| 1. |
- Chamoun, Sherley, et al.
(författare)
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Colistin Dependence in Extensively Drug-Resistant Acinetobacter baumannii Strain Is Associated with ISAjo2 and ISAba13 Insertions and Multiple Cellular Responses
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- The nosocomial opportunistic Gram-negative bacterial pathogen Acinetobacter baumannii is resistant to multiple antimicrobial agents and an emerging global health problem. The polymyxin antibiotic colistin, targeting the negatively charged lipid A component of the lipopolysaccharide on the bacterial cell surface, is often considered as the last-resort treatment, but resistance to colistin is unfortunately increasing worldwide. Notably, colistin-susceptible A. baumannii can also develop a colistin dependence after exposure to this drug in vitro. Colistin dependence might represent a stepping stone to resistance also in vivo. However, the mechanisms are far from clear. To address this issue, we combined proteogenomics, high-resolution microscopy, and lipid profiling to characterize and compare A. baumannii colistin-susceptible clinical isolate (Ab-S) of to its colistin-dependent subpopulation (Ab-D) obtained after subsequent passages in moderate colistin concentrations. Incidentally, in the colistin-dependent subpopulation the lpxA gene was disrupted by insertion of ISAjo2, the lipid A biosynthesis terminated, and Ab-D cells displayed a lipooligosaccharide (LOS)-deficient phenotype. Moreover, both mlaD and pldA genes were perturbed by insertions of ISAjo2 and ISAba13, and LOS-deficient bacteria displayed a capsule with decreased thickness as well as other surface imperfections. The major changes in relative protein abundance levels were detected in type 6 secretion system (T6SS) components, the resistance-nodulation-division (RND)-type efflux pumps, and in proteins involved in maintenance of outer membrane asymmetry. These findings suggest that colistin dependence in A. baumannii involves an ensemble of mechanisms seen in resistance development and accompanied by complex cellular events related to insertional sequences (ISs)-triggered LOS-deficiency. To our knowledge, this is the first study demonstrating the involvement of ISAjo2 and ISAba13 IS elements in the modulation of the lipid A biosynthesis and associated development of dependence on colistin.
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| 2. |
- Ballante, Flavio, et al.
(författare)
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Modified N-acyl-L-homoserine lactone compounds abrogate Las-dependent quorum-sensing response in human pathogen Pseudomonas aeruginosa
- 2023
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Ingår i: Frontiers in Molecular Biosciences. - : FRONTIERS MEDIA SA. - 2296-889X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quorum sensing (QS) is a mode of cell-cell communication that bacteria use to sense population density and orchestrate collective behaviors. The common opportunistic human pathogen Pseudomonas aeruginosa employs QS to regulate a large set of genes involved in virulence and host-pathogen interactions. The Las circuit positioned on the top of the QS hierarchy in P. aeruginosa makes use of N-acyl-L-homoserine lactones (AHLs) as signal molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL). Disabling QS circuits by certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), has been proposed as a strategy to attenuate bacterial pathogenicity. In this study, four new AHL analogs were designed by incorporating a tert-butoxycarbonyl Boc group in amide and beta-keto (3-oxo) moiety. Compounds were evaluated on a molecular and phenotypic basis as a QSI using the screening strategy linked to the assignment of the Las QS system in P. aeruginosa. Using a LasR-based bioreporter, we found that the compounds decreased LasR-controlled light activity and competed efficiently with natural 3O-C12-HSL. The compounds reduced the production of the cognate 3O-C12-HSL and certain virulence traits, like total protease activity, elastase activity, pyocyanin production, and extracellular DNA release. Furthermore, a quantitative proteomic approach was used to study the effect of the compounds on QS-regulated extracellular proteins. Among the four compounds tested, one of them showed the most significant difference in the appearance of the 3O-C12-HSL-responsive reference proteins related to QS communication and virulence, i.e., a distinct activity as a QSI. Moreover, by combining experimental data with computational chemistry, we addressed the effect of LasR protein flexibility on docking precision and assessed the advantage of using a multi-conformational docking procedure for binding mode prediction of LasR modulators. Thus, the four new AHL compounds were tested for their interaction with the AHL-binding site in LasR to identify the key interferences with the activity of LasR. Our study provides further insight into molecular features that are required for small-molecule modulation of LasR-dependent QS communication in P. aeruginosa. This should facilitate rational design of the next generation of antivirulence tools to study and manipulate QS-controlled fitness in bacteria and, thereby, handle bacterial infections in a new way.
