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RATIONALE: Gene therapy holds promise for a curative mutation-independent treatment applicable to all cystic fibrosis (CF) patients. The various viral vector-based clinical trials conducted in the past have demonstrated safety and tolerance of different vectors, but none have led to a clear and persistent clinical benefit. Recent clinical breakthroughs in adeno-associated virus-(rAAV) based gene therapy encouraged us to re-explore a rAAV approach for CF. OBJECTIVES: We evaluated the preclinical potential of rAAV gene therapy for CF to restore chloride and fluid secretion in two complementary models: intestinal organoids derived from CF subjects and a CF mouse model, an important milestone towards the development of a clinical rAAV candidate for CF gene therapy. METHODS: We engineered a rAAV vector containing a truncated CFTR (CFTRΔR) combined with a short promoter (CMV173) to ensure optimal gene expression. A rescue in chloride and fluid secretion after rAAV-CFTRΔR treatment was assessed by forskolin-induced swelling in CFTR-deficient organoids and by nasal potential differences in ΔF508 mice. MEASUREMENTS AND MAIN RESULTS: rAAV-CFTRΔR transduction of human CFTR-deficient organoids resulted in forskolin-induced swelling indicating a restoration of CFTR function. Nasal potential differences demonstrated a clear response to low chloride and forskolin perfusion in the majority of rAAV-CFTRΔR treated CF mice. CONCLUSIONS: Our study provides robust evidence that rAAV-mediated gene transfer of a truncated CFTR functionally rescues the CF phenotype across the nasal mucosa of CF mice and in patient-derived organoids. These results underscore the clinical potential of rAAV-CFTRΔR in offering a cure for all CF patients in the future.

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Een paar jaar geleden stelden een aantal partijen een verwijderingsbijdrage voor nieuwe kantoren voor. Dit werd niet direct met gejubel ontvangen. Het legt echter wel de vinger op de zere plek.

De vastgoed- en bouwsector is stevig in beweging. De markt ondergaat een verandering van aanbod- naar vraaggestuurd en van autonomie naar samenspel. Vastgoed is geen product meer, maar wordt een dienst, en gebouwen faciliteren een gebruikersproces. Ontwikkelaars gaan denken in meerwaarde voor de lange termijn in plaats van in winstmaximalisatie op de korte termijn.

De eerste week van 2014 is een ideale gelegenheid om de strategie voor het komende jaar te bepalen. Het bestuur van de faculteit Bouwkunde is zelfs nog vooruitstrevender en kijkt zelfs tot 2020 vooruit met het nieuwe strategiedocument ‘Building the Future’.

Doe met zo min mogelijk zoveel mogelijk voor bewoners van ebied dat is getroffen door een tyfoon of te kampen heeft met overstromingen. Dat is de opdracht van het Rode Kruis. Bouwkundeonderzoekers van de TU/e helpen daarbij via contractonderzoek in de vorm van S(p)eedkits. "Werken aan innovaties in de hulpverleningssector is helemaal anders dan we bij Bouwkunde gewend zijn."

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Onderzoekers Roel Gijsbers en Tim de Haas van TU Eindhoven deden in Zeeland een proef met tenten Artsen zonder Grenzen.

Background: Type 1 diabetes (T1D) results from an autoimmune attack against the insulin-producing β-cells of the pancreas. The present study aimed to reverse T1D by gene therapy. Methods: We used a novel surgical technique, which involves isolating the liver from the circulation before the delivery of a lentiviral vector carrying furin-cleavable human insulin (INS-FUR) or empty vector to the livers of diabetic non-obese diabetic mice (NOD). This was compared with the direct injection of the vector into the portal circulation. Mice were monitored for body weight and blood glucose. Intravenous glucose tolerance tests were performed. Expression of insulin and pancreatic transcription factors was determined by the reverse transcriptase-polymerase chain reaction and immunohistochemistry and immunoelectron microscopy was used to localise insulin. Results: Using the novel surgical technique, we achieved long-term transduction (42% efficiency) of hepatocytes, restored normoglycaemia for 150 days (experimental endpoint) and re-established normal glucose tolerance. We showed the expression of β-cell transcription factors, murine insulin, glucagon and somatostatin, and hepatic storage of insulin in granules. The expression of hepatic markers, C/EBP-β, G6PC, AAT and GLUI was down-regulated in INS-FUR-treated livers. Liver function tests remained normal, with no evidence of intrahepatic inflammation or autoimmune destruction of the insulin-secreting liver tissue. By comparison, direct injection of INS-FUR reduced blood glucose levels, and no pancreatic transdifferentiation or normal glucose tolerance was observed. Conclusions: This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D. © 2013 John Wiley & Sons, Ltd.

