Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human myeloid dendritic cells

Dendritic cells (DCs) respond to microbial infections by undergoing phenotypic maturation and by producing multiple cytokines. In the present study, we analyzed the ability of influenza A and Sendai viruses to induce DC maturation and activate tumor necrosis factor alpha (TNF-alpha), alpha/beta interferon (IFN-alpha/beta), and IFN-like interleukin-28A/B (IFN-lambda2/3) and IL-29 (IFN-lambda1) gene expression in human monocyte-derived myeloid DCs (mDC). The ability of influenza A virus to induce mDC maturation or enhance the expression of TNF-alpha, IFN-alpha/beta, interleukin-28 (IL-28), and IL-29 genes was limited, whereas Sendai virus efficiently induced mDC maturation and enhanced cytokine gene expression. Influenza A virus-induced expression of TNF-alpha, IFN-alpha, IFN-beta, IL-28, and IL-29 genes was, however, dramatically enhanced when cells were pretreated with IFN-alpha. IFN-alpha priming led to increased expression of Toll-like receptor 3 (TLR3), TLR7, TLR8, MyD88, TRIF, and IFN regulatory factor 7 (IRF7) genes and enhanced influenza-induced phosphorylation and DNA binding of IRF3. Influenza A virus also enhanced the binding of NF-kappaB to the respective NF-kappaB elements of the promoters of IFN-beta and IL-29 genes. In mDC IL-29 induced MxA protein expression and possessed antiviral activity against influenza A virus, although this activity was lower than that of IFN-alpha or IFN-beta. Our results show that in human mDCs viruses can readily induce the expression of IL-28 and IL-29 genes whose gene products are likely to contribute to the host antiviral response.     

Synthetic antibiotic peptides database

A computerized database for synthetic antibiotic peptides, the SAPD, has been created and is available on the Internet at web address, http://oma.terkko.helsinki.fi:8080/~SAPD. The SAPD is modelled on two pre-existing computer databases for naturally occurring peptide antibiotics, the Antimicrobial Sequences Database and the Peptaibol Database, and it will contain both chemical and biological information on all published synthetic antibiotic peptides.     

Lycopene,atherosclerosis, and coronary heart disease

Diets rich in fruits and vegetables containing carotenoids have been of interest because of their potential health benefit against chronic diseases such as cardiovascular diseases (CVD) and cancer. Interest particularly in lycopene is growing rapidly following the recent publication of epidemiological studies that have associated high lycopene levels with reductions in CVD incidence. Two studies were conducted. In the first one, we examined the role of lycopene as a risk-lowering factor with regard to acute coronary events and stroke in the prospective Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study. The subjects were 725 middle-aged men free of coronary heart disease and stroke at the study baseline. In a Cox's proportional hazards' model adjusting for covariates, men in the lowest quartile of serum levels of lycopene had a 3.3-fold (P < 0.001) risk of the acute coronary event or stroke as compared with others. In the second study, we assessed the association between plasma concentration of lycopene and intima-media thickness of the common carotid artery wall (CCA-IMT) in a cross-sectional analysis of the Antioxidant Supplementation in the Atherosclerosis Prevention (ASAP) study data in 520 asymptomatic men and women. In a covariance analysis adjusting for common cardiovascular risk factors, low plasma levels of lycopene were associated with an 18% increase of IMT in men as compared with men in whom plasma levels were higher than median (P = 0.003 for difference). In women, the difference did not remain significant after the adjustments. On the basis of these works, it is evident that the circulating levels of lycopene play some role with regard to cardiovascular health in Finland, at least in men. We conclude that circulating levels of lycopene, a biomarker of tomato-rich food, may play a role in early stages of atherogenesis and may have clinical and public health relevance.     