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| 3. |
- Josephson, Henrik, et al.
(författare)
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Pseudomonas aeruginosa N-3-Oxo-Dodecanoyl-Homoserine Lactone Impacts Mitochondrial Networks Morphology, Energetics, and Proteome in Host Cells
- 2020
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Ingår i: Frontiers in Microbiology. - : FRONTIERS MEDIA SA. - 1664-302X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria play crucial roles in cellular metabolism, signaling, longevity, and immune defense. Recent evidences have revealed that the host microbiota, including bacterial pathogens, impact mitochondrial behaviors and activities in the host. The pathogenicity of Pseudomonas aeruginosa requires quorum sensing (QS) cell-cell communication allowing the bacteria to sense population density and collectively control biofilm development, virulence traits, adaptation and interactions with the host. QS molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C-12-HSL), can also modulate the behavior of host cells, e.g., epithelial barrier properties and innate immune responses. Here, in two types of cells, fibroblasts and intestinal epithelial cells, we investigated whether and how P. aeruginosa 3O-C-12-HSL impacts the morphology of mitochondrial networks and their energetic characteristics, using high-resolution transmission electron microscopy, fluorescence live-cell imaging, assay for mitochondrial bioenergetics, and quantitative mass spectrometry for mitoproteomics and bioinformatics. We found that 3O-C-12-HSL induced fragmentation of mitochondria, disruption of cristae and inner membrane ultrastructure, altered major characteristics of respiration and energetics, and decreased mitochondrial membrane potential, and that there are distinct cell-type specific details of these effects. Moreover, this was mechanistically accompanied by differential expression of both common and cell-type specific arrays of components in the mitochondrial proteome involved in their structural organization, electron transport chain complexes and response to stress. We suggest that this effect of 3O-C-12-HSL on mitochondria may represent one of the events in the interaction between P. aeruginosa and host mitochondria and may have an impact on the pathogens strategy to hijack host cell activities to support their own survival and spreading.
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| 4. |
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| 5. |
- Aldrin, Emilia, 1982-, et al.
(författare)
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Socioonomastiska perspektiv på personnamn, djurnamn och företagsnamn : fem smärre studier
- 2017
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Ingår i: Ortnamnssällskapet i Uppsala årsskrift. - Uppsala : Ortnamnssällskapet i Uppsala. - 0473-4351. ; , s. 5-13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This article presents five undergraduate dissertations in socio-onomastics written by students from Halmstad University in 2016 and presented during a visit to the Department of Scandinavian Languages, Scandinavian Onomastics, at Uppsala University in 2017. Two of the dissertations deal with personal names (a social constructionist approach to personal names in children’s literature, and perceptions of name and identity among senior citizens). Two others focus on animal names in contemporary times (a gender analysis of names of horses, and a comparative analysis of names within different dog breeds). The last undergraduate dissertation concerns the process of naming companies.
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| 6. |
- Arriola, Edurne, et al.
