dataesr/scientific-paragraphs-categorization huggingface dataset:
In this model, Lys 46 /Arg 47 /Glu 49 from the MTase domain are in the vicinity of residue 512, giving a rather compact shape to the NS5. However, a single stable conformation for the isolated NS5 protein is not fully consistent with the small angle x-ray scattering data, which suggested that NS5 can adopt a range of conformations from compact to fully extended  (5). In this respect, the segment comprising amino acids 263-267 of the NS5 protein (DENV3 numbering; see Fig. 1a ) appears to be the major determinant that imparts flexibility between the MTase and RdRp domains. This hypothesis is supported by a recent structure of the fulllength NS5 protein from Japanese encephalitis virus (JEV) (24): a superposition of the DENV3 polymerase domain (Protein Data Bank code 4C11; this work) onto the full-length NS5 protein from JEV (Protein Data Bank code 4K6M) is shown in Fig.
Although progress has been made to control gene expression by using 'tet-off ' systems and/or promoters with more restricted patterns of expression, such as the neuropsin promoter, these are also often leaky;  32  (ii) most transgenic animals fail to model disease progression steps from pretangles to ghost tangles. The first step of a pathological process should be initiated after the local delivery, in a specific brain area, of pathological proteins. In this context, the emergence of efficient viral vectors for central  or LV-hTau46 P301L delivery, animals were killed, and their brains were processed for immunohistochemistry using the ADx215 primary antibody. Cresyl violet staining was performed to identify neurons. Bars represent 300 μm (in a,b,d, and e) or 80 μm (in c,f). (g) ADx215 immunoreactivity was quantified using Mercator software and expressed as a percentage of the immunoreactive surface relative to the entire quantified surface.
The p24 protein is a lentiviral capsid protein that is commonly used in ELISA assays to determine the physical titer of lentiviral batches per milliliter. The ability of LVs to induce the expression of Tau in vitro was tested by infecting 5 × 10 5 HEK293T cells with increasing amounts of viral vectors (200 and 400 ng of p24). Forty-eight hours later, cells were processed by western blotting (data not shown). (ii) The functional titer was determined in a limiting dilution assay to detect Tau expression by immunofluorescence. HEK293T cells (3 × 10 5 per well) were seeded onto six-well plates and transduced with increasing amounts (4,260 × 10 -5 to 1 × 10 -5 ng of p24 per cell) of LVs encoding hTau46 WT or hTau46 P301L in serum-free medium. Six hours later, complete medium was added to the well, and the cells were incubated for 48 hours at 37 °C.
5 mg/ml DAB (Vector Laboratories) in 50 mmol/l Tris-HCl, pH 7. 6, containing 0. 075% H 2 O 2. Brain sections were mounted on gelatin-coated slides, stained for 1 minute in a 0. 5% cresyl violet solution, washed with 2% acetic acid, dehydrated through a graded series of alcohol and toluene, and then mounted with Vectamount (Vector Laboratories) for microscopic analysis using a Leica DMRB microscope coupled with a Leica DC300 camera (Leica Microsystems, Nanterre, France). Image analysis. Tissue sections were quantitatively analyzed using stereology software (Mercator image analysis system; Explora Nova, La Rochelle, France). The software uses hue, saturation, and intensity to distinguish objects (cellular bodies) in the image field. Thresholds were established using accurately identified objects on a standard set of slides, and these segmentation thresholds remained constant throughout the analysis session (the region of interest was the whole hippocampus).
The Mercator software calculates the measurement parameters for the entire field of view at 500X magnification. For quantitative image analysis of IHC, we selected all brain sections from bregma -4. 8 to -6. 3 (10-15 sections were analyzed per animal). The area immunoreactive to the antibodies (ADx215, AT8, MC1 or AT100) was normalized to the whole area analyzed. For CA1/2 thickness measurements, quantification was performed based on cresyl violet coloration in all brain sections from bregma -4. 8 to -6. 3. In each individual section, the entire pyramidal layer was drawn using Mercator software (Explora Nova) to calculate the average thickness. Immunofluorescence. Brain sections (three or five rats per group) were washed with PBS-Triton 0. 2%, and nonspecific binding was blocked through incubation with goat serum (1/100 in PBS; Vector Laboratories) for 60 minutes.
