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Valcárcel B Würtz P Seich al Basatena NK Tukiainen T Kangas AJ Soininen P Järvelin MR Ala-Korpela M Ebbels TM de Iorio M 《PloS one》2011,6(9):e24702
Background
Variations in the pattern of molecular associations are observed during disease development. The comprehensive analysis of molecular association patterns and their changes in relation to different physiological conditions can yield insight into the biological basis of disease-specific phenotype variation.Methodology
Here, we introduce a formal statistical method for the differential analysis of molecular associations via network representation. We illustrate our approach with extensive data on lipoprotein subclasses measured by NMR spectroscopy in 4,406 individuals with normal fasting glucose, and 531 subjects with impaired fasting glucose (prediabetes). We estimate the pair-wise association between measures using shrinkage estimates of partial correlations and build the differential network based on this measure of association. We explore the topological properties of the inferred network to gain insight into important metabolic differences between individuals with normal fasting glucose and prediabetes.Conclusions/Significance
Differential networks provide new insights characterizing differences in biological states. Based on conventional statistical methods, few differences in concentration levels of lipoprotein subclasses were found between individuals with normal fasting glucose and individuals with prediabetes. By performing the differential analysis of networks, several characteristic changes in lipoprotein metabolism known to be related to diabetic dyslipidemias were identified. The results demonstrate the applicability of the new approach to identify key molecular changes inaccessible to standard approaches. 相似文献104.
Lindberg HK Falck GC Catalán J Koivisto AJ Suhonen S Järventaus H Rossi EM Nykäsenoja H Peltonen Y Moreno C Alenius H Tuomi T Savolainen KM Norppa H 《Mutation research》2012,745(1-2):58-64
In vitro studies have suggested that nanosized titanium dioxide (TiO(2)) is genotoxic. The significance of these findings with respect to in vivo effects is unclear, as few in vivo studies on TiO(2) genotoxicity exist. Recently, nanosized TiO(2) administered in drinking water was reported to increase, e.g., micronuclei (MN) in peripheral blood polychromatic erythrocytes (PCEs) and DNA damage in leukocytes. Induction of micronuclei in mouse PCEs was earlier also described for pigment-grade TiO(2) administered intraperitoneally. The apparent systemic genotoxic effects have been suggested to reflect secondary genotoxicity of TiO(2) due to inflammation. However, a recent study suggested that induction of DNA damage in mouse bronchoalveolar lavage (BAL) cells after intratracheal instillation of nanosized or fine TiO(2) is independent of inflammation. We examined here, if inhalation of freshly generated nanosized TiO(2) (74% anatase, 26% brookite; 5 days, 4 h/day) at 0.8, 7.2, and (the highest concentration allowing stable aerosol production) 28.5 mg/m(3) could induce genotoxic effects in C57BL/6J mice locally in the lungs or systematically in peripheral PCEs. DNA damage was assessed by the comet assay in lung epithelial alveolar type II and Clara cells sampled immediately following the exposure. MN were analyzed by acridine orange staining in blood PCEs collected 48 h after the last exposure. A dose-dependent deposition of Ti in lung tissue was seen. Although the highest exposure level produced a clear increase in neutrophils in BAL fluid, indicating an inflammatory effect, no significant effect on the level of DNA damage in lung epithelial cells or micronuclei in PCEs was observed, suggesting no genotoxic effects by the 5-day inhalation exposure to nanosized TiO(2) anatase. Our inhalation exposure resulted in much lower systemic TiO(2) doses than the previous oral and intraperitoneal treatments, and lung epithelial cells probably received considerably less TiO(2) than BAL cells in the earlier intratracheal study. 相似文献
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Mikko Hiltunen Vinoth K. M. Khandelwal Nagendra Yaluri Tea Tiilikainen Maija Tusa Henna Koivisto Marine Krzisch Saila Vepsäläinen Petra Mäkinen Susanna Kemppainen Pasi Miettinen Annakaisa Haapasalo Hilkka Soininen Markku Laakso Heikki Tanila 《Journal of cellular and molecular medicine》2012,16(6):1206-1222
