| 1. |
- Beck, Halfdan, et al.
(author)
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Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase
- 2010
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In: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 188:5, s. 629-638
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Journal article (peer-reviewed)abstract
- Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.
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| 2. |
- Fuks, Kateryna B., et al.
(author)
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Arterial blood pressure and long-term exposure to traffic-related air pollution : an analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE)
- 2014
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In: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Sciences (NIEHS). - 0091-6765 .- 1552-9924. ; 122:9, s. 896-905
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Research review (peer-reviewed)abstract
- BACKGROUND: Long-term exposure to air pollution is hypothesized to elevate arterial blood pressure (BP). The existing evidence is scarce and country-specific. OBJECTIVES: We investigated the cross-sectional association of long-term traffic-related air pollution with BP and prevalent hypertension in European populations. METHODS: Fifteen population-based cohorts, participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE), were analysed. Residential exposure to particulate matter and nitrogen oxides was modelled with land use regression using a uniform protocol. Traffic exposure was assessed with traffic indicator variables. We analysed systolic and diastolic BP in participants medicated and non-medicated with BP lowering medication (BPLM) separately, adjusting for personal and area-level risk factors and environmental noise. Prevalent hypertension was defined as ≥ 140 mmHg systolic, or ≥ 90 mmHg diastolic BP, or intake of BPLM. We combined cohort-specific results using random-effects meta-analysis. RESULTS: In the main meta-analysis of 113,926 participants, traffic load on major roads within 100 m of the residence was associated with increased systolic and diastolic BP in non-medicated participants (0.35 mmHg [95% CI: 0.02-0.68] and 0.22 mmHg [95% CI: 0.04-0.40] per 4,000,000 vehicles × m/day, respectively). The estimated odds ratio for prevalent hypertension was 1.05 [95% CI: 0.99-1.11] per 4,000,000 vehicles × m/day. Modelled air pollutants and BP were not clearly associated. CONCLUSIONS: In this first comprehensive meta-analysis of European population-based cohorts we observed a weak positive association of high residential traffic exposure with BP in non-medicated participants, and an elevated OR for prevalent hypertension. The relationship of modelled air pollutants with BP was inconsistent.
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| 3. |
- Kilsgård, Ola, et al.
(author)
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Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities.
- 2012
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In: American journal of respiratory cell and molecular biology. - 1535-4989 .- 1044-1549. ; 46:2, s. 240-8
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Journal article (peer-reviewed)abstract
- Bacterial colonization of the lower respiratory tract is frequently seen in chronic obstructive pulmonary disease (COPD), and may cause exacerbations leading to disease progression. Antimicrobial peptides comprise an important part of innate lung immunity, and not least the cathelicidin human cationic antimicrobial protein-18/LL-37. Peptidylarginine deiminases (PADIs) post-translationally modify proteins by converting cationic peptidylarginine residues to neutral peptidylcitrulline. An increased presence of PADI2 and citrullinated proteins was demonstrated in the lungs of smokers. In this study, preformed PADI4, stored in granulocytes and extracellularly in the lumina of bronchi, was found in lung tissue of individuals suffering from COPD. In vitro, recombinant human PADI2 and PADI4 both caused a time- and dose-dependent citrullination of LL-37. The citrullination resulted in impaired antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, and nontypable Haemophilus influenzae, but less so against Pseudomonas aeruginosa. Using artificial lipid bilayers, we observed discrete differences when comparing the disrupting activity of native and citrullinated LL-37, suggesting that differences in cell wall composition are important during interactions with whole bacteria. Furthermore, citrullinated LL-37 showed higher chemotactic activity against mononuclear leukocytes than did native LL-37, but was less efficient at neutralizing lipolysaccharide, and also in converting apoptotic neutrophils into a state of secondary necrosis. In addition, citrullinated LL-37 was more prone to degradation by proteases, whereas the V8 endopetidase of S. aureus cleaved the modified peptide at additional sites, compared with native LL-37. Together, these findings demonstrate novel mechanisms whereby the inflammation-dependent deiminases PADI2 and PADI4 can alter the activites of antibacterial polypeptides, affecting the course of inflammatory disorders such as COPD.
