The Energy Computation Paradox and ab initio Protein Folding

The routine prediction of three-dimensional protein structure from sequence remains a challenge in computational biochemistry. It has been intuited that calculated energies from physics-based scoring functions are able to distinguish native from nonnative folds based on previous performance with small proteins and that conformational sampling is the fundamental bottleneck to successful folding. We demonstrate that as protein size increases, errors in the computed energies become a significant problem. We show, by using error probability density functions, that physics-based scores contain significant systematic and random errors relative to accurate reference energies. These errors propagate throughout an entire protein and distort its energy landscape to such an extent that modern scoring functions should have little chance of success in finding the free energy minima of large proteins. Nonetheless, by understanding errors in physics-based score functions, they can be reduced in a post-hoc manner, improving accuracy in energy computation and fold discrimination

S66: A Well-balanced Database of Benchmark Interaction Energies Relevant to Biomolecular Structures

With numerous new quantum chemistry methods being developed in recent years and the promise of even more new methods to be developed in the near future, it is clearly critical that highly accurate, well-balanced, reference data for many different atomic and molecular properties be available for the parametrization and validation of these methods. One area of research that is of particular importance in many areas of chemistry, biology, and material science is the study of noncovalent interactions. Because these interactions are often strongly influenced by correlation effects, it is necessary to use computationally expensive high-order wave function methods to describe them accurately. Here, we present a large new database of interaction energies calculated using an accurate CCSD(T)/CBS scheme. Data are presented for 66 molecular complexes, at their reference equilibrium geometries and at 8 points systematically exploring their dissociation curves; in total, the database contains 594 points: 66 at equilibrium geometries, and 528 in dissociation curves. The data set is designed to cover the most common types of noncovalent interactions in biomolecules, while keeping a balanced representation of dispersion and electrostatic contributions. The data set is therefore well suited for testing and development of methods applicable to bioorganic systems. In addition to the benchmark CCSD(T) results, we also provide decompositions of the interaction energies by means of DFT-SAPT calculations. The data set was used to test several correlated QM methods, including those parametrized specifically for noncovalent interactions. Among these, the SCS-MI-CCSD method outperforms all other tested methods, with a root-mean-square error of 0.08 kcal/mol for the S66 data set

Children reading to dogs: a systematic review of the literature

Background Despite growing interest in the value of human-animal interactions (HAI) to human mental and physical health the quality of the evidence on which postulated benefits from animals to human psychological health are based is often unclear. To date there exist no systematic reviews on the effects of HAI in educational settings specifically focussing on the perceived benefits to children of reading to dogs. With rising popularity and implementation of these programmes in schools, it is essential that the evidence base exploring the pedagogic value of these initiatives is well documented. Methods Using PRISMA guidelines we systematically investigated the literature reporting the pedagogic effects of reading to dogs. Because research in this area is in the early stages of scientific enquiry we adopted broad inclusion criteria, accepting all reports which discussed measurable effects related to the topic that were written in English. Multiple online databases were searched during January-March 2015; grey literature searches were also conducted. The search results which met the inclusion criteria were evaluated, and discussed, in relation to the Oxford Centre for Evidence Based Medicine levels of evidence; 27 papers were classified as Level 5, 13 as Level 4, 7 as Level 2c and 1 as Level 2b. Conclusion The evidence suggests that reading to a dog may have a beneficial effect on a number of behavioural processes which contribute to a positive effect on the environment in which reading is practiced, leading to improved reading performance. However, the evidence base on which these inferences are made is of low quality. There is a clear need for the use of higher quality research methodologies and the inclusion of appropriate controls in order to draw causal inferences on whether or how reading to dogs may benefit children’s reading practices. The mechanisms for any effect remain a matter of conjectur

Empty nest, cohort, and employment in the well-being of midlife women

Whether the empty-nest experience has positive or negative consequences for women's well-being at midlife may depend on their historical cohort membership and employment status. In this study, it was posited that the empty nest was likely to be a negative experience among the particular cohort of women (Cohort II) who reached adulthood during the period of strong societal emphasis on women's maternal role known as the feminine mystique, would be experienced positively among the earlier cohort (Cohort I) who as young adults were encouraged to enter the labor force during World War II. Analyses of covariance tested the relationships among empty-nest status, cohort membership, and employment status, and three measures of psychological well-being, adjusted for age, education, and marital status. The results of this study show that cohort and employment each have important independent associations with women's well-being at midlife, but that the experience of the empty nest depends on these two factors, especially cohort experiences.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45589/1/11199_2004_Article_BF00287990.pd

Pulmonary Vascular Changes In Obese Leptin-deficient (ob/ob) Mice

RATIONALE: Leptin is a neuroendocrine peptide released by adipose tissue that enhances metabolism and acts on the hypothalamus suppressing appetite. It is also involved in relevant process in the cardiovascular system and low leptin serum levels have been associated with increased mortality in humans. We hypothesized that leptin deficiency in mice will have effects the pulmonary vasculature.METHODS: We examined two groups of C57BL/6 male mice, five ob/ob (B6.VLepob/ob) leptin-deficient and five wild type (WT) (C57BL/6) control mice, aged 12 weeks. Lung tissues obtained from ob/ob and control mice were inflated and embedded in optimal cutting temperature (OCT) compound. The sections were stained with hematoxylin and eosin (H&E) for morphological examination, F4/80 for macrophages, and FSP1/S100A4 for fibroblast. Sections were also stained for collagen, hyaluronan and smooth muscle actin. Changes in pulmonary vasculature were examined in the ob/ob and compared to WT littermates by histology, immunohistochemistry and immunofluorescence staining.RESULTS: The weight was higher in ob/ob mice [weight (g), mean±SD): ob/ob 52±2.5, wildtype 30±2.5; p<0.001]. Pulmonary arterial walls were significantly thicker in the ob/ob mice when compared with wild types [The distance in pixel (median (interquartile range)): ob/ob 0.13 (0.05-0.18), wild type 0.03 (0.02-0.04); p=0.001]. There was also significant right ventricular hypertrophy in the ob/ob mice compared to controls [RV thickness (mean±SD): ob/ob 0.75±0.19, wild type; 0.58±0.13 p<0.001]. In the ob/ob mice, there was marked macrophage infiltration in pulmonary arterioles associated with increased myofibroblasts, and fibroblasts. Moreover, hyaluronan showed greater intensity in ob/ob mice compared to wild type and co-localized with SMC-actin. CONCLUSIONS: Leptin deficient mice have pathological features of pulmonary hypertension in the pulmonary vasculature that are associated with right ventricular hypertrophy