| 1. |
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| 2. |
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| 3. |
- Power, M. J., et al.
(författare)
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Changes in fire regimes since the Last Glacial Maximum : an assessment based on a global synthesis and analysis of charcoal data
- 2008
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Ingår i: Climate Dynamics. - : Springer Science and Business Media LLC. - 0930-7575 .- 1432-0894. ; 30:7-8, s. 887-907
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Tidskriftsartikel (refereegranskat)abstract
- Fire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ∼11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ∼19,000 to ∼17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ∼13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ∼3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load.
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| 4. |
- Agirre, Jon, et al.
(författare)
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The CCP4 suite: integrative software for macromolecular crystallography
- 2023
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Ingår i: Acta Crystallographica Section D. - : INT UNION CRYSTALLOGRAPHY. - 2059-7983. ; 79, s. 449-461
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Tidskriftsartikel (refereegranskat)abstract
- The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.
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| 5. |
- Daniau, A. -L, et al.
(författare)
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predictability of biomass burning in response to climate changes
- 2012
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 26, s. GB4007-
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Tidskriftsartikel (refereegranskat)abstract
- Climate is an important control on biomass burning, but the sensitivity of fire to changes in temperature and moisture balance has not been quantified. We analyze sedimentary charcoal records to show that the changes in fire regime over the past 21,000 yrs are predictable from changes in regional climates. Analyses of paleo-fire data show that fire increases monotonically with changes in temperature and peaks at intermediate moisture levels, and that temperature is quantitatively the most important driver of changes in biomass burning over the past 21,000 yrs. Given that a similar relationship between climate drivers and fire emerges from analyses of the interannual variability in biomass burning shown by remote-sensing observations of month-by-month burnt area between 1996 and 2008, our results signal a serious cause for concern in the face of continuing global warming.
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| 6. |
- Trondman, Anna-Kari, et al.
(författare)
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Pollen-based quantitative reconstructions of Holocene regional vegetation cover (plant-functional types and land-cover types) in Europe suitable for climate modelling
- 2015
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 21:2, s. 676-697
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Tidskriftsartikel (refereegranskat)abstract
- We present quantitative reconstructions of regional vegetation cover in north-western Europe, western Europe north of the Alps, and eastern Europe for five time windows in the Holocene [around 6k, 3k, 0.5k, 0.2k, and 0.05k calendar years before present (bp)] at a 1 degrees x1 degrees spatial scale with the objective of producing vegetation descriptions suitable for climate modelling. The REVEALS model was applied on 636 pollen records from lakes and bogs to reconstruct the past cover of 25 plant taxa grouped into 10 plant-functional types and three land-cover types [evergreen trees, summer-green (deciduous) trees, and open land]. The model corrects for some of the biases in pollen percentages by using pollen productivity estimates and fall speeds of pollen, and by applying simple but robust models of pollen dispersal and deposition. The emerging patterns of tree migration and deforestation between 6k bp and modern time in the REVEALS estimates agree with our general understanding of the vegetation history of Europe based on pollen percentages. However, the degree of anthropogenic deforestation (i.e. cover of cultivated and grazing land) at 3k, 0.5k, and 0.2k bp is significantly higher than deduced from pollen percentages. This is also the case at 6k in some parts of Europe, in particular Britain and Ireland. Furthermore, the relationship between summer-green and evergreen trees, and between individual tree taxa, differs significantly when expressed as pollen percentages or as REVEALS estimates of tree cover. For instance, when Pinus is dominant over Picea as pollen percentages, Picea is dominant over Pinus as REVEALS estimates. These differences play a major role in the reconstruction of European landscapes and for the study of land cover-climate interactions, biodiversity and human resources.
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| 7. |
- Fyfe, Ralph M., et al.
(författare)
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The Holocene vegetation cover of Britain and Ireland : overcoming problems of scale and discerning patterns of openness
- 2013
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 73, s. 132-148
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Tidskriftsartikel (refereegranskat)abstract
- The vegetation of Europe has undergone substantial changes during the course of the Holocene epoch, resulting from range expansion of plants following climate amelioration, competition between taxa and disturbance through anthropogenic activities. Much of the detail of this pattern is understood from decades of pollen analytical work across Europe, and this understanding has been used to address questions relating to vegetation-climate feedback, biogeography and human impact. Recent advances in modelling the relationship between pollen and vegetation now make it possible to transform pollen proportions into estimates of vegetation cover at both regional and local spatial scales, using the Landscape Reconstruction Algorithm (LRA), i.e. the REVEALS (Regional Estimates of VEgetation Abundance from Large Sites) and the LOVE (Local VEgetation) models. This paper presents the compilation and analysis of 73 pollen stratigraphies from the British Isles, to assess the application of the LRA and describe the pattern of landscape/woodland openness (i.e. the cover of low herb and bushy vegetation) through the Holocene. The results show that multiple small sites can be used as an effective replacement for a single large site for the reconstruction of regional vegetation cover. The REVEALS vegetation estimates imply that the British Isles had a greater degree of landscape/woodland openness at the regional scale than areas on the European mainland. There is considerable spatial bias in the British Isles dataset towards wetland areas and uplands, which may explain higher estimates of landscape openness compared with Europe. Where multiple estimates of regional vegetation are available from within the same region inter-regional differences are greater than intra-regional differences, supporting the use of the REVEALS model to the estimation of regional vegetation from pollen data. (C) 2013 Elsevier Ltd. All rights reserved.
