Longitudinal associations between hearing loss and general cognitive ability:The Lothian Birth Cohort 1936

Hearing impairment is associated with poorer cognitive function in later life. We tested for the potential contribution of childhood cognitive ability to this relationship. Childhood cognitive ability is strongly related to cognitive function in older age, and may be related to auditory function through its association with hearing impairment risk factors. Using data from the Lothian Birth Cohort 1936, we tested whether childhood cognitive ability predicted later-life hearing ability then whether this association was mediated by demographic or health differences. We found that childhood cognitive ability was negatively associated with hearing impairment risk at age 76 (odds ratio = .834, p = .042). However, this association was non-significant following subsequent adjustment for potentially mediating demographic and health factors. Next, we tested whether associations observed in older age between hearing impairment and general cognitive ability level or change were accounted for by childhood cognitive ability. At age 76, in the minimally adjusted model, hearing impairment was associated with poorer general cognitive ability level (β = -.119, p = .030) but was not related to decline in general cognitive ability. The former association became non-significant following additional adjustment for childhood cognitive ability (β = -.068; p = .426) suggesting that childhood cognitive ability contributes (potentially via demographic and health differences) to the association between levels of hearing and cognitive function in older age. Further work is needed to test whether early-life cognitive ability also contributes to the association (documented in previous studies) between older-age hearing impairment and cognitive decline

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Mathematical treatment of adiabatic fast passage pulses for the computation of nuclear spin relaxation rates in proteins with conformational exchange

Although originally designed for broadband inversion and decoupling in NMR spectroscopy, recent methodological developments have introduced adiabatic fast passage (AFP) pulses into the field of protein dynamics. AFP pulses employ a frequency sweep, and have not only superior inversion properties with respect to offset effects, but they are also easily implemented into a pulse sequence. As magnetization is dragged from the +z to the −z direction, Larmor precession is impeded since magnetization becomes spin-locked, which is a potentially useful feature for the investigation of microsecond to millisecond dynamics. A major drawback of these pulses as theoretical prediction is concerned, however, results from their time-dependent offset: simulations of spin density matrices under the influence of a time-dependent Hamiltonian with non-commuting elements are costly in terms of computational time, rendering data analysis impracticable. In this paper we suggest several ways to reduce the computational time without compromising accuracy with respect to effects such as cross-correlated relaxation and modulation of the chemical shift

Dietary iodine exposure and brain structures and cognition in older people. Exploratory analysis in the Lothian Birth Cohort 1936

Background: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine influences brain health and cognitive functions. Methods: From 1091 participants initially enrolled in The Lothian Birth Cohort Study 1936, we obtained whole diet data from 882. Three years later, from 866 participants (mean age 72 yrs, SD ±0.8), we obtained cognitive information and ventricular, hippocampal and normal and abnormal tissue volumes from brain structural magnetic resonance imaging scans (n=700). We studied the brain structure and cognitive abilities of iodine-rich food avoiders/low consumers versus those with a high intake in iodine-rich foods (namely dairy and fish). Results: We identified individuals (n=189) with contrasting diets, i) belonging to the lowest quintiles for dairy and fish consumption, ii) milk avoiders, iii) belonging to the middle quintiles for dairy and fish consumption, and iv) belonging to the middle quintiles for dairy and fish consumption. Iodine intake was secured mostly though the diet (n=10 supplement users) and was sufficient for most (75.1%, median 193 μg/day). In individuals from these groups, brain lateral ventricular volume was positively associated with fat, energy and protein intake. The associations between iodine intake and brain ventricular volume and between consumption of fish products (including fish cakes and fish-containing pasties) and white matter hyperintensities (p=0.03) the latest being compounded by sodium, proteins and saturated fats, disappeared after type 1 error correction. Conclusion: In this large Scottish older cohort, the proportion of individuals reporting extreme (low vs. high)/medium iodine consumption is small. In these individuals, low iodine-rich food intake was associated with increased brain volume shrinkage, raising an important hypothesis worth being explored for designing appropriate guidelines

Probing Microsecond Time Scale Dynamics in Proteins by Methyl 1H Carr−Purcell−Meiboom−Gill Relaxation Dispersion NMR Measurements. Application to Activation of the Signaling Protein NtrCr

