Cumulative causation in the formation of a technological innovation system: The case of biofuels in the Netherlands

Despite its worldwide success, the innovation systems approach is often criticized for being theoretically underdeveloped. This article aims to contribute to the conceptual and methodical basis of the (technological) innovation systems approach. We propose an alteration that improves the analysis of dynamics, especially with respect to emerging innovation systems. We do this by expanding on the technological innovation systems and system functions literature, and by employing the method of 'event history analysis'. By mapping events, the interactions between system functions and their development over time can be analysed. Based on this it becomes possible to identify forms of positive feedback, i.e. cumulative causation. As an illustration of the approach, we assess the biofuels innovation system in The Netherlands as it evolved from 1990 to 2005.

Understanding the build-up of a Technological Innovation System around Hydrogen and Fuel Cell Technologies

This study provides insight into the development of hydrogen and fuel cell technologies in the Netherlands (1980-2007). This is done by applying a Technological Innovation System (TIS) approach. This approach takes the perspective that a technology is shaped by a surrounding network of actors, institutions and technologies. When a technology is in an early stage of development, a TIS has yet to be built up in order to propel technological progress. This paper focuses on the historical build-up of the hydrogen and fuel cell innovation system in the Netherlands. The research focuses on processes that accelerated or slowed down the developments of hydrogen and fuel cell technologies. We suggest that this framework is helpful for actors who intend to accelerate the development and deployment of hydrogen and fuel cells in other countries.fuel cell; technological innovation system; system functions; cumulative causation.

Understanding the formative stage of Technological Innovation System development. The case of natural gas as an automotive fuel

This study contributes to insights into mechanisms that influence the successes and failures of emerging energy technologies. It is assumed that for an emerging technology to fruitfully develop, it should be fostered by a Technological Innovation System (TIS), which is the network of actors, institutions and technologies in which it is embedded. For an emerging technology a TIS has yet to be built up. The research focuses on the dynamics of this build-up process by mapping the development of seven key activities: so-called system functions. The main contribution revolves around the notion of cumulative causation, or the phenomenon that the build-up of a TIS may accelerate due to system functions reinforcing each other over time. As an empirical basis, an analysis is provided of the historical development of the TIS around automotive natural gas technology in the Netherlands (1970-2007). The results show that this TIS undergoes a gradual build-up in the 1970s, followed by a breakdown in the 1980s and, again, a build-up from 2000-2007. It is shown that, underlying these trends, there are different forms of cumulative causation, here called motors of innovation. The study provides strategic insights for practitioners that aspire to support such motors of innovation.functions of technological innovation systems; cumulative causation; automotive natural gas.

Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model

PURPOSE: The reoperation rate for breast-conserving surgery is as high as 15-30% due to residual tumor in the surgical cavity after surgery. In vivo tumor-targeted optical molecular imaging may serve as a red-flag technique to improve intraoperative surgical margin assessment and to reduce reoperation rates. Cysteine cathepsins are overexpressed in most solid tumor types, including breast cancer. We developed a cathepsin-targeted, quenched fluorescent activity-based probe, VGT-309, and evaluated whether it could be used for tumor detection and image-guided surgery in syngeneic tumor-bearing mice. METHODS: Binding specificity of the developed probe was evaluated in vitro. Next, fluorescent imaging in BALB/c mice bearing a murine breast tumor was performed at different time points after VGT-309 administration. Biodistribution of VGT-309 after 24 h in tumor-bearing mice was compared to control mice. Image-guided surgery was performed at multiple time points tumors with different clinical fluorescent camera systems and followed by ex vivo analysis. RESULTS: The probe was specifically activated by cathepsins X, B/L, and S. Fluorescent imaging revealed an increased tumor-to-background contrast over time up to 15.1 24 h post probe injection. In addition, VGT-309 delineated tumor tissue during image-guided surgery with different optical fluorescent imaging camera systems. CONCLUSION: These results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques

Radiolabeled Monoclonal Antibody Against Colony-Stimulating Factor 1 Receptor Specifically Distributes to the Spleen and Liver in Immunocompetent Mice

