dataesr/scientific-paragraphs-categorization huggingface dataset:
Discussion of study design We chose to conduct a cluster randomised trial. This choice is justified with respect to the form of the intervention, which is carried out at the level of the clinical teams (through educational intervention and a computerised malnutrition alert system) and at the level of the dieticians (through a dashboard identifying malnourished children). The intervention was targeted at health care professionals with the aim of studying its impact on patient outcomes  [21]. No intervention was performed at the patient level. Data were gathered at the patient level, which means that our analysis had to take two levels into account: the patient level and the cluster level. Clusters were designed in order to carefully prevent healthcare workers form cross-ward contamination bias.
Only a few large sized clusters were available for study (six clusters). This small number of clusters could result in a relatively high probability of chance imbalance between arms. Clusters from our single pool were randomly assigned to the intervention condition or to the control condition. This completely randomised design is most suited to trials in which large numbers of clusters are available for randomisation. We could have opted for a pre-stratification or matching according to baseline characteristics. We will take into account any differences in the characteristics of the children between the clusters within the statistical analysis, by adjusting the models according to the variables of interest. We performed an observational baseline phase. For six months, prior to the randomised trial, we collected data pertaining to children presenting the inclusion criteria.
Background: Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment. Methods: We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria.
Search strategy and selection criteria The literature published from 1990 to  March 26, 2012  was systematically screened in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases according to PRISMA guidelines  [25]  using the following search terms in the title, abstract, or descriptors: (Alzheimer* and [humans or patients or inpatients or outpatients or persons or volunteers or participants or subjects] and [nutrition or nutritional or nutrient or nutrients or micronutrient or micronutrients or diet or diets or dietary or vitamin or vitamins or mineral or minerals or trace-element or trace-elements or fatty-acid or fatty-acids or pufa or pufas]) The search in the Cochrane Central Register of Controlled Trials, Embase, and Medline resulted in 4768 published studies that were imported into Endnote.
Statistical analysis All reported comparisons of plasma/serum levels in AD patients and controls were integrated and summarized into a final result per nutrient, using meta-analysis (regression) methods  [30] , according to the PRISMA statement  [25]. For each nutrient, we extracted from the articles the mean and standard deviation of plasma/serum levels in AD patients and in controls as well as the number of subjects and the average age per group. To allow comparison across studies, all plasma/serum levels were converted to the same unit value. These data were analyzed using the random-effects meta-analysis model  [30]  fitted by restricted maximum likelihood using the program metareg of Stata (StataCorp. 2001. Statistical Software: Release 12. 1. College Station, TX, USA)  [31]. For this analysis, a minimum of five studies is generally recognized to be required  [28, 29].
Funnel plots, which plot the standard error against the reported mean difference for each publication, can give an indication of the overestimation or underestimation of the actual difference occurring in the meta-analysis. We used Egger's test as implemented in the Stata program meta-bias  [31]  to test the association between standard error and effect size in the funnel plot. For this analysis, a minimum of eight publications is generally recognized to be required  [28, 29]. Statistically significant results of the funnel plot analysis are indicated in the Results section.
Fatty acids The electronic database search with our search string retrieved three publications that investigated DHA and EPA levels in PLs  [38, 41, 42]  and three that investigated these levels in the CE lipid moiety  [38, 42, 43]  in the plasma of AD patients and of cognitively intact elderly controls. Levels were expressed as weight percentage of total fatty acids in the particular lipid moiety. The publications by Corrigan and colleagues  [38, 42]  concerned two different   1 ). These studies comprised 80 control subjects and 69 AD patients. With regard to the CE moiety, one of the three publications (Corrigan et al. [38]  P ,. 01) reported a significantly higher weight percentage of DHA in AD patients versus controls. However, Tully et al. [43]  reported a significantly lower weight percentage of DHA in AD patients (P ,.
RESEARCH IN CONTEXT 1. Systematic review: To evaluate possible different systemic availability of micronutrients and fatty acids between AD patients and cognitively intact elderly controls, we searched in literature databases. We found many publications reporting various results but no comprehensive review of this area. Hence, we performed a systematic review and meta-analysis to generate an overview of this literature. 2. Interpretation: The highly significant effects across a range of nutrients provide conclusive evidence that plasma nutrients levels are lower in AD, and the lower levels may occur in the absence of, or precede, signs of protein and energy malnutrition. Provided the postulated roles for these nutrients in pathological processes of AD, the current observations provide a lead for nutritional strategies in AD.
