Technology companies promise that it will bring about a newly empowered, just, and equitable society, by removing physical barriers to social participation and enhancing human capabilities and... Show moreTechnology companies promise that it will bring about a newly empowered, just, and equitable society, by removing physical barriers to social participation and enhancing human capabilities and experiences. But there are many factors to consider when discussing what the metaverse should be, how significant it might become, and how it will affect both the individual and society. On the one hand, the report acknowledges the positive impact the metaverse could have in empowering individuals and enhancing human capabilities, particularly for those who experience vulnerability in the offline world. However, it also highlights the reinforcement of social inequalities due to the digital divide, limited access for certain groups, and the perpetuation of subordination and conformity within the virtual realm.The paper questions why the metaverse is being developed, how it will be created and accessed, who will be creating it, and how it is defined. It also explores the nuances and definitions of vulnerability and positions human vulnerability within the context of the metaverse to consider its impact.In light of these findings, the report presents a set of recommendations for governments and regulators. These include requiring businesses developing the metaverse to follow the UN Guiding Principles on Business and Human Rights, involving vulnerable groups in the design process, establishing guidelines for measuring the impact on human rights, and enacting new laws and policies to address gaps in the legal framework.As the metaverse continues to gain momentum and attract widespread interest, the potential risks and vulnerabilities must be acknowledged and mitigated. Show less
BackgroundMedical device certification has undergone significant changes in recent years. However, exploration of stakeholder experiences remains relatively limited, particularly in the context of... Show moreBackgroundMedical device certification has undergone significant changes in recent years. However, exploration of stakeholder experiences remains relatively limited, particularly in the context of software as a medical device. This study sought to explore stakeholder experiences of medical device certification across both the UK and EU.MethodsSemi-structured interviews (n = 22) analysed using inductive-thematic analysis, synthesised using activity theory.ResultsInnovators, consultants and notified bodies share more similarities than differences when discussing barriers and enablers to achieving medical device certification. Systemic tensions between existing rules, tools, community understanding and division of labour currently undermine the intended aim of certification processes. Existing rules are considered complex, with small and medium-sized enterprises considered disproportionality affected, resulting in several unintended outcomes including the perceived ‘killing’ of innovation. Existing certification processes are described as unfit for purpose, unethical and unsustainable.ConclusionStakeholder experiences suggest that the intention of establishing a robust and sustainable regulatory framework capable of ensuring a high level of safety whilst also supporting innovation is not yet being realised. Failure to enact desired changes may further jeopardise future innovations, outcomes and care quality. Show less
Harbinja, E.; Leiser, M.R.; Sutter, G.; Krokida, Z. 2022
'You can't roll the clock back and reverse the effects of experiences' Bruce McEwen used to say when explaining how allostasis labels the adaptive process. Here we will for once roll the clock back... Show more'You can't roll the clock back and reverse the effects of experiences' Bruce McEwen used to say when explaining how allostasis labels the adaptive process. Here we will for once roll the clock back to the times that the science of the glucocorticoid hormone was honored with a Nobel prize and highlight the discovery of their receptors in the hippocampus as inroad to its current status as master regulator in control of stress coping and adaptation. Glucocorticoids operate in concert with numerous neurotransmitters, neuropeptides, and other hormones with the aim to facilitate processing of information in the neurocircuitry of stress, from anticipation and perception of a novel experience to behavioral adaptation and memory storage. This action, exerted by the glucocorticoids, is guided by two complementary receptor systems, mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), that need to be balanced for a healthy stress response pattern. Here we discuss the cellular, neuroendocrine, and behavioral studies underlying the MR:GR balance concept, highlight the relevance of hypothalamic pituitary-adrenal (HPA)-axis patterns and note the limited understanding yet of sexual dimorphism in glucocorticoid actions. We conclude with the prospect that (i) genetically and epigenetically regulated receptor variants dictate cell-type-specific transcriptome signatures of stress-related neuropsychiatric symptoms and (ii) selective receptor modulators are becoming available for more targeted treatment. These two new developments to 'restart the clock' with the to resilience. Show less