ACKNOWLEDGMENTS This work was developed and supported through the  LABEX (excellence laboratory, Invest  for the Future) and  DISTALZ programs (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease)  programs. It was also supported by the  Inserm ,  CNRS, IMPRT (Institut de Médecine Prédictive et de RechercheThérapeutique, Lille), University of Lille 2, Région Nord/Pas-de-Calais ,  FEDER  and  DN2M  (VICTAUR), and grants from  ANR-08-MNPS-002/AMYTOXTAU  and the  European Community , including MEMOSAD (FP7 contract  200611 ) and  FRC  (" Fondation pour la Recherche sur le Cerveau "). We are also grateful to the IMPRT for access to core facilities (electron microscopy,  Cécile Allet  and confocal microscopy, Meryem Tardivel). We thank  KU Leuven-LRD (Leuven, Belgium)  for providing the ADx215 antibody for academic research purposes and  Eugeen Vanmechelen  ( Ghent, Belgium ) for advice.
e. , by incorporating uncertainty on individual parameter estimates. This could be done by reconstructing the a posteriori distribution, for instance using MCMC methods. The ultimate goal of viral kinetic modeling is to allow for individual parameter estimation and treatment tailoring. To achieve this goal, pharmacometricians will need reliable models and appropriate sampling designs that can provide precise parameter estimation. The information contained in a design can be a priori evaluated and optimized using the Fisher information matrix. This approach became a standard tool for pharmacokinetic/pharmacodynamic studies using NLMEM and was implemented in several software such as PFIM, PopED, POPDES, and POPT. 30 However, viral kinetic models have specific features that are not always properly addressed in these software such as the large proportion of BDL data  31, 32  and the need to achieve a good level of precision of both population and individual parameters.
We simulated N = 1,000 vectors of random effects η i to calculate individual parameters θ i from the population parameters of the true model. We then predicted the viral kinetics in these 1,000 in silico patients using the mathematical model (Eq. 1). Residual errors were then simulated and added to viral load data for all sampling times of D 24w to obtain dataset for D 24w design. As the four designs are nested, to generate datasets for other designs, we selected the simulated viral loads corresponding to the sampling times of the design of interest (Supplementary Material 4 online). As the same data of the same 1,000 simulated individuals were used to generate all the datasets, all the differences obtained in results were not due to Monte Carlo errors. We considered a limit of detection LOD = 45 IU/ml.
40 o estimate individual parameters for 1,000 simulated patients, individual random effects η i were first estimated and then used to calculate individual parameters. We supposed that population parameters were already known and fixed them at different sets of a priori values corresponding to M true , θ µ η M δε , M β to perform MAP. BDL data were handled using two approaches: taking into account BDL data in the likelihood function (likelihood-based approach or LBA) or omitting all BDL observations in the dataset (OMIT). iq q i q = ( ) exp ε µ µ µ η ε ε ε ε i i = + - ( ) - 1 ( ) exp η η η η η η i i i i i i i argmax p y argmax p y p p y i i = ( ) ( ) = ( )× ( ) ( )  | | | , , ψ ψ ψ         p y y y f t i i ij ij i ij y LOD ij | l og log lo η φ η σ , , , , ψ Φ ( )= ( ) ( ) ( ) ( ) × ∏ ∏ > 1 1 2 g g l og LOD f t i ij y LOD ij ( ) ( ) ( ) ( )≤ , , , η σ 2 1 To evaluate the ability of estimation of the component q of an individual parameter, we used the following criteria: Mean Relative Error (MRE) and Relative Root Mean Square Error (RRMSE) defined by:t (7) (8)   For ε, we evaluate the MRE and RRMSE of log 10 (1-ε).
