dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements: Based on observations obtained with  XMM-Newton , an  ESA  science mission with instruments and contributions directly funded by  ESA Member States  and  NASA. DE thanks  F. Vazza ,  S. Paltani  and  S. Molendi  for fruitful discussions. We thank  H. Ebeling ,  M. Limousin ,  B. Clément ,  H. Atek ,  D. Harvey ,  E. Egami ,  M. Rexroth  and  P. Natarajan  for their help with the writing of the XMM-Newton proposal. MJ, HI and RM acknowledge support from the  UK Science and Technology Facilities Council  (grant numbers  ST/L00075X/1 ,  ST/H005234/1 ), the  Leverhulme trust  (grant number  PLP-2011-003 ) and the  Royal Society. JPK acknowledges support from the  ERC  advanced grant LIDA and from  CNRS. HYS acknowledges support by a  Marie Curie International Incoming Fellowship  within the  7th European Community Framework Programme , and.
Finally, these mutations are able to induce neurodevelopmental defects in vivo (zebrafish), thus representing dominant-acting mutations. Thirteen subjects were included in this study. All individuals were clinically assessed by experienced clinical geneticists. 6] [7] [8]  Clinical features are described in detail in Table  S1. Clinical data and biological material collection and storage were attained from the participating families after written informed consent was secured, following procedures in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national). Genomic DNA was isolated from peripheral blood leukocytes, skin fibroblasts, hair bulb cells, and/or buccal mucosal epithelial cells, using standard protocols. We performed WES on genomic DNA extracted from circulating leukocytes of a single affected subject (case 8) (Figure  1A , CaGi_UCSC).
Exome capture was performed using NimbleGen SeqCap EZ Exome V. 3. 0 (Roche) and sequencing by a HiSeq2000 instrument (Illumina). WES data analysis was performed using an in-house implemented pipeline. 10 For sequencing statistics, see Table  S2. Data annotation predicted 11,168 high-quality variants having functional impact (i. e. , nonsynonymous and splice site changes). Among them, 259 private, rare (minor allele frequency < 0. 001), or clinically associated changes were retained for further analyses. After excluding the presence of variants compatible with autosomal recessive transmission (Table  S3 ), we reasoned that the clinical symptomatology might be caused by a de novo event. Candidates were stratified through a mixed filtering/prioritization strategy taking into account the predicted impact of each variant and the functional relevance of individual genes on the developmental processes altered in the disorder.
Only changes (private, clinically associated, or having unknown frequency or minor allele frequency < 0. 001) predicted to be deleterious by the Combined Annotation Dependent Depletion (CADD)  11  (score > 15. 0) or Database for Nonsynonymous SNPs' Functional Predictions (dbNSFP) Support Vector Machine (SVM)  12  (radial score > 0. 0) algorithm were retained and prioritized on the basis of the functional relevance of genes using GeneDistiller. Genes were ranked based on combinations of terms from the OMIM clinical synopsis for MIM 601088 and 601353 (i. e. , cataract, deafness, mental retardation, facial dysmorphism, short stature, and seizure) as keywords, using similarity of expression patterns and protein-protein interactions as major weights. We obtained the highest score for MAF, a gene whose mutations had previously been reported to cause autosomal dominant congenital cataracts and lens abnormalities (MIM 610202).
GSK3 and ten residue-long peptides of MAF corresponding to the segment that interacts directly with the GSK3 binding cleft, encompassing both the GSK3 target and pSer/ pThr primed residues (Table  S6 ). The starting coordinates for the ATP-bound GSK3 were taken from the crystallographic structure of GSK3B complexed with AMP-PNP (PDB entry 1pyx). 27 Each decapeptide was set in an extended conformation along the catalytic cleft of GSK3 as specified in Table  S6. The MD simulations were carried out according to the protocol previously described. 10 The Gromos 53a6 force field was used, with the exception of the partial charges of pSer/pThr,  28, 29  and the parameters for ATP, obtained from quantum mechanical calculation of the molecular system reported in Figure  S4. For p. Pro59-His and p. Pro59Leu decamers, the conformation of the trimer comprised between the substrate and primed residues was rearranged considerably during the simulations (Figure  2A  and Figure  S5 ), with the correct orientation of the substrate residue in the GSK3 active site being destabilized (Figure  2A ).