According to epidemiological studies, type‐2 diabetes increases the risk of Alzheimer’s disease. Here, we induced hyperglycaemia in mice overexpressing mutant amyloid precursor protein and presenilin‐1 (APdE9) either by cross‐breeding them with pancreatic insulin‐like growth factor 2 (IGF‐2) overexpressing mice or by feeding them with high‐fat diet. Glucose and insulin tolerance tests revealed significant hyperglycaemia in mice overexpressing IGF‐2, which was exacerbated by high‐fat diet. However, sustained hyperinsulinaemia and insulin resistance were observed only in mice co‐expressing IGF‐2 and APdE9 without correlation to insulin levels in brain. In behavioural tests in aged mice, APdE9 was associated with poor spatial learning and the combination of IGF‐2 and high‐fat diet further impaired learning. Neither high‐fat diet nor IGF‐2 increased β‐amyloid burden in the brain. In male mice, IGF‐2 increased β‐amyloid 42/40 ratio, which correlated with poor spatial learning. In contrast, inhibitory phosphorylation of glycogen synthase kinase 3β, which correlated with good spatial learning, was increased in APdE9 and IGF‐2 female mice on standard diet, but not on high‐fat diet. Interestingly, high‐fat diet altered τ isoform expression and increased phosphorylation of τ at Ser202 site in female mice regardless of genotype. These findings provide evidence for new regulatory mechanisms that link type‐2 diabetes and Alzheimer pathology. 相似文献
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Mäkinen VP Tynkkynen T Soininen P Forsblom C Peltola T Kangas AJ Groop PH Ala-Korpela M 《Metabolomics : Official journal of the Metabolomic Society》2012,8(3):369-375
Diabetic kidney disease, diagnosed by urinary albumin excretion rate (AER), is a critical symptom of chronic vascular injury in diabetes, and is associated with dyslipidemia and increased mortality. We investigated serum lipids in 326 subjects with type 1 diabetes: 56% of patients had normal AER, 17% had microalbuminuria (20?≤?AER?200?μg/min or 30?≤?AER?300?mg/24?h) and 26% had overt kidney disease (macroalbuminuria AER?≥?200?μg/min or AER?≥?300?mg/24?h). Lipoprotein subclass lipids and low-molecular-weight metabolites were quantified from native serum, and individual lipid species from the lipid extract of the native sample, using a proton NMR metabonomics platform. Sphingomyelin (odds ratio 2.53, P?10(-7)), large VLDL cholesterol (odds ratio 2.36, P?10(-10)), total triglycerides (odds ratio 1.88, P?10(-6)), omega-9 and saturated fatty acids (odds ratio 1.82, P?10(-5)), glucose disposal rate (odds ratio 0.44, P?10(-9)), large HDL cholesterol (odds ratio 0.39, P?10(-9)) and glomerular filtration rate (odds ratio 0.19, P?10(-10)) were associated with kidney disease. No associations were found for polyunsaturated fatty acids or phospholipids. Sphingomyelin was a significant regressor of urinary albumin (P?0.0001) in multivariate analysis with kidney function, glycemic control, body mass, blood pressure, triglycerides and HDL cholesterol. Kidney injury, sphingolipids and excess fatty acids have been linked in animal models-our exploratory approach provides independent support for this relationship in human patients with diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0343-y) contains supplementary material, which is available to authorized users. 相似文献
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Mika Kivim?ki P?ivi Leino-Arjas Ritva Luukkonen Hilkka Riihim?ki Jussi Vahtera Juhani Kirjonen 《BMJ (Clinical research ed.)》2002,325(7369):857
ObjectiveTo examine the association between work stress, according to the job strain model and the effort-reward imbalance model, and the risk of death from cardiovascular disease.DesignProspective cohort study. Baseline examination in 1973 determined cases of cardiovascular disease, behavioural and biological risks, and stressful characteristics of work. Biological risks were measured at 5 year and 10 year follow up.SettingStaff of a company in the metal industry in Finland.Participants812 employees (545 men, 267 women) who were free from cardiovascular diseases at baseline.ResultsMean length of follow up was 25.6 years. After adjustment for age and sex, employees with high job strain, a combination of high demands at work and low job control, had a 2.2-fold (95% confidence interval 1.2 to 4.2) cardiovascular mortality risk compared with their colleagues with low job strain. The corresponding risk ratio for employees with effort-reward imbalance (low salary, lack of social approval, and few career opportunities relative to efforts required at work) was 2.4 (1.3 to 4.4). These ratios remained significant after additional adjustment for occupational group and biological and behavioural risks at baseline. High job strain was associated with increased serum total cholesterol at the 5 year follow up. Effort-reward imbalance predicted increased body mass index at the 10 year follow up.ConclusionsHigh job strain and effort-reward imbalance seem to increase the risk of cardiovascular mortality. The evidence from industrial employees suggests that attention should be paid to the prevention of work stress.