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| 4. |
- Raaschou-Nielsen, Ole, et al.
(author)
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Air pollution and lung cancer incidence in 17 European cohorts : prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE)
- 2013
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In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 14:9, s. 813-822
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Journal article (peer-reviewed)abstract
- BACKGROUND: Ambient air pollution is suspected to cause lung cancer. We aimed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations.METHODS: This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and we assessed air pollution by land-use regression models for particulate matter (PM) with diameter of less than 10 μm (PM10), less than 2·5 μm (PM2·5), and between 2·5 and 10 μm (PMcoarse), soot (PM2·5absorbance), nitrogen oxides, and two traffic indicators. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses.FINDINGS: The 312 944 cohort members contributed 4 013 131 person-years at risk. During follow-up (mean 12·8 years), 2095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1·22 [95% CI 1·03-1·45] per 10 μg/m(3)). For PM2·5 the HR was 1·18 (0·96-1·46) per 5 μg/m(3). The same increments of PM10 and PM2·5 were associated with HRs for adenocarcinomas of the lung of 1·51 (1·10-2·08) and 1·55 (1·05-2·29), respectively. An increase in road traffic of 4000 vehicle-km per day within 100 m of the residence was associated with an HR for lung cancer of 1·09 (0·99-1·21). The results showed no association between lung cancer and nitrogen oxides concentration (HR 1·01 [0·95-1·07] per 20 μg/m(3)) or traffic intensity on the nearest street (HR 1·00 [0·97-1·04] per 5000 vehicles per day).INTERPRETATION: Particulate matter air pollution contributes to lung cancer incidence in Europe.FUNDING: European Community's Seventh Framework Programme.
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| 5. |
- Skovgaard, Mette, et al.
(author)
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Effect of microscale shear stresses on the martensitic phase transformation of nanocrystalline tetragonal zirconia powders
- 2010
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In: Journal of the European Ceramic Society. - : Elsevier BV. - 0955-2219 .- 1873-619X. ; 30:13, s. 2749-2755
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Journal article (peer-reviewed)abstract
- For the first time, the effect of microscale shear stress induced by both mechanical compression and ball-milling on the phase stability of nanocrystalline tetragonal zirconia (t-ZrO2) powders was studied in water free, inert atmosphere. It was found that nanocrystalline t-ZrO2 powders are extremely sensitive to both macroscopic uniaxial compressive strain and ball-milling induced shear stress and easily transform martensitically into the monoclinic phase. A linear relationship between applied compressive stress and the degree of tetragonal to monoclinic (t→m) phase transformation was observed. Ball-milling induced microscale stress has a similar effect on the t→m phase transformation. Furthermore, it was found that even very mild milling condition, such as 120 rpm, 1 h (0.5mm balls) was enough to induce phase transformation. Surfactant assisted ball-milling was found to be very effective in de-agglomeration of our nanocrystalline porous ZrO2 particles into discrete nanocrystals. However, the t→m phase transformation could not be avoided totally even at very mild milling condition. This suggests that the metastable t-ZrO2 is extreme sensitive to microscale shear stress induced by both mechanical compression and ball-milling. The findings presented in this work are very important in further understanding the stress-induced phase transformation of nanocrystalline t-ZrO2 powders in a water free atmosphere and their further stabilization in industrially relevant solvents.
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| 6. |
- Van Schijndel, Jessica E., et al.
(author)
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Dual association of a TRKA polymorphism with schizophrenia
- 2011
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In: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 21:3, s. 125-131
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Journal article (peer-reviewed)abstract
- OBJECTIVE: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.METHODS: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.RESULT: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.CONCLUSION: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
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| 7. |
- Wang, Meng, et al.
