The Significance of the Location of Mutations for the Native-State Dynamics of Human Lysozyme

The conversion of human lysozyme into amyloid fibrils is associated with a rare but fatal hereditary form of nonneuropathic systemic amyloidosis. The accumulation of large amounts of aggregated protein is thought to be initiated by the formation of transient intermediate species of disease-related lysozyme variants, essentially due to the loss of global cooperativity under physiologically relevant conditions. Interestingly, all five naturally occurring, amyloidogenic, single-point mutations are located in the β-domain of lysozyme, the region that is predominantly unfolded during the formation of the transient intermediate species. Given the lack of known naturally occurring, amyloidogenic, single-point mutations in the α-domain, we chose three specific mutations to address the effects that location may have on native-state dynamics, as studied by hydrogen-deuterium (HD) exchange experiments analyzed by NMR spectroscopy, and mass spectrometry. We compared the effect of a destabilizing α-domain mutation (I23A) with that of the well-characterized I59T β-domain variant. We also investigated the effect of a mutation that has minor effects on native-state stability at the domain interface (I56V) and compared it with that of a variant with similar stability within the C-helix (I89V). We show that when variants have similar reduced native-state stabilities, the location of the mutation (I23A versus I59T) is crucial to the native-state dynamics, with the α-domain mutation having a significantly lower ability to populate transient intermediate species under physiologically relevant conditions. Interestingly, the mutation at the interface (I56V) has a greater effect in facilitating the formation of transient intermediate species at elevated temperatures compared with the variants containing α-domain mutations, even though this mutation results in only minor changes to the native-state stability of lysozyme. These findings reveal that the location of specific mutations is an important factor in determining the native-state dynamical properties of human lysozyme in the context of its propensity to populate the aggregation-prone transient intermediate species associated with pathogenic amyloid formation.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/E019927/1 to C.M.D., C.V.R., and J.R.K.), the Medical Research Council (E.D.G. and C.M.D.), the Belgian Program of Interuniversity Attraction Poles administered by the Federal Office for Scientific Technical and Cultural Affairs (PAI numbers P6/19 and P7144 to C.M.D. and M.D.), the European Union’s Sixth Framework Program (LSHM-CT-2006-037525 to C.M.D. and M.D.), and Programme grants from the Wellcome Trust and the Leverhulme Trust (C.M.D.). It was also supported by a Korean Government Scholarship for Overseas Studies (M.A.), the Winston Churchill Foundation (C.L.H.), and Boerhinger Ingleheim funds (A.D.). The NMR facility at the Department of Chemistry, University of Cambridge, is supported in part by an EPSRC Core Capability grant (EP/K039520/1)

Engaging Undergraduates in Science Research: Not Just About Faculty Willingness.

Despite the many benefits of involving undergraduates in research and the growing number of undergraduate research programs, few scholars have investigated the factors that affect faculty members' decisions to involve undergraduates in their research projects. We investigated the individual factors and institutional contexts that predict faculty members' likelihood of engaging undergraduates in their research project(s). Using data from the Higher Education Research Institute's 2007-2008 Faculty Survey, we employ hierarchical generalized linear modeling to analyze data from 4,832 science, technology, engineering, and mathematics (STEM) faculty across 194 institutions to examine how organizational citizenship behavior theory and social exchange theory relate to mentoring students in research. Key findings show that faculty who work in the life sciences and those who receive government funding for their research are more likely to involve undergraduates in their research project(s). In addition, faculty at liberal arts or historically Black colleges are significantly more likely to involve undergraduate students in research. Implications for advancing undergraduate research opportunities are discussed

