The Art of Audit. Eight remarkable government auditors on stage

Accountability, good government and public trust are intricately linked. Supreme Audit Institutions fulfil an exceptional role in the public domain, checking if governments spend their money properly. They are like 'watchdogs' for citizens and parliaments with the purpose of auditing public expenditure and examining the effectiveness of policies. They aim to strengthen the trustworthiness of government institutions, all the more so in fragile democracies. They do so, for instance, in striving to disclose cases of corruption, not just in the highest echelons of government, but also in everyday petty bribery. And they can be found counting houses, roads and water taps, to see if government's promises are being kept. On the occasion of the retirement of Saskia J. Stuiveling as the president of the Netherlands Court of Audit, eight (former) heads of audit institutions talk candidly about their work and innovations in the area of public auditing, about how the financial crisis affected their profession, about the advent of open data and about the need for new skills to audit the oil industry. Each of them - Faiza Kefi (Tunisia), Josef Moser (Austria), Terence Nombembe (South Africa), Heidi Mendoza (Philippines), Alar Karis (Estonia), David Walker (USA), John Muwanga (Uganda) and Abdulbasit Turki Saeed (Iraq) - has made a difference in his or her country, often under difficult, adverse and sometimes outright dangerous circumstances

3D elemental imaging of the crustacean Ceriodaphnia by means of SR confocal micro-XRF

Daphnia is a freshwater crustacean (0.2-5 mm height) used for investigating the toxic effects of toxins (e.g. metals) on an ecosystem. Synchrotron radiation based micro X-ray fluorescence (SR micro-XRF) allows the investigation of the trace level metal distribution within these organisms in an essentially non-destructive manner. Several two-dimensional (2D), computed tomography (CT) and confocal micro-XRF experiments under conventional and cryogenic environments have been performed on Daphnia magna previously. However, due to its larger size (3 mm height) full three-dimensional (3D) imaging of the metal distributions is not practically feasible. In this contribution, we therefore report on the full 3D elemental imaging on Ceriodaphnia which is a smaller variant (1 mm height) by means of 3D confocal micro-XRF

Chronic exposure to simulated space conditions predominantly affects cytoskeleton remodeling and oxidative stress response in mouse fetal fibroblasts

Microgravity and cosmic rays as found in space are difficult to recreate on earth. However, ground-based models exist to simulate space flight experiments. In the present study, an experimental model was utilized to monitor gene expression changes in fetal skin fibroblasts of murine origin. Cells were continuously subjected for 65 h to a low dose. (55 mSv) of ionizing radiation (IR), comprising a mixture of high-linear energy transfer (LET) neutrons and low-LET gamma-rays, and/or simulated microgravity using the random positioning machine (RPM), after which microarrays were performed. The data were analyzed both by gene set enrichment analysis (GSEA) and single gene analysis (SGA). Simulated microgravity affected fetal murine fibroblasts by inducing oxidative stress responsive genes. Three of these genes are targets of the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which may play a role in the cell response to simulated microgravity. In addition, simulated gravity decreased the expression of genes involved in cytoskeleton remodeling, which may have been caused by the downregulation of the serum response factor (SRF), possibly through the Rho signaling pathway. Similarly, chronic exposure to low-dose IR caused the downregulation of genes involved in cytoskeleton remodeling, as well as in cell cycle regulation and DNA damage response pathways. Many of the genes or gene sets that were altered in the individual treatments (RPM or IR) were not altered in the combined treatment (RPM and IR), indicating a complex interaction between RPM and IR

Modulation of gene expression in endothelial cells in response to high LET nickel ion irradiation

Ionizing radiation can elicit harmful effects on the cardiovascular system at high doses. Endothelial cells are critical targets in radiation-induced cardiovascular damage. Astronauts performing a long-term deep space mission are exposed to consistently higher fluences of ionizing radiation that may accumulate to reach high effective doses. In addition, cosmic radiation contains high linear energy transfer (LET) radiation that is known to produce high values of relative biological effectiveness (RBE). The aim of this study was to broaden the understanding of the molecular response to high LET radiation by investigating the changes in gene expression in endothelial cells. For this purpose, a human endothelial cell line (EA.hy926) was irradiated with accelerated nickel ions (Ni) (LET, 183 keV/mu m) at doses of 0.5, 2 and 5 Gy. DNA damage was measured 2 and 24 h following irradiation by gamma-H2AX foci detection by fluorescence microscopy and gene expression changes were measured by microarrays at 8 and 24 h following irradiation. We found that exposure to accelerated nickel particles induced a persistent DNA damage response up to 24 h after treatment. This was accompanied by a downregulation in the expression of a multitude of genes involved in the regulation of the cell cycle and an upregulation in the expression of genes involved in cell cycle checkpoints. In addition, genes involved in DNA damage response, oxidative stress, apoptosis and cell-cell signaling (cytokines) were found to be upregulated. An in silico analysis of the involved genes suggested that the transcription factors, E2F and nuclear factor (NF)-kappa B, may be involved in these cellular responses

Exploring associations between residential exposure to pesticides and birth outcomes using the Dutch birth registry

