Publications

ABSTRACT As yet undiscovered rare variants are hypothesized to substantially influence an individual’s risk for common diseases and traits, but sequencing studies aiming to identify such variants have generally been underpowered. In isolated populations that have expanded rapidly after a population bottleneck, deleterious alleles that passed through the bottleneck may be maintained at much higher frequencies than in other populations. In an exome sequencing study of nearly 20,000 cohort participants from northern and eastern Finnish populations that exemplify this phenomenon, most novel trait-associated deleterious variants are seen only in Finland or display frequencies more than 20 times higher than in other European populations. These enriched alleles underlie 34 novel associations with 21 disease-related quantitative traits and demonstrate a geographical clustering equivalent to that of Mendelian disease mutations characteristic of the Finnish population. Sequencing studies in populations without this unique history would require hundreds of thousands to millions of participants for comparable power for these variants.

Abstract Objective Insulin degradation pathways may be related to Alzheimer's disease pathology. In preliminary analyses, we considered the relation of combined lower insulin secretion (c‐peptide) and higher insulin––possibly a phenotype for impaired insulin degradation––to cognitive decline. Method Fasting plasma c‐peptide and insulin were measured in 1,187 non‐diabetic Nurses' Health Study participants (mean age = 64 years). Cognitive testing began 10 years later. Participants completed three repeated assessments (over an average span of 4.4 years) of verbal memory, a strong predictor of Alzheimer disease development. C‐peptide and insulin distributions were dichotomized at their medians to create four cross‐tabulated categories. Multivariable linear mixed effects models were used to relate c‐peptide/insulin categories to cognitive decline. Results Compared to the lower c‐peptide/lower insulin group, women with lower c‐peptide/higher insulin had a significantly faster rate of verbal memory decline: the mean difference was ‐0.05 units/year (95% CI ‐0.09,‐0.01). This mean difference was similar to that which we found for women 5 years apart in age, indicating that having a profile of lower c‐peptide/higher insulin appeared cognitively equivalent to aging by five years on tests of verbal memory. For women with higher c‐peptide/higher insulin, the estimated mean difference in decline compared to those in the lower c‐peptide/lower insulin group was statistically significant, but slightly lower, at −0.04 units/year (95% CI: ‐0.07,‐0.02). Conclusion These preliminary analyses of a possible phenotype of impaired insulin degradation provide supportive evidence that deficits in insulin degradation may be related to late‐life verbal memory decline. Copyright © 2008 John Wiley & Sons, Ltd.

Extract Extended abstract of a paper presented at Microscopy and Microanalysis 2007 in Ft. Lauderdale, Florida, USA, August 5 – August 9, 2007

The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local electrical activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs.

Background— Previous studies on intake of linoleic acid (LA), the predominant n-6 fatty acid, and coronary heart disease (CHD) risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective cohort studies to summarize the evidence regarding the relation of dietary LA intake and CHD risk. Methods and Results— We searched MEDLINE and EMBASE databases through June 2013 for prospective cohort studies that reported the association between dietary LA and CHD events. In addition, we used unpublished data from cohort studies in a previous pooling project. We pooled the multivariate-adjusted relative risk (RR) to compare the highest with the lowest categories of LA intake using fixed-effect meta-analysis. We identified 13 published and unpublished cohort studies with a total of 310 602 individuals and 12 479 total CHD events, including 5882 CHD deaths. When the highest category was compared with the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals, 0.78–0.92; I 2 =35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% confidence intervals, 0.71–0.89; I 2 =0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% confidence intervals, 0.87–0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% confidence intervals, 0.82–0.94). Conclusions— In prospective observational studies, dietary LA intake is inversely associated with CHD risk in a dose–response manner. These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.

Background: Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 population cohorts (N=72 185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy ( R 2 =0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P =2×10 -7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on very-low-density lipoprotein lipids compared with statins for an equivalent lowering of low-density lipoprotein cholesterol, which potentially translate into smaller reductions in cardiovascular disease risk.

The language abilities of 42 8-year-old preterm children with birth weight <1750 g from a 1-year birth cohort in northern Finland was studied with four different language tests. Control children from the same birth cohort matched individually with their preterm pairs for age, sex, twinship, mother's education, place of residence, birth order and family type were also studied. In psycholinguistic test, auditory skills did not differ between the preterm and the full-term groups. Nor did any other linguistic subtest differentiate between the groups. Instead, the preterm children scored significantly poorer than their controls in visual subtests. The study also showed that the poor performance in visual tests was associated with neonatal morbidity, namely neonatal infections, need for continuous positive airway pressure (CPAP) treatment and patent ductus arteriosus (PDA). When studying the language abilities of preterm children, we suggest that qualitative methods should be used to analyse linguistic skills. We recommend versatile follow-up of preterm children until school age.

