| 1. |
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| 2. |
- McCrory, Gavin, 1990, et al.
(författare)
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Governing sustainability transitions: contrasting experimental arenas through the lens of Agenda 2030
- 2018
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In 2015, the necessity of fundamental societal change was outlined in a universal, transnational agreement with the headline of “transforming our world”. The UN 2030 Agenda for Sustainable Development includes 17 Sustainable Development Goals, ranging from ending poverty and establishing gender equality to halting climate change and sustainable cities and communities. Building on UN and scholarly debates, we put forward two key principles to guide the realization of Agenda 2030: transformation (to sustainability) and integration. Transformation refers to the understanding that fundamental change is necessary to achieve sustainability; Integration recognizes that such change is dependent upon different perspectives, such as sustainability dimensions and the SDGs themselves, and different actors. At the same time, laboratories in real world contexts have emerged from various discourses, and are portrayed as settings to host potentially transformative experimentation and innovation processes and integrate various perspectives and actors. Sustainability related labs contribute a significant share to all labs existing. Despite their proliferation across the local, regional and national levels, it remains unclear how different laboratory settings might relate to processes of integration and transformation. Labs have seldom been attached explicitly to Agenda 2030 in practice, and a systematic assessment of the suitability of labs to support agenda 2030 so far is lacking. Hence, the main aim of this work-in-progress paper is to situate existing lab approaches from real world contexts in relation to the ambitions of Agenda 2030. It is guided by the following main research question: What is the capacity of labs in real world contexts in contributing to agenda 2030 by processes of transformation and integration? The paper presents the progress of an ongoing study, which intends to employ a step-based systematic review approach. Firstly, we highlight and unpack the key principles to guide the realization of Agenda 2030: transformation (to sustainability) and integration, and propose an analytical framework related to these principles. Secondly, and currently ongoing, we investigate a breadth of lab approaches building on a systematic review to draw out their capacities to contribute to transformation and integration. Results of the first stage are presented, before the paper ends by outlining the ongoing data collection process, describes the sample and provides a brief outlook.
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| 3. |
- Abugabbara, Marwan, et al.
(författare)
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How to develop fifth-generation district heating and cooling in Sweden? : Application review and best practices proposed by middle agents
- 2023
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Ingår i: Energy Reports. - : Elsevier Ltd. - 2352-4847. ; 9, s. 4971-4983
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Tidskriftsartikel (refereegranskat)abstract
- Sweden has an ambitious plan to fully decarbonise district heating by 2030 and to contribute with negative emissions of greenhouse gases in 2050. The vagaries of the energy market associated with climate, political, and social changes entail cross-sectoral integration that can fulfill these national targets. Fifth-generation district heating and cooling (5GDHC) is a relatively new concept of district energy systems that features a simultaneous supply of heating and cooling using power-to-heat technologies. This paper presents best practices for developing 5GDHC systems in Sweden to reach a consensus view on these systems among all stakeholders. A mixed-method combining best practice and roadmapping workshops has been used to disseminate mixed knowledge and experience from middle agents representing industry professionals and practitioners. Four successful implementations of 5GDHC systems are demonstrated and the important learned lessons are shared. The best practices are outlined for system planning, system modeling and simulation, prevailing business models for energy communities, and system monitoring. A roadmap from the middle agents’ point of view is composed and can be utilised to establish industry standards and common regulatory frameworks. © 2023 The Author(s)
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| 4. |
- Ahlström, Johan, 1990, et al.
