ALL RIGHTS RESERVEDSCIENCE IN HIGH DIMENSIONS: MULTIPARAMETER MODELS AND BIG DATA

Complex multiparameter models such as in climate science, economics, systems biology, materials science, neural networks and machine learning have a large-dimensional space of undetermined parameters as well as a large-dimensional space of predicted data. These high-dimensional spaces of inputs and outputs pose many challenges. Recent work with a diversity of nonlinear predictive models, microscopic models in physics, and analysis of large datasets, has led to important insights. In particular, it was shown that nonlinear fits to data in a variety of multiparameter models largely rely on only a few stiff directions in parameter space. Chapter 2 explores a qualitative basis for this compression of parameter space using a model nonlinear system with two time scales. A systematic separation of scales is shown to correspond to an increasing insensitivity of parameter space directions that only affect the fast dynamics. Chapter 3 shows with the help of microscopic physics models that emergent theories in physics also rely on a sloppy compression of the parameter space where macroscopically relevant variables form the stiff directions. Lastly, in chapter 4, we will learn that the data space of historical daily stock returns of US public companies has an emergent simplex structure that makes it amenable to a low-dimensional representation. This leads t

Web Based Data Visualization and Data Preprocessing Tool

The escalating adoption of Machine Learning techniques has given a bigger picture to newbies trying to explore the usage of it. Our tool deals with the idea of helping them, in order to make their lives easier. Various visualizations and algorithms have been developed to help Machine Learning enthusiasts decide upon the best model. Deciding the perfect model needs enough time which now can be reduced by the solution provided in this tool. This interactive technique helps users with some expertise to explore and validate predictive as well as classification models. Once the user provides the dataset, the visualization techniques discussed in this tool lets the user decide to select the features that are most suitable for training the model. It allows one to decide upon the importance of a particular feature and know the dataset predictions across various algorithms used for regression and classification. The accuracy percentage or the precision, recall score for regression and classification models respectively can be seen in order to know the best model

Mineral maturity and crystallinity index are distinct characteristics of bone mineral

The purpose of this study was to test the hypothesis that mineral maturity and crystallinity index are two different characteristics of bone mineral. To this end, Fourier transform infrared microspectroscopy (FTIRM) was used. To test our hypothesis, synthetic apatites and human bone samples were used for the validation of the two parameters using FTIRM. Iliac crest samples from seven human controls and two with skeletal fluorosis were analyzed at the bone structural unit (BSU) level by FTIRM on sections 2–4 lm thick. Mineral maturity and crystallinity index were highly correlated in synthetic apatites but poorly correlated in normal human bone. In skeletal fluorosis, crystallinity index was increased and maturity decreased, supporting the fact of separate measurement of these two parameters. Moreover, results obtained in fluorosis suggested that mineral characteristics can be modified independently of bone remodeling. In conclusion, mineral maturity and crystallinity index are two different parameters measured separately by FTIRM and offering new perspectives to assess bone mineral traits in osteoporosis

Classification of fracture and non-fracture groups by analysis of coherent X-ray scatter

Osteoporotic fractures present a significant social and economic burden, which is set to rise commensurately with the aging population. Greater understanding of the physicochemical differences between osteoporotic and normal conditions will facilitate the development of diagnostic technologies with increased performance and treatments with increased efficacy. Using coherent X-ray scattering we have evaluated a population of 108 ex vivo human bone samples comprised of non-fracture and fracture groups. Principal component fed linear discriminant analysis was used to develop a classification model to discern each condition resulting in a sensitivity and specificity of 93% and 91%, respectively. Evaluating the coherent X-ray scatter differences from each condition supports the hypothesis that a causal physicochemical change has occurred in the fracture group. This work is a critical step along the path towards developing an in vivo diagnostic tool for fracture risk prediction

EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2013 . Scientific opinion on Dietary Reference Values for fluoride

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies (NDA) derived Dietary Reference Values (DRVs) for fluoride, which are provided as Adequate Intake (AI) from all sources, including non-dietary sources. Fluoride is not an essential nutrient. Therefore, no Average Requirement for the performance of essential physiological functions can be defined. Nevertheless, the Panel considered that the setting of an AI is appropriate because of the beneficial effects of dietary fluoride on prevention of dental caries. The AI is based on epidemiological studies (performed before the 1970s) showing an inverse relationship between the fluoride concentration of water and caries prevalence. As the basis for defining the AI, estimates of mean fluoride intakes of children via diet and drinking water with fluoride concentrations at which the caries preventive effect approached its maximum whilst the risk of dental fluorosis approached its minimum were chosen. Except for one confirmatory longitudinal study in US children, more recent studies were not taken into account as they did not provide information on total dietary fluoride intake, were potentially confounded by the use of fluoride-containing dental hygiene products, and did not permit a conclusion to be drawn on a dose-response relationship between fluoride intake and caries risk. The AI of fluoride from all sources (including non-dietary sources) is 0.05 mg/kg body weight per day for both children and adults, including pregnant and lactating women. For pregnant and lactating women, the AI is based on the body weight before pregnancy and lactation. Reliable and representative data on the total fluoride intake of the European population are not available