To study microsecond processes by relaxation dispersion NMR spectroscopy, low power deposition and short pulses are crucial and encourage the development of experiments that employ H-1 Carr-Purcell-Meiboom-Gill (CPMG) pulse trains. Herein, a method is described for the comprehensive study of microsecond to millisecond time scale dynamics of methyl groups in proteins, exploiting their high abundance and favorable relaxation properties. In our approach, protein samples are produced using [H-1, C-13]-D-glucose in similar to 100% D2O, which yields CHD2 methyl groups for alanine, valine, threonine, isoleucine, leucine, and methionine residues with high abundance, in an otherwise largely deuterated background. Methyl groups in such samples can be sequence-specifically assigned to near completion, using C-13 TOCSY NMR spectroscopy, as was recently demonstrated (Often, R.; et al. J. Am. Chem. Soc. 2010, 132, 2952-2960). In this Article, NMR pulse schemes are presented to measure H-1 CPMG relaxation dispersion profiles for CHD2 methyl groups, in a vein similar to that of backbone relaxation experiments. Because of the high deuteration level of methyl-bearing side chains, artifacts arising from proton scalar coupling during the CPMG pulse train are negligible, with the exception of Ile-delta 1 and Thr-gamma 2 methyl groups, and a pulse scheme is described to remove the artifacts for those residues. Strong C-13 scalar coupling effects, observed for several leucine residues, are removed by alternative biochemical and NMR approaches. The methodology is applied to the transcriptional activator NtrC(r), for which an inactive/active state transition was previously measured and the motions in the microsecond time range were estimated through a combination of backbone N-15 CPMG dispersion NMR spectroscopy and a collection of experiments to determine the exchange-free component to the transverse relaxation rate. Exchange contributions to the H-1 line width were detected for 21 methyl groups, and these probes were found to collectively report on a local structural rearrangement around the phosphorylation site, with a rate constant of (15.5 +/- 0.5) x 10(3) per second (i.e., tau(ex) = 64.7 +/- 1.9 mu s). The affected methyl groups indicate that, already before phosphorylation, a substantial, transient rearrangement takes place between helices 3 and 4 and strands 4 and 5. This conformational equilibrium allows the protein to gain access to the active, signaling state in the absence of covalent modification through a shift in a pre-existing dynamic equilibrium. Moreover, the conformational switching maps exactly to the regions that differ between the solution NMR structures of the fully inactive and active states. These results demonstrate that a cost-effective and quantitative study of protein methyl group dynamics by H-1 CPMG relaxation dispersion NMR spectroscopy is possible and can be applied to study functional motions on the microsecond time scale that cannot be accessed by backbone N-15 relaxation dispersion NMR. The use of methyl groups as dynamics probes extends such applications also to larger proteins

The Magnitude and Mechanism of Charge Enhancement of CH∙∙O H-bonds

Quantum calculations find that neutral methylamines and thioethers form complexes, with N-methylacetamide (NMA) as proton acceptor, with binding energies of 2–5 kcal/mol. This interaction is magnified by a factor of 4–9, bringing the binding energy up to as much as 20 kcal/mol, when a CH3+ group is added to the proton donor. Complexes prefer trifurcated arrangements, wherein three separate methyl groups donate a proton to the O acceptor. Binding energies lessen when the systems are immersed in solvents of increasing polarity, but the ionic complexes retain their favored status even in water. The binding energy is reduced when the methyl groups are replaced by longer alkyl chains. The proton acceptor prefers to associate with those CH groups that are as close as possible to the S/N center of the formal positive charge. A single linear CH··O hydrogen bond (H-bond) is less favorable than is trifurcation with three separate methyl groups. A trifurcated arrangement with three H atoms of the same methyl group is even less favorable. Various means of analysis, including NBO, SAPT, NMR, and electron density shifts, all identify the +CH··O interaction as a true H-bond

Understanding biomolecular motion, recognition, and allostery by use of conformational ensembles

We review the role conformational ensembles can play in the analysis of biomolecular dynamics, molecular recognition, and allostery. We introduce currently available methods for generating ensembles of biomolecules and illustrate their application with relevant examples from the literature. We show how, for binding, conformational ensembles provide a way of distinguishing the competing models of induced fit and conformational selection. For allostery we review the classic models and show how conformational ensembles can play a role in unravelling the intricate pathways of communication that enable allostery to occur. Finally, we discuss the limitations of conformational ensembles and highlight some potential applications for the future