(författare)
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Feasibility and User Experience of Digital Patient Monitoring for Real-World Patients With Lung or Breast Cancer
- 2024
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Ingår i: The Oncologist. - : OXFORD UNIV PRESS. - 1083-7159 .- 1549-490X. ; 29:4, s. e561-e569
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Tidskriftsartikel (refereegranskat)abstract
- Background Digital patient monitoring (DPM) tools can facilitate early symptom management for patients with cancer through systematic symptom reporting; however, low adherence can be a challenge. We assessed patient/healthcare professional (HCP) use of DPM in routine clinical practice.Materials and Methods Patients with locally advanced/metastatic lung cancer or HER2-positive breast cancer received locally approved/reimbursed drugs alongside DPM, with elements tailored by F. Hoffmann-La Roche Ltd, on the Kaiku Health DPM platform. Patient access to the DPM tool was through their own devices (eg, laptops, PCs, smartphones, or tablets), via either a browser or an app on Apple iOS or Android devices. Coprimary endpoints were patient DPM tool adoption (positive threshold: 60%) and week 1-6 adherence to weekly symptom reporting (positive threshold: 70%). Secondary endpoints included experience and clinical impact.Results At data cutoff (June 9, 2022), adoption was 85% and adherence was 76%. Customer satisfaction and effort scores for patients were 76% and 82%, respectively, and 83% and 79% for HCPs. Patients spent approximately 10 minutes using the DPM tool and completed approximately 1.0 symptom questionnaires per week (completion time 1-4 minutes). HCPs spent approximately 1-3 minutes a week using the tool per patient. Median time to HCP review for alerted versus non-alerted symptom questionnaires was 19.6 versus 21.5 hours. Most patients and HCPs felt that the DPM tool covered/mostly covered symptoms experienced (71% and 75%), was educational (65% and 92%), and improved patient-HCP conversations (70% and 83%) and cancer care (51% and 71%).Conclusion The DPM tool demonstrated positive adoption, adherence, and user experience for patients with lung/breast cancer, suggesting that DPM tools may benefit clinical cancer care. Digital patient monitoring tools can facilitate early symptom monitoring and management for cancer through systematic symptom reporting; however, low adherence can be a challenge. This study assessed patient and healthcare professional use of such tools in routine clinical practice.
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| 7. |
- Aspholm-Hurtig, Marina, et al.
(författare)
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Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
- 2004
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 305:5683, s. 519-22
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Tidskriftsartikel (refereegranskat)abstract
- Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.
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| 8. |
- Carlman, Peter, 1976-, et al.
(författare)
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Let the Right One in : Sports Leaders’ Shared Experiences of Including Refugee Girls and Boys in Sports Clubs
- 2020
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Ingår i: International Journal for Research on Extended Education. - : Verlag Barbara Budrich. - 2196-3673 .- 2196-7423. ; 8:1, s. 36-51
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Tidskriftsartikel (refereegranskat)abstract
- his study investigated how gender and sports capital are expressed in sports leaders’ talk about sports for young people with a refugee background. Empirical data were derived from four focus group interviews representing 21 sports club leaders in Sweden. The leaders defined boys and girls as distinct groups but also as groups within which there are differences. Compared with the boys, the girls were presented with lesser possibilities to participate in sports. According to the leaders, the differences in the group of girls rested on that the sports culture in the girls’ country of origin, which may be more or less permissive for girls to be engaged in sports, whereas differences within the group of boys were understood in terms of bodies and mentalities
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| 9. |
- Carlman, Peter, 1976-, et al.
(författare)
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Låt den rätte komma in : Idrottsledares tal om inkludering av flickor och pojkar med flyktingbakgrund
- 2019
