| 1. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 2. |
- Gallagher, Laura A., et al.
(författare)
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Impaired Alanine Transport or Exposure to D-Cycloserine Increases the Susceptibility of MRSA to beta-lactam Antibiotics
- 2020
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Ingår i: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 221:6, s. 1006-1016
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Tidskriftsartikel (refereegranskat)abstract
- Prolonging the clinical effectiveness of beta-lactams, which remain first-line antibiotics for many infections, is an important part of efforts to address antimicrobial resistance. We report here that inactivation of the predicted D-cycloserine (DCS) transporter gene cycA resensitized methicillin-resistant Staphylococcus aureus (MRSA) to beta-lactam antibiotics. The cycA mutation also resulted in hypersusceptibility to DCS, an alanine analogue antibiotic that inhibits alanine racemase and D-alanine ligase required for D-alanine incorporation into cell wall peptidoglycan. Alanine transport was impaired in the cycA mutant, and this correlated with increased susceptibility to oxacillin and DCS. The cycA mutation or exposure to DCS were both associated with the accumulation of muropeptides with tripeptide stems lacking the terminal D-ala-D-ala and reduced peptidoglycan cross-linking, prompting us to investigate synergism between beta-lactams and DCS. DCS resensitized MRSA to beta-lactams in vitro and significantly enhanced MRSA eradication by oxacillin in a mouse bacteremia model. These findings reveal alanine transport as a new therapeutic target to enhance the susceptibility of MRSA to beta-lactam antibiotics.
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| 3. |
- Albrecht, Lisa M.
(författare)
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Antibiotic Resistance : Selection in the Presence of Metals and Antimicrobials
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The external environment is complex: Antibiotics, metals and antimicrobials do not exist in isolation but in mixtures. Human activities such as animal husbandry, fertilization of agricultural fields and human medicine release high amounts these compounds into the environment. The work in this thesis contributes to our understanding of how the selection of bacterial antibiotic resistance can be facilitated by the pollution by metals and antimicrobials. We show that low levels of antibiotics, metals and combinations thereof can lead to the selection of chromosomally encoded antibiotic resistance genes as well as a multidrug resistance plasmid. The underlying genetic and cellular mechanisms of selection identified relate to mutational changes in a plasmid-encoded metal resistance operon, and metal-associated increases in cellular membrane permeability. We further show that exposure to quaternary ammonium compounds can result in cross-resistance to antibiotics following genetic changes in genes related to efflux, membrane synthesis and transcription/translation. Taken together, the work in this thesis suggests that the stewardship of antibiotics should include prudent use of metals and antimicrobials.
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| 4. |
- Crowe-McAuliffe, Caillan, et al.
(författare)
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Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.
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| 5. |
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| 6. |
- Liebens, Veerle R., et al.
(författare)
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Identification and characterization of an anti-pseudomonal dichlorocarbazol derivative displaying anti-biofilm activity
- 2014
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 24:23, s. 5404-5408
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomonas aeruginosa strains resistant towards all currently available antibiotics are increasingly encountered, raising the need for new anti-pseudomonal drugs. We therefore conducted a medium-throughput screen of a small-molecule collection resulting in the identification of the N-alkylated 3,6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol (MIC = 18.5 ?g mL-1). This compound, compound 1, is bacteriostatic towards a broad spectrum of Gram-positive and Gram-negative pathogens, including P. aeruginosa. Importantly, 1 also eradicates mature biofilms of P. aeruginosa. 1 displays no cytotoxicity against various human cell types, pointing to its potential for further development as a novel antibacterial drug.
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| 7. |
- Menkveld, Albert J., et al.
(författare)
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Nonstandard Errors
- 2024
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Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
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Tidskriftsartikel (refereegranskat)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 8. |
- Potts, Courtney, et al.