Next, we conducted gene-expression profiling analyses on primary skin fibroblasts from two unrelated subjects (4-1 and CaGi_UCSC) to explore more globally the impact of dysregulated MAF function on gene expression (Table  S8  for details). Approximately 6% of genes in mutation-positive subject-derived cells were expressed differentially compared to control fibroblasts (ATCC code PCS-201-012). Gene ontology enrichment analysis of these differen-tially expressed genes revealed an overrepresentation of genes coding for proteins associated with developmental programs (tissue morphogenesis, branching morphogenesis, urogenital system, and bone development) and cellular processes (cytoskeletal rearrangement, cell migration and adhesion, and response to extracellular stimuli) (Table  S8 ). Publicly available microarray data (ArrayExpress accession code E-GEOD-51231) allowed selection of genes whose expression is positively controlled by MAF.
0001; Figure  4 ). These data were concordant with our in vitro model and provided further evidence for the   S7 ). Experiments were performed as previously reported. 10 D) Transactivation assays were performed in COS1 cells transiently cotransfected with the IL4 promoter cloned into pGL3 vector reporter construct (kindly provided by Michael Lohoff, University of Marburg, Marburg, Germany) alone (black bar) or together with wild-type MAF (white bar) or each of the disease-causing MAF mutants (blue and red bars) (1:1 ratio), and 1:10 of Renilla luciferase control vector DNA (pRL-Act Renilla). After transfection (24 hr), firefly and Renilla luciferase activities were measured by the Dual Luciferase Reporter Assay System (Promega). Normalized luciferase activity (mean 5 SD) of six experiments performed is reported as fold increase relative to cells not expressing exogenous MAF.
Accession Numbers The ArrayExpress accession number for the microarray data generated in this paper is E-MTAB-3250, and the RefSNP numbers of the disease-causing mutations are rs727502766 (c. 161C>T), rs727502767 (c. 172A>G), rs727502768 (c. 206C>G), rs727502769 (c. 173C>T), rs727502770 (c. 176C>A, c. 176C>T), and rs727502771 (c. 185C>G).
Acknowledgments We are grateful to the individuals and their families who contributed to this study. We thank  Serenella Venanzi ,  Chiara Di Claudio , and  Francesca Maiorca  ( ISS, Rome, Italy ) for skillful technical assistance. We acknowledge submission of several DNA samples to the  Center for Mendelian Genomics (CMG) in Seattle , WA; disease gene identification occurred prior to and without the use of data from the  CMG. We thank  BGI (Hong Kong ) for the high-quality sequencing raw data. M. T. , G. B. , and L. S. acknowledge CINECA for computational resources (WES data and structural analyses). This work was supported in part by grants from  Telethon  ( GGP13107  to M. T. ),  Istituto Superiore di Sanita  `(Ricerca Corrente 2013 to M. T. ),  Nemours Foundation  (to K. S. -C. ) and  NIH  ( P20GM103464  and  P20GM103446  to K.
The amount of formazan was determined spectrophotometrically by measuring the absorbance at λ = 540 nm using a microplate reader (Model 3550-UV, Bio-Rad, Marnes-la-Coquette, France). Each concentration was tested in quadruplicate and three independent experiments were performed. Since absorbance is proportional to the number of living cells, cell viability was represented by the absorbance ratio of exposed to control cells. Since incubation with aluminum adjuvant was previously shown to increase the mitochondrial activity  [19]  which might interfere with MTT results, cell toxicity was confirmed by the Trypan blue test (data not shown).
1g, h ). This was confirmed by X-ray microanalysis and high resolution transmission electron microscopy (data not shown, see below). In bright field TEM images, the mfNDs have various crystal orientations with respect to the incident electron beam. The darker particles correspond to nanocrystals in Bragg's position on which the electron beam has been diffracted and then stopped by the objective aperture (Fig. 1a, g  and h ). AluDia particles stained by Morin to detect aluminum showed colocalization of the red fluorescence of mfNDs with the green fluorescence of the Morin-alum complex, without alteration of the typical mfND emission spectrum (Fig. 1i-l ). Thus, the association of mfNDs with alum does not disturb the fluorescent signature of mfNDs. Taken together, these results and the persistent colocalization observed at distant places from the injection point in mice (as will be shown later) strongly suggest that stable attractive interactions are created between aluminum oxyhydroxide and mfNDs.