In April 2019, the UK Government’s DCMS released its White Paper for ‘Online Harms’, which would establish in law a new duty of care towards users by platforms to be overseen by an independent... Show moreIn April 2019, the UK Government’s DCMS released its White Paper for ‘Online Harms’, which would establish in law a new duty of care towards users by platforms to be overseen by an independent regulator. Our earlier research outlines how we got to this point, sets out what the White Paper proposes, and criticises its key aspects. Our objections and criticism remain applicable to the UK Government’s Online Safety Bill. The Parliament is now scrutinising the Bill. The House of Lords Report sparked some optimism that the scrutiny could address critical concerns around free speech in particular. The Draft Online Safety Bill Joint Committee Report, however, suggest otherwise. This paper returns to key arguments as to why risk-based regulation and duty of care are not appropriate for policing content and expression online. We focus on the human rights implications of the Bill, in particular, the provider duties to ‘handle’ legal but harmful content. Here, we reemphasise the vague conceptualisation and nature of this harm, as well as the inadequate duties attached to it. We argue that the independence of OFCOM cannot be guaranteed. Show less
“Dark patterns” is a generic term used by the design community and an increasing number of data protection academics to describe a variety of manipulative design techniques that compromise legal... Show more“Dark patterns” is a generic term used by the design community and an increasing number of data protection academics to describe a variety of manipulative design techniques that compromise legal requirements like consent and privacy-by-design and legal principles like fairness and transparency. To assess the regulation of dark patterns, two legal frameworks of the European Union are compared and critiqued: first, an examination of relevant rules and principles of the General Data Protection Regulation (GDPR) leads to the conclusion that the principle of data-protection-by-design could be useful, but the lack of clarity about what constitutes fairness undermines the GDPR’s ability to regulate dark patterns. Second, an examination of the ‘fairness’ principle in the EU’s consumer protection acquis reveals a significantly further developed regime. After examination of the various enforcement mechanisms across both regimes, the Chapter concludes that a pluralistic approach that mixes the strengths of one regulatory regime while compensating for the weaknesses of the other is needed to harness manipulative design techniques like dark patterns. Show less
Defined as ‘tricks used in websites and apps that make you do things that you did not mean to, like buying or signing up for something’, much of the academic scholarship on the regulation of ‘dark... Show moreDefined as ‘tricks used in websites and apps that make you do things that you did not mean to, like buying or signing up for something’, much of the academic scholarship on the regulation of ‘dark patterns’ has focussed on privacy and data protection legislation. The term has been deployed to describe ‘deceptive’ and ‘manipulative’ design techniques implemented in a way that led to a user behaviour that would not have happened without the dark pattern. This article analyses to what extent the current EU Consumer Protection acquis is placed to make a substantial and complementary contribution towards curtailing the use of dark patterns. We do so through the lens of the European Commission’s adoption of a ‘New Deal for Consumers’ which strengthens enforcement mechanisms of EU consumer law and modernises the EU’s consumer protection rules in view of market developments Show less
Leiser, M.R.; Harbinja, E.; Blakely, M.; Romero, F.R.; Barker, K.; Coozigou, I. 2020
Co-authored response from BILETA to the EU's consultation on the Digital Services Act package with two main pillars: announced first, a proposal of new and revised rules to deepen the Single Market... Show moreCo-authored response from BILETA to the EU's consultation on the Digital Services Act package with two main pillars: announced first, a proposal of new and revised rules to deepen the Single Market for Digital Services, by increasing and harmonising the responsibilities of online platforms and information service providers and reinforce the oversight over platforms’ content policies in the EU; second, ex ante rules to ensure that markets characterised by large platforms with significant network effects acting as gatekeepers, remain fair and contestable for innovators, businesses, and new market entrants. Show less