(författare)
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Bark as feedstock for dual fluidized bed gasifiers. Operability, efficiency, and economics
- 2019
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Ingår i: International Journal of Energy Research. - : Hindawi Limited. - 1099-114X .- 0363-907X. ; 43:3, s. 1171-1190
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Tidskriftsartikel (refereegranskat)abstract
- The demand for biofuels and biochemicals is expected to increase in the future, which will in turn increase the demand for biomass feedstock. Large gasification plants fueled with biomass feedstock are likely to be a key enabling technology in a resource-efficient, bio-based economy. Furthermore, the costs for producing biofuels and biochemicals in such plants could potentially be decreased by utilizing inexpensive low-grade residual biomass as feedstock. This study investigates the usage of shredded tree bark as a feedstock for the production of biomethane in the GoBiGas demonstration plant in Gothenburg, Sweden, based on a 32 MWth industrial dual fluidized bed gasification unit. The plant was operated with bark feedstock for 12 000 hours during the period 2014 to 2018. Data from the measurement campaign were processed using a stochastic approach to establish the plant's mass and energy balances, which were then compared with operation of the plant with wood pellets. For this comparison, an extrapolation algorithm was developed to predict plant performance using bark dried to the same moisture content as wood pellets, ie, 8%w.b. Plant operation with bark feedstock was evaluated for operability, efficiency, and feedstock-related cost. The gas quality achieved during the test period was similar to that obtained for operation with wood pellets. Furthermore, no significant ash sintering or agglomeration problems were observed more than 750 hours of operation. The calculated biomass-to-biomethane efficiency is 43% to 47% (lower heating value basis) for operation with wet bark. However, the predicted biomass-to-biomethane efficiency can be increased to 55%–65% for operation with bark feedstock dried to 8% moisture content, with corresponding feedstock costs in the range of 24.2 to 32.7 EUR/MWh; ie, a cost reduction of about 40% compared with wood pellets.
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| 5. |
- Andersson, David, 1978, et al.
(författare)
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Reflections on evaluating Challenge Lab by applying a proposed scheme for Sustainability Transition Experiments
- 2016
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Ingår i: IST 2016 Book of Conference Papers.
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Konferensbidrag (refereegranskat)abstract
- The Challenge Lab (CLab) is a neutral arena for triple helix stakeholders and an educational platform for master students to addresses complex challenges and system lockins. By the end of its third year, the CLab will have hosted nearly 100 students, producing 23 master thesis projects and 13 course projects. We present an evaluative case using the scheme proposed by Luederitz et al. (2016) for sustainability transition experiments which includes four main questions and a set of indicators for each question. We end with some general reflections on the evaluation method.
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| 6. |
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| 7. |
- Björnfot, Cecilia, et al.
(författare)
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Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults : a 4D flow MRI study
- 2024
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016.
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Tidskriftsartikel (refereegranskat)abstract
- White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.
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| 8. |
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| 9. |
- Holmberg, John, 1963, et al.
(författare)
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A Sustainability Lighthouse—Supporting Transition Leadership and Conversations on Desirable Futures
- 2018
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Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Central in leadership for sustainability transitions is the capability to create transformative momentum in a sustainable (desirable) direction, calling for meaningful conversations on sustainable futures. The aim of this study is to develop a conceptual framework to inspire and support such conversations. A qualitative literature review of sustainability conceptualizations was conducted, followed by a thematic analysis. The resulting framework consists of an overarching question and an accompanying set of categories for four sustainability dimensions: the social, the economic, the ecological, and ‘human needs and wellbeing’. Furthermore, the framework is visualized as a lighthouse for pedagogical reasons. We foresee that the lighthouse might be of value in processes guiding socio-technical transitions towards sustainability in three different ways: (1) by attempting to bridge the issue of ‘transition’ with that of ‘sustainability’; (2) as part of a backcasting process; and (3) modes of transdisciplinary research where relevant actors take part in the conversation. The study is related to over 20 years of experience from working with a backcasting approach engaging with sustainability transitions in a variety of processes. We invite further dialogue on how one may approach the concept of sustainability to inspire and support conversations on sustainable futures.
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| 10. |
- Holmberg, John, 1963, et al.
(författare)
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Challenge Lab: A transformative and integrative approach for sustainability transitions
- 2015
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Ingår i: The International Sustainability Transitions Conference (IST 2015) at the University of Sussex (UK).
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Konferensbidrag (refereegranskat)abstract
- We present a model where master students act as change agents, inducing sustainability transitions insocio-technical systems by applying backcasting.Creating transitions in a complex socio-technical system, where universities need to collaborate with thepublic- and private sector (the triple helix) is often hindered by various kinds of lock-ins.In Sweden, previous attempts to solve this include companies, governmental bodies and researchersacting individually to bring together stakeholders to dislodge these lock-ins. To complement this, a neutral“Challenge Lab” arena was created, where master students run transformative backcasting projects.Interviews with triple helix stakeholders were conducted. Industrial stakeholders claim the students werein a unique position as unthreatening, yet challenging. Academic stakeholders highlight students asunravelling issues and going deeper in the questions resulting in quicker processes and trust in their owndialogue work. Public sector stakeholders claim dialogue resulted in true personal opinions coming to thesurface and another stakeholder modified their overall climate strategy as a result of the change agentdialogue.The study indicates that students are unthreatening yet challenging change agents, catalysing trust onvarious triple helix system levels. Other universities can adopt this model for engaging in sustainabilitytransitions.