Onze energievoorziening zal in de toekomst een nog grotere rol gaan spelen in onze maatschappij. Enerzijds wordt de vraag steeds groter en vanwege schaarste zal de aandacht moeten verschuiven naar de niet-eindige bronnen, waaronder zonne-energie. De zon voorziet meer dan ruimschoots in onze wereldwijde energiebehoefte.

Op de faculteit Bouwkunde wordt sinds een aantal jaren gewerkt aan oplossingen voor de meest extreme projectlocaties. Hier is vrijwel geen bouwmateriaal, nutsvoorziening, geschoold personeel en kennis aanwezig. De hevig getraumatiseerde gebruiker staat letterlijk te wachten op de ‘oplevering’. Sinds vijf jaar heeft de faculteit een samenwerking met het Rode Kruis om te innoveren op het gebied van noodhulphuisvesting, ofwel sheltering. Extreem bouwen pur sang.

Most buildings are hardly technically equipped to fulfil the ever changing user requirements. Stimulation of flexible use of buildings is a strategy that aims at extending the functional lifespan of buildings. Adaptability of building components is an important technical aid to facilitate flexible use. Due to the large number of variables and the many dependencies and uncertainties in the translation of (changing) user requirements into technical solutions, a methodical approach is indispensible. Therefore the CSA method is developed. The method is designed to impartially select and compare a number of adaptability measures. The degree of efficiency of the chosen measure is assessed by quantifying the required effort for an adaptation, costs and environmental impact. The initial (single) effects for these criteria are distinguished from the more often occurring effects that come with each adaptation. The uniqueness of the CSA method is that a best fit is sought from both the user point of view and the effects on/of the applied building technology. Operation of the CSA method proved to be valid by performing three case studies. In current building the initial phase is decisive for decision making. However, the case studies show that solutions with a high degree of adaptability are the most efficient for the long term, when adaptation occurs several times during the lifespan of a building.

De stagnerende nieuwbouwproductie en de grote leegstand van kantoren voedt de discussie over de levensduur van gebouwen. Uit onderzoek is bekend dat levensduurverlening de meest duurzame maatregel is om milieu-impact te verminderen, simpelweg omdat de belasting over meer jaren wordt verdeeld. Flexibel bouwen krijgt urgentie. In de praktijk is het echter niet gemakkelijk om de gewenste flexibiliteit te vertalen naar een bouwtechnisch systeem dat goed is afgestemd op veranderingen. De resultaten van een universitair onderzoek naar deze afstemming, met daarbij een focus op de draagconstructie.

Een gebouw gaat niet slechts twee jaar mee, zoals de gemiddelde smartphone, maar bij voorkeur zo lang mogelijk, bijvoorbeeld honderd jaar. Het blijkt moeilijk te zijn om zo ver vooruit te kijken en het ontwerp hierop af te stemmen. Wanneer functionaliteit, prijs en kwaliteit in balans blijven, is de kans groot dat een gebouw ook lange tijd naar tevredenheid gebruik wordt. Een duidelijke toekomstvisie, waarbij upgrades en veranderingen vooraf worden ingecalculeerd, is onontbeerlijk. De klant moet immers doorlopend tevreden worden gehouden.

In mijn vorige column sprak ik over klantenbinding, waarin ik de verbondenheid van de eindgebruiker met de producent (de bouwkolom) in de schijnwerpers zette. In omgekeerde richting is er natuurlijk ook een belangrijke rol voor het contact met de klant. Het product van het bouwproces wordt immers in opdracht gemaakt van een klant, die graag de eindgebruiker op maat wil bedienen, ook wanneer hij dat zelf is.

De gebruiker wordt steeds mondiger en krijgt in deze tijd ook meer ruimte voor inspraak. Dat is een goede ontwikkeling voor de toekomstwaarde van gebouwen, en ook voor de vernieuwing in de bouwsector.

Terwijl het Nederlands elftal faalt, lukt het het voetbalteam van de TU Eindhoven wel: wereldkampioen worden. Robotvoetbal welteverstaan. Deze robots spelen in teamverband een intelligent potje voetbal, waarbij volautomatisch wordt geanticipeerd op de acties van de tegenstander. Het doel van Robocup is het stimuleren van ontwikkelingen op gebied van robotica en kunstmatige intelligentie.

Aan de TU Eindhoven is de afgelopen jaren onderzocht op welke wijze flexibiliteit en aanpasbaarheid doelgericht geïntegreerd kunnen worden in de bouwtechniek. In het onderzoek is speciale aandacht voor de draagstructuur, die in grote mate bepalend is voor de ruimtelijke kwaliteit van het gebouw, maar ook voor de economische en milieutechnische consequenties van ontwerpkeuzes. In twee artikelen worden de belangrijkste bevindingen uit het onderzoek uiteengezet. Een herbezinning op flexibel bouwen wordt in dit artikel gepresenteerd.