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| 8. |
- Montanier, Cedric, et al.
(författare)
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The Active Site of a Carbohydrate Esterase Displays Divergent Catalytic and Noncatalytic Binding Functions
- 2009
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 7:3, s. 687-697
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Tidskriftsartikel (refereegranskat)abstract
- Multifunctional proteins, which play a critical role in many biological processes, have typically evolved through the recruitment of different domains that have the required functional diversity. Thus the different activities displayed by these proteins are mediated by spatially distinct domains, consistent with the specific chemical requirements of each activity. Indeed, current evolutionary theory argues that the colocalization of diverse activities within an enzyme is likely to be a rare event, because it would compromise the existing activity of the protein. In contrast to this view, a potential example of multifunctional recruitment into a single protein domain is provided by CtCel5C-CE2, which contains an N-terminal module that displays cellulase activity and a C-terminal module, CtCE2, which exhibits a noncatalytic cellulose-binding function but also shares sequence identity with the CE2 family of esterases. Here we show that, unlike other CE2 members, the CtCE2 domain displays divergent catalytic esterase and noncatalytic carbohydrate binding functions. Intriguingly, these diverse activities are housed within the same site on the protein. Thus, a critical component of the active site of CtCE2, the catalytic Ser-His dyad, in harness with inserted aromatic residues, confers noncatalytic binding to cellulose whilst the active site of the domain retains its esterase activity. CtCE2 catalyses deacetylation of noncellulosic plant structural polysaccharides to deprotect these substrates for attack by other enzymes. Yet it also acts as a cellulose-binding domain, which promotes the activity of the appended cellulase on recalcitrant substrates. The CE2 family encapsulates the requirement for multiple activities by biocatalysts that attack challenging macromolecular substrates, including the grafting of a second, powerful and discrete noncatalytic binding functionality into the active site of an enzyme. This article provides a rare example of "gene sharing,'' where the introduction of a second functionality into the active site of an enzyme does not compromise the original activity of the biocatalyst.
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| 9. |
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| 10. |
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| 11. |
- Fontani, F., et al.
(författare)
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Magnetically regulated fragmentation of a massive, dense, and turbulent clump
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 593
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Tidskriftsartikel (refereegranskat)abstract
- © ESO, 2016. Massive stars, multiple stellar systems, and clusters are born of the gravitational collapse of massive, dense, gaseous clumps, and the way these systems form strongly depends on how the parent clump fragments into cores during collapse. Numerical simulations show that magnetic fields may be the key ingredient in regulating fragmentation. Here we present ALMA observations at ∼ 0.25′′ resolution of the thermal dust continuum emission at ∼ 278 GHz towards a turbulent, dense, and massive clump, IRAS 16061-5048c1, in a very early evolutionary stage. The ALMA image shows that the clump has fragmented into many cores along a filamentary structure. We find that the number, the total mass, and the spatial distribution of the fragments are consistent with fragmentation dominated by a strong magnetic field. Our observations support the theoretical prediction that the magnetic field plays a dominant role in the fragmentation process of massive turbulent clumps.
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| 12. |
- Kleywegt, G J, et al.
(författare)
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Pound-wise but penny-foolish: How well do micromolecules fare in macromolecular refinement ?
- 2003
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Ingår i: Structure. ; 11, s. 1051-1059
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Forskningsöversikt (populärvet., debatt m.m.)abstract
- For the refinement of protein and nucleic acid structures, high-quality geometric restraint libraries are available. Unfortunately, for other compounds, such as physiological ligands, lead compounds, substrate analogs, etc., the situation is not as favorable. As a result, the structures of small molecules found in complexes with biomacromolecules are often less reliable than those of the surrounding amino or nucleic acids. Here, we briefly review the use of geometric restraints in structure refinement (be it against X-ray crystallographic or NMR-derived data) and simulation. In addition, we discuss methods to generate both restraint libraries and (idealized) coordinates for small molecules and provide some practical advice.
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| 13. |
- Larsson, Andreas, et al.
