| 1. |
- Heinrich, Kristina, et al.
(författare)
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A Kinase-Phosphatase Switch Transduces Environmental Information into a Bacterial Cell Cycle Circuit
- 2016
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- The bacterial cell cycle has been extensively studied under standard growth conditions. How it is modulated in response to environmental changes remains poorly understood. Here, we demonstrate that the freshwater bacterium Caulobacter crescentus blocks cell division and grows to filamentous cells in response to stress conditions affecting the cell membrane. Our data suggest that stress switches the membrane-bound cell cycle kinase CckA to its phosphatase mode, leading to the rapid dephosphorylation, inactivation and proteolysis of the master cell cycle regulator CtrA. The clearance of CtrA results in downregulation of division and morphogenesis genes and consequently a cell division block. Upon shift to non-stress conditions, cells quickly restart cell division and return to normal cell size. Our data indicate that the temporary inhibition of cell division through the regulated inactivation of CtrA constitutes a growth advantage under stress. Taken together, our work reveals a new mechanism that allows bacteria to alter their mode of proliferation in response to environmental cues by controlling the activity of a master cell cycle transcription factor. Furthermore, our results highlight the role of a bifunctional kinase in this process that integrates the cell cycle with environmental information.
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| 2. |
- Heinrich, Kristina, 1988-
(författare)
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Coping with Stress : Regulation of the Caulobacter crescentus cell cycle in response to environmental cues
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- All organisms have to respond to environmental changes to maintain cellular and genome integrity. In particular, unicellular organisms like bacteria must be able to analyze their surroundings and rapidly adjust their growth mode and cell cycle program in response to environmental changes, such as changes in nutrient availability, temperature, osmolarity, or pH. Additionally, they have to compete with other species for nutrients and evade possible predators or the immune system. Bacteria exhibit a myriad of sophisticated regulatory pathways that allow them to cope with various kinds of threats and ensure their survival. However, the precise molecular mechanisms underlying these responses remain in many cases incompletely described. This thesis focuses on the mechanisms that adjust growth and cell cycle progression of Caulobacter crescentus under adverse conditions.In paper I we describe a mechanism by which environmental information is transduced via the membrane-bound cell cycle kinase CckA into the cell division program of C. crescentus. This mechanism ensures rapid dephosphorylation and clearance of the cell cycle master regulator CtrA under salt and ethanol stress. The downregulation of CtrA leads to a cell division block and cell filamentation, which provides a growth advantage under these conditions.Cell filamentation of C. crescentus can also be observed in the late stationary phase, in which a small subpopulation of cells transforms into helical shaped filaments. In these cells not only CtrA but all major cell cycle regulators are cleared (paper II), leading to a situation in which cells block their cell cycle but continue to grow. We found that a combination of different stresses, namely phosphate starvation, high pH, and excess nitrogen, triggers this response. These stresses can also be observed in C. crescentus’ natural freshwater habitat during algae blooms. Furthermore, our results indicate that filamentous cells are able to reach beyond biofilm surfaces, possibly enabling cells to reach nutrients and to release progeny.While our studies highlight that cell filamentation is a common bacterial response to stress, some stress conditions, such as acute proteotoxic stress, lead to a growth arrest. In paper III we show that the regulatory interaction between the major chaperone DnaK and the heat shock sigma factor σ32 adjusts growth rate in response to changes of the global protein folding state. We show that high σ32 activity inhibits growth by re-allocating cellular resources from proliferative to maintenance functions. Under stress conditions when σ32 is active, this re-allocation likely helps cells to survive. However, under non-stress conditions unrepressed σ32 activity is detrimental. We demonstrate that in the absence of stress, the DnaK chaperone is absolutely necessary to limit σ32 activity and in this way to allow rapid proliferation.In summary, the described studies highlight critical pathways that allow C. crescentus to integrate environmental information with cell cycle and growth regulation and shed new light onto the mechanisms by which bacteria adapt to their environment and in this way ensure their survival.
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| 3. |
- Heinrich, Kristina, et al.
