Governing system innovation: assisted living experiments in the UK and Norway

[EN] Debates on how to address societal challenges have moved to the forefront of academic and policy concerns. Of particular importance is the growing awareness that to deal with issues such as ageing, it will be necessary to implement concerted efforts on technological, social, institutional or political fronts. Drawing on a number of theoretical perspectives ¿ including socio-technical transitions and embedded state theory ¿ the aim of this paper is to identify and understand different approaches to the governance of such system innovations by comparing state responses to assisted living in two contrasting national systems of care, namely that of the UK and Norway. Its findings highlight that state-supported and funded experimentation projects have been instrumental in designing and implementing system innovation: through their emphasis on co-design and co-creation, these projects demonstrated the value of early implementation pilots to explore the `fit¿ between novel technologies and prevailing practices and institutional structures in national systems of care. Still, competition, biases or conflicting interests should not be ignored between well-established agents and institutions and experimental solutions whose efficacy remains relatively untested and which involve a combination of new technical, social, organizational and institutional solutions.This project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 320131 (SmartSpec).Bugge, M.; Coenen, L.; Marques, P.; Morgan, K. (2017). Governing system innovation: assisted living experiments in the UK and Norway. European Planning Studies. 25(12):2138-2156. https://doi.org/10.1080/09654313.2017.1349078S213821562512Benner, M. (2014). From smart specialisation to smart experimentation. Zeitschrift für Wirtschaftsgeographie, 58(1). doi:10.1515/zfw.2014.0003Bovens, M. (2007). Analysing and Assessing Accountability: A Conceptual Framework. European Law Journal, 13(4), 447-468. doi:10.1111/j.1468-0386.2007.00378.xBulkeley, H., Broto, V. C., & Edwards, G. (2012). Bringing climate change to the city: towards low carbon urbanism? Local Environment, 17(5), 545-551. doi:10.1080/13549839.2012.681464Coenen, L., Benneworth, P., & Truffer, B. (2012). Toward a spatial perspective on sustainability transitions. Research Policy, 41(6), 968-979. doi:10.1016/j.respol.2012.02.014Coenen, L., Raven, R., & Verbong, G. (2010). Local niche experimentation in energy transitions: A theoretical and empirical exploration of proximity advantages and disadvantages. Technology in Society, 32(4), 295-302. doi:10.1016/j.techsoc.2010.10.006Devlin, A. M., McGee-Lennon, M., O’Donnell, C. A., Bouamrane, M.-M., Agbakoba, R., … O’Connor, S. (2015). Delivering digital health and well-being at scale: lessons learned during the implementation of the dallas program in the United Kingdom. Journal of the American Medical Informatics Association, 23(1), 48-59. doi:10.1093/jamia/ocv097Evans, P. B. (1995). Embedded Autonomy. doi:10.1515/9781400821723Geels, F. W. (2002). Technological transitions as evolutionary reconfiguration processes: a multi-level perspective and a case-study. Research Policy, 31(8-9), 1257-1274. doi:10.1016/s0048-7333(02)00062-8Geels, F. W., Hekkert, M. P., & Jacobsson, S. (2008). The