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- Khodaparast, Ladan, et al.
(författare)
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Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.
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- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- Malinovschi, Andrei, et al.
(författare)
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FeNO as a predictor of asthma control improvement after starting inhaled steroid treatment
- 2014
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Ingår i: Nitric oxide. - : Elsevier BV. - 1089-8603 .- 1089-8611. ; 40, s. 110-116
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The fraction of NO in exhaled air (FeNO) is a marker of inflammation in asthma. The aim of the present study was to assess, in a real-world setting, whether only high ( >= 50 ppb) FeNO levels predict improvement in asthma control when being treated with inhaled corticosteroids (ICS), as suggested by current guidelines on the clinical use of FeNO. Methods: FeNO and asthma control were assessed in a retrospective observational study in 153 non-smoking, steroid-nave, adult subjects with asthma with a mean age of 40 years both before and after 6 weeks (median follow-up time) of treatment with 500 mu g beclomethasone (median). Results: Having at the initial visit intermediate FeNO ( >= 25 and <50 ppb) and high FeNO ( >= 50 ppb), compared to normal FeNO (<25 ppb), were associated with a larger proportion of subjects achieving an improvement of Asthma Control Questionnaire (ACQ) score with >= 1 (78% and 67% vs 43%, p <0.05) or both >= 1 improvement and asthma control at follow-up (31% and 37% vs 4%, p < 0.05). These associations were consistent in multiple logistic regression models after adjustments for confounders. Conclusions: It is not only high but also intermediate FeNO levels that are associated with a significant improvement in asthma control after starting ICS treatment. This challenges current clinical guidelines stating that only high FeNO levels predict response to ICS treatment.
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- Michils, Alain, et al.
(författare)
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Different patterns of exhaled nitric oxide response to β2-agonists in asthmatic patients according to the site of bronchodilation
- 2016
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 137:3, s. 806-812
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In asthmatic patients undergoing airway challenge, fraction of exhaled nitric oxide (Feno) levels decrease after bronchoconstriction. In contrast, model simulations have predicted both decreased and increased Feno levels after bronchodilation, depending on the site of airway obstruction relief.OBJECTIVE: We sought to investigate whether β2-agonists might induce divergent effects on Feno values in asthmatic patients as a result of airway obstruction relief occurring at different lung depths.METHODS: Feno, FEV1, and the slope of phase III of the single-breath washout test (S) of He (SHe) and sulfur hexafluoride (SSF6) were measured in 68 asthmatic patients before and after salbutamol inhalation. SHe and SSF6 decreases reflected preacinar and intra-acinar obstruction relief, respectively. Changes (Δ) were expressed as a percentage from the baseline.RESULTS: No Feno change (|ΔFeno| ≤ 10%) was found in 16 patients (mean [SD]: 2.5% [5.2%]; ie, Feno= group); a ΔFeno value of greater than 10% was found in 23 patients (31.7% [20.3%]; ie, the Feno+ group); and a ΔFeno value of less than -10% was found in 29 patients (-31.5% [17.3%]; ie, the Feno- group). All groups had similar ΔFEV1 values. In the Feno= group neither SHe nor SSF6 changed, in the Feno+ group only SHe decreased significantly (-21.8% [SD 28.5%], P = .03), and in the Feno- group both SHe (-29.8% [24.0%], P < .001) and SSF6 (-27.2% [23.3%], P < .001) decreased.DISCUSSION: Three Feno behaviors were observed in response to β2-agonists: a decrease likely caused by relief of an intra-acinar airway obstruction that we propose reflects amplification of nitric oxide back-diffusion, an increase likely associated with a predominant dilation up to the preacinar airways, and Feno stability when obstruction relief involved predominantly the central airways. In combination, these results suggest a new role for Feno in identifying the site of airway obstruction in asthmatic patients.
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- Rubens, Ulysse, et al.
(författare)
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BIAFLOWS : A Collaborative Framework to Reproducibly Deploy and Benchmark Bioimage Analysis Workflows.
- 2020
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Ingår i: Patterns (New York, N.Y.). - : Elsevier BV. - 2666-3899. ; 1:3
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Tidskriftsartikel (refereegranskat)abstract
- Image analysis is key to extracting quantitative information from scientific microscopy images, but the methods involved are now often so refined that they can no longer be unambiguously described by written protocols. We introduce BIAFLOWS, an open-source web tool enabling to reproducibly deploy and benchmark bioimage analysis workflows coming from any software ecosystem. A curated instance of BIAFLOWS populated with 34 image analysis workflows and 15 microscopy image datasets recapitulating common bioimage analysis problems is available online. The workflows can be launched and assessed remotely by comparing their performance visually and according to standard benchmark metrics. We illustrated these features by comparing seven nuclei segmentation workflows, including deep-learning methods. BIAFLOWS enables to benchmark and share bioimage analysis workflows, hence safeguarding research results and promoting high-quality standards in image analysis. The platform is thoroughly documented and ready to gather annotated microscopy datasets and workflows contributed by the bioimaging community.
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