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| 11. |
- Holmberg, John, 1963, et al.
(författare)
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Challenge Lab – Learning by Engaging in Society’s Sustainability Transitions
- 2017
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Ingår i: 10th International Conference on Researching Work and Learning, 6-8 December 2017 Rhodes University, Grahamstown South Africa.
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Konferensbidrag (refereegranskat)abstract
- The United Nations (UN) 2030 Agenda for Sustainable Development with its 17 Sustainable Development Goals devotes goal 4 specifically to education, but sustainable development is altogether a large societal learning process. Education with its institutions therefore have a key role to play. The different aspects of this role are discussed within education for sustainable development (ESD) and several interesting examples of real-world ESD learning initiatives have been developed and realized. Yet, they are rarely evaluated in depth to understand why, how and what kind of learning that occurs. In this paper, Challenge Lab (C-Lab) is analysed, where students are provided support and space to engage with complex real-world sustainability challenges in society. The results indicate that C-Lab is in line with the ESD ambition, but is more explicit on: perspective awareness, experimentation, leadership and the unique role students can play in society’s transition. The results also indicate that C-Lab relates to education and learning concepts of expansion, dialogue, values, authenticity, scaffolding, reflection. The backcasting process used at C-Lab gives the expansion a direction toward sustainability, which is also the ambition of ESD.
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| 12. |
- Holmberg, John, 1963, et al.
(författare)
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Challenge Lab - Students guiding sustainability transitions in society
- 2017
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Ingår i: Den 6:e utvecklingskonferensen för Sveriges ingenjörsutbildningar.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The United Nations (UN) 2030 Agenda for Sustainable Development “Transforming our world” with its 17 Sustainable Development Goals (SDGs) devotes SDG 4 specifically to education, but sustainable development is altogether a large societal learning process. Education with its institutions therefore have a key role to play. The different aspects of this role are discussed within Education for sustainable development (ESD). The UN decade for ESD (2005-2014) is now continued with the Global Action Programme on ESD, and several interesting examples of real-world ESD learning environments are developed and realized. Yet, they are rarely evaluated in depth to understand why, how and what kind of learning that occurs. In this paper, Challenge Lab (C-Lab) is analysed, where students are provided support and space to engage with complex real-world sustainability challenges in society. An analytical framework is developed, informed by sustainability, education and learning research to catch essential aspects and ambitions of ESD: expansion, dialogue, values, authenticity, scaffolding, reflection. The results indicate that C-Lab is in line with the ESD ambition, but is more explicit on: perspective awareness, experimentation, leadership and the unique role students can play in society’s transition. Coupling exist between the C-Lab intention and the actual experiences/actions from the students, but further analysis is needed. The backcasting approach followed at C-Lab can be understood as an expansive cycle acknowledging the inherent complexity and uncertainty in the process of creating sustainable futures; initiated by a dialogue around sustainability principles and values serving as a basis for questioning. This gives the expansion a direction toward sustainability, which also are the main characteristics of ESD in general.
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| 13. |
- Holmberg, John, 1963, et al.
(författare)
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Students guiding societal transitions - examples from Challenge Lab at Chalmers University of Technology, Gothenburg, Sweden
- 2016
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Ingår i: 8th Conference on Engineering Education for Sustainable Development (EESD) in Bruges, Belgium.
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Konferensbidrag (refereegranskat)abstract
- Engaging in sustainability transitions of socio-technical systems, where universities need to collaborate with the public- and private sector (together forming the triple helix) is often hindered by various kinds of lock-ins. Actors are in general divided in silo-settings dealing with one issue at a time having narrow perspectives, vested interests and serve goals of sub-systems (or even individual departments) instead of the system as a whole. Furthermore, established socio-technical regimes are subject to path dependencies and incremental realignments. In Sweden, previous attempts to solve this include companies, governmental bodies and researchers acting individually to bring together stakeholders to address the lock-ins. As a complement, a neutral “Challenge Lab” arena built around master students from Chalmers University was established at one of the science parks in Gothenburg. The students may have a unique role to play in the transitions since they are knowledgeable yet unthreatening fostering dialogue between triple helix stakeholders. Interviews with involved actors indicate that students can act as a bonding medium by building trust between stakeholders yet challenging underlying assumptions. Other universities can adopt this model for educating students and engaging in sustainability transitions, even beyond the triple helix.