To evaluate the gain of using modeling approach compared to empirical rules used in clinics, we also evaluated the predictive ability for SVR of "rapid virologic response," RVR-defined as undetectable viral load at W4. We also considered a shorter treatment that was stopped at W12 in order to evaluate the ability of outcome prediction in a challenging case. All simulation was using R 2. 14. 0. Parameter estimation (Supplementary Material 5 online) was performed using MONOLIX 4. 1. 2. 3 Viral kinetic models can be used for treatment outcome prediction in hepatitis C virus infected patient. Individual parameters can be estimated using Bayesian approach and a priori information on population model. WHaT QUESTIOn THIS STUDY aDDRESSED? 3 We evaluated the influence of a priori information, viral load sampling designs, and methods handling data below detection limit (BDL) on individual parameter estimation and treatment outcome prediction.
Data on age, gender, and marital status was collected. Several dimensions of socio-economic position (SEP) were taken into account such as education, profession and household welfare level  [6]. For the education and the profession of the subject, the last school class attended by the subject and the professional category were collected based on detailed classifications from the national statistical institutes in each country. For analysis purposes, they were then recoded into three categories of education and profession (Table  1 ). Separately for each country, an asset-based index of household welfare was derived by multiple correspondence analysis of a set of items pertaining to housing characteristics and ownership of appliances. A detailed analysis of the relationships between the items and the first principal component was then performed, which enabled its interpretation as a continuous gradient of wealth (material living conditions).
Overall adiposity was assessed by body mass index (BMI) = weight/height 2. Thinness was defined as BMI ,18. 5 kg/m 2 , overweight (including obesity) as BMI $25. 0 and obesity as BMI $30  [20]. Abdominal adiposity was assessed using the waist-to-height ratio (WHtR) and for both men and women the same $0. 50 and $0. 60 thresholds defined increasing levels of abdominal adiposity  [21, 22]. Data collection. Surveys were conducted during home visits by trained field workers using standardized anthropometric measurements and socio-demographic questionnaires.
Data Management and Statistical Analysis Epidata software version 3. 1 was used for data entry and validation and Stata 12 for data management and analysis  [23, 24]. For continuous anthropometric response variables, linear models  [25]  estimated associations by crude and adjusted means and/or differences in means. For binary anthropometric response variables, logistic regression models were used to assess crude and adjusted prevalence odds-ratios (OR) and/or prevalence proportions  [26]. Except for the specific issue of within country gender contrasts, relationships of obesity with area and socioeconomic factors were analyzed in each country separately for each gender, so as to compare and discuss the measures of association ''between countries within gender''. The type I error risk was set at 0.
The project was organised in three main aims: Collect, collate and combat. These aims were achieved through eight work packages (WPs) with a scientific focus, 1 WP specifically addressing ethical issues and 2 WPs dealing with overall study management and training of emerging scientists. In this special issue of Biogerontology we report the detailed methodology and phenotype data collected from 504 young and older healthy men and women. Biological material (muscle biopsies, muscle cell cultures, blood and serum samples) were collected from these well characterised young and old sedentary and active subjects and was used by all research groups to try to correlate the age related physiological modifications to cellular and molecular mechanisms. The different chapters in this issue highlight some of the findings of this study.
The results of this work provide a detailed insight into ''normal, healthy'' ageing as well as disease and link wholebody function and systems-biology to the structure and function of the neuromuscular systems and the molecular characteristics of skeletal muscle. The work will be used to define guidelines for public health promotion in older age. All data have been retained in a database. A biobank including blood and muscle tissue samples is being maintained and we welcome opportunities to collaborate and further develop our understanding of the impact of ageing on neuromuscular function and health. Finally, several workshops were organized for young students and scientists, thus paving the way to a body of confirmed scientists within the field of muscle ageing. In conclusion, the concerted research projects conducted within MYOAGE, and which associated clinicians, cell and molecular biologists and physiologists, most of the members having multiple expertise, confirmed some data described on animal models, but also infirmed others, thus designing a new landscape representing human muscle ageing.
Image analysis and quantification All the slides were analyzed by an investigator blind to the nutritional status of the animals. Single and double labelled sections were analyzed and documented using a fluorescence microscope attached to an Axioplan imaging Apotome apparatus (Carl Zeiss S. A. S. , Le Pecq, France). Processing of digital images was performed using the softwares AXIOVISION (Carl Zeiss) and the number of immunopositive cells was automatically determined using automated image analysis software (VolocityH). At least three slices per animal spanning the mediobasal hypothalamus, including the arcuate nucleus (ARC) and the ventromedial hypothalamic nucleus (VMH), or the paraventricular nucleus (PVN) were used to quantify the number of labelled cells. To determine the number of POMC-positive cells expressing pmTOR, six to eight areas per slice were analyzed based on the number of immunostained nuclei and their uniform fluorescence intensity.