(författare)
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Quantitative studies of the binding of the class II PapG adhesin from uropathogenic Escherichia coli to oligosaccharides.
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 11:10, s. 2255-2261
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Tidskriftsartikel (refereegranskat)abstract
- Binding of the class II PapG adhesin, found at the tip of filamentous pili on Escherichia coli, to the carbohydrate moiety of globoseries glycolipids in the human kidney is a key step in development of pyelonephritis, a severe form of urinary tract infection. An assay based on surface plasmon resonance for quantification of the binding of the class II PapG adhesin to oligosaccharides has been developed. Using this assay dissociation constants ranging from 80 to 540 M were determined for binding of the PapG adhesin to di-pentasaccharide fragments from the globoseries of glycolipids. A series of galabiose derivatives, modified at the anomeric position, O-2′ or O-3′, was also investigated. The anomeric position appeared to be the most promising for development of improved inhibitors of PapG-mediated adhesion of E. coli. p-Methoxyphenyl galabioside was found to be most potent (Kd=140 M), and binds to PapG almost as well as the Forssman pentasaccharide.
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| 14. |
- Nguyen, Dan D., et al.
(författare)
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Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease
- 2023
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 81:17, s. 1697-1709
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial.METHODS: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure.RESULTS: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged $75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29).CONCLUSIONS: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients.
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| 15. |
- Bodger, K., et al.
(författare)
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Altered colonic glycoprotein expression in unaffected monozygotic twins of inflammatory bowel disease patients
- 2006
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 55:7, s. 973-977
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose beta1, 3 N-acetylgalactosamine alpha-), among the same IBD twins. MATERIALS AND METHODS: Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn's disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor kappaB (NFkappaB) activation with investigators blinded to the diagnosis. RESULTS: Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p<0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NFkappaB was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p=0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NFkappaB. CONCLUSIONS: Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect "preinflammatory" NFkappaB activation.
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| 16. |
- de Jong, R, et al.
(författare)
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Climate and Peatlands
- 2010
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Ingår i: Changing Climates, Earth Systems, and Society. - 9789048187157 - 9789048187164 ; , s. 85-122
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 17. |
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| 18. |
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| 19. |
- Greene, Sarah E., et al.
(författare)
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Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic Escherichia coli
- 2014
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Ingår i: mBio. - 2161-2129 .- 2150-7511. ; 5:6, s. UNSP e02038-
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Tidskriftsartikel (refereegranskat)abstract
- Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240's inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.
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| 20. |
- Marquer, Laurent, et al.
(författare)
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Holocene changes in vegetation composition in northern Europe: why quantitative pollen-based vegetation reconstructions matter
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 90, s. 199-216
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Tidskriftsartikel (refereegranskat)abstract
- We present pollen-based reconstructions of the spatio-temporal dynamics of northern European regional vegetation abundance through the Holocene. We apply the Regional Estimates of VEgetation Abundance from Large Sites (REVEALS) model using fossil pollen records from eighteen sites within five modern biomes in the region. The eighteen sites are classified into four time-trajectory types on the basis of principal components analysis of both the REVEALS-based vegetation estimates (RVs) and the pollen percentage (PPs). The four trajectory types are more clearly separated for RVs than PPs. Further, the timing of major Holocene shifts, rates of compositional change, and diversity indices (turnover and evenness) differ between RVs and PPs. The differences are due to the reduction by REVEALS of biases in fossil pollen assemblages caused by different basin size, and inter-taxonomic differences in pollen productivity and dispersal properties. For example, in comparison to the PPs, the RVs show an earlier increase in Corylus and Ulmus in the early-Holocene and a more pronounced increase in grassland and deforested areas since the mid-Holocene. The results suggest that the influence of deforestation and agricultural activities on plant composition and abundance from Neolithic times was stronger than previously inferred from PPs. Relative to PPs, RVs show a more rapid compositional change, a largest decrease in turnover, and less variable evenness in most of northern Europe since 5200 cal yr BP. All these changes are primarily related to the strong impact of human activities on the vegetation. This study demonstrates that RV-based estimates of diversity indices, timing of shifts, and rates of change in reconstructed vegetation provide new insights into the timing and magnitude of major human distribution on Holocene regional, vegetation, feature that are critical in the assessment of human impact on vegetation, land-cover, biodiversity, and climate in the past. (C) Elsevier Ltd.All tights reserved.
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| 21. |
- Marquer, Laurent, et al.