Macrophages can promote tumor development. Preclinically, targeting macrophages by colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) monoclonal antibodies (mAbs) enhances conventional therapeutics in combination treatments. The physiological distribution and tumor uptake of CSF1R mAbs are unknown. Therefore, we radiolabeled a murine CSF1R mAb and preclinically visualized its biodistribution by PET. CSF1R mAb was conjugated to N-succinyl-desferrioxamine (N-suc-DFO) and subsequently radiolabeled with zirconium-89 ((89)Zr). Optimal protein antibody dose was first determined in non-tumor-bearing mice to assess physiological distribution. Next, biodistribution of optimal protein dose and (89)Zr-labeled isotype control was compared with PET and ex vivo biodistribution after 24 and 72 h in mammary tumor-bearing mice. Tissue autoradiography and immunohistochemistry determined radioactivity distribution and tissue macrophage presence, respectively. [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb optimal protein dose was 10 mg/kg, with blood pool levels of 10 ± 2% injected dose per gram tissue (ID/g) and spleen and liver uptake of 17 ± 4 and 11 ± 4%ID/g at 72 h. In contrast, 0.4 mg/kg of [(89)Zr]Zr-DFO-N-suc-CSF1R mAb was eliminated from circulation within 24 h; spleen and liver uptake was 126 ± 44% and 34 ± 7%ID/g, respectively. Tumor-bearing mice showed higher uptake of [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb in the liver, lymphoid tissues, duodenum, and ileum, but not in the tumor than did (89)Zr-labeled control at 72 h. Immunohistochemistry and autoradiography showed that (89)Zr was localized to macrophages within lymphoid tissues. Following [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb administration, tumor macrophages were almost absent, whereas isotype-group tumors contained over 500 cells/mm(2). We hypothesize that intratumoral macrophage depletion by [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb precluded tumor uptake higher than (89)Zr-labeled control. Translation of molecular imaging of macrophage-targeting therapeutics to humans may support macrophage-directed therapeutic development

Development and evaluation of interleukin-2 derived radiotracers for PET imaging of T-cells in mice

Recently, N-(4-18F-fluorobenzoyl)-interleukin-2 (18F-FB-IL2) was introduced as a PET tracer for T cell imaging. However, production is complex and time-consuming. Therefore, we developed 2 radiolabeled IL2 variants, namely aluminum 18F-fluoride-(restrained complexing agent)-IL2 (18F-AlF-RESCA-IL2) and 68Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL2 (68Ga-Ga-NODAGA-IL2), and compared their in vitro and in vivo characteristics with 18F-FB-IL2. Methods: Radiolabeling of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 was optimized, and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60, and 90 min after tracer injection. In vivo binding characteristics were studied in severe combined immunodeficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMC inoculation, and a 60-min dynamic PET scan was acquired, followed by ex vivo biodistribution studies. Specific uptake was determined by coinjection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. Results:68Ga-Ga-NODAGA-IL2 and 18F-AlF-RESCA-IL2 were produced with radiochemical purity of more than 95% and radiochemical yield of 13.1% ± 4.7% and 2.4% ± 1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with more than 90% being intact tracer after 1 h. In vitro, both tracers displayed preferential binding to activated hPBMCs. Ex vivo biodistribution studies on BALB/c mice showed higher uptake of 18F-AlF-RESCA-IL2 than of 18F-FB-IL2 in liver, kidney, spleen, bone, and bone marrow. 68Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than 18F-FB-IL2 uptake. In vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 and in the Matrigel control group. In addition, 18F-AlF-RESCA-IL2 yielded the highest-contrast PET images of target lymph nodes. Conclusion: Production of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 is simpler and faster than that of 18F-FB-IL2. Both tracers showed good in vitro and in vivo characteristics, with high uptake in lymphoid tissue and hPBMC xenografts

Granule size affects substitution on amylopectin populations in potato and sweet potato starches

Specific enzymatic degradation in combination with chromatographic and spectrometric techniques was used to understand acetyl group distribution over the amylopectin populations of differently sized granule fractions from potato and sweet potato starches. The hydrolysates obtained after ¿-amylase, ß-amylase, pullulanase, and the combination of pullulanase, ¿-amylase and amyloglucosidase treatment were investigated by high-performance size-exclusion chromatography (HPSEC), high-performance anion-exchange chromatography (HPAEC) and Maldi-Tof-MS (Matrix-Assisted Laser Desorption/Ionisation Time-Of-Flight Mass Spectrometry). The acetyl groups were found to be located near the branching point, in the external chain and in the internal chain regions. The acetyl group distributions were different for amylopectin from different granule size fractions. Higher DP (degree of polymerization) fragments were present in the digests of acetylated amylopectin populations of the small size granule starches. Our studies confirmed that acetyl groups were unevenly distributed over the amylopectin populations

Effects of broiler weight and strain on skin collagen characteristics and their applicability for co-extruded sausage casings

For centuries people around the world enjoyed traditional sausages made from meat stuffed into natural casings. An alternative new technology is to extrude collagen gel, originating from bovine hides, directly onto the product and later cross-link it. Collagen producers are searching for other sources and consequently they are interested in factors influencing extracted collagen quality. One of the alternative sources is chicken skin, where extracted collagen properties have been shown to be influenced by the age of the chickens. In this study, the biochemical and physical properties of chicken skin collagen preparations from two different broiler strains (slow and fast-growing) and two different weights (1.6 and 2.2 kg) were investigated. Rheological measurements showed for all dispersions a decrease in elasticity at 40 °C. Differential Scanning Calorimetry (DSC) measurements of the dispersions showed Tonset ranging from 38.7° to 39.1°C. After salt precipitation, the Tonset increased to 50.1 – 55.9 °C. Mechanical strength of the films from fast and slow growing chickens ranged from 63 to 67 KPa and 53–57 KPa, respectively. Considering the biochemical and physical properties, all four chicken collagen dispersions have the potential of being a suitable collagen source for the co-extrusion process of sausages