Liefaard, Ton; Rap, Stephanie; Rodrigues, Peter 2019
This first volume in the Monitoring Children’s Rights in the Netherlands series pays tribute to the 30th anniversary of the CRC and includes a report on the rights of children in the Netherlands,... Show moreThis first volume in the Monitoring Children’s Rights in the Netherlands series pays tribute to the 30th anniversary of the CRC and includes a report on the rights of children in the Netherlands, presenting key facts and figures relating to the rights of children. The report shows that there are significant concerns relating to discrimination, exclusion and disparities in the implementation of children’s rights in the Netherlands. It also demonstrates that there are reasons for concern with regard to the protection of children against violence, including child abuse and neglect. Children living in poverty are disproportionately affected by this. Moreover, children’s participation rights have increasingly received attention in the past years. At the same time, it is concluded that there are some persistent challenges, among others, in citizenship education, and that it is remarkable that the Dutch government has, as of yet, neither signed nor ratified the Optional Protocol to the Convention on a Communications Procedure. The book also includes an editorial highlighting the significance of children’s rights monitoring, and an in-depth study on the new European General Data Protection Regulation (GDPR) and its implications for children’s rights Show less
Complement is a key component of the innate immune defence and in addition forms a bridge to the adaptive immune responses. As such complement is of vital importance for efficient protection... Show moreComplement is a key component of the innate immune defence and in addition forms a bridge to the adaptive immune responses. As such complement is of vital importance for efficient protection against infections. However, the activity of the complement system can also aberrantly be directed against the tissues of the body itself and contribute to organ damage in a variety of diseases. In several rheumatic diseases complement activation is suggested to play a pronounced role. This review will highlight the role of both complement activation and complement regulation in rheumatic disease.A contribution of complement to the disease process is often suggested based on the presence of complement activation fragments in the target tissues or the presence of complement activation fragments in the circulation. The role that complement plays in different rheumatic diseases is often unknown but is thought to contribute to tissue damage as a consequence of autoantibody mediated immune complex formation and deposition. In addition reduced complement inhibition mediated by endogenous complement regulators can also enhance complement activity and tissue damage. In observational studies, it is difficult to distinguish whether complement activation is a result of enhanced activation or decreased regulation. Until recently, strong conclusions on the relative importance of complement activation to the pathology were largely restricted to animal experiments. Usage of complement targeting therapeutics in humans will hopefully give us the opportunity to study the actual contribution of complement activation towards disease progression and tissue damage in rheumatic disease into more detail. Show less
Bacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments. Actinobacteria, with their... Show moreBacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments. Actinobacteria, with their beautiful morphologies and complex multicellular life cycle, are a striking example. These filamentous bacteria produce many enzymes and natural products, including two-thirds of all known antibiotics, which makes them highly relevant for medical, biotechnological and industrial applications. In Streptomyces, complex and intertwining regulatory networks, consisting of pathway-specific and global regulators, control development and antibiotic production in response to environmental stimuli and stresses. This thesis explores how the model organism Streptomyces coelicolor senses environmental signals, related to oxygen stress and the availability of aminosugars, and how the bacterium translates these into appropriate responses. Show less