Acknowledgments The authors thank  Dr. M. C. de Wilde  and  N. van Wijk  for useful discussions and for carefully reading the manuscript. They are also grateful for the contributions of  B. Draijer  and  Dr. S. Swinkels  to the statistical analysis. Contributors: S. L. S. , M. G. , and J. S. designed the study. S. L. S. and S. E. obtained and analyzed the data. T. S. performed the statistical analyses and produced the figures. S. L. S. prepared the first and revised drafts of this manuscript according to the suggestions from co-authors. S. L. S. , J. S. , M. G. , K. Y. , J. L. , P. K. , B. V. , and T. S. interpreted the data and revised the manuscript. All authors approved the final version.
Reference values, including metal treatment without cells, were subtracted from all data sets and compared with nontreated control cells, set to 100% survival. Mean values for multiple repeat Ϯ S. E. values are shown. Cell survival data obtained using WST-1 was confirmed by microscopy. Approximate LC 50 values obtained from the combined data sets are indicated in the figure legends of each experiment. Protein Induction and Purification-Escherichia coli Rosetta(DE3)pLysS (Novagen) cells were transformed with pET28a harboring the WT human PARK7 gene. Protein expression was performed for 20 h in auto-induction ZYM-5052 media at 28 °C  (69). Expressed protein was initially isolated with TALON affinity resin (Clontech) and eluted by thrombin (GE Healthcare) cleavage of the engineered N-terminal thrombin cleavage site in PBS, pH 7.
5. The eluate was incubated with benzamidine-Sepharose (GE Healthcare) to remove residual thrombin, following another TALON affinity resin purification step to ensure complete removal of uncleaved protein and maximized protein purity as verified by SDS-PAGE (Fig. 1A ). The purified protein was further prepared for mass spectrometric analysis  (70). LC-MS/MS sequencing of the trypsinized protein was performed using an Acquity UPLCcoupled Q-TOF Micro (Waters Associates, Milford, MA) and peptide elution with acetonitrile in either a 0. 1% ammonium hydroxide or a 0. 1% formic acid environment. Combination of generated MS/MS data resulted in a 97. 4% sequence coverage matching human DJ-1 using SwissProt database and Mascot (Matrix Sciences) search algorithm. Peptide mass tolerance was 100 ppm, and fragment tolerance was 0.
Data were normalized on the Compton peak maximum and smoothed. Atomic Absorption Spectroscopy-For AAS analysis, 0. 1 mg/ml WT or point-mutated recombinant human DJ-1 was dialyzed for 24 h against AAS binding buffer (20 mM MOPS buffer, pH 7. 2, 150 mM NaCl, 5 mM ascorbic acid, 10% glycerol) containing 10 M CuCl, followed by a second dialysis for 24 h in the same buffer without metal salt. For the recombinant pro-tein, the samples were diluted six times in distilled H 2 O by a Hamilton microlab 500 dispenser system prior to AAS analysis by use of an AAnalyst 300 from PerkinElmer Life Sciences. AAS data were normalized to a copper standard curve and correlated to final DJ-1 protein concentrations, as assessed by the Bradford method. Microscale Thermophoresis-Copper (I, II) and mercury binding affinities to WT recombinant human DJ-1 or pointmutated human DJ-1 variants were measured by MST using a Monolith NT.
Images were taken with Nikon Plan Apo VC ϫ60/1 40 oil objective and NIS elements AR 4. 00. 07 software of several different XY focal planes for 60 and 90 min at 1-and 2-min intervals, respectively. The specimen was excited in-line scanning mode with 408 and 488 nm wavelengths, and emission was collected at 525/550 nm. To minimize the fluorescence bleaching, the laser power was set at the lowest intensity and was equal for both excitation wavelengths. All other parameters that were shown to affect the resulting ratio were always kept the same for every experiment. Pixel intensities of images were controlled to vary between 500 and 3000 to avoid both saturation and false ratios due to insufficient brightness of the reporter. Metal treatments were added at minute 6 of the experiment, and imaging was continued 50 s later with almost no delays.