(författare)
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Molecular Basis and Ecological Relevance of Caulobacter Cell Filamentation in Freshwater Habitats
- 2019
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Ingår i: mBio. - : AMER SOC MICROBIOLOGY. - 2161-2129 .- 2150-7511. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- All living cells are characterized by certain cell shapes and sizes. Many bacteria can change these properties depending on the growth conditions. The underlying mechanisms and the ecological relevance of changing cell shape and size remain unclear in most cases. One bacterium that undergoes extensive shape-shifting in response to changing growth conditions is the freshwater bacterium Caulobacter crescentus. When incubated for an extended time in stationary phase, a subpopulation of C. crescentus forms viable filamentous cells with a helical shape. Here, we demonstrated that this stationary-phase-induced filamentation results from downregulation of most critical cell cycle regulators and a consequent block of DNA replication and cell division while cell growth and metabolism continue. Our data indicate that this response is triggered by a combination of three stresses caused by prolonged growth in complex medium, namely, the depletion of phosphate, alkaline pH, and an excess of ammonium. We found that these conditions are experienced in the summer months during algal blooms near the surface in freshwater lakes, a natural habitat of C. crescentus, suggesting that filamentous growth is a common response of C. crescentus to its environment. Finally, we demonstrate that when grown in a biofilm, the filamentous cells can reach beyond the surface of the biofilm and potentially access nutrients or release progeny. Altogether, our work highlights the ability of bacteria to alter their morphology and suggests how this behavior might enable adaptation to changing environments.
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| 4. |
- Jansson, Kristina, 1969, et al.
(författare)
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A role for Myh1 in DNA repair after treatment with strand-breaking and crosslinking chemotherapeutic agents
- 2013
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Ingår i: Environmental and Molecular Mutagenesis. - : Wiley. - 0893-6692 .- 1098-2280. ; 54:5, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- The highly conserved DNA glycosylase MutY is implicated in repair of oxidative DNA damage, in particular in removing adenines misincorporated opposite 7,8-dihydro-8-oxoguanine (8-oxo-G). The MutY homologues (MutYH) physically associate with proteins implicated in replication, DNA repair, and checkpoint signaling, specifically with the DNA damage sensor complex 9-1-1 proteins. Here, we ask whether MutYH could have a broader function in sensing and repairing different types of DNA damage induced by conventional chemotherapeutics. Thus, we examined if deletion of the Schizosaccharomyces pombe MutY homologue, Myh1, alone or in combination with deletion of either component of the 9-1-1 sensor complex, influences survival after exposure to different classes of DNA damaging chemotherapeutics that do not act primarily by causing 8-oxoG lesions. We show that Myh1 contributes to survival on genotoxic stresses induced by the oxidizing, DNA double strand break-inducing, bleomycins, or the DNA crosslinking platinum compounds, particularly in a rad1 mutant background. Exposure of cells to cisplatin leads to a moderate overall accumulation of Myh1 protein. Interestingly, we found that DNA damage induced by phleomycin results in increased chromatin association of Myh1. Further, we demonstrate that Myh1 relocalizes to the nucleus after exposure to hydrogen peroxide or chemotherapeutics, most prominently seen after phleomycin treatment. These observations indicate a wider role of Myh1 in DNA repair and DNA damage-induced checkpoint activation than previously thought
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| 5. |
- Kristiansen, Jesper, et al.
(författare)
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Work stress, worries, and pain interact synergistically with modelled traffic noise on cross-sectional associations with self-reported sleep problems
- 2011
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 84:2, s. 211-224
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Tidskriftsartikel (refereegranskat)abstract
- To examine the risk of sleep problems associated with work stress (job strain, job demands, and decision authority), worries and pain and to investigate the synergistic interaction between these factors and traffic noise. Sleep problems and predictor variables were assessed in a cross-sectional public health survey with 12,093 respondents. Traffic noise levels were assessed using modelled A-weighted energy equivalent traffic sound levels at the residence. The risk of sleep problems was modelled using multiple logistic regression analysis. With regard to sleep problems not attributed to any external source (general sleep problems), independent main effects were found for traffic noise (women), decision authority (women), job strain, job demands, suffering from pain or other afflictions, worries about losing the job, experiencing bullying at work, having troubles paying the bills, and having a sick, disabled, or old relative to take care of (women). Significant synergistic effects were found for traffic noise and experiencing bullying at work in women. With regard to sleep problems attributed to traffic noise, strong synergistic interactions were found between traffic noise and, respectively, job demands (men), having pain or other afflictions, taking care of a sick, old, or disabled relative, and having troubles paying the bills. Main effects were found for worries about losing the job, experiencing bullying at work, job strain (men), and decision authority (men). Synergistic interactions could potentially contribute with 10-20% of the sleep problems attributed to traffic noise in the population. Work stress, pain, and different worries were independently associated with general sleep problems and showed in general no synergistic interaction with traffic noise. In contrast, synergistic effects between traffic noise and psychological factors were found with regard to sleep problems attributed to traffic noise. The synergy may contribute significantly to sleep problems attributed to traffic noise in the population.
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| 6. |
- Persson, Roger, et al.