(author)
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Long-term exposure to elemental constituents of particulate matter and cardiovascular mortality in 19 European cohorts : Results from the ESCAPE and TRANSPHORM projects
- 2014
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In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 66, s. 97-106
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Journal article (peer-reviewed)abstract
- Background: Associations between long-term exposure to ambient particulate matter (PM) and cardiovascular (CVD) mortality have been widely recognized. However, health effects of long-term exposure to constituents of PM on total CVD mortality have been explored in a single study only. Aims: The aim of this study was to examine the association of PM composition with cardiovascular mortality. Methods: We used data from 19 European ongoing cohorts within the framework of the ESCAPE (European Study of Cohorts for Air Pollution Effects) and TRANSPHORM (Transport related Air Pollution and Health impacts Integrated Methodologies for Assessing Particulate Matter) projects. Residential annual average exposure to elemental constituents within particle matter smaller than 2.5 and 10 pm (PM2.5 and PM10) was estimated using Land Use Regression models. Eight elements representing major sources were selected a priori (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc). Cohort-specific analyses were conducted using Cox proportional hazards models with a standardized protocol. Random-effects metaanalysis was used to calculate combined effect estimates. Results: The total population consisted of 322,291 participants, with 9545 CVD deaths. We found no statistically significant associations between any of the elemental constituents in PM2.5 or PM10 and CVD mortality in the pooled analysis. Most of the hazard ratios (HRs) were close to unity, e.g. for PM10 Fe the combined HR was 0.96 (0.84-1.09). Elevated combined HRs were found for PM2.5 Si (1.17, 95% Cl: 0.93-1.47), and S in PM2.5 (1.08,95% Cl: 0.95-1.22) and PM10 (1.09,95% Cl: 0.90-132). Conclusion: In a joint analysis of 19 European cohorts, we found no statistically significant association between long-term exposure to 8 elemental constituents of particles and total cardiovascular mortality.
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| 8. |
- Wiborg, Irene, et al.
(author)
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Bridging the gaps between science, regulation and practice in water environment management
- 2011
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In: Science for the environment - environment for society. - Aarhus : Aarhus University. ; , s. 31-31
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Conference paper (other academic/artistic)abstract
- AQUARIUS is an interreg North Sea Programme project carried out by 15 partners from 6 countries (Norway, Sweden, Germany, Holland, Scotland, and Denmark) all dealing with the implementation of the Water Frame Directive. A primary objective of the project is to find ways for sustainable water environment management which by AQUARIUS is defined as management that in respect of the rules both leads to “good water environment”, enables continued viable agricultural production, and is cost efficient in the interest of society. AQUARIUS works from social-ecological management perspective emphasizing the intricate linkages between ecological and social systems and the interdependent relationships among humans, that are mediated through interactions with biophysical and non-human biological units. As a project AQUARIUS copies the presently ongoing struggle by all EU member countries to create a public participatory approach to water management planning and implementation such as is launched by the EU Water Water Frame directive. it does so by engaging central water authorities, representatives from agriculture including agricultural advisors as well as research institutions in carrying out localized pilot studies in 7 pilot areas. Drawing on localized experiments with and locally founded experiences with different measures the project derives recommendations that may contribute to an EU policy approach. The special session aims at discussing the preliminary findings of the ongoing project. It includes the presentation of a heuristic tool consisting of relevant considerations to beware of when engaging in stakeholder collaboration on specific measurements whilst acknowledging the farmer as the central water management practitioner. The session also discusses some of the different pilot approaches to bridging the gaps between science, regulation and practice i.e. the concrete challenges faced by the approaches in trying to create outcomes that are mutually beneficial to various stakeholder interests. How can different stakeholders challenges be solved in cooperation creating a win-win situation for all? How can stakeholders (landowners) willingness to participate increase by seeing them as professional providers of eco-system services? When do stakeholders’ overlapping interests allow for collaborative action and when do they hinder it? These questions are among the issues to be addressed. One legal recommendation that may be derived from project experiences is a need to further to take the precautionary principle in public administration into account. In order to make sustainable solutions in an ever changing complexity, authorities need to make room for dynamic collaboration between science and practice.
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