnant or breast feeding.
Patient clinical assessment and primary outcome A screening visit was conducted during which eligibility was assessed. Baseline data were obtained regarding demographics, diagnoses, current treatments and psychopathology: PANSS total score and sub-scores, overall severity of symptoms assessed using the Clinical Global Impression (CGI) scale  26  , depression assessed using the Calgary Depression Scale for Schizophrenia (CDSS)  27  and social functioning assessed using the Personal and Social Performance Scale (PSP)  28. Recreational drug use was also assessed. Data were collected at baseline and 4-5 weeks later. All patients were treated for 4 weeks with up to 800 mg/ day amisulpride in an open design. The primary outcome was symptomatic remission according to the criteria of Andreasen et al.
The data were acquired on the V-PLEX® Sector Imager 2400 plate reader and analyzed using the Discovery Workbench 3. 0 software (MSD). The standard curves for each cytokine were generated using the premixed lyophilized standards provided in the kits. Serial twofold dilutions of the standards were run to generate a 13-standard concentration set, and the diluent alone was used as a blank. The cytokine concentrations were determined from the standard curve using a 4-parameter logistic curve fit to transform the mean light intensities into concentrations. The lower limit of detection (LLOD) was determined for each cytokine and for each plate as the signal recorded for the blank plus 2 standard deviations (SDs).
Statistical analysis In univariate analysis, Mann-Whitney-Wilcoxon tests were performed to assess statistical significance of non-Gaussian distributed data. To develop a predictive model for remission we used the elastic net, which is a regularized regression model, i. e. , general linear model with penalties to avoid extreme parameters that could cause overfitting  30. Elastic net is also a method of selection of variables that addresses the issue of multicollinearity that arises in our dataset because cytokines and chemokines are not independent of each other. To minimize variation across testing datasets, we repeated fivefold crossvalidation 100 times with independent random dataset partitions to optimize stability  31. We tuned the hyperparameters α and λ 10 times for each partition via fivefold cross-validation with the optimal tuning parameter values chosen to maximize the area under the receiver operating characteristics (ROC) curve (AUC)  32.
As a second attempt to predict remission, we investigated the association between serum protein levels and remission using regularized logistic regression after adjustment for age, gender, body mass index (BMI), waist circumference, use of recreational drugs and seropositivity to T. gondii, CMV and HSV-1. Applying this method to the dataset did not allow for identifying proteins whose serum levels were associated with increased odds of being non-remitters (not shown). One obvious explanation for this negative result could be that none of the studied serum proteins is relevant for discriminating remitters and non-remitters among FEP patients. Alternatively, the heterogeneity of psychotic disorders in terms of symptomatology and likely etiology and pathophysiology may impede the identification of underlying remission predictors in a general population of FEP patients.
Patient clustering We sought to stratify patients in clusters in which patients within one cluster would be more similar (cohesion) than patients in the others (separation). We applied a two-step hierarchical unsupervised clustering method to a dataset consisting of the 30 individual PANSS scores of the 325 patients in the OPTiMiSE study sample, therefore resulting in four clusters: C1A and C1B, and C2A and C2B. We compared two methods for data clustering: principal component analysis (PCA)-Kmeans  42  that is a popular method for cluster analysis, and K-sparse* that is a modified version of K-sparse  38. While both methods were successful at stratifying the 325 patients of the OPTiMiSE study sample, K-sparse* outperformed PCA-K-means as demonstrated by both a higher mean silhouette value (0.
Acknowledgements We thank all the patients who participated in the OPTiMiSE study. The OPTiMiSE study was funded by the  European Commission  within the  7th Program  ( HEALTH-F2-2010-242114 ). This work was also supported by the  Investissements d'Avenir program  managed by the  Agence Nationale pour la Recherche (ANR)  under reference  ANR-11-IDEX-0004-02  ( Labex BioPsy)  (to W. B. H. A. ). Additional financial supports were obtained from the  Fondation de France  (to N. G. ) and the  Fondation FondaMental  (to N. G. ). Additional supports were obtained by the  LABEX   SIGNALIFE  (# ANR-11-LABX-0028-01 ) and the  FHU OncoAge. The Leboyer's team is affiliated with the  Paris School of Neuroscience (ENP)  and the  BioPsy Laboratory of Excellence. Members of the OPTiMiSE study group are R.