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Can Alpha-Glucosidase Activity in Plasma or Leukocytes Serve as a Biomarker for Future Gene Therapy in Classic Infantile Pompe Disease?
No full textWe studied alpha-glucosidase activity in plasma and leukocytes after an infusion of 40 mg/kg of recombinant alglucosidase alpha in patients with classic infantile Pompe disease to assess the pharmacokinetics and identify potential surrogate efficacy markers of gene therapy in patients on enzyme replacement therapy. Samples were collected by pharmacokinetic curves (n = 5) and random samples (n = 21 patients). Alpha-glucosidase activity was measured in plasma (substrate 4-methylumbelliferyl-α-d-glucopyranoside, MU) and leukocytes (substrate glycogen, Gn, and MU). Plasma peak concentration occurred at the end of the infusion, reaching concentrations > 5000 and > 100,000 times higher than the control and untreated patient levels, with a median half-life of 3.1 h (1.3–4.2 h). In leukocytes, plasma peak concentration occurred 24 h after the start of enzyme replacement therapy; plasma peak concentration did not exceed the control level (0.7 [Gn] and 0.9 [MU] times higher than controls). The estimated half-life was 2–4 days. Seven days after enzyme replacement therapy, median enzyme activity was 1.3 times higher than the control levels in plasma and within the control range in leukocytes; after 14 days, median values in plasma and leukocytes were below the control level. These findings suggest alpha-glucosidase activity in plasma and leukocytes may serve as an efficacy marker for gene therapy studies in patients with classic infantile Pompe disease receiving enzyme replacement therapy. Similar studies with next-generation enzyme replacement therapy are advised.</p
The passive voice in juvenile criminal law language: On language difficulties, complex grammatical constructions and the importance of linguistic-legal research in juvenile criminal law
No full textNet als in veel andere landen zijn strafrechtelijke procedures in Nederland en Vlaanderen gebaseerd op zeer verbale processen die een hoge taalvaardigheid vereisen. Het is onwaarschijnlijk dat jeugdigen die in aanraking komen met het strafrecht een dergelijk taalniveau hebben. Deze bijdrage beoogt het vergroten van het bewustzijn onder jeugd(straf)rechtsjuristen van complex taalgebruik en de mogelijke gevolgen hiervan. De focus ligt hierbij op grammaticale constructies waarvan is aangetoond dat ze vaak niet begrepen worden door jeugdigen met een lager- dan-gemiddelde taalvaardigheid. Het gebruik van te complexe grammaticale constructies in jeugdstrafrechttaal doet afbreuk aan het effectief kunnen uitoefenen van eerlijk- procesrechten door jeugdige verdachten
Anchoring climate policy integration:progress and limitations under the European Green Deal
No full textThis article investigates how and to what extent climate policy integration (CPI) has been legally anchored in the EU’s governance framework under the European Green Deal (EGD). First, we establish an assessment framework that brings the legal anchoring of three dimensions of CPI–strength, sectoral scope and quality–into focus. Second, we assess the progress made in the legal anchoring of CPI in the EU governance framework under the EGD against these criteria. Third, we synthesise the main findings and discuss their wider repercussions. Overall, we identify tangible progress in anchoring CPI in EU governance, especially through the enshrining of the EU’s interim and long-term climate targets in EU law, the introduction of climate-consistency checks under the European Climate Law, and the anchoring of the do-no-significant-harm principle, especially with respect to finance and investment. Remaining shortcomings include a lack of effective implementation and substantive CPI into policy outputs, neglect of the potential for synergy and coherence, and gaps in the sectoral coverage of CPI (including economic governance and agricultural policy). While options for addressing these shortcomings exist, disruptive contemporary politics and mounting climate backlash arguably undermine both the effective implementation of existing CPI rules and their further development.</p
Verschenen publicaties: decentrale taken en bekostiging
No full textIn deze editie van de rubriek verschenen publicaties behandel ik verschenen literatuur over de onderwerpen 'decentrale taken en bekostiging', 'Overheid en markt, publiek-private samenwerking', 'WOZ en OZB' en 'Bekostiging gebiedsontwikkeling'
No passage for pass-on?