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| 14. |
- Johansen, Karin, 1990-, et al.
(författare)
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Laparoscopic distal pancreatectomy is more cost-effective than open resection: results from a Swedish randomized controlled trial
- 2023
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Ingår i: HPB. - : ELSEVIER SCI LTD. - 1365-182X .- 1477-2574. ; 25:8, s. 972-979
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundLaparoscopic distal pancreatectomy is being implemented worldwide. The aim of this study was to perform a cost-effectiveness analysis from a health care perspective.MethodsThis cost-effectiveness analysis was based on the randomized controlled trial LAPOP, where 60 patients were randomized to open or laparoscopic distal pancreatectomy. For the follow-up of two years, resource use from a health care perspective was recorded, and health-related quality of life was assessed using the EQ-5D-5L. The per-patient mean cost and quality-adjusted life years (QALYs) were compared using nonparametric bootstrapping.ResultsFifty-six patients were included in the analysis. The mean health care costs were lower, €3863 (95% CI: -€8020 to €385), for the laparoscopic group. Postoperative quality of life improved with laparoscopic resection and resulted in a gain in QALYs of 0.08 (95% CI: −0.09 to 0.25). The laparoscopic group had lower costs and improved QALYs in 79% of bootstrap samples. With a cost-per-QALY threshold of €50 000, 95.4% of the bootstrap samples were in favour of laparoscopic resection.ConclusionLaparoscopic distal pancreatectomy is associated with numerically lower health care costs and improvements in QALYs compared with the open approach. The results support the ongoing transition from open to laparoscopic distal pancreatectomies.
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| 15. |
- Kraupner, Nadine, et al.
(författare)
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Selective concentration for ciprofloxacin resistance in Escherichia coli grown in complex aquatic bacterial biofilms
- 2018
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 116, s. 255-268
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Tidskriftsartikel (refereegranskat)abstract
- There is concern that antibiotics in the environment can select for and enrich bacteria carrying acquired antibiotic resistance genes, thus increasing the potential of those genes to emerge in a clinical context. A critical question for understanding and managing such risks is what levels of antibiotics are needed to select for resistance in complex bacterial communities. Here, we address this question by examining the phenotypic and genotypic profiles of aquatic communities exposed to ciprofloxacin, also evaluating the within-species selection of resistant E. coli in complex communities. The taxonomic composition was significantly altered at ciprofloxacin exposure concentrations down to 1 μg/L. Shotgun metagenomic analysis indicated that mobile quinolone resistance determinants (qnrD, qnrS and qnrB) were enriched as a direct consequence of ciprofloxacin exposure from 1 μg/L or higher. Only at 5–10 μg/L resistant E.coli increased relative to their sensitive counterparts. These resistant E. coli predominantly harbored non-transferrable, chromosomal triple mutations (gyrA S83 L, D87N and parC S80I), which confer high-level resistance. In a controlled experimental setup such as this, we interpret effects on taxonomic composition and enrichment of mobile quinolone resistance genes as relevant indicators of risk. Hence, the lowest observed effect concentration for resistance selection in complex communities by ciprofloxacin was 1 μg/L and the corresponding no observed effect concentration 0.1 μg/L. These findings can be used to define and implement discharge or surface water limits to reduce risks for selection of antibiotic resistance in the environment. © 2018 Elsevier Ltd
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| 16. |
- Larsson, Johan, 1990, et al.
(författare)
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Backcasting from sustainability principles – a case from a regional climate policy process in West Sweden
- 2016
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Ingår i: IST 2016 Book of Conference Papers.
-
Konferensbidrag (refereegranskat)abstract
- Global sustainability goals and radical innovation put many of today’s societal systems under pressure. It is a question of transitions, where new governance- approaches are sought after to guide, induce and accelerate the transitions into desirable pathways. In this paper a regional policy process aiming at creating a new climate strategy for the region is studied. The process in which 100 stakeholders took part followed a backcasting-approach from sustainability principles and had the ambition to integrate social, economical and ecological dimensions of sustainability. The results point at that principles- based approaches can play a role in addressing the complex issues ahead as they: (1) can open up for transformation by guiding thinking beyond today’s unsustainable and locked-in systems; (2) support the handling of complex issues and frame challenges for integrated measures, and; (3) form a common ground as shared mental models to in dialogue foster perspective awareness, trust-building and create new actor-constellations for future collaboration.