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- IntroduktionBland politiker i Europa finns en stark tilltro till idrotten som en integrationsarena (Agergaard, 2018). Elling och Knoppers (2005) menar att idrott inte enbart fungerar som en integrationsarena utan också kan bidra till exkludering och diskriminering, eftersom tillgängligheten till idrott påverkas av normativa föreställningar om genus och etnicitet. Med stöd av Smith, Spaaij och McDonald (2018) menar vi att idrottsledare har en stor betydelse för att skapa strukturer som möjliggör inkludering av deltagare med flyktingbakgrund. Syfte och teoretisk ramStudiens syfte är att undersöka hur genus och idrottskapital kommer till uttryck i idrottsledares tal om inkludering av unga med flyktingbakgrund. Studiens teoretiska referensram har utgångspunkt i Bourdieus (Bourdieu & Wacquant, 1992) begrepp kapital och Connells (1995) perspektiv på femininitet och maskulinitet.MetodStudien bygger på preliminära analyser av fyra fokusgruppsintervjuer med 21 föreningsledare (2 x 6, 1 x 5, 1 x 4) från 19 idrottsföreningar (två föreningar önskade att komma med två representanter). ResultatI ledarnas diskussioner kom det till uttryck att flickor och pojkar har med sig olika idrottskapital när de kommer till Sverige, och är mer eller mindre lämpliga för att kunna delta i den organiserade föreningsidrotten. Flickorna beskrevs i hög grad som en grupp som hade väldigt lite erfarenhet av idrott och fysisk aktivitet och som saknade idrottsliga förmågor. Men även pojkar beskrevs i avsaknad av idrottskapital, i meningen förståelse av själva organiseringen av idrotten. Ledarna beskrev pojkar och flickor som distinkta grupper men också som grupper inom vilka det finns skillnader. Skillnaden mellan flickor beskrevs vara en följd av att kultur och traditioner i deras ursprungsländer kan vara mer eller mindre tillåtande i synen på flickor som idrottande subjekt. Även pojkarna som idrottande subjekt relaterades till deras ursprungsländer, men då främst i meningen att deras ursprung kunde förklara upplevda kroppsliga och mentala skillnader inom gruppen pojkar. ”95% är ju väldigt klena i kroppen, så de har ju liksom inte, de väger ju ingenting. I en närkamp när de började spela mot de svenska, äldre gubbarna så gjorde de bara så här, så flög de ju.” ”Ja det är allihop i stort sett, de här nerifrån Somalia och Eritrea” ”Ja där har du sugrör och så mot en afghan, där har du liksom ett riktigt dynamithuvud. Det är ju jättestor skillnad.” Diskussion och slutsatserStudien visar både på stereotypa föreställningar om flickor och pojkar och föreställningar om variationer inom dessa grupper. Resultat pekar på en vanligt förekommande och stereotyp bild av flickor med migrationsbakgrund som icke idrottare och som underrepresenterade i organiserad idrott. Givet att pojkar med migrationsbakgrund är väl representerade i föreningsidrotten (se exempelvis Strandbu et al., 2017) finns en risk att förbise att vissa pojkar eller grupper av pojkar kan stå utanför eller i högre omfattning slutar med idrott. Med stöd av Connells (1995) teori om den hierarkiska relationen mellan olika maskulinitetspositioner, menar vi att de fysiskt svaga pojkarna positioneras som underordnade i ledarnas tal. I vidare forskning skulle det vara förtjänstfullt att fördjupa kunskapen om vilka pojkar som inkluderas och vilka som exkluderas i skilda idrottskontexter.
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| 10. |
- Daleke-Schermerhorn, Maria H., et al.
(författare)
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Decoration of Outer Membrane Vesicles with Multiple Antigens by Using an Autotransporter Approach
- 2014
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Ingår i: Applied and Environmental Microbiology. - 0099-2240 .- 1098-5336. ; 80:18, s. 5854-5865
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Tidskriftsartikel (refereegranskat)abstract
- Outer membrane vesicles (OMVs) are spherical nanoparticles that naturally shed from Gram-negative bacteria. They are rich in immunostimulatory proteins and lipopolysaccharide but do not replicate, which increases their safety profile and renders them attractive vaccine vectors. By packaging foreign polypeptides in OMVs, specific immune responses can be raised toward heterologous antigens in the context of an intrinsic adjuvant. Antigens exposed at the vesicle surface have been suggested to elicit protection superior to that from antigens concealed inside OMVs, but hitherto robust methods for targeting heterologous proteins to the OMV surface have been lacking. We have exploited our previously developed hemoglobin protease (Hbp) autotransporter platform for display of heterologous polypeptides at the OMV surface. One, two, or three of the Mycobacterium tuberculosis antigens ESAT6, Ag85B, and Rv2660c were targeted to the surface of Escherichia coli OMVs upon fusion to Hbp. Furthermore, a hypervesiculating Delta tolR Delta tolA derivative of attenuated Salmonella enterica serovar Typhimurium SL3261 was generated, enabling efficient release and purification of OMVs decorated with multiple heterologous antigens, exemplified by the M. tuberculosis antigens and epitopes from Chlamydia trachomatis major outer membrane protein (MOMP). Also, we showed that delivery of Salmonella OMVs displaying Ag85B to antigen-presenting cells in vitro results in processing and presentation of an epitope that is functionally recognized by Ag85B-specific T cell hybridomas. In conclusion, the Hbp platform mediates efficient display of (multiple) heterologous antigens, individually or combined within one molecule, at the surface of OMVs. Detection of antigen-specific immune responses upon vesicle-mediated delivery demonstrated the potential of our system for vaccine development.
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