(författare)
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Trait anxiety and modeled exposure as determinants of Self-Reported Annoyance to Sound, Air Pollution and Other Environmental Factors in the home
- 2007
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 81:2, s. 179-191
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Tidskriftsartikel (refereegranskat)abstract
- Objectives We examined to what degree annoyance ratings to noise, air pollution and other common environmental factors in the home environment could be considered to mirror personality disposition in terms of habitual anxiety level and, when appropriate, objectively modeled noise and nitrogen emission (NOx). Methods A trait anxiety scale was introduced in a cross-sectional public health survey with 2,856 respondents. Of these, 705 had self-reported asthma and the rest constituted gender-matched referents. Annoyance to ten specific factors in the residential environment, mainly focusing on source-specific noise and air pollution, was assessed on a six-point likert scale. A-weighted energy equivalent continuous sound pressure level during a full day (24 h; L (Aeq,24)) as well as annual average NOx levels (mu g/m(3)) at the residential address were modeled with high resolution, using a road data base and a detailed emission data base for NOx. Results The two most prevalent complaints were annoyance to traffic noise and sounds from neighbors, which was reported by about 8% of the participants. Unadjusted logistic regression analyses using the continuous trait anxiety score as a predictor showed positive associations with ratings of annoyance from total traffic noise, sounds from neighbors, sound from ventilation, exhaust fumes from traffic, sounds from other installations, and vibrations from traffic (ORs between 1.37 and 2.14). Modeled noise and NOx exposure were positively related with annoyance to traffic noise and exhaust fumes, respectively. Adjustment of the trait anxiety scores for other individual characteristics and potential determinants did not change the overall pattern of results. Conclusion Trait anxiety scores were often mirrored in ratings of annoyance, which suggests caution when using annoyance reports either as a surrogate measure for environmental exposure on the individual-level in epidemiologic studies or when studying the moderating effects of annoyance on health outcomes.
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| 7. |
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| 8. |
- Sallnäs Pysander, Eva-Lotta, et al.
(författare)
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Pointing in Multi-Disciplinary Medical Meetings
- 2011
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Ingår i: 2011 24TH INTERNATIONAL SYMPOSIUM ON COMPUTER-BASED MEDICAL SYSTEMS (CBMS). - NEW YORK, NY : IEEE. - 9781457711909
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Konferensbidrag (refereegranskat)abstract
- In this paper a field study of using laser-pointing during multi-disciplinary medical meetings is presented. The pointing behaviour adopted by radiologists and surgeons to communicate about and collaboratively analyse patient data such as CT images today is illustrated based on field observations of pre-operative meetings. In a field test, laser-pointers were introduced in pre-operative meetings. How the dialogue and gesturing changed compared to meetings where laser-pointers were not present were investigated. Results from our study show that the multi-disciplinary medical meetings are clearly affected by the introduction of laser-pointer devices and we believe that the participants would benefit from a future gesturing tool if it was carefully designed. The implementation of an application that provides touch feedback in three dimensions of the anatomical structure of blood vessels as well as tumours is described and related to our results.
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| 9. |
- Schramm, Frederic D., et al.
(författare)
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An essential regulatory function of the DnaK chaperone dictates the decision between proliferation and maintenance in Caulobacter crescentus
- 2017
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Hsp70 chaperones are well known for their important functions in maintaining protein homeostasis during thermal stress conditions. In many bacteria the Hsp70 homolog DnaK is also required for growth in the absence of stress. The molecular reasons underlying Hsp70 essentiality remain in most cases unclear. Here, we demonstrate that DnaK is essential in the alpha-proteobacterium Caulobacter crescentus due to its regulatory function in gene expression. Using a suppressor screen we identified mutations that allow growth in the absence of DnaK. All mutations reduced the activity of the heat shock sigma factor sigma(32) , demonstrating that the DnaK-dependent inactivation of sigma(32) is a growth requirement. While most mutations occurred in the rpoH gene encoding sigma(32) , we also identified mutations affecting sigma(32) activity or stability in trans, providing important new insight into the regulatory mechanisms controlling sigma(32) activity. Most notably, we describe a mutation in the ATP dependent protease HslUV that induces rapid degradation of sigma(32) , and a mutation leading to increased levels of the house keeping sigma(70) that outcompete sigma(32) for binding to the RNA polymerase. We demonstrate that sigma(32) inhibits growth and that its unrestrained activity leads to an extensive reprogramming of global gene expression, resulting in upregulation of repair and maintenance functions and downregulation of the growth-promoting functions of protein translation, DNA replication and certain metabolic processes. While this re-allocation from proliferative to maintenance functions could provide an advantage during heat stress, it leads to growth defects under favorable conditions. We conclude that Caulobacter has coopted the DnaK chaperone system as an essential regulator of gene expression under conditions when its folding activity is dispensable.
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| 10. |
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