No full textAfter a scientifically questionable journey to establish a 5%standard for the overcharge amount in various truck cartelcases (in Spain, Germany, the UK, Portugal), the next damagescomponent in line is pass-on, which arguably is inseparablyconnected with the emergence of the volume effect
Pathways toward a nature-positive financial system
No full textAs human activities increasingly threaten Earth's systems, the influence of the financial system on human endeavor and nature is gaining recognition. However, discussions on sustainable finance often overlook a key insight from transformative change and complex systems research: the need to interrogate the paradigms that shape behavior. Conceptualizing finance as a complex system and drawing on the concept of “leverage points,” this paper proposes three paradigm shifts that target the system's deepest level—its intent. These shifts open pathways for transformation across macro (nature-society-economy), meso (inter-institutional), and micro (intra-institutional) scales. Building on them, we identify concrete and coherent interventions targeting macro-financial supervision, regulatory frameworks, and corporate governance. Our approach contributes by (1) offering a holistic view of transformation across system scales; (2) re-centering sustainable finance on normative concerns and human agency, challenging prevailing technocratic framing; and (3) linking long-term visions with actionable interventions, connecting deep and shallow levers of change.</p
Private Entrepreneurship and European Imperialism:Dutch Entrepreneurs in the Scramble for Africa, 1830s-1910s
No full textThis open access book presents a groundbreaking new perspective on European imperialism in Africa, by focusing on the role of Dutch private entrepreneurs in colonial activities during the so-called ‘Scramble for Africa’. Distinguishing between a state-based ‘Partition of’ and an actor-based ‘Scramble for’ Africa, the book illustrates this process by tracking the entrepreneurial strategy of a group of Dutch entrepreneurs in the Scramble, at a time when the Dutch state itself largely withdrew from the African continent. This book thus investigates why and how nineteenth-century Dutch entrepreneurs from the port city of Rotterdam invested significant resources in West and West Central Africa between the 1830s and the 1910s. It demonstrates the trans-national nature of colonial investments in the Scramble for Africa, highlighting the crucial role Dutch entrepreneurs played in trade, production and investment in empires across West and West Central Africa (the Congo Free State, French Congo and Portuguese Angola). The book aims to rethink the Dutch role in European imperialism more broadly and its repercussions in the present day.The book takes into account the social and political implications of colonial entrepreneurship as much as the economic and business implications, going beyond a strictly entrepreneurial analysis of success and failure. It will be essential reading for scholars of economic and business history, as well as historians of imperialism, colonialism and trans-imperial relations
Unravelling the molecular mechanisms of direct and cross presentation on MHC class I molecules
No full textTo maintain a healthy body, continuous surveillance by both parts of immune system, innate and adaptive is necessary. The adaptive will spring into action when the innate system cannot protect the body sufficiently. The adaptive immune system is capable of learning to recognize new intruders, such as cancer cells or viruses. One of the most important strategies of this system is based on checking the proteins produced by every cell in the body. Indeed, if a virus has entered a cel, or if a cell has transformed into a cancer cell, the proteins produced in this cell will also change. The presentation of proteins on the cell surface is also called direct presentation and takes place on a special stage, called major histocompatibility complex class I or MHC-I for short. These proteins are then viewed by the so-called T-cells of the adaptive immune system, and if these proteins are ‘abnormal’, the cell will be cleared. To ensure the T-cells know which proteins are normal which are abnormal, they are instructed by professional presenting cells. These cells are able to show proteins from other cells on their own stage, and will instruct the T-cells which ones are abnormal and dangerous and which are not. This process is called cross-presentation. In this thesis the molecular details of direct presentation and cross-presentation are further investigated, in the hope of improving both processes. Improvement in these processes will help in the development of vaccines against bacteria/viruses and immunotherapies against cancer.<br/
Modeling kidney fibrosis and tubular regeneration in iPSC-derived kidney organoids
No full textBackground: Kidney fibrosis is one of the pathological hallmarks of chronic kidney disease, likely contributing to the loss of kidney function. The mechanisms leading to kidney fibrosis and its reversibility is only partially understood, which hampers the development of therapeutic targets. Therefore, it is crucial to establish a robust human in vitro model that can be used to study kidney fibrosis and potential regeneration. Methods: Human induced pluripotent stem cells (iPSC) were differentiated into kidney organoids. Fibrotic injury was induced by mimicking hypoxia (1% O2 48 h), inflammation (interleukin-1 beta (IL-1β) 96 h) or a combination (hypoxia and IL-1β). Organoids were harvested at injury onset and up to 2 weeks post-injury. Fibrosis was assessed by mRNA and protein expression of fibronectin (FN1) and collagen type I, regeneration was evaluated through the presence of CD133+ and CD24+ progenitor cells and markers for differentiated kidney cell types.Results: The combination of hypoxia and IL-1β induced the strongest fibrotic response with significant upregulation of FN1 and collagen type I, and loss of tubular and glomerular markers. Over time, FN1 levels realigned with the control group, whereas collagen type I remained elevated. Tubular markers (Villin and ECAD) recovered to near-control levels, coinciding with increased CD133+ and CD24+ cell population and Ki67 expression. In contrast, PODXL+ glomerular structures showed limited recovery. Conclusions: We present a reproducible human kidney organoid model that captures both fibrotic remodeling and tubular regeneration following clinically relevant injury. This platform offers a valuable tool for studying kidney-specific fibrosis dynamics and testing anti-fibrotic or pro-regenerative strategies.</p