| 11. |
- 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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| 12. |
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| 15. |
- Adolfsson, Per I., et al.
(författare)
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Characterization of EDG receptor expression and proliferative response in cultured human BPH smooth muscle cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The endogenous phospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both known to generate a Vvide variety of effects in various cell systems by the endothelial differentiation gene (Edg) receptor family, including 7 different G-protein coupled Edg receptors.In this study, expression of LPA- and SlP Edg receptors was examined, and so was the effect with respect to proliferation on cultured BPH smooth muscle cells smc. Mmeover, theresponse on cAMP levels was examined. Finally, a potential link between activation of the MAP kinase cascade and the LPA stimulated proliferation was investigated.First, the RT-PCR analysis of the Edg receptors in BPH smc, demonstrated a heterogeneous expression including all receptors except the Edg6 subtype. Further, in contrast to LPA, the mitogen effect of SIP, demonstrated a concentration-dependent biphasic response, including stimulation below 1μM, whereas inhibition was obtained at higher concentrations. Forskolin induced a rapid and transient cAMP response in LPA stimulated cells, with a peak-value after 3 minutes. After 15 minutes the cAMP level had retmned to base-line level. However a gradual increase to 15% of maximum value was obtained after additional 30 minutes, and thereafter a gradual reduction was observed. The mentioned antiproliferative response generated by SIP could not be conelated to an intracellular cAMP increase. Finally, when the LPA treated smc was co-incubated with the MAPK kinase inhibitor PD98059 (10 μM) the mitogen response was eliminated.The cAIVIP increase, which was induced by forskolin, corresponds with mentioned antiproliferative effect whereas a similar con-elation was not obtained regarding SIP. The intracellular signal mechanisms triggered by LPA and S1P in BPH smc remain to be further investigated.
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| 16. |
- Ambite, Ines, et al.
(författare)
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Fimbriae reprogram host gene expression - Divergent effects of P and type 1 fimbriae
- 2019
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 15:6, s. 1007671-1007671
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Tidskriftsartikel (refereegranskat)abstract
- Pathogens rely on a complex virulence gene repertoire to successfully attack their hosts. We were therefore surprised to find that a single fimbrial gene reconstitution can return the virulence-attenuated commensal strain Escherichia coli 83972 to virulence, defined by a disease phenotype in human hosts. E. coli 83972pap stably reprogrammed host gene expression, by activating an acute pyelonephritis-associated, IRF7-dependent gene network. The PapG protein was internalized by human kidney cells and served as a transcriptional agonist of IRF-7, IFN-β and MYC, suggesting direct involvement of the fimbrial adhesin in this process. IRF-7 was further identified as a potent upstream regulator (-log (p-value) = 61), consistent with the effects in inoculated patients. In contrast, E. coli 83972fim transiently attenuated overall gene expression in human hosts, enhancing the effects of E. coli 83972. The inhibition of RNA processing and ribosomal assembly indicated a homeostatic rather than a pathogenic end-point. In parallel, the expression of specific ion channels and neuropeptide gene networks was transiently enhanced, in a FimH-dependent manner. The studies were performed to establish protective asymptomatic bacteriuria in human hosts and the reconstituted E. coli 83972 variants were developed to improve bacterial fitness for the human urinary tract. Unexpectedly, P fimbriae were able to drive a disease response, suggesting that like oncogene addiction in cancer, pathogens may be addicted to single super-virulence factors.
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| 17. |
- Andersson, Jan, et al.
(författare)
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Traffic safety effects when overtaking 30 meter trucks
- 2012
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Ingår i: Advances in Human Factors and Ergonomics 2012- 14 Volume Set. - : Taylor & Francis. - 146655262X - 9781466552623
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Konferensbidrag (refereegranskat)abstract
- The purpose of this paper is to investigate if the introduction of extra-long and heavy trucks has an effect on traffic safety on Swedish roads, especially in relation to overtaking maneuvers. Traffic safety effects will be measured in terms of road user behavior concerning accelerations and time slots. First, focus group interviews with heavy truck drivers. Truck drivers that do not drive extra-long trucks believe that the introduction of extra-long trucks will create a number of traffic safety problems especially in terms of conflicts with ordinary road users. The drivers of extra-long trucks do not experience the problems that ordinary truck drivers predict. The problems they experience can be taken care of with more planning (thinking ahead). They also believe that the traffic sign on the back of the extra-long vehicle has a positive effect. The truck company, working environment and truck equipment are other important aspects mentioned by the drivers of the extra-long vehicles.The simulator study investigates overtaking situations on a 2+1-lane highway, with extra-long trucks (30.4 m) and ordinary trucks (18.75 m). The results reveal that the distance from the rear/front of the truck to the point where only one lane exists affects car drivers’ decision to overtake, independently of truck length. If the truck is in the relatively same position, the timeslot for a safe overtaking maneuver before next one-lane section was reduced significantly for extra-long trucks compared to ordinary trucks. The conclusion is that there exist small tendencies which point in the direction of enhanced traffic safety problems with the introduction of extra-long trucks. The results should, however, be interpreted with caution as the number of data points was few and collected in specific situations and in specific conditions. It was neither considered how the introduction of longer and heavier trucks, given a constant amount of goods, reduces the number of heavy trucks on the road network.
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