Vermindering van regeldruk maakt al decennialang deel uit van het Nederlandse overheidsbeleid. Zowel op rijksniveau als op lokaal niveau hebben verschillende programma’s de revue gepasseerd om... Show moreVermindering van regeldruk maakt al decennialang deel uit van het Nederlandse overheidsbeleid. Zowel op rijksniveau als op lokaal niveau hebben verschillende programma’s de revue gepasseerd om het aantal regels terug te brengen, regels efficiënter te maken en het toezicht beter af te stemmen. De voortgangsrapportages van de overheid zeggen dat de aanpak succesvol is: deze zou het bedrijfsleven reeds miljarden aan besparingen hebben opgeleverd. Ondernemers zeggen daar echter weinig van te merken. Ook de Algemene Rekenkamer constateerde in 2006 dat de successen in de samenleving niet als zodanig voelbaar waren. In deze studie onderzoekt Esmeralda Vergeer het fenomeen regeldruk. Ze brengt in beeld hoe de regeldrukaanpak van de Nederlandse overheid zich in de loop der jaren ontwikkelde en hoe er in de wetenschap naar regeldruk wordt gekeken. Verschillende definities van regeldruk passeren de revue, maar geen ervan blijkt onomstreden. Vergeer richt zich op ondernemers en constateert dat zij een eigen, geheel nieuwe definitie toekennen aan regeldruk. Ze onderscheidt drie factoren die van invloed zijn op de ervaring van regeldruk: kosten, werkbaarheid en gepercipieerd nut. Het onderzoek biedt zo nieuwe inzichten om regeldruk voor ondernemers merkbaar te verminderen. Show less
The research considers structures and practices of regulatory inspections and enforcement, and particularly the relevance and effects of purported “smarter inspections” methods, e.g. risk... Show more The research considers structures and practices of regulatory inspections and enforcement, and particularly the relevance and effects of purported “smarter inspections” methods, e.g. risk-based ones, and how they compare with previously existing practices. Specifically, it considers efficiency and effectiveness of inspections in terms of achieving public welfare, and their economic impact. The first part considers the history of regulatory inspections and how specific inspection institutions started to appear from the 19th century onwards. Of particular interest is how path dependency resulted in important differences in structures and methods between different fields and countries, and how these in turn produced different effects for the public. The second part looks at existing research on the interconnected issues of regulatory compliance drivers, regulatory discretion and risk and regulation. It concludes to the importance of combining several compliance drivers to achieve better results, to the appropriateness of structuring discretion in inspections and enforcement, and to the adequacy of “risk” as an instrument to do so. The third part looks at several case studies (in particular occupational safety and health in Britain and Germany) to consider whether risk-based, ‘smart’ approaches effectively deliver better results with lower burden, and tentatively concludes to the affirmative. Show less
In this thesis, we have addressed aspects of two main arms of the adaptive immune system; the B cell and antibody arm and the T cell arm. This led to a division in the presentation of the... Show more In this thesis, we have addressed aspects of two main arms of the adaptive immune system; the B cell and antibody arm and the T cell arm. This led to a division in the presentation of the results described in this thesis into two sections. In the first section, we present the results regarding the characterization of ACPA responses, B cells and ACPA secreting plasmablasts/-cells in RA as well as autoantibody responses and their regulation by an effective anti-rheumatic drug, abatacept, in the arthritis mouse model; Collagen Induced Arthritis (CIA). The second section is compiled of results obtained from studies examining the regulatory and other aspects of CD49b+CD4+ T cells on proinflammatory responses involved in the pathogenesis of arthritis. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial membrane of the joints, culminating in destruction of cartilage and deformity of the joints if remains untreated. Infiltration of inflammatory immune cells such as B cells and T cells into the inflamed joints is a characteristic feature of RA. These immune cells are in continuous interaction with each other and create a viscous circle that sustains persistent synovitis and damage to articular cartilage. Show less
