| 1. |
- Engdahl, Cecilia, et al.
(författare)
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Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae : Functional Characterization and Comparisons with Vertebrate Orthologues
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE.
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| 2. |
- Engdahl, Cecilia, et al.
(författare)
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Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:20, s. 9409-9421
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.
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| 3. |
- Hellberg, Sofie, 1979, et al.
(författare)
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Don efter population? Utbildning för hållbar utveckling och det globala biopolitiska GAPet
- 2018
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Ingår i: Pedagogisk forskning i Sverige. - 1401-6788. ; 23:3-4, s. 172-191
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Tidskriftsartikel (refereegranskat)abstract
- Världen över implementeras just nu det globala handlingsprogrammet för utbildning för hållbar utveckling (GAP). Ett återkommande budskap är att programmet förenar mänskligheten i en gemensam strävan mot ett bättre, jämlikare och ”grönare” liv för alla. Men är det verkligen så? Föreliggande artikel driver tesen att mänskligheten snarare delas upp. Med utgångspunkt i biopolitisk teoribildning sätter artikeln således fokus på differentiering och på vilka typer av kunskap(er) och livsstilsanspråk som olika populationer erbjuds i den hållbara utvecklingens namn. Ytterst är frågan om utbildning för hållbar utveckling riskerar att reproducera det globala gap som skiljer rika och fattiga människors livsstilar åt. Artikeln, som främst utgör ett teoretiskt och metodologiskt bidrag till den nordiska miljö- och hållbarhetsutbildningsforskningen, argumenterar för globala utblickar och biopolitiskt informerade undersökningar av hur GAP implementeras visavi olika populationer i olika sammanhang. Vidare diskuteras de metodologiska konsekvenserna av det biopolitiska perspektivet, d.v.s. vilka typer av frågor som blir relevanta att ställa och hur dessa kan beforskas.
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| 4. |
- Hellberg, Sofie, 1979, et al.
(författare)
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Sustaining the life-chance divide? Education for sustainable development and the global biopolitical regime
- 2018
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Ingår i: Critical Studies in Education. - : Informa UK Limited. - 1750-8487 .- 1750-8495. ; 59:1, s. 93-107
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Tidskriftsartikel (refereegranskat)abstract
- What is being sustained in education for sustainable development (ESD)? Drawing on biopolitical theory, this article puts forth the hypothesis that it is in fact the very life-chance gulf that separates wealthy ‘sustainable’ mass consumers from poor ‘sustainable’ subsistence-level populations. Hence, in sharp contrast to the cosmopolitan buzz that characterizes the international policy discourse on ESD, it is argued that ESD feeds into the global life-chance divide as it prepares different populations for entirely different lives and lifestyles. In previous research that has dealt with global aspects of ESD, a dividing line can be drawn between scholars who emphasize tendencies towards neoliberal homogenization and those who highlight contingency, local re-articulations and spaces of contestation. This paper offers a third theoretical position that while sharing a deep unease with global neoliberal government is primarily concerned with its ‘will to divide’. As a corollary of this biopolitical perspective, the paper makes a case for critical empirical research that can lay bare the cracks and contradictions in the grand narrative of ESD as a cosmopolitan ethical enterprise.
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| 5. |
- Knutsson, Sofie, et al.
(författare)
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N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
- 2017
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 134, s. 415-427
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Tidskriftsartikel (refereegranskat)abstract
- Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N'-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.
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| 6. |
- Knutsson, Sofie, et al.
(författare)
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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:23, s. 10545-10557
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Tidskriftsartikel (refereegranskat)abstract
- Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
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| 7. |
- Knutsson, Sofie, 1983-
(författare)
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Towards Mosquitocides for Prevention of Vector-Borne Infectious Diseases : discovery and Development of Acetylcholinesterase 1 Inhibitors
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diseases such as malaria and dengue impose great economic burdens and are a serious threat to public health, with young children being among the worst affected. These diseases are transmitted by mosquitoes, also called disease vectors, which are able to transmit both parasitic and viral infections. One of the most important strategies in the battle against mosquito-borne diseases is vector control by insecticides and the goal is to prevent people from being bitten by mosquitoes. Today’s vector control methods are seriously threatened by the development and spread of insecticide-resistant mosquitos warranting the search for new insecticides. This thesis has investigated the possibilities of vector control using non-covalent inhibitors targeting acetylcholinesterase (AChE); an essential enzyme present in mosquitoes as well as in humans and other mammals. A key requirement for such compounds to be considered safe and suitable for development into new public health insecticides is selectivity towards the mosquito enzyme AChE1. The work presented here is focused on AChE1 from the disease transmitting mosquitoes Anopheles gambiae (AgAChE1) and Aedes aegypti (AaAChE1), and their human (hAChE) and mouse (mAChE) counterparts. By taking a medicinal chemistry approach and utilizing high throughput screening (HTS), new chemical starting points have been identified. Analysis of the combined results of three different HTS campaigns targeting AgAChE1, AaAChE1, and hAChE allowed the identification of several mosquito-selective inhibitors and a number of compound classes were selected for further development. These compounds are non-covalent inhibitors of AChE1 and thereby work via a different mechanism compared to current anti-cholinergic insecticides, whose activity is the result of a covalent modification of the enzyme. The potency and selectivity of two compound classes have been explored in depth using a combination of different tools including design, organic synthesis, biochemical assays, protein X-ray crystallography and homology modeling. Several potent inhibitors with promising selectivity for the mosquito enzymes have been identified and the insecticidal activity of one new compound has been confirmed by in vivo experiments on mosquitoes. The results presented here contribute to the field of public health insecticide discovery by demonstrating the potential of selectively targeting mosquito AChE1 using non-covalent inhibitors. Further, the presented compounds can be used as tools to study mechanisms important in insecticide development, such as exoskeleton penetration and other ADME processes in mosquitoes.
