| 1. |
- Chesov, Elena, et al.
(författare)
-
Emergence of bedaquiline resistance in a high tuberculosis burden country
- 2022
-
Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 59:3
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: Bedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.Objectives: We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.Methods: In a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62 out of 203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.Measurements and main results: At baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient was re-infected with a second bedaquiline-resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline-containing regimen with WGS-predicted resistance at baseline (OR 1.92 per unit increase, 95% CI 1.15–3.21; p=0.012).Conclusions: MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.
|
|
| 2. |
- Cockell, Charles S., et al.
(författare)
-
Subsurface scientific exploration of extraterrestrial environments (MINAR 5) : analogue science, technology and education in the Boulby Mine, UK
- 2019
-
Ingår i: International Journal of Astrobiology. - : Cambridges Institutes Press. - 1473-5504 .- 1475-3006. ; 18:2, s. 157-182
-
Tidskriftsartikel (refereegranskat)abstract
- The deep subsurface of other planetary bodies is of special interest for robotic and human exploration. The subsurface provides access to planetary interior processes, thus yielding insights into planetary formation and evolution. On Mars, the subsurface might harbour the most habitable conditions. In the context of human exploration, the subsurface can provide refugia for habitation from extreme surface conditions. We describe the fifth Mine Analogue Research (MINAR 5) programme at 1 km depth in the Boulby Mine, UK in collaboration with Spaceward Bound NASA and the Kalam Centre, India, to test instruments and methods for the robotic and human exploration of deep environments on the Moon and Mars. The geological context in Permian evaporites provides an analogue to evaporitic materials on other planetary bodies such as Mars. A wide range of sample acquisition instruments (NASA drills, Small Planetary Impulse Tool (SPLIT) robotic hammer, universal sampling bags), analytical instruments (Raman spectroscopy, Close-Up Imager, Minion DNA sequencing technology, methane stable isotope analysis, biomolecule and metabolic life detection instruments) and environmental monitoring equipment (passive air particle sampler, particle detectors and environmental monitoring equipment) was deployed in an integrated campaign. Investigations included studying the geochemical signatures of chloride and sulphate evaporitic minerals, testing methods for life detection and planetary protection around human-tended operations, and investigations on the radiation environment of the deep subsurface. The MINAR analogue activity occurs in an active mine, showing how the development of space exploration technology can be used to contribute to addressing immediate Earth-based challenges. During the campaign, in collaboration with European Space Agency (ESA), MINAR was used for astronaut familiarization with future exploration tools and techniques. The campaign was used to develop primary and secondary school and primary to secondary transition curriculum materials on-site during the campaign which was focused on a classroom extra vehicular activity simulation.
|
|
| 3. |
- Escala-Garcia, Maria, et al.
(författare)
-
A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
|
|
| 4. |
- Farinotti, Daniel, et al.
(författare)
-
Results from the Ice Thickness Models Intercomparison eXperiment Phase 2 (ITMIX2)
- 2021
-
Ingår i: Frontiers in Earth Science. - : Frontiers Media S.A.. - 2296-6463. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Knowing the ice thickness distribution of a glacier is of fundamental importance for a number of applications, ranging from the planning of glaciological fieldwork to the assessments of future sea-level change. Across spatial scales, however, this knowledge is limited by the paucity and discrete character of available thickness observations. To obtain a spatially coherent distribution of the glacier ice thickness, interpolation or numerical models have to be used. Whilst the first phase of the Ice Thickness Models Intercomparison eXperiment (ITMIX) focused on approaches that estimate such spatial information from characteristics of the glacier surface alone, ITMIX2 sought insights for the capability of the models to extract information from a limited number of thickness observations. The analyses were designed around 23 test cases comprising both real-world and synthetic glaciers, with each test case comprising a set of 16 different experiments mimicking possible scenarios of data availability. A total of 13 models participated in the experiments. The results show that the inter-model variability in the calculated local thickness is high, and that for unmeasured locations, deviations of 16% of the mean glacier thickness are typical (median estimate, three-quarters of the deviations within 37% of the mean glacier thickness). This notwithstanding, limited sets of ice thickness observations are shown to be effective in constraining the mean glacier thickness, demonstrating the value of even partial surveys. Whilst the results are only weakly affected by the spatial distribution of the observations, surveys that preferentially sample the lowest glacier elevations are found to cause a systematic underestimation of the thickness in several models. Conversely, a preferential sampling of the thickest glacier parts proves effective in reducing the deviations. The response to the availability of ice thickness observations is characteristic to each approach and varies across models. On average across models, the deviation between modeled and observed thickness increase by 8.5% of the mean ice thickness every time the distance to the closest observation increases by a factor of 10. No single best model emerges from the analyses, confirming the added value of using model ensembles.