Previous regulatory models for the online environment have been designed with a foundation and premise that users are fictional Homo Economicus – beings capable of optimizing all available... Show morePrevious regulatory models for the online environment have been designed with a foundation and premise that users are fictional Homo Economicus – beings capable of optimizing all available information into order to make sound decisions. Sometime these decisions will be rational and predictable. However, on other occasions users will make irrational, yet predictable mistakes; other times those errors will be unpredictably irrational. To overcome these shortcomings in rational economist models, behavioural economists like Daniel Kahneman, Amos Tversky and Richard Thaler and lawyers like Cass Sunstein have advocated using lessons from psychology to help people make better decisions. By deploying 'choice’ architecture to overcome less than rational decisions, Homo Sapiens can be 'nudged' to making better choices. Building from this foundation, our paper inquires what role big data may play in developing better regulation. For example, can insights from big data help to overcome erroneous assumptions that regulators may make about the way users rationally behave in online environments? What potential is there for harnessing ‘big data’ to provide insights into user behaviour? Can big data be used as an additional tool by lawmakers to improve regulatory settlements? Show less
Belo, N.A.H.; Driel, J.H. van; Veen, K. van; Verloop, N. 2014
Members of the order Nidovirales (Coronaviridae, Arteriviridae, and Roniviridae) employ genomes with mRNA polarity (plus-strand) and encode one of the most complex RNA virus replicases currently... Show moreMembers of the order Nidovirales (Coronaviridae, Arteriviridae, and Roniviridae) employ genomes with mRNA polarity (plus-strand) and encode one of the most complex RNA virus replicases currently known. This replicase is expressed from the viral genome by translation of two large 5__-proximal ORFs into two polyproteins, which are processed by virus-encoded proteases in 13-16 individual nonstructural proteins (nsps). The nsps direct the formation of an RNA-synthesizing complex that mediates viral genome replication, as well as the synthesis of a 3__-coterminal nested set of subgenomic (sg) mRNAs, from which the viral genes located downstream of the replicase gene are expressed. Arteriviruses and coronaviruses presumably employ a unique mechanism of discontinuous minus-strand extension to generate subgenome-length templates for sg mRNA synthesis. This thesis focused on the functional characterization of two replicase subunits and their roles in coupling different processes in the replicative cycle of equine arteritis virus (EAV), the arterivirus prototype. The biological importance of a conserved domain unique to nidoviruses (NendoU), mapping to arterivirus nsp11 and proposed to function as an endoribonuclease, was addressed. We demonstrated the recombinant nsp11 exhibits pyrimidine-specific endoribonuclease activity, and showed the critical importance of the NendoU domain for EAV RNA synthesis. In addition, we identified a multidomain replicase subunit, EAV nsp1, as a key coordinator of EAV genome replication, sg mRNA synthesis, and virus production. Our results reveal that the relative abundance of EAV mRNAs is tightly controlled by nsp1 and is critical for efficient production of new virus particles. The protein was implicated in modulating the accumulation of full-length and subgenome-length minus-strand templates for EAV mRNA synthesis. A protocol for purification of soluble recombinant nsp1, which can be used in future research on the molecular mechanisms of nsp1 function, is described. Show less
The topic of this thesis is the molecular regulation of Hypoxia-Inducible Factors (HIFs) by sumoylation. Hypoxia-Inducible Factors are transcriptional regulators that mediate cell survival during... Show moreThe topic of this thesis is the molecular regulation of Hypoxia-Inducible Factors (HIFs) by sumoylation. Hypoxia-Inducible Factors are transcriptional regulators that mediate cell survival during reduced oxygen conditions (hypoxia). HIFs are extensively controlled by post-translational modifications. The aim of this thesis was to obtain novel insight in the posttranslational modification of HIFs by sumoylation. Chapters 1 and 2 are introductions on sumoylation and Hypoxia-Inducible Factors, respectively. A summary of current knowledge is provided based on published literature on both systems. Chapter 3 describes the regulation of HIF-1_ transcriptional activity by sumoylation via a novel SUMO acceptor site. Chapter 4 describes crosstalk between sumoylation and ubiquitination, two similar but distinct post-translational modifications that act in concert to regulate the proteasomal degradation of a subset of protein targets. Chapter 5 shows that sumoylation of HIF-2_ marks it for proteasomal degradation during hypoxia, facilitated by E3 ubiquitin ligases RNF4 and VHL. Chapter 6 presents data on the formation of SUMO chains made up of a mix of SUMO-1 and SUMO-2/3 and we show that HIF-1_ is a target for SUMO chains in vitro. Chapter 7 provides a summary and overall discussion of the thesis. Show less