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| 8. |
- Timm, Rainer, et al.
(författare)
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Self-cleaning and surface chemical reactions during hafnium dioxide atomic layer deposition on indium arsenide
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Atomic layer deposition (ALD) enables the ultrathin high-quality oxide layers that are central to all modern metal-oxide-semiconductor circuits. Crucial to achieving superior device performance are the chemical reactions during the first deposition cycle, which could ultimately result in atomic-scale perfection of the semiconductor-oxide interface. Here, we directly observe the chemical reactions at the surface during the first cycle of hafnium dioxide deposition on indium arsenide under realistic synthesis conditions using photoelectron spectroscopy. We find that the widely used ligand exchange model of the ALD process for the removal of native oxide on the semiconductor and the simultaneous formation of the first hafnium dioxide layer must be significantly revised. Our study provides substantial evidence that the efficiency of the self-cleaning process and the quality of the resulting semiconductor-oxide interface can be controlled by the molecular adsorption process of the ALD precursors, rather than the subsequent oxide formation.
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| 9. |
- Troian, Andrea, et al.
(författare)
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InAs-oxide interface composition and stability upon thermal oxidation and high-k atomic layer deposition
- 2018
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Ingår i: AIP Advances. - : AIP Publishing. - 2158-3226. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Defects at the interface between InAs and a native or high permittivity oxide layer are one of the main challenges for realizing III-V semiconductor based metal oxide semiconductor structures with superior device performance. Here we passivate the InAs(100) substrate by removing the native oxide via annealing in ultra-high vacuum (UHV) under a flux of atomic hydrogen and growing a stoichiometry controlled oxide (thermal oxide) in UHV, prior to atomic layer deposition (ALD) of an Al2O3 high-k layer. The semiconductor-oxide interfacial stoichiometry and surface morphology are investigated by synchrotron based X-ray photoemission spectroscopy, scanning tunneling microscopy, and low energy electron diffraction. After thermal oxide growth, we find a thin non-crystalline layer with a flat surface structure. Importantly, the InAs-oxide interface shows a significantly decreased amount of In3+, As5+, and As0 components, which can be correlated to electrically detrimental defects. Capacitance-voltage measurements confirm a decrease of the interface trap density in gate stacks including the thermal oxide as compared to reference samples. This makes the concept of a thermal oxide layer prior to ALD promising for improving device performance if this thermal oxide layer can be stabilized upon exposure to ambient air.
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| 10. |
- Yngman, Sofie, et al.
(författare)
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Surface smoothing and native oxide suppression on Zn doped aerotaxy GaAs nanowires
- 2019
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 125:2
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Tidskriftsartikel (refereegranskat)abstract
- Aerotaxy, a recently invented aerosol-based growth method for nanostructures, has been shown to hold great promise in making III-V nanowires more accessible for cheap mass-production. Aerotaxy nanowire surface structure and chemistry, however, remains unexplored, which is unfortunate since this can influence (opto)electronic properties. We investigate the surfaces of aerotaxy grown GaAs nanowires using synchrotron based high resolution X-ray photoelectron spectroscopy and high resolution atomic force microscopy. We observe that increasing the concentration of the p-type dopant diethylzinc to very high levels during nanowire growth significantly changes the surface morphology and leads to a strong suppression of native surface oxide formation. Our findings indicate that up to 1.8 monolayers of Zn are present on the nanowire surface after growth. Finally, we find that this also influences the Fermi level pinning of the surface. We suggest that Zn present on the surface after growth could play a role in the strongly hindered oxidation of the III-V compound when exposed to air. The aerotaxy nanowires generally exhibit a round cross section, while a significant smoothening of the surface morphology along the nanowire appears for very high nominal doping levels likely as a result of slight reshaping during growth in the presence of Zn. Given that surface oxide and a rough morphology can be detrimental to nanowire electrical and optical performance, the ability to reduce them as a side effect of dopant introduction will benefit future applications. Finally, the observed hindering of oxidation during air transport can allow for reliable post-growth processing in separate systems.
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