A machine learning and directed network optimization approach to uncover TP53 regulatory patterns

TP53, the Guardian of the Genome, is the most frequently mutated gene in human cancers and the functional characterization of its regulation is fundamental. To address this we employ two strategies: machine learning to predict the mutation status of TP53 from transcriptomic data, and directed regulatory networks to reconstruct the effect of mutations on the transcipt levels of TP53 targets. Using data from established databases (Cancer Cell Line Encyclopedia, The Cancer Genome Atlas), machine learning could predict the mutation status, but not resolve different mutations. On the contrary, directed network optimization allowed to infer the TP53 regulatory profile across: (1) mutations, (2) irradiation in lung cancer, and (3) hypoxia in breast cancer, and we could observe differential regulatory profiles dictated by (1) mutation type, (2) deleterious consequences of the mutation, (3) known hotspots, (4) protein changes, (5) stress condition (irradiation/hypoxia). This is an important first step toward using regulatory networks for the characterization of the functional consequences of mutations, and could be extended to other perturbations, with implications for drug design and precision medicine

Review of induced seismicity in geothermal systems worldwide and implications for geothermal systems in the Netherlands

Geothermal energy is a viable alternative to gas for the heating of buildings, industrial areas and greenhouses, and can thus play an important role in making the transition to sustainable energy in the Netherlands. Heat is currently produced from the Dutch subsurface through circulation of water between two wells in deep (1.5–3 km) geothermal formations with temperature of up to ∼100 °C. As the number of these so-called doublets is expected to increase significantly over the next decades, and targeted depths and temperatures increase, it is important to assess potential show-stoppers related to geothermal operations. One of these potential hazards is the possibility of the occurrence of felt seismic events, which could potentially damage infrastructure and housing, and affect public support. Such events have been observed in several geothermal systems in other countries. Here we review the occurrence (or the lack) of felt seismic events in geothermal systems worldwide and identify key factors influencing the occurrence and magnitude of these events. Based on this review, we project the findings for seismicity in geothermal systems to typical geothermal formations and future geothermal developments in the Netherlands. The case study review shows that doublets that circulate fluids through relatively shallow, porous, sedimentary aquifers far from the crystalline basement are unlikely to generate felt seismic events. On the other hand, stimulations or circulations in or near competent, fractured, basement rocks and production and reinjection operations in high-temperature geothermal fields are more prone to induce felt events, occasionally with magnitudes of M > 5.0. Many of these operations are situated in tectonically active areas, and stress and temperature changes may be large. The presence of large, optimally oriented and critically stressed faults increases the potential for induced seismicity. The insights from the case study review suggest that the potential for the occurrence of M > 2.0 seismicity for geothermal operations in several of the sandstone target formations in the Netherlands is low, especially if faults can be avoided. The potential for induced seismicity may be moderate for operations in faulted carbonate rocks. Induced seismicity always remains a complex and site-specific process with large unknowns, and can never be excluded entirely. However, assessing the potential for inducing felt seismic events can be improved by considering the relevant (site-specific) geological and operational key factors discussed in this article

Review of induced seismicity in geothermal systems worldwide and implications for geothermal systems in the Netherlands