(författare)
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A Multilingual Digital Mental Health and Well-Being Chatbot (ChatPal): Pre-Post Multicenter Intervention Study
- 2023
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Ingår i: Journal of Medical Internet Research. - : JMIR Publications. - 1438-8871. ; 25
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Tidskriftsartikel (refereegranskat)abstract
- Background: In recent years, advances in technology have led to an influx of mental health apps, in particular the development of mental health and well-being chatbots, which have already shown promise in terms of their efficacy, availability, and accessibility. The ChatPal chatbot was developed to promote positive mental well-being among citizens living in rural areas. ChatPal is a multilingual chatbot, available in English, Scottish Gaelic, Swedish, and Finnish, containing psychoeducational content and exercises such as mindfulness and breathing, mood logging, gratitude, and thought diaries.Objective: The primary objective of this study is to evaluate a multilingual mental health and well-being chatbot (ChatPal) to establish if it has an effect on mental well-being. Secondary objectives include investigating the characteristics of individuals that showed improvements in well-being along with those with worsening well-being and applying thematic analysis to user feedback.Methods: A pre-post intervention study was conducted where participants were recruited to use the intervention (ChatPal) for a 12-week period. Recruitment took place across 5 regions: Northern Ireland, Scotland, the Republic of Ireland, Sweden, and Finland. Outcome measures included the Short Warwick-Edinburgh Mental Well-Being Scale, the World Health Organization-Five Well-Being Index, and the Satisfaction with Life Scale, which were evaluated at baseline, midpoint, and end point. Written feedback was collected from participants and subjected to qualitative analysis to identify themes.Results: A total of 348 people were recruited to the study (n=254, 73% female; n=94, 27% male) aged between 18 and 73 (mean 30) years. The well-being scores of participants improved from baseline to midpoint and from baseline to end point; however, improvement in scores was not statistically significant on the Short Warwick-Edinburgh Mental Well-Being Scale (P=.42), the World Health Organization-Five Well-Being Index (P=.52), or the Satisfaction With Life Scale (P=.81). Individuals that had improved well-being scores (n=16) interacted more with the chatbot and were significantly younger compared to those whose well-being declined over the study (P=.03). Three themes were identified from user feedback, including “positive experiences,” “mixed or neutral experiences,” and “negative experiences.” Positive experiences included enjoying exercises provided by the chatbot, while most of the mixed, neutral, or negative experiences mentioned liking the chatbot overall, but there were some barriers, such as technical or performance errors, that needed to be overcome.Conclusions: Marginal improvements in mental well-being were seen in those who used ChatPal, albeit nonsignificant. We propose that the chatbot could be used along with other service offerings to complement different digital or face-to-face services, although further research should be carried out to confirm the effectiveness of this approach. Nonetheless, this paper highlights the need for blended service offerings in mental health care.
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| 9. |
- Sweeney, Colm, et al.
(författare)
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Can Chatbots Help Support a Person’s Mental Health? Perceptions and Views from Mental Healthcare Professionals and Experts
- 2021
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Ingår i: ACM Transactions on Computing for Healthcare. - : ACM Digital Library. - 2691-1957 .- 2637-8051. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to understand the attitudes of professionals who work in mental health regarding the use of conversational user interfaces, or chatbots, to support people’s mental health and wellbeing. This study involves an online survey to measure the awareness and attitudes of mental healthcare professionals and experts. The findings from this survey show that more than half of the participants in the survey agreed that there are benefits associated with mental healthcare chatbots (65%, p < 0.01). The perceived importance of chatbots was also relatively high (74%, p < 0.01), with more than three-quarters (79%, p < 0.01) of respondents agreeing that mental healthcare chatbots could help their clients better manage their own health, yet chatbots are overwhelmingly perceived as not adequately understanding or displaying human emotion (86%, p < 0.01). Even though the level of personal experience with chatbots among professionals and experts in mental health has been quite low, this study shows that where they have been used, the experience has been mostly satisfactory. This study has found that as years of experience increased, there was a corresponding increase in the belief that healthcare chatbots could help clients better manage their own mental health.
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| 10. |
- Wilson, Daniel N., et al.
(författare)
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Target protection as a key antibiotic resistance mechanism
- 2020
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Ingår i: Nature Reviews Microbiology. - : Nature Publishing Group. - 1740-1526 .- 1740-1534. ; 18:11, s. 637-648
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Forskningsöversikt (refereegranskat)abstract
- Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways.
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| 11. |
- Yokoyama, Maho, et al.
(författare)
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Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA
- 2018
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-7596 .- 1474-760X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. Results: Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic. Conclusions: With dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information.
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| 12. |
- Niemi, MEK, et al.
(författare)
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- 2021
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