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| 17. |
- Larsson, Johan, 1990-, et al.
(författare)
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Combining endocannabinoids with retigabine for enhanced M-channel effect and improved KV7 subtype selectivity
- 2020
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Ingår i: The Journal of General Physiology. - : ROCKEFELLER UNIV PRESS. - 0022-1295 .- 1540-7748. ; 152:8
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Tidskriftsartikel (refereegranskat)abstract
- Retigabine is unique among anticonvulsant drugs by targeting the neuronal M-channel, which is composed of KV7.2/KV7.3 and contributes to the negative neuronal resting membrane potential. Unfortunately, retigabine causes adverse effects, which limits its clinical use. Adverse effects may be reduced by developing M-channel activators with improved KV7 subtype selectivity. The aim of this study was to evaluate the prospect of endocannabinoids as M-channel activators, either in isolation or combined with retigabine. Human KV7 channels were expressed in Xenopus laevis oocytes. The effect of extracellular application of compounds with different properties was studied using two-electrode voltage clamp electrophysiology. Site-directed mutagenesis was used to construct channels with mutated residues to aid in the mechanistic understanding of these effects. We find that arachidonoyl-L-serine (ARA-S), a weak endocannabinoid, potently activates the human M-channel expressed in Xenopus oocytes. Importantly, we show that ARA-S activates the M-channel via a different mechanism and displays a different KV7 subtype selectivity compared with retigabine. We demonstrate that coapplication of ARA-S and retigabine at low concentrations retains the effect on the M-channel while limiting effects on other KV7 subtypes. Our findings suggest that improved KV7 subtype selectivity of M-channel activators can be achieved through strategically combining compounds with different subtype selectivity.
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| 18. |
- Larsson, Johan, 1990
(författare)
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Guiding Sustainability Transitions: Backcasting, Experimentation and Social learning
- 2019
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sustainability challenges including climate change, social injustice, resource depletion and biodiversity loss are becoming increasingly apparent. These challenges can be understood as partly resulting from unsustainable socio-technical systems in society, assumed to require transitions to become sustainable in time. When moving beyond more conventional attempts to analyse and describe sustainability challenges, there is an increasing research interest in solutions-oriented and prescriptive approaches to meaningfully engage with sustainability challenges in various contexts. The aim of this thesis is to contribute knowledge on how societal transitions can be guided into desirable and sustainable pathways, where social learning is assumed a key process. The many designs and frameworks for engaging with sustainability transitions that prevail in literature seldom provide insights into the contingent nature of its application in its particular context, the prior knowledge and beliefs of participating actors, or an unpacking of how and why (transformative) social learning processes might unfold. Through inter- and transdisciplinary research and drawing on case studies and ethnographic methods, this thesis includes further development and an empirical evaluation of a backcasting-from-principles process in two settings: a ‘Challenge Lab’ arena that creates space for students to lead sustainability transitions (Paper I), and a regional multi-stakeholder process related to climate policy (Paper II). These studies represent initial attempts to better understand conditions and mechanisms into the kinds of learning that occur in these spaces. Finally, this thesis develops hypotheses on capabilities of sustainability principles in navigating transitions, and particular tools that may be used within and beyond backcasting settings to provide structure in inspiring and supporting conversations on sustainable and desirable futures (Paper III).
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| 19. |
- Larsson, Johan, 1990, et al.
(författare)
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Guiding Systemic Change: A cross-case analysis of ‘transition labs’ in Canada and Sweden
- 2018
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Agenda 2030 presents a global ambition to transform our world into sustainability. In this study we seek to advance knowledge on how sustainable systemic change can be guided in practice, and how the keywords of Agenda 2030 can provide value in such work. We argue that the conception of sustainability and desire for positive change may form strong coalitions and motivators for realizing transitions challenging the status quo. This study seeks to make a practical contribution into some of the methodologies, processes, tools and techniques that may be useful in guiding systemic change: with an emphasis on backcasting and a multi-level model for transitions. The study is exploratory in its approach, building on a description, comparison and cross-case analysis of two lab methodologies and insights from their application in concrete cases: the Energy Futures Lab in Alberta, Canada and the Challenge Lab in West Sweden. The analysis is guided by a novel analytical framework operationalizing keywords of Agenda 2030 to shed light on how sustainability transition processes (including transition labs) may contribute to sustainability transitions. The framework itself, and the explorative comparison and analysis pose some questions that may inspire further development of transition lab methodologies to have a transformative impact across systems.
