Publications

Fetal and postnatal growth have been associated with adult blood pressure (BP), but findings about the relative importance of growth at different stages of life on BP are inconsistent.The study population comprised 5198 participants from the Northern Finland Birth Cohort 1966 with data on birth weight, height and weight measurements until adolescence, systolic and diastolic BP at 31 years and several covariates. Structural equation modelling was used in the analysis.Negative direct effects of birth weight on adult systolic BP were observed (standardised regression coefficients: -0.08 (-0.14 to -0.03) in males and -0.04 (-0.09 to 0.01) in females, equalling -1.99 (-3.32 to -0.65) and -1.01 (-2.33 to 0.32) mm Hg/kg, respectively). Immediate postnatal growth was associated with adult BP only indirectly via growth later in life. In contrast, growth from adiposity rebound onwards had large direct, indirect and total effects on adult BP. Current body mass index was the strongest growth-related predictor of adult BP (0.36 (0.30 to 0.41) in males and 0.31 (0.24, 0.37) in females, equalling 1.29 (1.09 to 1.48) and 0.81 (0.63 to 0.99) mm Hg/(kg/m(2)), respectively).Our path analytical approach provides evidence for the importance of both fetal growth and postnatal growth, especially from adiposity rebound onwards, in determining adult BP, together with genetic predisposition and behavioural factors.

This paper describes a technique that uses mixed self-assembled monolayers of two alkanethiolates (-S(CH2)11(OCH2CH2)6OR, R = a hydrophobic group, and -S(CH2)11(OCH2CH2)nOH, n = 3, 6, EGnOH), in combination with surface plasmon resonance spectroscopy, to study the influence of the size and shape of R, and its density at the surface, on the hydrophobic adsorption of proteins at solid−liquid interfaces. Detailed results were obtained for β-galactosidase, carbonic anhydrase, lysozyme, and RNase A using R = C(C6H5)3, CH(C6H5)2, and CH2(C6H5). A hard-sphere model is used to rationalize the adsorption; this model, although very approximate, helps to interpret qualitative trends in the data. Using this model, the extent to which adsorbed proteins undergo conformational rearrangements appears to depend on the density of the hydrophobic groups at the surface and on the concentration of protein in solution. This paper describes the first step toward the development of a system that will allow the study of hydrophobic interactions of proteins with surfaces presenting organic groups of well-defined shape.

The hydrophobic effect, the free-energetically favorable association of nonpolar solutes in water, makes a dominant contribution to binding of many systems of ligands and proteins. The objective of this study was to examine the hydrophobic effect in biomolecular recognition using two chemically different but structurally similar hydrophobic groups, aliphatic hydrocarbons and aliphatic fluorocarbons, and to determine whether the hydrophobicity of the two groups could be distinguished by thermodynamic and biostructural analysis. This paper uses isothermal titration calorimetry (ITC) to examine the thermodynamics of binding of benzenesulfonamides substituted in the para position with alkyl and fluoroalkyl chains (H(2)NSO(2)C(6)H(4)-CONHCH(2)(CX(2))(n)CX(3), n = 0-4, X = H, F) to human carbonic anhydrase II (HCA II). Both alkyl and fluoroalkyl substituents contribute favorably to the enthalpy and the entropy of binding; these contributions increase as the length of chain of the hydrophobic substituent increases. Crystallography of the protein-ligand complexes indicates that the benzenesulfonamide groups of all ligands examined bind with similar geometry, that the tail groups associate with the hydrophobic wall of HCA II (which is made up of the side chains of residues Phe131, Val135, Pro202, and Leu204), and that the structure of the protein is indistinguishable for all but one of the complexes (the longest member of the fluoroalkyl series). Analysis of the thermodynamics of binding as a function of structure is compatible with the hypothesis that hydrophobic binding of both alkyl and fluoroalkyl chains to hydrophobic surface of carbonic anhydrase is due primarily to the release of nonoptimally hydrogen-bonded water molecules that hydrate the binding cavity (including the hydrophobic wall) of HCA II and to the release of water molecules that surround the hydrophobic chain of the ligands. This study defines the balance of enthalpic and entropic contributions to the hydrophobic effect in this representative system of protein and ligand: hydrophobic interactions, here, seem to comprise approximately equal contributions from enthalpy (plausibly from strengthening networks of hydrogen bonds among molecules of water) and entropy (from release of water from configurationally restricted positions).

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Single-walled carbon nanotube (SWNT) tips have been used to image nanostructures with high resolution. Studies of gold nanocrystal standards showed that SWNT tips provide a significant improvement in lateral resolution with respect to multi-walled nanotube tips and microfabricated Si tips. The nanotube tips were also used to resolve substructure within SWNTs deposited on surfaces. These results suggest that observed 1.5 nm high structures can correspond to several SWNTs aligned in parallel. In addition, SWNT tips exhibited superior resolution compared to conventional tips when imaging biological nanostructures, such as double-stranded DNA. The potential and future challenges of SWNT tips are discussed.