We found that circulating miRNA-146a levels were significantly elevated in new-T2DM patients compared with healthy controls. Whether expression of circulating miRNA-146a holds predictive value for T2DM warrants further investigations.

No abstract is provided for this article.

The aim of this study was to assess the association between obesity and the risk of intensive care unit (ICU) admission and death among patients hospitalized for influenza A (H1N1) viral infection. A systematic review of the Medline and Cochrane databases using 'obesity', 'hospitalization', 'influenza A viral infection', various synonyms, and reference lists of retrieved articles from January 2009 to January 2010. Studies comparing the prevalence of obesity among patients with confirmed infection for influenza A virus and who were either hospitalized or admitted to ICU/died were included. A total of 3059 subjects from six cross-sectional studies, who were hospitalized for influenza A (H1N1) viral infection, were included in this meta-analysis. Severely obese H1N1 patients (body mass index ≥ 40 kg m(-2), n = 804) were as twice as likely to be admitted to ICU or die (odds ration: 2.01, 95% confidence interval: 1.29-3.14, P < 0.002) compared with H1N1 patients who were not severely obese. Having a body mass index ≥ 30 kg m(-2) was similarly associated with a more than twofold increased risk of ICU admission or death although this did not reach statistical significance (2.14, 0.92-4.99, P < 0.07). This meta-analysis supports the view that obesity is associated with higher risks of ICU admission or death in patients with influenza A (H1N1) infection. Therefore, morbid obese patients should be monitored more intensively when hospitalized.

Functional kinked nanowires (KNWs) represent a new class of nanowire building blocks, in which functional devices, for example, nanoscale field-effect transistors (nanoFETs), are encoded in geometrically controlled nanowire superstructures during synthesis. The bottom-up control of both structure and function of KNWs enables construction of spatially isolated point-like nanoelectronic probes that are especially useful for monitoring biological systems where finely tuned feature size and structure are highly desired. Here we present three new types of functional KNWs including (1) the zero-degree KNW structures with two parallel heavily doped arms of U-shaped structures with a nanoFET at the tip of the "U", (2) series multiplexed functional KNW integrating multi-nanoFETs along the arm and at the tips of V-shaped structures, and (3) parallel multiplexed KNWs integrating nanoFETs at the two tips of W-shaped structures. First, U-shaped KNWs were synthesized with separations as small as 650 nm between the parallel arms and used to fabricate three-dimensional nanoFET probes at least 3 times smaller than previous V-shaped designs. In addition, multiple nanoFETs were encoded during synthesis in one of the arms/tip of V-shaped and distinct arms/tips of W-shaped KNWs. These new multiplexed KNW structures were structurally verified by optical and electron microscopy of dopant-selective etched samples and electrically characterized using scanning gate microscopy and transport measurements. The facile design and bottom-up synthesis of these diverse functional KNWs provides a growing toolbox of building blocks for fabricating highly compact and multiplexed three-dimensional nanoprobes for applications in life sciences, including intracellular and deep tissue/cell recordings.

We extend a model of a two‐dimensional self‐healing slip pulse, propagating dynamically in steady state with slip‐weakening failure criterion, to the supershear regime in order to study the off‐fault stressing induced by such a slip pulse and investigate features unique to the supershear range. Specifically, we show that there exists a nonattenuating stress field behind the Mach front that radiates high stresses arbitrarily far from the fault (practically this would be limited to distances comparable to the depth of the seismogenic zone), thus being capable of creating fresh damage or inducing Coulomb failure in known structures at large distances away from the main fault. We allow for both strike‐slip and dip‐slip failure induced by such a slip pulse. We show that off‐fault damage is controlled by the speed of the slip‐pulse, scaled stress drop, and principal stress orientation of the prestress field. We apply this model to study damage features induced during the 2001 Kokoxili (Kunlun) event in Tibet, for which it has been suggested that much of the rupture was supershear. We argue that an interval of simultaneous induced normal faulting is more likely due to a slip partitioning mechanism suggested previously than to the special features of supershear rupture. However, those features do provide an explanation for otherwise anomalous ground cracking at several kilometers from the main fault. We also make some estimates of fracture energy which, for a given net slip and dynamic stress drop, is lower than for a sub‐Rayleigh slip pulse because part of the energy fed by the far‐field stress is radiated back along the Mach fronts.