|
|
| 5. |
- Kapoor, Pooja Middha, et al.
(författare)
-
Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
-
Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
|
|
| 6. |
- Koehler, Niklas, et al.
(författare)
-
Pretomanid-resistant tuberculosis
- 2023
-
Ingår i: Journal of Infection. - : W B SAUNDERS CO LTD. - 0163-4453 .- 1532-2742. ; 86:5, s. 520-524
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 7. |
- Lindblom, Anders, et al.
(författare)
-
The intrinsic factor-vitamin B12 receptor, cubilin, is assembled into trimers via a coiled-coil alpha-helix
- 1999
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 274:10, s. 6374-6380
-
Tidskriftsartikel (refereegranskat)abstract
- A large protein was purified from bovine kidney, using selective extraction with EDTA to solubilize proteins anchored by divalent cation-dependent interactions. An antiserum raised against the purified protein labeled the apical cell surface of the epithelial cells in proximal tubules and the luminal surface of small intestine. Ten peptide sequences, derived from the protein, all matched the recently published sequences for rat (Moestrup, S. K., Kozyraki, R., Kristiansen, M., Kaysen, J. H., Holm Rasmussen, H., Brault, D., Pontillon, F., Goda, F. O., Christensen, E. I., Hammond, T. G., and Verroust, P. J. (1998) J. Biol. Chem. 273, 5235-5242) and human cubilin, a receptor for intrinsic factor-vitamin B12 complexes, identifying the protein as bovine cubilin. In electron microscopy, a three-armed structure was seen, indicating an oligomerization of three identical subunits. This model was supported by the Mr values of about 1,500,000 for the intact protein and 440,000 for its subunits obtained by analytical ultracentrifugation. In a search for a potential assembly domain, we identified a region of heptad repeats in the N-terminal part of the cubilin sequence. Computer-assisted analysis supported the presence of a coiled-coil alpha-helix between amino acids 103 and 132 of the human cubilin sequence and predicted the formation of a triple coiled-coil. We therefore conclude that cubilin forms a noncovalent trimer of identical subunits connected by an N-terminal coiled-coil alpha-helix.
|
|
| 8. |
- Maurer, Michael, et al.
(författare)
-
Toxic Activation of an AAA plus Protease by the Antibacterial Drug Cyclomarin A
- 2019
-
Ingår i: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 26:8, s. 1169-1179
-
Tidskriftsartikel (refereegranskat)abstract
- ATP-driven bacterial AAA+ proteases have been recognized as drug targets. They possess an AAA+ protein (e.g., ClpC), which threads substrate proteins into an associated peptidase (e.g., ClpP). ATPase activity and substrate selection of AAA+ proteins are regulated by adapter proteins that bind to regulatory domains, such as the N-terminal domain (NTD). The antibacterial peptide Cyclomarin A (CymA) kills Mycobacterium tuberculosis cells by binding to the NTD of ClpC. How CymA affects ClpC function is unknown. Here, we reveal the mechanism of CymA-induced toxicity. We engineered a CymA-sensitized ClpC chimera and show that CymA activates ATPase and proteolytic activities. CymA mimics adapter binding and enables autonomous protein degradation by ClpC/ClpP with relaxed substrate selectivity. We reconstitute CymA toxicity in E. coli cells expressing engineered ClpC and ClpP, demonstrating that gain of uncontrolled proteolytic activity causes cell death. This validates drug-induced overriding of AAA+ protease activity control as effective antibacterial strategy.
|
|
| 9. |
- Merker, Matthias, et al.