Generation Scotland: Donor DNA Databank; A control DNA resource

<p>Abstract</p> <p>Background</p> <p>Many medical disorders of public health importance are complex diseases caused by multiple genetic, environmental and lifestyle factors. Recent technological advances have made it possible to analyse the genetic variants that predispose to complex diseases. Reliable detection of these variants requires genome-wide association studies in sufficiently large numbers of cases and controls. This approach is often hampered by difficulties in collecting appropriate control samples. The Generation Scotland: Donor DNA Databank (GS:3D) aims to help solve this problem by providing a resource of control DNA and plasma samples accessible for research.</p> <p>Methods</p> <p>GS:3D participants were recruited from volunteer blood donors attending Scottish National Blood Transfusion Service (SNBTS) clinics across Scotland. All participants gave full written consent for GS:3D to take spare blood from their normal donation. Participants also supplied demographic data by completing a short questionnaire.</p> <p>Results</p> <p>Over five thousand complete sets of samples, data and consent forms were collected. DNA and plasma were extracted and stored. The data and samples were unlinked from their original SNBTS identifier number. The plasma, DNA and demographic data are available for research. New data obtained from analysis of the resource will be fed back to GS:3D and will be made available to other researchers as appropriate.</p> <p>Conclusions</p> <p>Recruitment of blood donors is an efficient and cost-effective way of collecting thousands of control samples. Because the collection is large, subsets of controls can be selected, based on age range, gender, and ethnic or geographic origin. The GS:3D resource should reduce time and expense for investigators who would otherwise have had to recruit their own controls.</p

The feasibility and utility of grocery receipt analyses for dietary assessment

OBJECTIVE: To establish the feasibility and utility of a simple data collection methodology for dietary assessment. DESIGN: Using a cross-sectional design, trained data collectors approached adults (~20 – 40 years of age) at local grocery stores and asked whether they would volunteer their grocery receipts and answer a few questions for a small stipend ($1). METHODS: The grocery data were divided into 3 categories: "fats, oils, and sweets," "processed foods," and "low-fat/low-calorie substitutions" as a percentage of the total food purchase price. The questions assessed the shopper's general eating habits (eg, fast-food consumption) and a few demographic characteristics and health aspects (eg, perception of body size). Statistical Analyses Performed. Descriptive and analytic analyses using non-parametric tests were conducted in SAS. RESULTS: Forty-eight receipts and questionnaires were collected. Nearly every respondent reported eating fast food at least once per month; 27% ate out once or twice a day. Frequency of fast-food consumption was positively related to perceived body size of the respondent (p = 0.02). Overall, 30% of the food purchase price was for fats, oils, sweets, 10% was for processed foods, and almost 6% was for low-fat/low-calorie substitutions. Households where no one was perceived to be overweight spent a smaller proportion of their food budget on fats, oils, and sweets than did households where at least one person was perceived to be overweight (p = 0.10); household where the spouse was not perceived to be overweight spent less on fats, oils, and sweets (p = 0.02) and more on low-fat/low-calorie substitutions (p = 0.09) than did households where the spouse was perceived to be overweight; and, respondents who perceived themselves to be overweight spent more on processed foods than did respondents who did not perceive themselves to be overweight (p = 0.06). CONCLUSION: This simple dietary assessment method, although global in nature, may be a useful indicator of dietary practices as evidenced by its association with perceived weight status

The risk of child and adolescent overweight is related to types of food consumed

<p>Abstract</p> <p>Background/Aims</p> <p>To investigate the association between the risk of overweight and the consumption of food groups in children and adolescents.</p> <p>Methods</p> <p>We studied 1764 healthy children and adolescents (age 6-19y) attending 16 Seventh-Day Adventist schools and 13 public schools using a 106-item non-quantitative food frequency questionnaire from the late 1980 Child-Adolescent Blood Pressure Study. Logistic regression models were used to compute the risk of overweight according to consumption of grains, nuts, vegetables, fruits, meats/fish/eggs, dairy, and, low nutrient-dense foods (LNDF).</p> <p>Results</p> <p>The frequency of consumption of grains, nuts, vegetables and LNDF were inversely related to the risk of being overweight and dairy increased the risk. Specifically, the odds ratio (95% CI) for children in the highest quartile or tertile of consumption compared with the lowest quartile or tertile were as follows: grains 0.59(0.41-0.83); nuts 0.60(0.43-0.85); vegetables 0.67(0.48-0.94); LNDF 0.43(0.29-0.63); and, dairy 1.36(0.97, 1.92).</p> <p>Conclusion</p> <p>The regular intake of specific plant foods may prevent overweight among children and adolescents.</p