(författare)
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Quantifying the effects of land use and climate on Holocene vegetation in Europe
- 2017
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Ingår i: Quaternary Science Reviews. - : Pergamon Press. - 0277-3791 .- 1873-457X. ; 171, s. 20-37
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Tidskriftsartikel (refereegranskat)abstract
- Early agriculture can be detected in palaeovegetation records, but quantification of the relative importance of climate and land use in influencing regional vegetation composition since the onset of agriculture is a topic that is rarely addressed. We present a novel approach that combines pollen-based REVEALS estimates of plant cover with climate, anthropogenic land-cover and dynamic vegetation modelling results. This is used to quantify the relative impacts of land use and climate on Holocene vegetation at a sub-continental scale, i.e. northern and western Europe north of the Alps. We use redundancy analysis and variation partitioning to quantify the percentage of variation in vegetation composition explained by the climate and land-use variables, and Monte Carlo permutation tests to assess the statistical significance of each variable. We further use a similarity index to combine pollen based REVEALS estimates with climate-driven dynamic vegetation modelling results. The overall results indicate that climate is the major driver of vegetation when the Holocene is considered as a whole and at the sub-continental scale, although land use is important regionally. Four critical phases of land-use effects on vegetation are identified. The first phase (from 7000 to 6500 BP) corresponds to the early impacts on vegetation of farming and Neolithic forest clearance and to the dominance of climate as a driver of vegetation change. During the second phase (from 4500 to 4000 BP), land use becomes a major control of vegetation. Climate is still the principal driver, although its influence decreases gradually. The third phase (from 2000 to 1500 BP) is characterised by the continued role of climate on vegetation as a consequence of late-Holocene climate shifts and specific climate events that influence vegetation as well as land use. The last phase (from 500 to 350 BP) shows an acceleration of vegetation changes, in particular during the last century, caused by new farming practices and forestry in response to population growth and industrialization. This is a unique signature of anthropogenic impact within the Holocene but European vegetation remains climatically sensitive and thus may continue to respond to ongoing climate change. (C) 2017 Elsevier Ltd. All rights reserved.
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| 22. |
- Nye, Taylor M., et al.
(författare)
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Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : PNAS. - 0027-8424 .- 1091-6490. ; 119:43
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Tidskriftsartikel (refereegranskat)abstract
- The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.
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| 23. |
- Omattage, Natalie S., et al.
(författare)
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Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli
- 2018
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Ingår i: Nature Microbiology. - : NATURE PUBLISHING GROUP. - 2058-5276. ; 3:12, s. 1362-1368
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Tidskriftsartikel (refereegranskat)abstract
- Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases(1). During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane beta-barrel translocation domain, a beta-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2)(2-6). Despite extensive structural and functional characterization, the mechanism by which the usher is activated to initiate pilus biogenesis is unknown. Here, we present the crystal structure of the full-length PapC usher from Escherichia coli in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state, elucidating molecular details of how the usher is specifically engaged by allosteric interactions with its substrate preceding activation and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly. This work elucidates the intricate workings of a molecular machine that catalyses chaperone-usher pathway pilus assembly and opens the door for the development of potent inhibitors to block pilus biogenesis.
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| 24. |
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| 25. |
- Zheng, Weili, et al.
(författare)
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Cryo-Em Structure of Type 1 Pilus
- 2018
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Ingår i: Biophysical Journal. - : Biophysical Society. - 0006-3495 .- 1542-0086. ; 114:3, s. 370a-370a
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Urinary tract infections (UTIs) are caused by a wide range of pathogens, but the most common causative agent of UTIs is uropathogenic Escherichia coli (UPEC). Virtually all uropathogenic strains of E. coli encode filamentous surface adhesive organelles called type 1 pili, which are a subset of Chaperone-usher pathway (CUP) pili. CUP pili are also ubiquitously expressed on the surface of many other Gram-negative bacterial pathogens. They are important virulence factors facilitating host-pathogen interactions that are crucial for the establishment and persistence of an infection, and involved in regulating other key processes such as biofilm formation. We have solved the 4.2 Å resolution cryo-EM structure of the type 1 pilus, which was present as a background contaminant in a prep of type 4 pili. We have taken advantage of the strength of cryo-EM to separate different molecules and conformations present in solution to show that filament images which might otherwise have been discarded as a contaminant can actually be used to build an atomic model. The model reveals the residues that allow a long chain of FimA subunits, linked by the insertion of a β-strand of one subunit into the β-sheet of an adjacent subunit, to coil into a rigid rod. We show that site-specific mutation of these residues reduces the force needed to unwind the rod. Strikingly, one mutation (A22R) which showed the greatest reduction in unwinding force, eliminated bladder infections in a mouse model. This is presumably due to the fact that the altered mechanics of the A22R pilus rod cannot withstand the shear forces due to urinary flow in the bladder and bacteria harboring this mutation are cleared from the bladder. This provides new insights into the important role of pili mechanics in bacterial pathogenesis.
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