Acknowledgements Marie-Odile David ,  Laetitia Henry ,  Vandana Joshi  and  Patrick Curmi 's research is supported by  INSERM  and  Université-Val d'Essone. Marie-Hélène Berger ' research is supported by  CNRS  and  Ecole des Mines de Paris. Josette Cadusseau  and  Romain Gherardi 's research is supported by  INSERM  and  Université Paris Est-Créteil. Housam Eidi  and  Guillemette Crépeaux  benefited from post-doc positions attributed to  Patrick Curmi  and  Romain Gherardi 's labs by  Région Ile-de-France: DIM (Discipline d'Intérêt Majeur)  and  NeRF (Neuropole de Recherche Francilien) , the  Dwoskin Foundation  (award "Nano-in-brain" to  Romain Gherardi ) and  Agence Nationale de Sécurité du Médicament et des produits de santé -ANSM -(award "Biopersistance et neuromigration des adjuvants aluminiques" to Romain Gherardi).
Results Attrition rates were 17% and 63% at 3 and 24 months respectively. At 24 months, there was significantly more attrition in the control arm (70. 6%) compared to the intervention arm (55. 2%). Five independent predictors of early attrition were identified: having already had an abortion; having greater attachment insecurity as measured with the Vulnerable Data Availability Statement: The data underlying the findings cannot be made freely available because of ethical and legal restrictions. The French Data Protection Authority strictly forbids to make data from clinical trial freely available because, when combined the ones to the others, they can lead to re-identifying subjects, and then collecting health or behaviour information on these persons. However, they can be obtained upon request from the CAPEDP steering committee.
The protocol is described in detail elsewhere  [27] , as are the principle results  [28, 29]. The trial was registered as ClinicalTrials. gov number NCT0039284 and approved by the Institutional Review Board 'Comité de Protection des Personnes Ile de France IV' (IRB authorization 2006/37) and by the French Data Protection Authority. Written consent was obtained from all participants. The CAPEDP home-visiting intervention was tailored to improve mothers' knowledge and skills with regard to parenting, develop infant-mother attachment security, and enhance social and professional integration. A major specificity of the CAPEDP trial was that the entire home-visiting program was conducted and evaluated by qualified psychologists. It was hypothesized that professionals who were more highly trained in psychology would be more competent in recognizing the elements in play with regard to the determinants of infant mental health, more skilled in acting upon these determinants, and more skilled in evaluating outcomes.
In cases where families accepted phone contact but were reticent to receive further home visits, assessments took place over the telephone, excluding those instruments that required direct observation. If phone contact proved to be impossible, questionnaires were sent to families via the post. An assessment visit typically lasted approximately 90 minutes. The mothers received no payment for their participation. Socio-demographic data collected included: mother's age; country of birth; number of years in France if migrant; number of years in current home; educational level; employment status; income; perception of financial situation; access to health services; use of social services; tobacco, alcohol and drug consumption. Data related to family structure included marital status, number of years with current partner, and death, separation or divorce of the mother's own parents.
Medico-obstetrical characteristics such as prior voluntary termination(s) of pregnancy, planning of the current pregnancy, and the number of health visits in the preceding year related to the current pregnancy, including visits to gynaecologists, midwives, paediatric nurses, and PMI services, were collected. All these data were collected at the initial assessment interview during the prenatal period, with the exception of the mother's employment status which was assessed at both the first and the second assessment interviews. Data related to parenting were collected using validated scales investigating the mother's knowledge of infant development (Knowledge of Infant Development Inventory, KIDI), her perception of her attitude, competence and emotional investment towards her child using the Parental Cognitions and Conduct Toward the Infant Scale (PACOTIS)  [30] , the quality of the home environment using the Home Observation for the Measurement of the Environment (HOME) inventory  [31, 32]  and the Parental Stress Inventory (PSI)  [33].