Regular Exercise or Changing Diet Does Not Influence Aortic Valve Disease Progression in LDLR Deficient Mice

BACKGROUND: The development and progression of calcific aortic valve disease (CAVD) shares a number of similarities with atherosclerosis. Recently we could demonstrate that regular exercise training (ET) as primary prevention prevents aortic valve disease in LDL-receptor deficient (LDLR(-/-)) mice. We aimed to investigate the impact of exercise training on the progression of CAVD in LDLR(-/-) mice in the setting of secondary prevention METHODS AND RESULTS: Sixty-four LDLR(-/-) mice were fed with high cholesterol diet to induce aortic valve sclerosis. Thereafter the animals were divided into 3 groups: group 1 continuing on high cholesterol diet, group 2 continuing with cholesterol diet plus 1 h ET per day, group 3 continuing with normal mouse chow. After another 16 weeks the animal were sacrificed. Histological analysis of the aortic valve thickness demonstrated no significant difference between the three groups (control 98.3±4.5 µm, ET 88.2±6.6 µm, change in diet 87.5±4.0). Immunohistochemical staining for endothelial cells revealed a disrupted endothelial cell layer to the same extend in all groups. Furthermore no difference between the groups was evident with respect to the expression of inflammatory, fibroblastic and osteoblastic markers. CONCLUSION: Based on the present study we have to conclude that once the development of a CAVD is initiated, exercise training or a change in diet does not have the potential to attenuate the progress of the CAVD

Sex Differences in Obesity Associated with Total Fertility Rate

The identification of biological and ecological factors that contribute to obesity may help in combating the spreading obesity crisis. Sex differences in obesity rates are particularly poorly understood. Here we show that the strong female bias in obesity in many countries is associated with high total fertility rate, which is well known to be correlated with factors such as low average income, infant mortality and female education. We also document effects of reduced access to contraception and increased inequality of income among households on obesity rates. These results are consistent with studies that implicate reproduction as a risk factor for obesity in women and that suggest the effects of reproduction interact with socioeconomic and educational factors. We discuss our results in the light of recent research in dietary ecology and the suggestion that insulin resistance during pregnancy is due to historic adaptation to protect the developing foetus during famine. Increased access to contraception and education in countries with high total fertility rate might have the additional benefit of reducing the rates of obesity in women

Design and evaluation protocol of "FATaintPHAT", a computer-tailored intervention to prevent excessive weight gain in adolescents

<p>Abstract</p> <p>Background</p> <p>Computer tailoring may be a promising technique for prevention of overweight in adolescents. However, very few well-developed, evidence-based computer-tailored interventions are available for this target group. We developed and evaluated a computer-tailored intervention for adolescents targeting energy balance-related behaviours: i.e. consumption of snacks, sugar-sweetened beverages, fruit, vegetables, and fibre, physical activity, and sedentary behaviours. This paper describes the planned development of a school-based computer-tailored intervention aimed at improving energy balance-related behaviours in order to prevent excessive weight gain in adolescents, and the protocol for evaluating this intervention.</p> <p>Methods/design</p> <p>Intervention development: Informed by the Precaution Adoption Process Model and the Theory of Planned Behaviour, the computer-tailored intervention provided feedback on personal behaviour and suggestions on how to modify it. The intervention (VETisnietVET translated as 'FATaintPHAT') has been developed for use in the first year of secondary school during eight lessons.</p> <p>Evaluation design: The intervention will be evaluated in a cluster-randomised trial including 20 schools with a 4-months and a 2-years follow-up. Outcome measures are BMI, waist circumference, energy balance-related behaviours, and potential determinants of these behaviours. Process measures are appreciation of and satisfaction with the program, exposure to the program's content, and implementation facilitators and barriers measured among students and teachers.</p> <p>Discussion</p> <p>This project resulted in a theory and evidence-based intervention that can be implemented in a school setting. A large-scale randomised controlled trial with a short and long-term follow-up will provide sound statements about the effectiveness of this computer-tailored intervention in adolescents.</p> <p>Trial Registration</p> <p>ISRCTN15743786</p