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| 20. |
- Larsson, Johan, 1990, et al.
(författare)
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Learning while creating value for sustainability transitions: The case of Challenge Lab at Chalmers University of Technology
- 2018
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Ingår i: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 172, s. 4411-4420
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Tidskriftsartikel (refereegranskat)abstract
- To achieve a sustainable future, a variety of societal systems need to be transformed and new ways of social collaboration created. Higher education institutions play an important role in guiding these changes, through education, research, and outreach. In this paper, we study a lab-based learning environment, the Challenge Lab, where master’s degree students engage in, and create value in support of, the transition to a sustainable society. Three student cases are analyzed in-depth to understand how the Lab functions as an expansive learning process and provides space for transformative and integrative value creation. The Lab’s guiding methodology is based on backcasting from principles, combined with clarifying the students’ core values and drivers. The role of the teacher in such a learning environment is to provide the basis for the process by facilitating and guiding. Provided with the right conditions, these students have the ability to challenge underlying assumptions about how systems work and to build trust by facilitating dialogue among actors in society. The students perceived the opportunity to engage in real-world challenges as meaningful, drew valuable lessons for their future, and got to know themselves better. In this transitional period of achieving ambitious sustainability goals and targets, students’ ability to be a source of change – maybe the most important source inside higher education institutions – deserves much more attention.
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| 21. |
- Larsson, Johan, 1990-
(författare)
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Molecular mechanisms of modulation of KV7 channels by polyunsaturated fatty acids and their analogues
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ion channels are membrane proteins that regulate the permeability of ions across the cell membrane. The sequential opening of different types of ion channels produces action potentials in excitable cells. Action potentials are a way for the body to, for example, transmit signals quickly over a long distance.The KV7 family is an important group of voltage-gated potassium channels. Mutations that cause dysfunction in members of the KV7 family are associated with several forms of disease. Compounds that can activate KV7 channels have previously been shown to work as medical treatments. However, the previously available antiepileptic drug retigabine, has been withdrawn due to adverse effects. Thus, there is a need for further development of compounds that target these channels. PUFA and PUFA analogs have previously been demonstrated to activate KV7.1 through an electrostatic mechanism. This thesis investigates new aspects of the interaction between KV7 channels and PUFA-related compounds.The data in this thesis are from human KV7 channels expressed in Xenopus laevis oocytes. The currents produced by the channels expressed in the oocytes have been studied using twoelectrode voltage clamp. Our aim was to study the mechanism for the activation of KV7 channels by PUFA and PUFA analogs. More specifically, we intended to study why the beta subunit KCNE1 abolishes the activating effect of PUFA on KV7.1 and how PUFAs activate KV7.2 and KV7.3. Additionally, we wanted to study aspects that may affect whether these compounds are viable as medical treatments. For instance, whether these compounds can activate channels containing disease-causing mutations and whether we can improve compound selectivity towards certain KV7 channels.In Paper I, we introduce disease-causing mutations found in patients into KV7.1 and KCNE1. The characterization showed that these channels had altered biophysical properties compared to wild type channels. A PUFA analog was found to activate and, to a large degree, restore wild type-like biophysical properties in the mutated channels regardless of the localization of the mutation in the channel.In Paper II, we demonstrate why PUFA is unable to activate KV7.1 co-expressed with beta subunit KCNE1. KCNE1 induces a conformational change of KV7.1 that moves the S5-Phelix loop closer to the PUFA binding site. This causes negative charges of the loop to attract protons that reduce local pH at the PUFA binding site. The decreased local pH leads to protonation of PUFA and the PUFAs therefore lose their negative charge. Thus, PUFA cannot activate KV7.1 when it is co-expressed with KCNE1.In Paper III, we study a group of PUFA-related substances, endocannabinoids, on KV7 channels. One endocannabinoid, Arachidonoyl-L-Serine (ARA-S), was identified as a potent activator of the neuronal M-channel, comprising KV7.2 and KV7.3 heteromers. We study the activating mechanism of ARA-S in KV7.2 and KV7.3, demonstrating how the activating effect is linked to two parts of the channel protein, one in the voltage sensor domain and the other in the pore domain. ARA-S was also found to activate KV7.1 and KV7.5 but not KV7.4, which instead was inhibited. Retigabine, a compound that activates the M-channel but has a different KV7 subtype selectivity compared to ARA-S, was used in combination with ARA-S to maintain a potent effect on the M-channel while limiting the activation of other KV7 channels.In conclusion, the activating effect of PUFA analogs on KV7 channels may be helpful in the development of future drug candidates for diseases such as arrhythmia and epilepsy.
