Toward a Computer Assisted Analysis of NOESY Spectra: A Multivariate Data Analysis of an RNA NOESY Spectrum

Abstract

A multivariate data-representation of a portion of the ¹H-NOESY spectrum of an RNA octamer duplex was used to explore the possibility of using Principal Component Analysis and Partial Least Squares Discrimination for pattern recognition. In this case, it is found that the methods can: (i) distinguish slices containing signal from those containing only noise, (ii) locate slices containing overlapping signals, and (iii) in some cases to segregate slices with unique aspects such as those from terminal nucleotides, overlapping signals, purine-H8, pyrimidine-H6 and adenine-H2 containing slices. These properties can easily be included in a scheme to automate spectral analysis. The formulation described here does not distinguish patterns needed to automate sequential assignment of resonances in NOESY spectra of RNA.     

Perceptual distance and the moon illusion

The elevated moon usually appears smaller than the horizon moon of equal angular size. This is the moon illusion. Distance cues may enable the perceptual system to place the horizon moon at an effectively greater distance than the elevated moon, thus making it appear as larger. This explanation is related to the size-distance invariance hypothesis. However, the larger horizon moon is usually judged as closer than the smaller zenith moon. A bias to expect an apparently large object to be closer than a smaller object may account for this conflict. We designed experiments to determine if unbiased sensitivity to illusory differences in the size and distance of the moon (as measured by d') is consistent with SDIH. A moon above a 'terrain' was compared in both distance and size to an infinitely distant moon in empty space (the reduction moon). At a short distance the terrain moon was adjudged as both closer and smaller than the reduction moon. But these differences could not be detected at somewhat greater distances. At still greater distances the terrain moon was perceived as both more distant and larger than the reduction moon. The distances at which these transitions occurred were essentially the same for both distance and size discrimination tasks, thus supporting SDIH.     

Trivers-Willard at birth and one year: evidence from US natality data 1983-2001

Trivers & Willard (TW) hypothesized that evolution would favour deviations from the population sex ratio in response to parental condition: parents in good condition would have more sons and parents in poor condition would have more daughters. We analyse the universe of US linked births and infant deaths to white mothers 1983-2001, covering 48 million births and 310,000 deaths. We find that (i) married, better educated and younger mothers bore more sons and (ii) infant deaths were more male if the mother was unmarried and young. Our findings highlight the potential role of offspring sex ratio as an indicator of maternal status, and the role of infant mortality in shaping a TW pattern in the breeding population.     

The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse

Obesity is typically associated with elevated levels of free fatty acids (FFAs) and is linked to glucose intolerance and type 2 diabetes. FFAs exert divergent effects on insulin secretion from beta cells: acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs insulin secretion. The G protein-coupled receptor GPR40 is selectively expressed in beta cells and is activated by FFAs. We show here that GPR40 mediates both acute and chronic effects of FFAs on insulin secretion and that GPR40 signaling is linked to impaired glucose homeostasis. GPR40-deficient beta cells secrete less insulin in response to FFAs, and loss of GPR40 protects mice from obesity-induced hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, increased hepatic glucose output, hyperglycemia, and glucose intolerance. Conversely, overexpression of GPR40 in beta cells of mice leads to impaired beta cell function, hypoinsulinemia, and diabetes. These results suggest that GPR40 plays an important role in the chain of events linking obesity and type 2 diabetes.     

Observing the invisible through imaging mass spectrometry, a window into the metabolic exchange patterns of microbes

Many microbes can be cultured as single-species communities. Often, these colonies are controlled and maintained via the secretion of metabolites. Such metabolites have been an invaluable resource for the discovery of therapeutics (e.g. penicillin, taxol, rapamycin, epothilone). In this article, written for a special issue on imaging mass spectrometry, we show that MALDI-imaging mass spectrometry can be adapted to observe, in a spatial manner, the metabolic exchange patterns of a diverse array of microbes, including thermophilic and mesophilic fungi, cyanobacteria, marine and terrestrial actinobacteria, and pathogenic bacteria. Dependent on media conditions, on average and based on manual analysis, we observed 11.3 molecules associated with each microbial IMS experiment, which was split nearly 50:50 between secreted and colony-associated molecules. The spatial distributions of these metabolic exchange factors are related to the biological and ecological functions of the organisms. This work establishes that MALDI-based IMS can be used as a general tool to study a diverse array of microbes. Furthermore the article forwards the notion of the IMS platform as a window to discover previously unreported molecules by monitoring the metabolic exchange patterns of organisms when grown on agar substrates.     

Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350

SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0^4,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K_i = 0.36 nM) and viral replication (replicon EC₅₀ = 7.8 nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics.     

A predictive model for respiratory syncytial virus (RSV) hospitalisation of premature infants born at 33–35 weeks of gestational age,based on data from the Spanish FLIP study

Background

The aim of this study, conducted in Europe, was to develop a validated risk factor based model to predict RSV-related hospitalisation in premature infants born 33–35 weeks'' gestational age (GA).

Methods

The predictive model was developed using risk factors captured in the Spanish FLIP dataset, a case-control study of 183 premature infants born between 33–35 weeks'' GA who were hospitalised with RSV, and 371 age-matched controls. The model was validated internally by 100-fold bootstrapping. Discriminant function analysis was used to analyse combinations of risk factors to predict RSV hospitalisation. Successive models were chosen that had the highest probability for discriminating between hospitalised and non-hospitalised infants. Receiver operating characteristic (ROC) curves were plotted.

Results

An initial 15 variable model was produced with a discriminant function of 72% and an area under the ROC curve of 0.795. A step-wise reduction exercise, alongside recalculations of some variables, produced a final model consisting of 7 variables: birth ± 10 weeks of start of season, birth weight, breast feeding for ≤ 2 months, siblings ≥ 2 years, family members with atopy, family members with wheeze, and gender. The discrimination of this model was 71% and the area under the ROC curve was 0.791. At the 0.75 sensitivity intercept, the false positive fraction was 0.33. The 100-fold bootstrapping resulted in a mean discriminant function of 72% (standard deviation: 2.18) and a median area under the ROC curve of 0.785 (range: 0.768–0.790), indicating a good internal validation. The calculated NNT for intervention to treat all at risk patients with a 75% level of protection was 11.7 (95% confidence interval: 9.5–13.6).

Conclusion

A robust model based on seven risk factors was developed, which is able to predict which premature infants born between 33–35 weeks'' GA are at highest risk of hospitalisation from RSV. The model could be used to optimise prophylaxis with palivizumab across Europe.