dynamics of sustainable innovation journeys. Technology Analysis & Strategic Management, 20(5), 521-536. doi:10.1080/09537320802292982Hausmann, R., & Rodrik, D. (2003). Economic development as self-discovery. Journal of Development Economics, 72(2), 603-633. doi:10.1016/s0304-3878(03)00124-xJacobsson, B., Pierre, J., & Sundström, G. (2015). Governing the Embedded State. doi:10.1093/acprof:oso/9780199684168.001.0001Jensen, M. B., Johnson, B., Lorenz, E., & Lundvall, B. Å. (2007). Forms of knowledge and modes of innovation. Research Policy, 36(5), 680-693. doi:10.1016/j.respol.2007.01.006Kemp, R., Schot, J., & Hoogma, R. (1998). Regime shifts to sustainability through processes of niche formation: The approach of strategic niche management. Technology Analysis & Strategic Management, 10(2), 175-198. doi:10.1080/09537329808524310Laranja, M., Uyarra, E., & Flanagan, K. (2008). Policies for science, technology and innovation: Translating rationales into regional policies in a multi-level setting. Research Policy, 37(5), 823-835. doi:10.1016/j.respol.2008.03.006Meadowcroft, J. (2011). Engaging with the politics of sustainability transitions. Environmental Innovation and Societal Transitions, 1(1), 70-75. doi:10.1016/j.eist.2011.02.003Sabel, C. F., & Zeitlin, J. (2012). Experimentalist Governance. Oxford Handbooks Online. doi:10.1093/oxfordhb/9780199560530.013.0012Schot, J., & Geels, F. W. (2008). Strategic niche management and sustainable innovation journeys: theory, findings, research agenda, and policy. Technology Analysis & Strategic Management, 20(5), 537-554. doi:10.1080/09537320802292651Sengers, F., & Raven, R. (2014). Metering motorbike mobility: informal transport in transition? Technology Analysis & Strategic Management, 26(4), 453-468. doi:10.1080/09537325.2013.870991Seyfang, G., & Smith, A. (2007). Grassroots innovations for sustainable development: Towards a new research and policy agenda. Environmental Politics, 16(4), 584-603. doi:10.1080/09644010701419121Shove, E., & Walker, G. (2007). Caution! Transitions Ahead: Politics, Practice, and Sustainable Transition Management. Environment and Planning A: Economy and Space, 39(4), 763-770. doi:10.1068/a39310Smith, A., & Raven, R. (2012). What is protective space? Reconsidering niches in transitions to sustainability. Research Policy, 41(6), 1025-1036. doi:10.1016/j.respol.2011.12.012Smith, A., Voß, J.-P., & Grin, J. (2010). Innovation studies and sustainability transitions: The allure of the multi-level perspective and its challenges. Research Policy, 39(4), 435-448. doi:10.1016/j.respol.2010.01.023Steward, F. (2012). Transformative innovation policy to meet the challenge of climate change: sociotechnical networks aligned with consumption and end-use as new transition arenas for a low-carbon society or green economy. Technology Analysis & Strategic Management, 24(4), 331-343. doi:10.1080/09537325.2012.663959Weber, K. M., & Rohracher, H. (2012). Legitimizing research, technology and innovation policies for transformative change. Research Policy, 41(6), 1037-1047. doi:10.1016/j.respol.2011.10.015Klein Woolthuis, R., Lankhuizen, M., & Gilsing, V. (2005). A system failure framework for innovation policy design. Technovation, 25(6), 609-619. doi:10.1016/j.technovation.2003.11.00