Geothermal energy is a viable alternative to gas for the heating of buildings, industrial areas and greenhouses, and can thus play an important role in making the transition to sustainable energy in the Netherlands. Heat is currently produced from the Dutch subsurface through circulation of water between two wells in deep (1.5–3 km) geothermal formations with temperature of up to ∼100 °C. As the number of these so-called doublets is expected to increase significantly over the next decades, and targeted depths and temperatures increase, it is important to assess potential show-stoppers related to geothermal operations. One of these potential hazards is the possibility of the occurrence of felt seismic events, which could potentially damage infrastructure and housing, and affect public support. Such events have been observed in several geothermal systems in other countries. Here we review the occurrence (or the lack) of felt seismic events in geothermal systems worldwide and identify key factors influencing the occurrence and magnitude of these events. Based on this review, we project the findings for seismicity in geothermal systems to typical geothermal formations and future geothermal developments in the Netherlands. The case study review shows that doublets that circulate fluids through relatively shallow, porous, sedimentary aquifers far from the crystalline basement are unlikely to generate felt seismic events. On the other hand, stimulations or circulations in or near competent, fractured, basement rocks and production and reinjection operations in high-temperature geothermal fields are more prone to induce felt events, occasionally with magnitudes of M > 5.0. Many of these operations are situated in tectonically active areas, and stress and temperature changes may be large. The presence of large, optimally oriented and critically stressed faults increases the potential for induced seismicity. The insights from the case study review suggest that the potential for the occurrence of M > 2.0 seismicity for geothermal operations in several of the sandstone target formations in the Netherlands is low, especially if faults can be avoided. The potential for induced seismicity may be moderate for operations in faulted carbonate rocks. Induced seismicity always remains a complex and site-specific process with large unknowns, and can never be excluded entirely. However, assessing the potential for inducing felt seismic events can be improved by considering the relevant (site-specific) geological and operational key factors discussed in this article

Designing Competence-Based Vocational Curricula at the School-Work Boundary

<p>In this chapter, competence-based education (CBE) will be studied from the perspective of the curriculum. We will give an overview of what CBE entails, and review current practice and research on the status quo of CBE in Dutch VET. For this, we shall use peer-reviewed research and more practical, so-called ‘grey publications’. After a brief historical sketch of its rise in the Netherlands, we will give a characterisation of CBE. The conclusion is that CBE curricula in the Netherlands share the following characteristics: (1) integration of knowledge, skills, and attitude in competencies; (2) orientation on acting and integration in the professional domain, both in learning and assessment processes; (3) focus on the individual (i.e. flexibility) supported by the teachers; and, (4) focus on the development of the individual’s career competencies. The main difficulties of CBE implementation are introduced, which are pedagogical, conceptual, and cultural in nature and may help to explain why implementing CBE to its full extent is a time-consuming process. Although all the difficulties described hinder smooth CBE implementation, the difficulty in connecting learning in schools with learning in the workplace must be considered the central problem in implementing CBE in VET curricula. The remainder of this chapter takes a closer look at insights concerning the school-work boundary; it is first explored at the institutional level of co-development between education and workplaces, second with the aid of learning mechanisms in learning environments and after that through the means of a two-dimensional model. The chapter concludes with a closer look inside a learning environment at the intersection of the school-work-boundary that is the result of co-development efforts.</p

Designing Competence-Based Vocational Curricula at the School-Work Boundary

In this chapter, competence-based education (CBE) will be studied from the perspective of the curriculum. We will give an overview of what CBE entails, and review current practice and research on the status quo of CBE in Dutch VET. For this, we shall use peer-reviewed research and more practical, so-called ‘grey publications’. After a brief historical sketch of its rise in the Netherlands, we will give a characterisation of CBE. The conclusion is that CBE curricula in the Netherlands share the following characteristics: (1) integration of knowledge, skills, and attitude in competencies; (2) orientation on acting and integration in the professional domain, both in learning and assessment processes; (3) focus on the individual (i.e. flexibility) supported by the teachers; and, (4) focus on the development of the individual’s career competencies. The main difficulties of CBE implementation are introduced, which are pedagogical, conceptual, and cultural in nature and may help to explain why implementing CBE to its full extent is a time-consuming process. Although all the difficulties described hinder smooth CBE implementation, the difficulty in connecting learning in schools with learning in the workplace must be considered the central problem in implementing CBE in VET curricula. The remainder of this chapter takes a closer look at insights concerning the school-work boundary; it is first explored at the institutional level of co-development between education and workplaces, second with the aid of learning mechanisms in learning environments and after that through the means of a two-dimensional model. The chapter concludes with a closer look inside a learning environment at the intersection of the school-work-boundary that is the result of co-development efforts.</p