Comparing genome-scale DNA methylation and CNV marks between adult human cultured ITGA6+ testicular cells and seminomas to assess in vitro genomic stability

Autologous transplantation of spermatogonial stem cells is a promising new avenue to restore fertility in infertile recipients. Expansion of the initial spermatogonial stem cell pool through cell culturing is a necessary step to obtain enough cells for effective repopulation of the testis after transplantation. Since in vitro propagation can lead to (epi-)genetic mutations and possibly malignant transformation of the starting cell population, we set out to investigate genome-wide DNA methylation status in uncultured and cultured primary testicular ITGA6+ sorted cells and compare them with germ cell tumor samples of the seminoma subtype. Seminomas displayed a severely global hypomethylated profile, including loss of genomic imprinting, which we did not detect in cultured primary testicular ITGA6+ cells. Differential methylation analysis revealed altered regulation of gamete formation and meiotic processes in cultured primary testicular ITGA6+ cells but not in seminomas. The pivotal POU5F1 marker was hypomethylated in seminomas but not in uncultured or cultured primary testicular ITGA6+ cells, which is reflected in the POU5F1 mRNA expression levels. Lastly, seminomas displayed a number of characteristic copy number variations that were not detectable in primary testicular ITGA6+ cells, either before or after culture. Together, the data show a distinct DNA methylation patterns in cultured primary testicular ITGA6+ cells that does not resemble the pattern found in seminomas, but also highlight the need for more sensitive methods to fully exclude the presence of malignant cells after culture and to further study the epigenetic events that take place during in vitro culture

How safe is safe enough?

Disasters can never be completely ruled out. The Dutch national government has therefore committed itself to the concept of risk rather than the false promise of absolute safety. The objectives of this study were to evaluate current regulatory practices in the domains of industrial and flood safety in the Netherlands, and to formulate proposals for improvement. The outcomes of such an endeavor depend heavily on the chosen yardstick to distinguish between superior and inferior policy alternatives. Throughout the thesis, social improvements are defined in a way that is consistent with the approach followed in societal cost-benefit analyses. The three main topics covered by the thesis are: 1. The Dutch industrial and flood safety policies: underlying rationales, current practices, opportunities for mutual learning. 2. Methods for risk evaluation and their conformity with a utilitarian ethic: cost-benefit analysis, FN-criteria, the precautionary principle. 3. Dealing with losses: optimizing disaster preparedness, the (un)insurability of large-scale floods, the relations between insurance and system safety.Civil Engineering and Geoscience

De observatiemethode in de geotechniek: De theorie achter de methode

De observatiemethode wordt gedefinieerd als een geegreerd bouw- en ontwerpproces waarbij de uiteindelijke bouwwijze of het uiteindelijke ontwerp wordt vastgesteld door gebruik te maken van meetgegevens tijdens de bouwfase (naar Van de Kamp en Van Baars, 2003). Hoewel de observatiemethode in de geotechniek al vaker is toegepast en volgens Eurocode 7 is toegestaan, ontbreekt een risicotechnische onderbouwing van de methode. Zonder dit inzicht is het veelal onmogelijk om vooraf te stellen dat toepassing van de observatiemethode een goede beslissing is. De hoofdvraag van dit afstudeeronderzoek is tweeledig: wat bepaalt het rendement van de observatiemethode? Wat betekent dit voor het toepassingsgebied en de vormgeving van de observatiemethode? Om de hoofdvraag te beantwoorden is een risicobenadering gevolgd, waarbij de verwachtingswaarden van de kosten van een conventioneel Risk Based Optimised-ontwerp en een ontwerp met observatiemethode zijn vergeleken. Om het onderzoek te structureren is onderscheid gemaakt tussen onzekerheden in de tijd en onzekerheden in de ruimte. De bevindingen zijn uiteindelijk getoetst door deze te vergelijken met beschrijvingen van toepassingen van de observatiemethode in de literatuur. Ook zijn de bevindingen getoetst met casestudies: sterk geschematiseerde projecten die met een wiskundig programma zijn gesimuleerd. Een belangrijke beperking voor de analyses wordt gevormd door de afhankelijkheden van de kanscomponenten bij een ontwerp met observatiemethode. Zo beloeden de waarnemingsresultaten de faalkansen en de kansen op volgende waarnemingsresultaten. Ook zijn de faalkansen afhankelijk van de kans dat het ontwerp wordt aangepast. Vaak is MonteCarlo simulatie door het grote aantal benodigde trekkingen geen optie om vooraf de verwachtingswaarde van de kosten van een ontwerp met observatiemethode te berekenen. Bestaande voorwaarden voor toepassing van de observatiemethode zijn beoordeeld en waar nodig aangepast. Ook zijn aanvullende voorwaarden opgesteld. Verder is gekeken naar de situaties waarin toepassing van de observatiemethode het grootste potentieel heeft om kostenbesparingen te leveren. Er zijn enkele algemene aanbevelingen gedaan ten aanzien van de vormgeving van de methode. Het gaat dan om de keuze voor het startontwerp en de opzet van het monitoringsprogramma. In de bestaande literatuur over de observatiemethode zijn enkele onvolkomenheden geconstateerd. Zo is de vaak gehanteerde conclusie dat toepassing van de observatiemethode (vooraf) gunstig was omdat deze (achteraf) een besparing leverde, niet valide gebleken.Civil Engineering and Geoscience