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| 22. |
- Larsson, Johan, 1990-, et al.
(författare)
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Polyunsaturated Fatty Acids as Modulators of K(V)7 Channels
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 11
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Forskningsöversikt (refereegranskat)abstract
- Voltage-gated potassium channels of the K(V)7 family are expressed in many tissues. The physiological importance of K(V)7 channels is evident from specific forms of disorders linked to dysfunctional K(V)7 channels, including variants of epilepsy, cardiac arrhythmia and hearing impairment. Thus, understanding how K(V)7 channels are regulated in the body is of great interest. This Mini Review focuses on the effects of polyunsaturated fatty acids (PUFAs) on K(V)7 channel activity and possible underlying mechanisms of action. By summarizing reported effects of PUFAs on K(V)7 channels and native K(V)7-mediated currents, we conclude that the generally observed effect is a PUFA-induced increase in current amplitude. The increase in current is commonly associated with a shift in the voltage-dependence of channel opening and in some cases with increased maximum conductance. Auxiliary KCNE subunits, which associate with K(V)7 channels in certain tissues, may influence PUFA effects, though findings are conflicting. Both direct and indirect activating PUFA effects have been described, direct effects having been most extensively studied on K(V)7.1. The negative charge of the PUFA head-group has been identified as critical for electrostatic interaction with conserved positively charged amino acids in transmembrane segments 4 and 6. Additionally, the localization of double bonds in the PUFA tail tunes the apparent affinity of PUFAs to K(V)7.1. Indirect effects include those mediated by PUFA metabolites. Indirect inhibitory effects involve K(V)7 channel degradation and re-distribution from lipid rafts. Understanding how PUFAs regulate K(V)7 channels may provide insight into physiological regulation of K(V)7 channels and bring forth new therapeutic strategies.
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| 23. |
- Larsson, Viktor, et al.
(författare)
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Outlier rejection for absolute pose estimation with known orientation
- 2016
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Ingår i: British Machine Vision Conference 2016, BMVC 2016. ; 2016-September, s. 45.1-45.12
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Konferensbidrag (refereegranskat)abstract
- Estimating the pose of a camera is a core problem in many geometric vision applications. While there has been much progress in the last two decades, the main difficulty is still dealing with data contaminated by outliers. For many scenes, e.g. with poor lightning conditions or repetitive textures, it is common that most of the correspondences are outliers. For real applications it is therefore essential to have robust estimation methods. In this paper we present an outlier rejection method for absolute pose estimation. We focus on the special case when the orientation of the camera is known. The problem is solved by projecting to a lower dimensional subspace where we are able to efficiently compute upper bounds on the maximum number of inliers. The method guarantees that only correspondences which cannot belong to an optimal pose are removed. In a number of challenging experiments we evaluate our method on both real and synthetic data and show improved performance compared to competing methods.
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| 24. |
- Ling, Gustav, et al.
(författare)
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Fuel-efficient Model Predictive Control for Heavy Duty Vehicle Platooning using Neural Networks
- 2018
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Ingår i: 2018 American Control Conference (ACC). - : IEEE. - 9781538654286 - 9781538654279 - 9781538654293 ; , s. 3994-4001
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Konferensbidrag (refereegranskat)abstract
- The demand for fuel-efficient transport solutions are steadily increasing with the goal of reducing environmental impact and increasing efficiency. Heavy-Duty Vehicle (HDV) platooning is a promising concept where multiple HDVs drive together in a convoy with small intervehicular spacing. By doing this, the aerodynamic drag is reduced which in turn lowers fuel consumption. We propose a novel Model Predictive Control (MPC) framework for longitudinal control of the follower vehicle in a platoon consisting of two HDVs when no vehicle-to-vehicle communication is available. In the framework, the preceding vehicle's velocity profile is predicted using artificial neural networks which uses a topographic map of the road as input and is trained offline using synthetic data. The gear shifting and mass of consumed fuel for the controlled follower vehicle is modeled and used within the MPC controller. The efficiency of the proposed framework is verified in simulation examples and is benchmarked with a currently available control solution.
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| 25. |
- Mezheyeuski, Artur, et al.
(författare)
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An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.
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