Although it has been hypothesized that maternal thyroid dysfunction and/or positive thyroid antibodies during gestation are associated with certain pregnancy complications and an increased risk of later maternal cardiovascular diseases or diabetes, existing data is inconsistent. The aim of this population-based cohort study was to investigate the association between maternal thyroid dysfunction and/or antibodies detected during pregnancy and the occurrence of pregnancy complications or later maternal hypertension, diabetes, and thyroid disease over a 20-year follow-up period. The study population was comprised of mothers with singleton pregnancies who enrolled in the Northern Finland Birth Cohort 1986 and had sufficient early pregnancy serum samples in storage (n = 5805); these were tested for thyroid function and antibody analyses. Data from 3 registries were obtained to determine the health of these women in the 20 years since their index pregnancy; data included whether these women had diseases requiring medication, as well as hospital discharge diagnoses and causes of death. Women whose tested serum samples had results consistent with thyroid dysfunction (n = 786) were grouped into 5 categories (overt hypothyroidism, subclinical hypothyroidism, subclinical hyperthyroidism, overt hyperthyroidism, and hypothyroxinemia) and compared to women with normal thyroid function tests (n = 4719) who served as controls. The primary outcome measures were pre-eclampsia and gestational diabetes during the index pregnancy, later morbidity (maternal hypertension, diabetes, and thyroid disease), and total mortality. No association was found between thyroid dysfunction or thyroid antibodies and preeclampsia or gestational diabetes. The most important factor that predicted subsequent thyroid disease was overt hypothyroidism during pregnancy, with more than a 17-fold independent risk (hazard ratio [HR]: 17.7; 95% confidence interval [CI]: 7.8–40.6). Overt hypothyroidism during gestation was also associated with a 6-fold increased risk of diabetes (HR: 6.0; 95% CI: 2.2–16.4). Other predictive risk factors associated with later thyroid disease included subclinical hypothyroidism (HR: 3.3; 95% CI: 1.6–6.9), thyroid peroxidase antibody positivity (HR: 4.2; 95% CI: 2.3–7.4), and thyroglobulin antibody positivity (HR: 3.3; 95% CI: 1.9–6.0). There was no association between thyroid dysfunction or antibodies during pregnancy and later hypertension or overall mortality. The findings indicate that hypothyroidism and thyroid antibodies in early pregnancy are predictive risk factors for subsequent thyroid disease. Overt hypothyroidism during pregnancy seems to be a major risk factor for the development of diabetes.

Introduction: High alcohol consumption is a major cause of morbidity, yet moderate alcohol intake is favorably associated with cardiovascular disease and many risk factors. We aimed to characterize the associations of regular alcohol consumption with a comprehensive systemic metabolic profile. Methods: 86 circulating lipids, fatty acids and metabolites were quantified by high-throughput NMR metabolomics. Cross-sectional associations of alcohol intake with the metabolomic biomarkers were assessed for ≈10,000 individuals from three population-based cohorts from Finland aged 24-45 years. Metabolic changes associated with change in alcohol intake during 6-year follow-up were examined for 1466 individuals. Results: Increased alcohol intake was associated with circulating biomarkers across multiple metabolic pathways, including increased levels of monounsaturated fatty acids and decreased levels of omega-6 fatty acids, lower concentrations of glutamine and citrate as well as higher lipid concentrations in HDL subclasses and smaller LDL particle size (P Conclusions: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk and may help to explain mediation of cardiovascular risk related to alcohol intake.

This article describes a class of robots-"arthrobots"-inspired, in part, by the musculoskeletal system of arthropods (spiders and insects, inter alia). Arthrobots combine mechanical compliance, lightweight and simple construction, and inexpensive yet scalable design. An exoskeleton, constructed from thin organic polymeric tubes, provides lightweight structural support. Pneumatic joints modeled after the hydrostatic joints of spiders provide actuation and inherent mechanical compliance to external forces. An inflatable elastomeric tube (a "balloon") enables active extension of a limb; an opposing elastic tendon enables passive retraction. A variety of robots constructed from these structural elements demonstrate (i) crawling with one or two limbs, (ii) walking with four or six limbs (including an insect-like triangular gait), (iii) walking with eight limbs, or (iv) floating and rowing on the surface of water. Arthrobots are simple to fabricate and are able to operate safely in contact with humans.

Abstract Objectives Previous studies have shown good correlation between polycystic ovarian morphology (PCOM) and serum anti-Müllerian hormone (AMH) levels. We evaluated the utility of AMH as a surrogate for PCOM as a part of the polycystic ovary syndrome (PCOS) diagnosis by describing how the use of different AMH cut-off values would change the prevalence of PCOS. Methods A general population-based birth cohort study. Anti-Müllerian hormone concentrations were measured from serum samples taken at age 31 years (n = 2917) using the electrochemiluminescence immunoassay (Elecsys). Anti-Müllerian hormone data were combined with data on oligo/amenorrhoea and hyperandrogenism to identify women with PCOS. Results The addition of AMH as a surrogate marker for PCOM increased the number of women fulfilling at least two PCOS features in accordance with the Rotterdam criteria. The prevalence of PCOS was 5.9% when using the AMH cut-off based on the 97.5% quartile (10.35 ng/mL) and 13.6% when using the recently proposed cut-off of 3.2 ng/mL. When using the latter cut-off value, the distribution of PCOS phenotypes A, B, C, and D was 23.9%, 4.7%, 36.6%, and 34.8%, respectively. Compared with the controls, all PCOS groups with different AMH concentration cut-offs showed significantly elevated testosterone (T), free androgen index (FAI), luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH) ratio, body mass index (BMI), waist circumference, and homoeostatic model assessment of insulin resistance (HOMA-IR) values, as well as significantly decreased sex hormone-binding globulin (SHBG) values. Conclusions Anti-Müllerian hormone could be useful surrogate for PCOM in large data sets, where transvaginal ultrasound is not feasible, to aid the capturing of women with typical PCOS characteristics. Anti-Müllerian hormone measurement from archived samples enables retrospective PCOS diagnosis when combined with oligo/amenorrhoea or hyperandrogenism.