| 1. |
- Durcik, Martina, et al.
(författare)
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New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:6, s. 3968-3994
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Tidskriftsartikel (refereegranskat)abstract
- A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.
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| 2. |
- Ali, Muhammad, et al.
(författare)
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Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:5
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Tidskriftsartikel (refereegranskat)abstract
- Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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| 3. |
- Cotman, Andrej Emanuel, et al.
(författare)
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Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:2, s. 1380-1425
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Tidskriftsartikel (refereegranskat)abstract
- We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
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| 4. |
- Kola, M., et al.
(författare)
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Application of the design process in the light of the Anthropocene: A conceptual study
- 2022
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Ingår i: Science and Technology Teacher Education in the Anthropocene: Addressing Challenges in the North and South. - London : Routledge. - 9781000587326 ; , s. 97-113
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Bokkapitel (refereegranskat)abstract
- The ability to influence the environment began during the Palaeolithic as technology amplified and extended human skills from using stones as tools to lethality attainable through a pointed projectile. Technology became a progressively critical component in a system of artefacts leading to an increase in the likelihood of human survival and enabling population growth. All technology has an essential impact on society, nature and sustainability as a tool for building capacity for living and learning but also as a problem for sustaining the planet. Education is the key to awareness of the consequences of technology. The question is to what extent these environmental issues are part of the design process where technology solutions are developed in technology education today. We investigate examples of how the design process is used in technology education in South Africa and Sweden in relation to the environmental situation in the Anthropocene. What is emphasised in the technology classroom in relation to sustainability? A conclusion is that learners are not aware of the effect of their actions. The culture of recycling and reuse is a springboard for sustainability and the phenomenon, cradle-to-cradle, ought to be embraced by technology teachers in education.
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| 5. |
- Lindeman, Sofie, et al.
(författare)
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Digitalisation in early childhood education : A domestication theoretical perspective on teachers’ experiences
- 2021
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Ingår i: Education and Information Technologies. - : Springer. - 1360-2357 .- 1573-7608. ; 26:4, s. 4879-4903
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study is to increase knowledge of teachers’ understanding and experiences of using, or not using, digital tools in Early Childhood Education (ECE). The study takes a domestication theoretical approach based on interviews with twelve teachers from nine ECE institutions working with play-based learning with children aged 1–5 years from four diferent municipalities in Sweden. The study answers the following two research questions: In what ways, and to what extent, do teachers integrate digital tools in their work? What practical, symbolic or cognitive aspects afect their work with digital tools? The teachers have integrated the digital tools to diferent extent. The most useful tools for working with the children are tablets and beamers, which are devices that can be used in various ways. Digital tools used for administration are domesticated to a greater extent than the tools teachers use with the children. The study further shows that important factors in the successful domestication of digital tools in ECE include digital competence, including pedagogical aspects, in combination with personal drive and professional learning and development.
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| 6. |
- Svensson, Maria, 1969, et al.
(författare)
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Preschool teachers’ experiences of technical concepts in relation to everyday situations in the preschool.
- 2023
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Ingår i: Design and Technology Education: An International Journal. - 2040-8633. ; 28:2, s. 107-121
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Tidskriftsartikel (refereegranskat)abstract
- Communicating technological concepts in preschool is of vital importance for developing the quality of the technology teaching practice and children’s language skills within the content area. The aim of this study is to describe how preschool teachers discern technology in relation to everyday situations in preschool. The study is part of a larger practice-based research and development project focusing on language development and technology teaching practice in preschool, while simultaneously developing and trying a collaborative model between preschool teachers and researchers. The empirical data for this study is generated by semi-structured interviews with preschool teachers. Data analysis employs a phenomenographic approach. Focus is directed towards how preschool teachers experience technological concepts in everyday situations in preschool. The findings include four qualitatively different ways of experiencing technology; exploring techniques;exploring techniques using artefacts; exploring artefacts as technologyand developing constructions using artefacts.
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| 7. |
- Svensson, Maria, 1969, et al.
(författare)
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Technology Content and Concepts in Preschool Teaching–A Practice-based Collaboration.
- 2021
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Ingår i: Techne series : Research in sloyd education and crafts science. A. - Oslo : Oslo Metropolitan University. - 1238-9501 .- 1893-1774.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The purpose with the project is to develop a model for sustainable collaboration between preschool teachers and researchers with a focus on language for teaching technology in preschool. The aim is also to study how teaching can be planned and implemented such that children's opportunities to learn technology interact with the use of technical concepts. The importance of communicating a scientific language and technical words in varied situations has been shown to be important for developing the quality of technology teaching practice as well as the children’s language skills. Language research in preschool contexts is well established, however there are few studies where language and technology are combined. This study is emanating from preschool teachers' own questions about technology and language use in preschool. The project includes 12 preschool teachers, four teacher educators and researchers at a University as well as one researcher employed by a municipality. We present results from the first phase of the project which aims to explore technology content and related concepts that teachers express as relevant in preschool based on their experience. Data was collected by semi-structured qualitative, open interviews that were analyzed using a phenomenographic research approach. Focus is directed toward the technology that teachers associate with an everyday situation in preschool. We identify four qualitatively different ways of experiencing technology including exploring techniques, exploring techniques using artefacts, exploring artefacts as technology, and building and constructing with artefacts. The results also indicate that preschool teachers are aware of the importance of using subject specific concepts, however they express uncertainty about what relevant technology specific concepts are.
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