The following limitations should be considered when interpreting the present results. Firstly, no data could be collected concerning the 61 women who dropped out just after randomization, apart from eligibility criteria. This initial attrition may have been linked to the fact that the trial recruitment process was conducted at a crucial point in the health care pathway: in the second trimester of pregnancy in the same maternity ward in which they were due to have their babies. Although all eligible subjects were informed, both orally and in writing, that they were free to participate or not in the study and that, if they accepted, they were free to withdraw at any moment with no impact on their access to care or the quality of care provided, some women may have not taken sufficient time to reflect upon the implications of participating or may have wanted to please their maternity doctor by agreeing to participate, although without giving enough thought to what their participation would entail.
Acknowledgments The authors acknowledge the 440 families who participated in the study, and the members of the home-visiting team and the research assistants, without whom this project would have been impossible:  Joan Augier ,  Amel Bouchouchi ,  Anna Dufour ,  Cécile Glaude ,  Audrey Hauchecorne ,  Gaëlle Hoisnard ,  Virginie Hok ,  Alexandra Jouve ,  Anne Legge ,  Céline Ménard ,  Marion Milliex ,  Alice Tabareau ,  Francine Messeguem. We also thank the team of the  Binet Children Community Mental Health Center ,  Sebastien Favriel  and the research team of l'EPS.
The CAPEDP study was supported by research grants from the  French Ministry of Health Programme Hospitalier de Recherche Clinique  (PHRC:  AOM05056 ), the  Institut National de Prévention et d'Education à la santé  (INPES:  DAS 08/2006 DAS 018/09 DAS 084/10 ), and the  Institut de Recherche en Santé Publique  (IReSP:  REV0702 ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Sequencing and assembly of the C. convexus mitochondrial genome The C. convexus mitochondrial genome was assembled from data generated as part of the sequencing of the Wolbachia endosymbiont of C. convexus (M. Badawi, B. Moumen, P. Grève, and R. Cordaux, unpublished data). Briefly, gonads of 30 C. convexus female individuals (all sisters), from our laboratory line CCw (derived from individuals caught in Avanton, France, in 1993) were pooled, and total genomic DNA extraction was performed using a standard phenolchlorophorm protocol. The sample was sequenced by GenoScreen (Lille, France) on 1/4 and 1/8 runs of a 454 GS FLX sequencer using the Titanium chemistry, providing a total of $110 Mb of sequence data. Read quality was checked with FastQC and reads were assembled de novo (including quality filtering and trimming) using the gsAssemler software implemented in Newbler version 2.
Annotation The T. rathkei mitochondrial genome was initially annotated using the MITOS web server  (Bernt et al. 2013) , which identifies proteincoding and rRNA genes using homology searches, and a variant of the MITFI algorithm  (Juhling et al. 2012)  to identify putative tRNA genes. We used the invertebrate mitochondrial genetic code, and the default settings for all other parameters. We also used ARWEN  (Laslett and Canback 2008)  to provide a complementary set of predicted tRNA genes. Finally, the annotations for the protein-coding and rRNA were manually corrected, aided by BLAST searches against other isopod mitochondrial genes, because in many cases the initial sequences generated by the automated software lacked start or stop codons or were obviously incomplete (e. g. , rRNA genes were too short).
2007; Kilpert et al. 2012)  (Figure  1 ). The positioning of putative tRNA genes, however, was more variable between the two species (Figure  1 ). As a whole, the mitochondrial genomes of the two species displayed $72% sequence identity when aligned by ClustalW2  (Larkin et al. 2007 ). The assembled sequences and annotations have been deposited in GenBank under accession numbers KR013001 and KR013002. Heteroplasmic sites in T. rathkei Coverage across the T. rathkei mitochondrial genome was quite high,. 300• across most of the genome in each sample, except at the very ends of the monomer sequence (Figure  2 ). There were no fixed sequence differences between the two individuals sequenced. However, eight heteroplasmic sites were identified (Figure  2 , Table  1 ). Six of these heteroplasmic sites were detected with confidence in both individuals, and each allele occurred at a frequency of approximately 0.
ACKNOWLEDGMENTS We thank  Roberto Joachim  for assistance in the laboratory and two anonymous reviewers for helpful suggestions on earlier versions of this manuscript. This work was funded by a  Rice Creek Associates Small Grant  to CHC, a  European Research Council   Starting Grant  ( FP7/2007-2013  grant  260729 EndoSexDet ) to R. C. and intramural funds from the  Centre National de la Recherche Scientifique  and the  French Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche.