Acknowledgments-We thank  Dr. Darren Moore  at the  Brain Mind Institute, EPFL, Switzerland , for providing the rabbit anti-DJ-1-N antibody. We thank  Dr. Huaibin Cai ,  National Institute on Aging, National Institutes of Health, Bethesda, MD , for MEF cells from WT and DJ-1 Ϫ/Ϫ mice. We also thank  Dr. C. Plieth ,  University of Kiel, Germany , for the sequence of redox-sensitive S3roGFP.
The Ty active site is not symmetric and it is composed of two copper atoms, each coordinated by three histidine residues. This dissymmetry is clear in the structure of a met form of the bacterial S. castaneoglobisporus Ty (Figure  1 ; PDB code: 2AHK),  [2a]  in which the geometry around the CuA center is close to a square pyramid (t = 0. 22), whereas the geometry around the CuB center is intermediate between a square pyramid and a trigonal bipyramid (t = 0. 48); (t = 0 for a regular square pyramid and t = 1 for the regular trigonal bipyramid geometry). [16] n order to mimic this dissymmetry, we pursued our investigations by generating an unsymmetrical complex, [Cu 2 - (3), which was obtained from the new unsymmetrical 2-[bis(2-pyridylethyl)-aminomethyl]-6-[bis(2-pyridylmethyl)-aminomethyl]-4-methylphenol (HBPMEP) ligand (Scheme 2).
The results obtained highlight   [14]  and  [15]  and the characterized or possible binding modes for HOPNO at the dicopper(II) centers. A C H T U N G T R E N N U N G (BPMEP)A C H T U N G T R E N N U N G (m-OH)]A C H T U N G T R E N N U N G (ClO 4 ) 2 A C H T U N G T R E N N U N G (BPMP)A C H T U N G T R E N N U N G (m-OH)]A C H T U N G T R E N N U N G (ClO 4 ) 2 (1) [Cu 2 A C H T U N G T R E N N U N G (BPEP)A C H T U N G T R E N N U N G (m-OH)]- A C H T U N G T R E N N U N G (ClO 4 ) 2 (2) Figure  1. Graphical representation of the met form of the bacterial Streptomyces castaneoglobisporus Ty active site (PDB code: 2AHK)  [2a]  showing the dissymmetry of the coordination of the two copper centers. the importance of a serine residue that is close to the active site in the enzyme.
These data are reported in Table  2 , together with the binding constants (K b ) of HOPNO to 1-3, determined from the refinement of absorbance data versus the HOPNO concentration by the Specfit software. The series of curves exhibit an isosbestic point, which indicates that one absorbing species is formed. The K b value found with 3 is significantly higher than those obtained for complexes 2 and 1, respectively,  [15]  and the stoichiometry of the adduct is found to be 1:1. The UV/Vis spectrum from isolat-Table  2. UV/Vis spectral data and binding constants for 3 and for adducts 1-OPNO, 2-OPNO, and 3-OPNO (10). (z = 2) for [Cu 2 A C H T U N G T R E N N U N G (BPMEP)A C H T U N G T R E N N U N G (OPNO)] + A C H T U N G T R E N N U N G (ClO 4 ) and [Cu 2 A C H T U N G T R E N N U N G (BPMEP)- A C H T U N G T R E N N U N G (OPNO)] 2 + , respectively (Figure UV/Vis: l max [nm], (e [m À1 cm À1 ]) Binding constant (K b ) [m À1 ] LMCT d-d 3  [a]  337 (  1440 ) 386 (  1220 ) 645 (  200 ) 1-OPNO  [b,15]  430 (  610 ) 700 (  212 ) 440 AE 70 2-OPNO  [b,15]  429 (5200) 670 (  490 ) 8000 AE 400 3-OPNO  [b]  420 (  1530 ) 650 (  170 ) 27100 AE 9750 [a] Determined at 25 8C from 2.