Literature search PubMed/MEDLINE and EMBASE were searched to identify the primary literature on IFDs (Supplementary Table  1 ). Searches were limited to results published in English; during the last 10 years (2000 to early 2011); and having reported on human subjects. Abstracts from clinical congresses [International Society for Pharmacoeconomics and Outcomes Research (ISPOR), Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), IDSA and the European Society of Clinical Microbiology and Infectious Diseases (ECCMID)] were searched for data that may still have been in press. Abstract searches were limited to results published in English; during the last 5 years (2005 to 2010); and having reported on human subjects. Key review papers and reports issued by disease surveillance agencies were utilised to define targeted searches.
A prospective, randomised clinical study comparing empirical and diagnostic-driven (pre-emptive) therapy in patients with acute leukaemia or undergoing allogeneic SCT is ongoing in European centres (NCT01288378). Studies assessing the economic burden of IFDs are limited; the incremental cost burden is estimated to be between €10,530 and €51,033, depending on the certainty of infection and the duration of follow-up. Drivers of HCRU burden included hospitalisation, diagnostic testing and medications. To demonstrate a clear cost benefit, further evidence that a pre-emptive strategy decreases antifungal use compared with a standard empirical approach is needed. In conclusion, the primary evidence reported here demonstrates the importance of IFDs in Europe and highlights the need for early and appropriate therapy, facilitated by new techniques for more rapid diagnosis.
Conflicts of interest: Matteo Cesari has been consultant for Nutricia, Sanofi and Nestlé, and has a research project funded by Pfizer. The other authors had no conflicts of interest to disclose related to this manuscript. This work was supported by an unrestricted educational grant from Nestlé Health Science (NHSc). NHSc had no role in the choice of members of the Consensus Group, but had the right to have an observer member at the meeting. Members of the Consensus Group received no salary in the preparation of this manuscript.
5-2. 3 mm anterior to the interaural line) of the hypothalamus and in the NTS (3. 7 mm posterior to the interaural line) and AP (3. 7 mm posterior to the interaural line) of the brainstem  (Franklin and Paxinos, 1997). NPY neurons were visualized using GFP fluorescence. GFPpositive cell bodies expressing cFos were quantified unilaterally under 40× magnification using a confocal SP5 microscope (Leica, Wetzlar, Germany). Co-localizations were determined with the Image-J software (http://rsbweb. nih. gov/ij/) on series of continuous optical sections with 0. 5 µm increment along the z-axis of the section.
ACKNOWLEDGMENTS This work was supported by an  IPSEN grant  to  Virginie Tolle  and  Jacques Epelbaum. We are grateful to  Alice Cougnon  for the care of the animals and to  Julie Cognet  for technical assistance. The compounds utilized in this study,  BIM-28131  and  BIM-28163 , are now known as  RM131  and  RM163. RM131 is currently in clinical development by  Rhythm, Boston, MA, USA.
Patients suffering from IMF and essential thrombocythemia have significantly elevated circulating levels of plasma PDGF. Pretreatment of normal NK cells with concentrated PDGF-containing plateletpoor plasma from patients with these diseases significantly inhibits NK cytotoxicity. This inhibitory effect is reversed by neutralization of plasma PDGF with anti-PDGF  (17, 49). All these data suggest that PDGF is probably a key factor of NK functional deficiency in MPS. Interaction between tumor cells and NK impairs NK-cellmediated cytotoxicity and thus induces tolerance to tumor invasion. Up-regulation of the immunosuppressive cell surface glycoprotein CD200 and of soluble GITRL (glucocorticoid-induced TNFR related protein ligand) on AML cells specifically compromises NK-cell anti-tumor responses  (50, 51)  and is a poor prognosis factor.