Aan de TU Eindhoven is de afgelopen jaren onderzocht op welke wijze flexibiliteit en aanpasbaarheid doelgericht geïntegreerd kunnen worden in de bouwtechniek. In het onderzoek worden, naast speciale aandacht voor de draagstructuur, ook economische en milieutechnische consequenties van ontwerpkeuzes uitgelicht. In dit tweede en laatste artikel worden de resultaten van dit onderzoek uiteengezet.

Een goed product verkoopt zichzelf. Wellicht het grootste misverstand in innovatieland. Voordat een productde markt bereikt zijn er namelijk vele hordes te nemen

Marketeers en innovatiegoeroes hameren erop dat je juist in crisistijd moet innoveren om voorop te lopen in een aantrekkende markt. Die positie is misschien van levensbelang om te overleven in de volgende crisis.

Rapport is vertrouwelijk / Report is confidential

In current building engineering it is accepted as self-evident that the building structure cannot be altered in order to enable a flexible use of buildings. This thesis describes the research that has investigated whether the adoption of this unproven but commonly shared proposition is justified. Stimulation of flexible use of buildings is a strategy that aims at extending the functional lifespan of buildings. A large percentage of the building stock currently does not meet the quality requirements, due to functional limitations, whilst it is hardly equipped to fulfill the ever changing user requirements on the long term. Buildings are often no longer fully functional long before the intended service life has ended, resulting in untimely demolition. The demolition of buildings which are technically still in good condition is hardly justifiable. Moreover, the building sector heavily leaves its mark on societal problems such as environmental impact, energy use and generation of waste, and can be characterized as an inefficient industry due to high failure costs, small profits and a large contribution to the use of raw materials and to road transport. As a response to these issues the Slimbouwen strategy was developed, aiming to reform the sector into an efficient and environmentally responsible industry. The current research is positioned within the framework of Slimbouwen. More concrete, the target is to reduce the amount of materials used and to minimize the gross building volume, while maintaining flexible use and user comfort. Flexibility is a broad term. In this study a distinct order is introduced to classify the various forms of building flexibility and the required measures to realize flexible use. Adaptability is an important technical aid that facilitates flexible use. In this research, adaptability is defined as: ‘the ability of a building part to continuously undergo physical changes to the benefit of flexibility-in-use, with no or only minor effects on other building parts'. In current construction industry adaptability measures are primarily focused on the infill parts and in some cases on building services and façade cladding. The load bearing structure is only provided with passive flexibility measures, such as a large floor and beam spans offering a freely dividable floor plan or providing structural overcapacity, which enhances possible application of multiple functions. These measures have proven to be effective in practice, yet also very inefficient. The building structure is on average responsible for 60% of the total building weight. The application of large spans results in heavy structural components and consequently to an excessive use of materials and to a large portion of non-usable building volume. In accordance with Slimbouwen principles, the current research investigates whether it is possible to prevent excessive usage of materials and volume by reducing span sizes of structural elements, while still providing sufficient planning freedom. Active flexibility measures, such as adaptability, can be considered as the key to this. The main research question is: ‘under what conditions is it possible to increase the flexibility-in-use of the usable space by means of adaptability of parts of the building structure?’ The design of the bearing structure has a strong impact on functional use of space. Adaptability measures for the building structure do not seem to exist in practice, but may have a large impact on the possibilities for the extension and optimization of the functional lifespan of the building. Applying this principle could lead to a fundamentally different approach in the (technical) design of buildings. The focus of the research is on new buildings with multiple floors, constructed with a steel skeleton structure. More specifically, the focus is on residential buildings (also combined with care) and office buildings, because these buildings are structurally quite similar. Furthermore, for these user groups the rate of change of user needs is fairly high during the functional lifespan of the building. It appears to be possible to make a substantial improvement in terms of material and volume reduction by choosing products that are not often used conventionally, for example by applying a lightweight, hollow and accessible floor type (like the Slimline floor), instead of a more commonly used heavy, inflexible concrete floor type (like a hollow core floor). In addition, also an improvement can be achieved on the level of flexibility to enhance the functionality of the building. Furthermore an optimal structural grid size is searched for, to minimize material use and maximize the ratio between net and gross building volume. This exploration shows that a reduction of roughly 50% is achievable compared to more conventional construction methods, for both the structural weight as for the non-usable building volume (gross volume minus net building volume). The dimensions of an optimized grid size are 3.6 x 3.6 meters when using a Slimline floor. With such small grid dimensions, it is likely that the presence of columns will hinder free division of the floor plan. Adaptability of the structure may then bring relief. The technological implementation of adaptable building components is only useful if it proves to effectively contribute to flexibility-in-use. In addition, a positive effect on ecological and economic aspects is aimed at, taking into account all phases in the lifespan of a building (from design to construction, use, maintenance, renovation and demolition). Due to the large number of variables and the