Flow cytometer Bone marrow engraftment was determined 1 month after engraftment on a blood drop sample using anti-CD45. 1/PE (BD Pharmingen ™ , BD Biosciences, San José, California, USA) and anti-CD45. 2/FITC (BD Pharmingen ™ , BD Biosciences) antibodies. Flow cytometer analysis was performed on a BD Biosciences FACScalibur™ with CellQuest software (BD Biosciences).
Sections were covered with DAPI-containing mounting medium (Vector Vectashield). Tumors were first analyzed using epifluorescence microscopy (Leica DM 5500B, Leica, Wetzlar, Germany) before being examined on a confocal microscope (Leica TCS SP2). Bones were analyzed using epifluorescence microscopy. All images were acquired with Metamorph software and processed using ImageJ software.
Objectives: A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labeled peptide doses, as well as the delay between their injections. Methods: Three cohorts of three patients received the anti-CEA × anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88 nmol/ m 2 of TF2 followed by 4. 4 nmol/m 2 , 185 MBq, of 111 In-labeled IMP288) and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m 2 of TF2 followed by 24 nmol/m 2 , 1. 1 GBq/ m 2 , of 177 Lu-labeled IMP288). The pretargeting delay was 24 or 48 h. The dose schedule was defined based on preclinical TF2 pharmacokinetic (PK) studies, on our previous clinical data using the previous anti-CEA-pretargeting system, and on clinical results observed in the first patients injected using the same system in Netherlands.
Modeling of the serum concentration PK was performed using a two-compartment model for the bispecific antibody (TF2) and two or three compartment models for the radiolabeled hapten (IMP288), using a population PK software package, developed in the laboratory and validated against Monolix  (20). Patients' body surface areas (BSAs) were used as covariables. In the hapten PK analyses, several covariables were tested to represent the effect of TF2 on the kinetics of IMP288. Finally, the molar ratio of injected hapten to the amount of TF2 present in the patients' serum (MR), calculated as the concentration of TF2 extrapolated to the time of hapten injection multiplied by the central compartment volume (Vc) obtained in the TF2 PK analysis, was the covariable used to take the effect of TF2 on IMP288 PK into account.
For the PK analysis of tissue distribution from image quantification, the WB kinetics was used as an input function, and the IMP288 distribution in tissues of interest was modeled using a tissue-specific distribution compartment and a fraction of the activity in the central compartment. The on and off rate constants, kon and koff, and the fraction of activity (fraction) were adjustable parameters. ). Blood samples were collected at selected time intervals during and after each infusion and centrifuges. TF2 concentrations were measured using a specific ELISA. The pharmacokinetics was then modeled using a two-compartment model and a population approach. Data collected after both infusions were fitted using a single set of parameters. Results (open squares) are plotted as a semilog plot with the population (dashed lines) and individual (solid lines) fitted curves.
Dosimetry Quantitative imaging was performed on tomographic reconstructions (OSEM 30 iterations, eight subsets) taking into account attenuation, Compton scattering (correction performed on projections), and collimator response corrections as expressed in international guidelines  (22). Initial estimated system sensitivity reported in Table  2  was used to translate detected count into activity for 111 In and 177 Lu acquisitions. Patients' organ masses were derived from automatic or manual CT images segmentation performed with 3D Slicer (23) software. Trabecular bones in L2-L4 lumbar vertebras were also segmented in order to evaluate bone marrow-absorbed dose  (24). Tumor volumes were segmented on emission-reconstructed images and performed on images where the tumor-to-background ratio was visually designed as optimum.
Tumor labeled volumes were subsequently exported as DICOM-RT structure set and integrated into the patient labeled-organs images after registration. In order to obtain time-activity curves for volumes of interest, labeled images were registered against CT images performed at every imaging session using the MedInria software  (25). Then, organ time-activity curves were adjusted with nls package of R software (26) using mono-or biexponential functions depending on the number of time points available to perform the regression analysis and submitted to a population PK analysis using the laboratory software package. To estimate patient's organ-absorbed doses at pretherapeutic and therapeutic stages, MIRD S factors were scaled by patient organ masses. Time integration of fitted functions was calculated to derive cumulated activities at both sessions.