(författare)
-
Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex
- 2020
-
Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). Methods We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cut-off values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays.
|
|
| 10. |
- Middha, Pooja K., et al.
(författare)
-
A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
-
Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
|
|
| 11. |
- Piecha, D, et al.
(författare)
-
Matrilin-2 interacts with itself and with other extracellular matrix proteins
- 2002
-
Ingår i: Biochemical Journal. - 0264-6021. ; 367:3, s. 715-721
-
Tidskriftsartikel (refereegranskat)abstract
- Matrilin-2 is a component of extracellular filamentous networks. To study the interactions by which it can be integrated into such assemblies, full-length and truncated forms of matrilin-2 were recombinantly expressed in HEK-293 cells and purified from conditioned medium. The recombinant proteins, when used in interaction assays, showed affinity to matrilin-2 itself, but also to other collagenous and non-collagenous extracellular matrix proteins. The interaction between matrilin-2 and collagen I was studied in greater detail and could be shown to occur at distinct sites on the collagen I molecule and to have a K-D of about 3 x 10(-8) M. Interactions with some non-collagenous protein ligands were even stronger, with matrilin-2 binding to fibrillin-2, fibronectin and laminin-1-nidogen-1 complexes, with K-D values in the range of 10(-8)-10(-11) M. Co-localization of matrilin-2 with these ligands in the dermal-epidermal basement membrane, in the microfibrils extending from the basement membrane into the dermis, and in the dermal extracellular matrix, indicates a physiological relevance of the interactions in the assembly of supramolecular extracellular matrix structures.
|
|
| 12. |
- Pihlajamaa, T, et al.
(författare)
-
Characterization of recombinant amino-terminal NC4 domain of human collagen IX - Interaction with glycosaminoglycans and cartilage oligomeric matrix protein
- 2004
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 279:23, s. 24265-24273
-
Tidskriftsartikel (refereegranskat)abstract
- The N-terminal NC4 domain of collagen IX is a globular structure projecting away from the surface of the cartilage collagen fibril. Several interactions have been suggested for this domain, reflecting its location and its characteristic high isoelectric point. In an attempt to characterize the NC4 domain in more detail, we set up a prokaryotic expression system to produce the domain. The purified 27.5-kDa product was analyzed for its glycosaminoglycan-binding potential by surface plasmon resonance and solid-state assays. The results show that the NC4 domain of collagen IX specifically binds heparin with a K-d of 0.6 muM, and the full-length recombinant collagen IX has an even stronger interaction with heparin, with an apparent K-d of 3.6 nM. The heparin-binding site of the NC4 domain was located in the extreme N terminus, containing a heparin-binding consensus sequence, whereas electron microscopy suggested the presence of at least three additional heparin-binding sites on full-length collagen IX. The NC4 domain was also shown to bind cartilage oligomeric matrix protein. This interaction and the association of cartilage oligomeric matrix protein with other regions of collagen IX were found to be heparin-competitive. Circular dichroism analyses of the NC4 domain indicated the presence of stabilizing disulfide bonds and a thermal denaturation point of about 80degreesC. The pattern of disulfide bond formation within the NC4 domain was identified by tryptic peptide mass mapping of the NC4 in native and reduced states. A similar pattern was demonstrated for the NC4 domain of full-length recombinant collagen IX.
|
|
| 13. |
-
Proceedings of the 9th International DSM Conference : Munich: 16 - 18 October 2007
- 2007
-
Proceedings (redaktörskap) (refereegranskat)abstract
- The proceedings contain 33 PowerPoint presentations. The topics discussed include: from product/service complexity management to innovation; managing complexity in automotive engineering; social network techniques applied to design structure matrix analysis. the case of a new engine development at Ferrari SpA; analyzing core competence and core products for developing agile and adaptable corporation; analyzing communication dependencies in product development using the design structure matrix; benefits derived from use of DSM as part of the ADePT approach to managing engineering projects; DMM partitioning analysis for design study procedure optimization; a simulation model to predict impacts of alterations in development processes; the projection relationship between object process models (OPM) and design system matrices (DSM); and function driven process design for the development of mechatronic systems.
|
|