Obesity in transgenic female mice with constitutively elevated luteinizing hormone secretion

Transgenic (TG) female mice, expressing a chimeric bovine luteinizing hormone (LH) beta-subunit/human chorionic gonadotropin beta-subunit COOH-terminal extension (bLHbeta-CTP) gene, produce high levels of circulating LH and serve as a model for functional ovarian hyperandrogenism and follicular cysts. We report here that obesity is a typical feature of these female mice. The mean body weight of the bLHbeta-CTP females was significantly higher than in controls at, and beyond 5 wk of age, and at 5 mo, it was 32% increased. At this age, the amount of white adipose tissue in the bLHbeta-CTP females was significantly increased, as reflected by the weight difference of the retroperitoneal fat pad. In addition, the expression of leptin mRNA in white adipose tissue of the TG females was elevated about twofold. Serum leptin and insulin levels, and food intake, were also increased significantly in the TG females. Brown adipose tissue (BAT) thermogenic activity, as measured by GDP binding to BAT mitochondria, was reduced (P < 0.05). Ovariectomy at the age of 3 wk totally prevented the development of obesity. In summary, the present results show that intact female bLHbeta-CTP mice are obese, have increased food consumption, and reduced BAT thermogenic activity. The weight gain can be explained partly by elevated androgens but is probably also contributed to the increased adrenal steroidogenesis. Hence, the bLHbeta-CTP mice provide a useful model for studying obesity related to elevated LH secretion, with consequent alterations in ovarian and adrenal function.     

Joint regression and association modeling of longitudinal ordinal data

We propose models for longitudinal, or otherwise clustered, ordinal data. The association between subunit responses is characterized by dependence ratios (Ekholm, Smith, and McDonald, 1995, Biometrika 82, 847-854), which are extended from the binary to the multicategory case. The joint probabilities of the subunit responses are expressed as explicit functions of the marginal means and the dependence ratios of all orders, obtaining a computational advantage for likelihood-based inference. Equal emphasis is put on finding regression models for the univariate cumulative probabilities, and on deriving the dependence ratios from meaningful association-generating mechanisms. A data set on the effects of treatment with Fluvoxamine, which has been analyzed in parts before (Molenberghs, Kenward, and Lesaffre, 1997, Biometrika 84, 33-44), is analyzed in its entirety. Selection models are used for studying the sensitivity of the results to drop-out.     

Coenzyme Q10: absorption, antioxidative properties, determinants, and plasma levels

The purpose of this article is to summarise our studies, in which the main determinants and absorption of plasma coenzyme Q10 (Q10, ubiquinone) have been assessed, and the effects of moderate dose oral Q10 supplementation on plasma antioxidative capacity, lipoprotein oxidation resistance and on plasma lipid peroxidation investigated. All the supplementation trials carried out have been blinded and placebo-controlled clinical studies. Of the determinants of Q10, serum cholesterol, serum triglycerides, male gender, alcohol consumption and age were found to be associated positively with plasma Q10 concentration. A single dose of 30 mg of Q10, which is the maximum daily dose recommended by Q10 producers, had only a marginal elevating effect on plasma Q10 levels in non-Q10-deficient subjects. Following supplementation, a dose-dependent increase in plasma Q10 levels was observed up to a daily dose of 200 mg, which resulted in a 6.1-fold increase in plasma Q10 levels. However, simultaneous supplementation with vitamin E resulted in lower plasma Q10 levels. Of the lipid peroxidation measurements, Q10 supplementation did not increase LDL TRAP, plasma TRAP, VLDL+LDL oxidation resistance nor did it decrease LDL oxidation susceptibility ex vivo. Q10 with minor vitamin E dose neither decreased exercise-induced lipid peroxidation ex vivo nor muscular damage. Q10 supplementation might, however, decrease plasma lipid peroxidation in vivo , as assessed by the increased proportion of plasma ubiquinol (reduced form, Q10H 2 ) of total Q10. High dose vitamin E supplementation decreased this proportion, which suggests in vivo regeneration of tocopheryl radicals by ubiquinol.     

Impact of polymer surface affinity of novel antifouling agents

In a previous study we found two agents, the alpha(2)-agonist medetomidine ((+/-)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole) and the alpha(2)-agonist clonidine (2-(2,6-dichloroanilino)-2-imidazoline), that specifically and efficiently impede settlement of the barnacle Balanus improvisus, one of the most serious biofouling organisms in Swedish waters. Medetomidine, but not clonidine, is known to adsorb to solid polystyrene (PS) surfaces in the presence of salt, a feature that is of particular interest in attempts to develop an efficient antifouling surface. We show that medetomidine, but not clonidine, has a significant ability to adsorb to untreated (hydrophobic) PS in two different incubation media: filtered seawater (FSW) and deionized water (mQ). At negatively charged (hydrophilic) PS, medetomidine displays a strong interaction with the surface in both incubation media. At the hydrophilic PS, clonidine also displays a significant interaction with the surface when incubated in mQ and a weaker, but not significant, interaction when incubated in FSW. By studying the effects of time, incubation media, and pH on the adsorption of medetomidine and clonidine, we suggest that medetomidine is associated to hydrophobic PS by means of hydrophobic interactions, while the adsorption of medetomidine and clonidine to hydrophilic PS contains elements of electrostatic interaction. Using time-of-flight secondary ion mass spectroscopy (TOF-SIMS) we detected only weak signals from medetomidine on the hydrophobic PS surfaces, while strong medetomidine signals were observed on hydrophilic PS. This suggests that the adsorbed medetomidine, to a greater extent, desorbed from the hydrophobic rather than from the hydrophilic PS surfaces during exposure to vacuum. The strong surface affinity of medetomidine on both types of surfaces and the preserved antifouling activity are valuable features in designing a marine coating.     