7 10 À4 m solution in H 2 O/DMSO (95/5) buffered at pH 7 (HEPES, 50 mm). [b] Determined from the electronic spectra calculated from the refinement of absorbance data by the Specfit program. ed 3-OPNO (10; 2. 7 10 À4 m) displays bands at 416 nm (e % 1629 m À1 cm À1 ) and 649 nm (e % 191 m À1 cm À1 ), values that are consistent with those obtained from the calculated electronic spectrum (Table  2 ). [21] R spectroscopy: The EPR spectra were measured at 100 K in a frozen solution in 1 mm H 2 O/DMSO (1/1) buffered at pH 7 with 50 mm HEPES. Complex 3 is EPR silent, in accordance with the strong antiferromagnetic-coupling (S = 0) ground spin state between the two copper atoms. This observation is consistent with the doubly bridged structure and the short Cu…Cu distance These data show that some of the copper ions released from 10 in solution are complexed by HOPNO as a mononuclear species.
For the two binding modes in the enzyme, the aromatic ring of the OPNO ligand is p stacked with His194 of the enzyme. Figure  4  illustrates this interaction for the two structures. The distances between the OPNO ligand and His194 are similar in the two structures, which suggests an interaction of the same strength. This interaction was already observed in the crystallographic structures of type-3 copper enzymes. For example, it was found between the in-hibitor phenylthiourea (PTU) and a histidine residue close to the active site of a catechol oxidase (PDB code: 1BUG). [24] o compare the two binding modes, we can look at the QM/MM energy of the system. However, the monodentate mode (Figure  4 B ) has an extra water molecule on the free copper atoms of the active site. So, a single-point calculation has been performed for the monodentate mode without the water molecule.
Experimental Section General: All starting materials were commercially available and used as purchased, unless stated. ESI mass spectra were recorded on an Esquire 300 plus Bruker Daltonis instrument. Elemental analyses were performed at the analysis facilities of the Department of Chemistry of the University of Grenoble, France. UV/Vis absorption spectra were obtained by using a Varian Cary 50 spectrophotometer operating in the 200-1000 nm range with quartz cells. The temperature was maintained at 25 8C with a tem- perature-control unit. 1 H NMR data were recorded on a Bruker Advance 300 spectrometer at 323 K with the deuterated solvent as a lock. X-band EPR spectra were recorded at 100 K with a Bruker ESP EMX Plus spectrometer equipped with a nitrogen-flow cryostat and operating at 9. 3 GHz (X band).
Determination of stability constants: The binding constants of the inhibitor to the dinuclear Cu II complexes were determined by spectrophotometric titration in water/DMSO (95/5) solutions buffered at pH 7. 0 with 50 mm HEPES. The titrations were carried out by adding small aliquots of a concentrate solution of the inhibitor to solutions of the complexes. The spectral data were refined with the Specfit program. [19] techol oxidase activity and kinetics: UV/Vis spectra and kinetics were recorded by using a quartz cuvette (1. 0 cm) and a Varian Cary 50 UV/Vis spectrophotometer equipped with a Peltier thermostating accessory. The kinetics of the 3,5-DTBC oxidation was determined by the initial-rates method by monitoring the increase in the product (3,5-DTBQ) at 400 nm. All of the kinetic experiments were conducted at a constant temperature of 25 8C, monitored with a thermostat.
[25] he data were then integrated and scaled with EvalCCD software. [26] The structures were solved by direct methods and refined by full-matrix leastsquare methods with the SHELXL program  [27]  implemented in Olex2 software. [28] For both structures, all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were generated in idealized positions, riding on the carrier atoms, with isotropic thermal parameters, except for the hydrogen atom of the hydroxy group, which was localized on a difference Fourier map and was added. Pertinent crystallographic data and refinement details are summarized in Table  4. CCDC 881633 (3•THF) and CCDC 881634 (10•solvate) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.
Acknowledgements The authors thank the  French Agence Nationale pour la Recherche  for financial support ( ANR-09-BLAN-0028-01/02 ) and for grants to C. B. and C. D. We are grateful to  Florian Molton  ( DCM ) for measuring EPR spectra. This work has been carried out in the framework of  COST action   CM1003 (WG 2 ) and of  Labex ARCANE.