Effect of exercise on fluoride metabolism in adult humans: a pilot study

An understanding of all aspects of fluoride metabolism is critical to identify its biological effects and avoid fluoride toxicity in humans. Fluoride metabolism and subsequently its body retention may be affected by physiological responses to acute exercise. This pilot study investigated the effect of exercise on plasma fluoride concentration, urinary fluoride excretion and fluoride renal clearance following no exercise and three exercise intensity conditions in nine healthy adults after taking a 1-mg Fluoride tablet. After no, light, moderate and vigorous exercise, respectively, the mean (SD) baseline-adjusted i) plasma fluoride concentration was 9.6(6.3), 11.4(6.3), 15.6(7.7) and 14.9(10.0) ng/ml; ii) rate of urinary fluoride excretion over 0–8 h was 46(15), 44(22), 34(17) and 36(17) μg/h; and iii) rate of fluoride renal clearance was 26.5(9.0), 27.2(30.4), 13.1(20.4) and 18.3(34.9) ml/min. The observed trend of a rise in plasma fluoride concentration and decline in rate of fluoride renal clearance with increasing exercise intensity needs to be investigated in a larger trial. This study, which provides the first data on the effect of exercise with different intensities on fluoride metabolism in humans, informs sample size planning for any subsequent definitive trial, by providing a robust estimate of the variability of the effect

Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy Calculations

The comparative dynamics and inhibitor binding free energies of group-1 and group-2 pathogenic influenza A subtype neuraminidase (NA) enzymes are of fundamental biological interest and relevant to structure-based drug design studies for antiviral compounds. In this work, we present seven generalized Born molecular dynamics simulations of avian (N1)- and human (N9)-type NAs in order to probe the comparative flexibility of the two subtypes, both with and without the inhibitor oseltamivir bound. The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion. End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes. We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains

Independent-Trajectories Thermodynamic-Integration Free-Energy Changes for Biomolecular Systems: Determinants of H5N1 Avian Influenza Virus Neuraminidase Inhibition by Peramivir

Free-energy changes are essential physicochemical quantities for understanding most biochemical processes. Yet, the application of accurate thermodynamic-integration (TI) computation to biological and macromolecular systems is limited by finite-sampling artifacts. In this paper, we employ independent-trajectories thermodynamic-integration (IT-TI) computation to estimate improved free-energy changes and their uncertainties for (bio)molecular systems. IT-TI aids sampling statistics of the thermodynamic macrostates for flexible associating partners by ensemble averaging of multiple, independent simulation trajectories. We study peramivir (PVR) inhibition of the H5N1 avian influenza virus neuraminidase flexible receptor (N1). Binding site loops 150 and 119 are highly mobile, as revealed by N1-PVR 20-ns molecular dynamics. Due to such heterogeneous sampling, standard TI binding free-energy estimates span a rather large free-energy range, from a 19% underestimation to a 29% overestimation of the experimental reference value (−62.2 ± 1.8 kJ mol−1). Remarkably, our IT-TI binding free-energy estimate (−61.1 ± 5.4 kJ mol−1) agrees with a 2% relative difference. In addition, IT-TI runs provide a statistics-based free-energy uncertainty for the process of interest. Using ∼800 ns of overall sampling, we investigate N1-PVR binding determinants by IT-TI alchemical modifications of PVR moieties. These results emphasize the dominant electrostatic contribution, particularly through the N1 E277−PVR guanidinium interaction. Future drug development may be also guided by properly tuning ligand flexibility and hydrophobicity. IT-TI will allow estimation of relative free energies for systems of increasing size, with improved reliability by employing large-scale distributed computing

Haemolytic and cytotoxic activities of the Tween 80-extracted putative haemolysin of Pasteurella multocida B:2

The objective of this study was to investigate the haemolytic and cytotoxic activity of Pasteurella multocida B:2 strains, originally from cases of haemorrhagic septicaemia in cattle. All six P. multocida B:2 strains were non-haemolytic on sheep blood agar (SBA) and horse blood agar (HBA) when grown aerobically and on SBA anaerobically but they were haemolytic on HBA when grown anaerobically. No haemolytic activity against horse red blood cells was detected in culture supernates from aerobically or anaerobically grown cultures and only very weak haemolytic activity was obtained in supernates or pellet fractions from sonicated cells. However, after repeated extraction of sonicated cells with Tween 80, haemolytic activity was found in various cell fractions, both Tween-soluble and -insoluble. The Tween-extracted putative haemolysin and other bacterial fractions were also cytotoxic for mouse macrophage-like J774.2 cells. Further characterisation of the putative haemolysin revealed it to be a heat-labile, non-pore-forming protein of molecular weight >10ákDa whose activity was completely destroyed by trypsin and greatly reduced with protease and proteinase K treatment. Congo red also reduced the haemolytic activity. Non-denaturing gel-electrophoresis and RBC agar overlay revealed clear haemolytic zones but suggested that Tween was bound to some component of the P. multocida B:2 fractions and was responsible, to some extent, for the haemolytic activity observed. However, the effect of heat and other reagents on the Tween-extracted fractions and the lack of haemolytic activity in different Tween-extracted cell fractions of organisms other than P. multocida suggested that some proteinaceous component of the organism could indeed act as a haemolysin. This putative haemolysin may be one of the virulence attributes of P. multocida, but its characterisation and role in pathogenesis require further stud