Fgf9 signaling regulates inner ear morphogenesis through epithelial-mesenchymal interactions

The mammalian inner ear comprises the cochleovestibular labyrinth, derived from the ectodermal otic placode, and the encasing bony labyrinth of the temporal bone. Epithelial-mesenchymal interactions are thought to control inner ear development, but the modes and the molecules involved are largely unresolved. We show here that, during the precartilage and cartilage stages, Fgf9 is expressed in specific nonsensory domains of the otic epithelium and its receptors, Fgfr1(IIIc) and Fgfr2(IIIc), widely in the surrounding mesenchyme. To address the role of Fgf9 signaling, we analyzed the inner ears of mice homozygous for Fgf9 null alleles. Fgf9 inactivation leads to a hypoplastic vestibular component of the otic capsule and to the absence of the epithelial semicircular ducts. Reduced proliferation of the prechondrogenic mesenchyme was found to underlie capsular hypoplasticity. Semicircular duct development is blocked at the initial stages, since fusion plates do not form. Our results show that the mesenchyme directs fusion plate formation and they give direct evidence for the existence of reciprocal epithelial-mesenchymal interactions in the developing inner ear. In addition to the vestibule, in the cochlea, Fgf9 mutation caused defects in the interactions between the Reissner's membrane and the mesenchymal cells, leading to a malformed scala vestibuli. Together, these data show that Fgf9 signaling is required for inner ear morphogenesis.     

Selection for increased brood size in historical human populations

Human twinning rates are considered to either reflect the direct fitness effects of twinning in variable environments, or to be a maladaptive by-product of selection for other maternal reproductive traits (e.g., polyovulation). We used historical data (1710-1890) of Sami populations from Northern Scandinavia to contrast these alternative hypotheses. We found that women who produced twins started their reproduction younger, ceased it later, had higher lifetime fecundity, raised more offspring to adulthood, and had higher fitness (individual lambda) than mothers of singletons in all populations studied. For example, an average of 1.2 offspring survived to adulthood from a twin delivery, irrespective of its sex ratio, whereas only 0.8 offspring survived to adulthood from a singleton delivery. Only if mothers started reproduction at very late age (> 37 yr), or had a very long reproductive life span (> 20 yr), was it more beneficial to produce only singletons. These findings suggest that twin deliveries among Sami could not be explained as a maladaptive by-product of selection for other maternal reproductive traits. In contrast, our results suggest that twinning was under natural selection, although the strength of selection was likely to have been context dependent.     

Coexistence of the social types: genetic population structure in the ant Formica exsecta

The ant Formica exsecta has two types of colonies that exist in sympatry but usually as separate subpopulations: colonies with simple social organization and single queens (M type) or colonial networks with multiple queens (P type). We used both nuclear (DNA microsatellites) and mitochondrial markers to study the transition between the social types, and the contribution of males and females in gene flow within and between the types. Our results showed that the social types had different spatial genetic structures. The M subpopulations formed a fairly uniform population, whereas the P subpopulations were, on average, more differentiated from each other than from the nearby M subpopulations and could have been locally established from the M-type colonies, followed by philopatric behavior and restricted emigration of females. Thus, the relationship between the two social types resembles that of source (M type) and sink (P type) populations. The comparison of mitochondrial (phiST) and nuclear (FST) differentiation indicates that the dispersal rate of males is four to five times larger than that of females both among the P-type subpopulations and between the social types. Our results suggest that evolution toward complex social organization can have an important effect on genetic population structure through changes in dispersal behavior associated with different sociogenetic organizations.