Inclusion and Clinical Management Clinical data on admission, at day 3 and at discharge were recorded in a standardized case report form designed for the study. In the case of death, clinical data from the last examination before death along with detailed treatment information were captured. The cause of death was assessed by the medical doctor on call according to the last medical examination (prior to death), medical history and laboratory examinations. Every medical record, including the medical records of the children who died, was then reviewed by 2 medical doctors (the study research assistant and the principal investigator of the study). Children were treated according to WHO therapeutic guidelines for complicated SAM  [4, 5]  adapted by MSF. Dietary treatment included 8 daily meals of F-75 milk for stabilization in intensive care or transition unit, followed by F-100 milk for nutritional rehabilitation in cases exiting intensive care prior to discharge.
Acknowledgments We wish to thank  Monique Dehoux , from  Hopital Bichat-Claude Bernard in Paris , who performed the biochemical analyses. We would also like to thank all the persons who helped in the study set-up, result analysis or interpretation:  Christelle Vallet ,  Sarah Hustache ,  Celine Langendorf ,  Melissa McRae ,  Alexandre Blake ; as well as the study scientific committee:  Prof Antoine Andremont ,  Prof Philippe Reinert ,  Prof Dominique Gendrel. We are grateful to  Patricia Kahn  for her helpful comments and corrections in the manuscript. The Chromagar media used in the study were provided free of charge by  Chromagar, Paris, France. The protocols, primers and probes for the molecular diagnosis of influenza virus were provided by the  National Reference Center for Influenza for Northern France.
d. , 15 g of Si 60 silica gel, particle size 40-63 lm, Geduran, Merck) which was preactivated with 10 mL of CHCl 3. Elution was performed at a flow rate of 4 mL/min. First, neutral lipids such as triacylglycerols and carotenoids were removed by 250 mL of CHCl 3. Then, PL were eluted with 200 mL of CH 3 OH/1M aqueous formic acid (adjusted to pH = 3 with triethylamine) (98:2, v/v) mixture. The solvent was removed by rotary evaporation, and the residue containing pure PL was stored at -20 °C for the chromatographic separation. A chromatographic system, made of a 616 controller, a 2424 ELS detector and a 717 Plus autosampler (Waters, Saint-Quentin-Fallavier, France) controlled with Empower 2 software (Waters), was used to analyze PL classes. Highpurity nitrogen from a nitrogen generator (Domnik Hunter, Villefranche-sur-Saone, France) was used as a nebulizing gas at a pressure of 310 kPa.
The fatty acid composition of diets and the analytical data of walnut oil phytosterols, tocopherols and phospholipids are summarized in Tables  2  and 3 , respectively. Food intake was measured daily and body weight four times a week. At the end of the feeding period, the animals were fasted overnight, deeply anesthetized by carbon dioxide and killed by decapitation. Liver tissues were collected and stored at -80 °C. All animal experiments were approved by the Animal Care Committee of the Regional Administrative Authority, Karlsruhe (35-9185. 81/G-89/09), and all animal care and handling were conducted in accordance with the guidelines of the German law on animal care.
The p values that were given in the text and figures result from these post hoc tests. To test for the assumptions that have to be met for the GLS-ANOVA, we made plots to visually inspect residuals. Studentized residuals were plotted against fitted values to assess homoscedasticity. QQ-plots were used to test normal distribution of the residuals. Further, both plots were used to identify outliers. All calculations were carried out by R 2. 15. 2  [42]. GLS-ANOVAs were calculated by R package nlme  [43].
Acknowledgments We thank  D. Haase ,  E. Hoch ,  C. Hoffmann ,  D. Kolbinger  and  A. Waldheim  for their excellent technical assistance and  Dr. A. Jaudszus  and  Dr. R. Kru ¨ger  for helpful discussions and careful revision of the manuscript. This work was performed in frame of the nutrhi. net-project,funded by the  EC IntergReg IVa Program.
Anthropometry Selected women and children were invited to the Commune Health Center early morning. Children and women were weighed without shoes or sandals and wearing light clothes by using a balance with a precision of 0. 1 kg (Body Composition Monitor Scale Tanita BC-543, Japan). Height was measured by using a height measuring device with a precision of 0. 1 cm (wooden height board, UNICEF). For children under two years, measurement of recumbent length was taken on an adjustable child length measuring board with a precision of 0. 1 cm (wooden length board, UNICEF). For children from 6 months to 6 years, anthropometric z-scores were calculated based on the National Center for Health Statistics/WHO growth reference data of 2006  [21] , and using the Access Visual Basic program incorporating tables from the WHO Anthro software for standard population.