BACKGROUND: Maternal occupational exposure to pesticides has been linked to adverse birth outcomes but associations with residential pesticide exposures are inconclusive. OBJECTIVES: To explore associations between residential exposure to specific pesticides and birth outcomes using individual level exposure and pregnancy/birth data. METHODS: From all 2009-2013 singleton births in the Dutch birth registry, we selected mothers > 16 years old living in non-urban areas, who had complete address history and changed addresses at most once during pregnancy (N = 339,947). We estimated amount (kg) of 139 active ingredients (AI) used within buffers of 50, 100, 250 and 500 m around each mother's home during pregnancy. We used generalized linear models to investigate associations between 12 AIs with evidence of reproductive toxicity and gestational age (GA), birth weight (BW), perinatal mortality, child́s sex, prematurity, low birth weight (LBW), small for gestational age (SGA) and large for gestational age (LGA), adjusting for individual and area-level confounders. For the remainder 127 AIs, we used minimax concave penalty with a stability selection step to identify those that could be related to birth outcomes. RESULTS: Regression analyses showed that maternal residential exposure to fluroxypyr-meptyl was associated with longer GA, glufosinate-ammonium with higher risk of LBW, linuron with higher BW and higher odds of LGA, thiacloprid with lower odds of perinatal mortality and vinclozolin with longer GA. Variable selection analysis revealed that picoxystrobin was associated with higher odds of LGA. We found no evidence of associations with other AIs. Sensitivity and additional analysis supported these results except for thiacloprid. DISCUSSION: In this exploratory study, pregnant women residing near crops where fluroxypyr-meptyl, glufosinate-ammonium, linuron, vinclozolin and picoxystrobin were applied had higher risk for certain potentially adverse birth outcomes. Our findings provide leads for confirmatory investigations on these compounds and/or compounds with similar modes of action

Air pollution exposure and mortality from neurodegenerative diseases in the Netherlands: A population-based cohort study

Background: Long-term exposure to ambient air pollution has been linked with all-cause mortality and cardiovascular and respiratory diseases. Suggestive associations between ambient air pollutants and neurodegeneration have also been reported, but due to the small effect and relatively rare outcomes evidence is yet inconclusive. Our aim was to investigate the associations between long-term air pollution exposure and mortality from neurodegenerative diseases. Methods: A Dutch national cohort of 10.8 million adults aged ≥30 years was followed from 2013 until 2019. Annual average concentrations of air pollutants (ultra-fine particles (UFP), nitrogen dioxide (NO2), fine particles (PM2.5 and PM10) and elemental carbon (EC)) were estimated at the home address at baseline, using land-use regression models. The outcome variables were mortality due to amyotrophic lateral sclerosis (ALS), Parkinson's disease, non-vascular dementia, Alzheimer's disease, and multiple sclerosis (MS). Hazard ratios (HR) were estimated using Cox models, adjusting for individual and area-level socio-economic status covariates. Results: We had a follow-up of 71 million person-years. The adjusted HRs for non-vascular dementia were significantly increased for NO2 (1.03; 95% confidence interval (CI) 1.02–1.05) and PM2.5 (1.02; 95%CI 1.01–1.03) per interquartile range (IQR; 6.52 and 1.47 μg/m3, respectively). The association with PM2.5 was also positive for ALS (1.02; 95%CI 0.97–1.07). These associations remained positive in sensitivity analyses and two-pollutant models. UFP was not associated with any outcome. No association with air pollution was found for Parkinson's disease and MS. Inverse associations were found for Alzheimer's disease. Conclusion: Our findings, using a cohort of more than 10 million people, provide further support for associations between long-term exposure to air pollutants (PM2.5 and particularly NO2) and mortality of non-vascular dementia. No associations were found for Parkinson and MS and an inverse association was observed for Alzheimer's disease

Radiation-induced alternative transcription and splicing events and their applicability to practical biodosimetry

Accurate assessment of the individual exposure dose based on easily accessible samples (e.g. blood) immediately following a radiological accident is crucial. We aimed at developing a robust transcription-based signature for biodosimetry from human peripheral blood mononuclear cells irradiated with different doses of X-rays (0.1 and 1.0 Gy) at a dose rate of 0.26 Gy/min. Genome-wide radiation-induced changes in mRNA expression were evaluated at both gene and exon level. Using exon-specific qRT-PCR, we confirmed that several biomarker genes are alternatively spliced or transcribed after irradiation and that different exons of these genes exhibit significantly different levels of induction. Moreover, a significant number of radiation-responsive genes were found to be genomic neighbors. Using three different classification models we found that gene and exon signatures performed equally well on dose prediction, as long as more than 10 features are included. Together, our results highlight the necessity of evaluating gene expression at the level of single exons for radiation biodosimetry in particular and transcriptional biomarker research in general. This approach is especially advisable for practical gene expression-based biodosimetry, for which primer-or probe-based techniques would be the method of choice

Construction of a secondary metabolite deficient penicillium chrysogenum strain as a generic production host for secondary metabolites

Secondary metabolism of the filamentous fungus Penicillium chrysogenum has been intensively explored to relate specific secondary metabolites to their respective biosynthetic gene clusters. We have removed the three main biosynthetic gene clusters that specify the antibiotic penicillin, the mycotoxin roquefortine and the yellow pigment chrysogine, in order to generate a secondary metabolite deficient strain. This strain produces increased levels of other secondary metabolites some of which have not been detected before. The strain and its biosynthetic potential will now be further investigated for the expression of novel enzymes and biosynthetic pathways to make the synthesis of antibiotics and other secondary metabolites more specific and efficient. Using structure guided protein engineering new enzymes will be further designed and optimized for the construction of a newly designed biosynthetic pathway into a novel platform strain