Another attractive therapeutic approach consists in blocking the NK inhibitory receptors. A phase 1 trial has tested the IPH2101, a fully humanized IgG4 anti-KIR monoclonal antibody, in patients with relapsed/refractory AML (clinical trial registration number NCT01256073) and MM (clinical trial registration number NCT00999830). IPH2101 promotes immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable and that this approach warrants further development in MM and AML (80-82) as we are waiting for clinical results. Several studies revealed ADCC as one major mode of action of antibody-based therapeutics and stimulated more interest in how to mobilize, expand, and activate NK cells in humans  (83).
Acknowledgments The authors thank the patient's family members for their willingness to participate in this study. The authors thank  Michelle N'Guyen ,  Martine Courat , and  Tony Leclerc  for secretarial and technical assistance. The  Laboratory of Human Genetics of Infectious Diseases  is supported in part by grants from  BNP-Paribas  and  Schlumberger Foundations , the  March of Dimes , the  Dana Foundation , the  St. Giles Foundation , and the  Agence Nationale de la Recherche Médicale. The Immunodeficiencies Research Unit is supported in part by  Fundacion Mexicana para Niñas y niños con Inmunodeficiencias Primarias (FUMENI). Marjorie Hubeau  is supported by a fellowship grant from the  Société Francaise d'Hématologie.
Data analysis Due to low participation in both races prior to 2000, only data between 2000 and 2012 were considered. Since we intended to analyze the change in age-related performance, all finishers who were ranked without age were excluded from the analysis. In order to compare performance between the two races, running speed was calculated as: Running speed [km/hour] = Running distance [km]/ Running time [hours] (1) The changes in running performance and in the age of peak performance of the top five overall men and women runners were analyzed for both races. The sex-based effects on running performance were also analyzed. Sex difference was calculated as: we decided to analyze only the best annual performance (ie, fastest annual running speed) per age group, sex, and race.
One particularly successful member of this family is CA(1-7)M(2-9), which we have been studying by a variety of biophysical methods. 55, 56 e peptide has a random structure in aqueous solution, and acquires an a-helix secondary structure in the presence of membranes. Thus (i) the temperature dependence of proton mobilities (averaged mean square proton mobilities), hu 2 i, of three peptide samples were calculated -a nominally dry peptide (residual specific hydration h = 0. 060 g/g), an H 2 O-hydrated one (h = 0. 49) and a D 2 O-hydrated one (h = 0. 51); and (ii) the trends of C p values calculated from the neutron derived VDOS functions for both H 2 O and D 2 O hydrated samples were compared with the heat capacity (C p ) data obtained by adiabatic low temperature heat capacity calorimetry, in a large temperature range.
Peptides scatter neutrons coherently as well as incoherently, and both components yield structural and dynamical information in the form of dynamic structure factors S coh (Q,o) and S inc (Q,o) which relate closely to fundamental space-time correlation functions. 58 The large proton incoherent scattering dominates by a factor of B10 over all other contributions even after D 2 O exchange and low-level D 2 O hydration. The datasets obtained thus represent S inc (Q,o) functions which form the basis for analysis in terms of g(o) and hu 2 i. Table  1  shows the calculated total neutron scattering cross-sections s inc and s coh for the H 2 O and D 2 O hydrated samples in order to provide a rough idea of the relative scattering powers expected for the sample conditions used. 2. 2. 2. For adiabatic calorimetry.
The detector efficiency was determined by running the spectra of a vanadium sample having the same geometry of the sample. The spectrum of the empty container was also recorded, and used to correct all experiments. 2. 3. 2. Data analysis. QENSH,  59  the standard data analysis software of MIBEMOL, was used to correct the data, to normalise them with respect to monitor counts and vanadium run and to analyse them as described below. Neither multiple-scattering nor multi-phonon corrections were applied since their effect on integral properties of the spectra was considered negligible and detailed lineshape analyses were not required in the present context. Since for H 2 O and D 2 O hydrated biomolecules the scattering is incoherent to a good approximation, the window-integrated (range À2R o ho o 2R) elastic intensity, S qe (Q,T), is essentially proportional to a proton-weighted Debye-Waller factor in regions where the dynamic behavior is adequately described by a system of harmonic or quasi-harmonic oscillators.