many dependencies and uncertainties in the translation of (changing) user requirements into technical solutions, a methodical approach is indispensible, so that a balanced choice can be made for an adaptability measure. The Comparative Selection method for Adaptability measures (CSA method) The CSA method, which is developed in this research, is applicable to all building parts, not specifically to elements of the building structure. The method is designed to impartially compare a number of effective adaptability measures. In the CSA method firstly an effective adaptability measure is selected based on (future) requirements of the user. Subsequently, the degree of efficiency of the chosen measure is assessed by quantifying the required effort for an adaptation, costs and environmental impact. In this quantification the initial (single) effects are distinguished from the more often occurring effects that come with an adaptation. When the full lifespan of a building is considered, this distinction is essential to ensure a well-founded decision for the most appropriate adaptability measure. The uniqueness of the CSA method is that a best fit is sought from both the user point of view and the effects on or of the applied building technology. The CSA method makes it possible to derive an optimized solution from the wide array of solutions in a structured way. Operation of the CSA method proved to be valid with the help of three case studies. It became clear that the sequence of steps in the method is logic, while the segmented approach provides a wellorganized and verifiable selection process. The case studies show that solutions with a high degree of adaptability are the most efficient for the long term. The reason is that the efficiency scores as a result of each adaptation are more decisive than the initial scores that only accompany the construction phase. Some solutions may initially be cheaper and have less impact, but cause large effort, costs and environmental damage when an adaptation is necessary. Moreover, adaptation might occur several times during the lifespan of a building. In current building the initial phase is decisive for decision making. However, the trend is that a long term vision, concerning the whole lifespan of a building, is becoming increasingly important. This awareness creates space and legitimacy for methods such as the CSA method. The CSA method is a tool developed for the designer that can bridge the gap between (future) user needs and the functional performance of the building over time. A lasting balance between demanded and supplied building performance increases the chance of effectively extending the functional life span the building. Application of the CSA method in design practice can facilitate this. Movability of columns Structural adaptability is regarded as a promising solution strategy to increase the possibilities for functional use of a structure with a small grid size. When the density of columns in the floor plan is high, moving columns is an obvious, however unconventional solution. Moving columns only is useful to increase the options for a freely dividable floor plan when it really is an added value to the flexible use of the building. An experiment with designers shows that the division of the floor plan is hampered by the presence of columns in the freely dividable space, when the grid size is below 5.4 x 6.0 meters. When the grid size decreases, the added value of moving columns significantly increases. About fifty percent of the free standing columns (not located in the façade zone) should be movable and should ideally be able to move up to 1.2 meters in two directions (a displacement range of 2.4 meters). The efficiency and the technical feasibility of moving columns are investigated by means of a product development trajectory. Gradually a product came into being in a systematic and analytical way, using methods from the industrial product development, which has been further elaborated in more technical detail. Prior to this development process the structural feasibility has been indicated. Another critical requirement is that the moving of a column must be achieved with minimal effort, within the duration of one day and with minimal inconvenience for the user. Despite the rigorous and challenging design conditions the principle proves to be technically feasible. A product solution for a movable column, applicable in a braced steel frame structure, is acting as the evidence. With the help of the CSA method it is tested whether the application of the movable column results in the predicted advantages in regard to more conventional strategies, such as the application of larger grid sizes. The case study of an office building shows that the column is more efficient cost wise to a limited number of seven moves (per moveable column) during the service life of the building. The result is that the application of a movable column saves 4% on the total structural weight including floors (both when using a Slimline floor of 300 kg/m2), and saves 19% on the total use of steel in the bearing structure. This research has shown that adaptability of the building structure is an effective solution that can be applied in an efficient manner. The axiom of the unchangeable support is thus negated. The theories regarding flexibility of building can be altered and expanded based on the results of this study. The implementation of adaptability in all building parts arms a building against the constantly changing conditions during the service life. A high level of the capability of the building to change (in technical sense) provides space in building engineering for the integration of technical innovations and for alteration to new regulations and user requirements. Adaptability has the potential to directly or indirectly contribute to a maintaining level of sustainability of the future building stock. This accounts also for adaptability of less obvious building components, such as parts of the load bearing structure. In addition, it is also important that the designers taken the responsibility to minimize the ecological footprint of buildings. Slimbouwen in general and adaptability of the building structure and the CSA method in particular, provide the tools to do so.

Rapport is vertrouwelijk / Report is confidential

Rapport is vertrouwelijk / Report is confidential

Rapport is vertrouwelijk / Report is confidential