Editorial: Climate change, coasts and coastal risk

Hydraulic Structures and Flood Ris

A risk-informed approach to coastal zone management

Economic and population growth have led to an unprecedented increase in the value at risk in coastal zones over the last century. To avoid excessive future losses, particularly in the light of projected climate change impacts, coastal zone managers have various instruments at their disposal. These primarily concern land-use planning (establishing buffer zones) and engineering solutions (beach nourishment and coastal protection). In this paper, we focus on risk mitigation through the implementation of buffer zones (setback lines). Foregoing land-use opportunities in coastal regions and protecting coasts is costly, but so is damage caused by inundation and storm erosion. Defining appropriate setback lines for land-use planning purposes is a balancing act. It is, however, unclear what level of protection is facilitated by current approaches for defining setback lines, and whether this is, at least from an economic perspective, sufficient. In this paper, we present an economic model to determine which setback lines would be optimal from an economic perspective. The outcomes of the model provide a useful reference point in the political debate about the acceptability of risk in coastal zones. The main conclusions are: (i) that it is useful to define setback lines on the basis of their exceedance probabilities; (ii) that the exceedance probability of an economically efficient setback line will typically be in the order of magnitude of 1/100 per year; (iii) that it is important to distinguish between situations in which morphological conditions are stationary and non-stationary; and (iv) that long-term uncertainties (eg. due to climate change) influence the exceedance probability of efficient setback lines but only to a limited extent. The economic model stresses the need for a probabilistic approach to beach erosion modelling. The recently-developed Probabilistic Coastal Setback Line was applied at Narrabeen beach, Sydney, Australia, to illustrate how economically optimal setback lines can be derived for specific sites

A risk-informed approach to coastal zone management

Economic and population growth have led to an unprecedented increase in the value at risk in coastal zones over the last century. To avoid excessive future losses, particularly in the light of projected climate change impacts, coastal zone managers have various instruments at their disposal. These primarily concern land-use planning (establishing buffer zones) and engineering solutions (beach nourishment and coastal protection). In this paper, we focus on risk mitigation through the implementation of buffer zones (setback lines). Foregoing land-use opportunities in coastal regions and protecting coasts is costly, but so is damage caused by inundation and storm erosion. Defining appropriate setback lines for land-use planning purposes is a balancing act. It is however unclear what level of protection is facilitated by current approaches for defining setback lines, and whether this is, at least from an economic perspective, sufficient. In this paper, we present an economic model to determine which setback lines would be optimal from an economic perspective. The results provide a useful reference point in the political debate about the acceptability of risk in coastal zones. The main conclusions are (i) that it is useful to define setback lines on the basis of their exceedance probabilities, (ii) that the exceedance probability of an economically efficient setback line will typically be in the order of magnitude of 1/100 per year, (iii) that it is important to distinguish between situations in which morphological conditions are stationary and non-stationary, and (iv) that long-term uncertainties (e.g. due to climate change) influence the exceedance probability of efficient setback lines but only to a limited extent.Hydraulic EngineeringCivil Engineering and Geoscience

The use of individual and societal risk criteria within the Dutch flood safety policy-nationwide estimates of societal risk and policy applications

The Dutch government is in the process of revising its flood safety policy. The current safety standards for flood defences in the Netherlands are largely based on the outcomes of cost-benefit analyses. Loss of life has not been considered separately in the choice for current standards. This article presents the results of a research project that evaluated the potential roles of two risk metrics, individual and societal risk, to support decision-making about new flood safety standards. These risk metrics are already used in the Dutch major hazards policy for the evaluation of risks to the public. Individual risk concerns the annual probability of death of a person. Societal risk concerns the probability of an event with many fatalities. Technical aspects of the use of individual and societal risk metrics in flood risk assessments as well as policy implications are discussed. Preliminary estimates of nationwide levels of societal risk are presented. Societal risk levels appear relatively high in the South Western part of the country where densely populated dike rings are threatened by a combination of river and coastal floods. It was found that cumulation, the simultaneous flooding of multiple dike rings during a single flood event, has significant impact on the national level of societal risk. Options for the application of the individual and societal risk in the new flood safety policy are presented and discussed.Hydraulic EngineeringCivil Engineering and Geoscience

An innovative approach to determine economically optimal coastal setback lines for risk informed coastal zone management

Current methods used to determine Coastal setback lines have several limitations. Furthermore, the historical practice of defining setback lines based on a single deterministic estimate is also proving inadequate with the emergence of risk management style coastal planning frameworks which require probabilistic estimates of coastal recession. This paper describes an innovative approach for the determination of the economically optimal coastal setback line which combines an economic risk model and a process based, probabilistic coastal setback line model. It is anticipated that this new approach is highly suitable to provide vital information for risk informed coastal zone management.Hydraulic EngineeringCivil Engineering and Geoscience

A pragmatic, performance-based approach to levee safety assessments

Flood prone areas are often protected against flooding by an extensive network of flood defenses. To ensure their structural integrity, these flood defenses are periodically assessed. Many levees have been functioning well for decades, and have survived several relatively high hydraulic loads within their lifetime. However, information on survived load conditions is seldom included in levee safety assessments. Observed degradation from levee inspections is also not taken into account. That way, information that is useful to improve the accuracy of estimations of the actual strength of the levee remains unexploited. This study proposes a pragmatic approach to include observations of survived loads and levee degradation in the levee safety assessment. This approach consists of three steps: (1) a prior estimation of the failure probability, based on levee characteristics, (2) a posterior estimation of the failure probability, based on observed hydraulic loads, and (3) correction of the posterior failure probability estimation, based on levee inspections. In a case study, the estimated failure probabilities using this approach were much lower than when information on levee performance was not included. This study demonstrates the value of levee performance observations and how they could be included to improve levee safety assessments.Coastal EngineeringHydraulic Structures and Flood Ris