CRISPR-Cas9–based treatment of myocilin-associated glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss worldwide, with elevated intraocular pressure (IOP) a major risk factor. Myocilin (MYOC) dominant gain-of-function mutations have been reported in ∼4% of POAG cases. MYOC mutations result in protein misfolding, leading to endoplasmic reticulum (ER) stress in the trabecular meshwork (TM), the tissue that regulates IOP. We use CRISPR-Cas9–med iated genome editing in cultured human TM cells and in a MYOC mouse model of POAG to knock down expression of mutant MYOC, resulting in relief of ER stress. In vivo genome editing results in lower IOP and prevents further glaucomatous damage. Importantly, using an ex vivo human organ culture system, we demonstrate the feasibility of human genome editing in the eye for this important disease. Keywords: myocilin; CRISPR; glaucoma; trabecular meshwork; genome editingNational Institutes of Health (U.S.) (Grant R01 EY024259)National Institutes of Health (U.S.) (Grant R01 EY026177)National Institutes of Health (U.S.) (Grant R00 EY022077

MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix

Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder

Differential diagnosis between childhood onset attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) remains a challenge, mainly due to overlapping symptoms and high rates of comorbidity. Despite this, genetic correlation reported for these disorders is low and non-significant. Here we aimed to better characterize the genetic architecture of these disorders utilizing recent large genome-wide association studies (GWAS). We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls) and BD (20,352 cases and 31,358 controls) applying the conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases the power to detect novel phenotype-specific and shared loci by leveraging the combined power of two GWAS. We observed cross-trait polygenic enrichment for ADHD conditioned on associations with BD, and vice versa. Leveraging this enrichment, we identified 19 novel ADHD risk loci and 40 novel BD risk loci at condFDR <0.05. Further, we identified five loci jointly associated with ADHD and BD (conjFDR < 0.05). Interestingly, these five loci show concordant directions of effect for ADHD and BD. These results highlight a shared underlying genetic risk for ADHD and BD which may help to explain the high comorbidity rates and difficulties in differentiating between ADHD and BD in the clinic. Improving our understanding of the underlying genetic architecture of these disorders may aid in the development of novel stratification tools to help reduce these diagnostic difficulties.acceptedVersio

Topical ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma

PURPOSE. Mutations in the myocilin gene (MYOC) are the most common known genetic cause of primary open-angle glaucoma (POAG). The purpose of this study was to determine whether topical ocular sodium 4-phenylbutyrate (PBA) treatment rescues glaucoma phenotypes in a mouse model of myocilin-associated glaucoma (Tg-MYOC Y437H mice). METHODS. Tg-MYOC Y437H mice were treated with PBA eye drops (n ϭ 10) or sterile PBS (n ϭ 8) twice daily for 5 months. Long-term safety and effectiveness of topical PBA (0.2%) on glaucoma phenotypes were examined by measuring intraocular pressure (IOP) and pattern ERG (PERG), performing slit lamp evaluation of the anterior chamber, analyzing histologic sections of the anterior segment, and comparing myocilin levels in the aqueous humor and trabecular meshwork of Tg-MYOC Y437H mice. Sci. 2012;53: 1557-1565 RESULTS. Tg-MYO

Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling

Obesity is a major public health problem in most developed countries and a major risk factor for diabetes and cardiovascular disease. Emerging evidence indicates that ciliary dysfunction can contribute to human obesity but the underlying molecular and cellular mechanisms are unknown. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Here, we show that BBS proteins are required for leptin receptor (LepR) signaling in the hypothalamus. We found that Bbs2−/−, Bbs4−/− and Bbs6−/− mice are resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. In addition, activation of hypothalamic STAT3 by leptin is significantly decreased in Bbs2−/−, Bbs4−/− and Bbs6−/− mice. In contrast, downstream melanocortin receptor signaling is unaffected, indicating that LepR signaling is specifically impaired in Bbs2−/−, Bbs4−/− and Bbs6−/− mice. Impaired LepR signaling in BBS mice was associated with decreased Pomc gene expression. Furthermore, we found that BBS1 protein physically interacts with the LepR and that loss of BBS proteins perturbs LepR trafficking. Our data indicate that BBS proteins mediate LepR trafficking and that impaired LepR signaling underlies energy imbalance in BBS. These findings represent a novel mechanism for leptin resistance and obesity

BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes

There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet–Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7−/− mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect

Be prepared: communism and the politics of scouting in 1950s Britain

This article examines the exposure, and in some cases dismissal, of Boy Scouts who belonged or sympathised with the Young Communist League in Britain during the early 1950s. A focus on the rationale and repercussions of the organisation's approach and attitudes towards ‘Red Scouts’ found within their ‘ranks’ extends our understanding of youth movements and their often complex and conflicting ideological foundations. In particular, the post-World War Two period presented significant challenges to these spaces of youth work in terms of broader social and political change in Britain. An analysis of the politics of scouting in relation to Red Scouts questions not only the assertion that British McCarthyism was ‘silent’, but also brings young people firmly into focus as part of a more everyday politics of communism in British society

A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened

Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia. However, the mechanisms governing ciliary trafficking by BBS proteins are not well understood. Here, we show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with a BBS protein complex known as the BBSome and regulates ciliary trafficking of this complex. We also show that all BBSome subunits and BBS3 (also known as ARL6) are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3 and BBS5 depleted cells. Finally, we found that BBS proteins and LZTFL1 regulate ciliary trafficking of hedgehog signal transducer, Smoothened. Our findings suggest that LZTFL1 is an important regulator of BBSome ciliary trafficking and hedgehog signaling

Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC

This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as $3$ ab$^{-1}$ of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as $15$ ab$^{-1}$ of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by $20-50\%$ on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics