| 1. |
- Bhadani, Kanishk, 1991, et al.
(författare)
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Applied Calibration and Validation Method of Dynamic Process Simulation for Crushing Plants
- 2021
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Ingår i: Minerals. - : MDPI AG. - 2075-163X. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- There is a need within the production industry for digitalization and the development of meaningful functionality for production operation. One such industry is aggregate production, characterized by continuous production operation, where the digital transformation can bring operational adaptability to customer demand. Dynamic process simulations have the ability to capture the change in production performance of aggregate production over time. However, there is a need to develop cost-efficient methodologies to integrate calibrations and validation of models. This paper presents a method of integrating an experimental and data-driven approach for calibration and validation for crushing plant equipment and a process model. The method uses an error minimization optimization formulation to calibrate the equipment models, followed by the validation of the process model. The paper discusses various details such as experimental calibration procedure, applied error functions, optimization problem formulation, and the future development needed to completely realize the procedure for industrial use. The validated simulation model can be used for performing process planning and process optimization activities for the crushing plant's operation.
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| 2. |
- Schnitzer, Barbara Maria, 1992, et al.
(författare)
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The effect of stress on biophysical characteristics of misfolded protein aggregates in living Saccharomyces cerevisiae cells
- 2022
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 162
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Forskningsöversikt (refereegranskat)abstract
- Aggregation of misfolded or damaged proteins is often attributed to numerous metabolic and neurodegenerative disorders. To reveal underlying mechanisms and cellular responses, it is crucial to investigate protein aggregate dynamics in cells. Here, we used super-resolution single-molecule microscopy to obtain biophysical characteristics of individual aggregates of a model misfolded protein ∆ssCPY* labelled with GFP. We demonstrated that oxidative and hyperosmotic stress lead to increased aggregate stoichiometries but not necessarily the total number of aggregates. Moreover, our data suggest the importance of the thioredoxin peroxidase Tsa1 for the controlled sequestering and clearance of aggregates upon both conditions. Our work provides novel insights into the understanding of the cellular response to stress via revealing the dynamical properties of stress-induced protein aggregates.
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| 3. |
- Schnitzer, Barbara Maria, 1992, et al.
(författare)
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The synergy of damage repair and retention promotes rejuvenation and prolongs healthy lifespans in cell lineages
- 2020
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Damaged proteins are inherited asymmetrically during cell division in the yeast Saccharomyces cerevisiae, such that most damage is retained within the mother cell. The consequence is an ageing mother and a rejuvenated daughter cell with full replicative potential. Daughters of old and damaged mothers are however born with increasing levels of damage resulting in lowered replicative lifespans. Remarkably, these prematurely old daughters can give rise to rejuvenated cells with low damage levels and recovered lifespans, called second-degree rejuvenation. We aimed to investigate how damage repair and retention together can promote rejuvenation and at the same time ensure low damage levels in mother cells, reflected in longer health spans. We developed a dynamic model for damage accumulation over successive divisions in individual cells as part of a dynamically growing cell lineage. With detailed knowledge about single-cell dynamics and relationships between all cells in the lineage, we can infer how individual damage repair and retention strategies affect the propagation of damage in the population. We show that damage retention lowers damage levels in the population by reducing the variability across the lineage, and results in larger population sizes. Repairing damage efficiently in early life, as opposed to investing in repair when damage has already accumulated, counteracts accelerated ageing caused by damage retention. It prolongs the health span of individual cells which are moreover less prone to stress. In combination, damage retention and early investment in repair are beneficial for healthy ageing in yeast cell populations.
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| 4. |
- Schnitzer, Barbara
(författare)
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Mathematical Modelling of Cellular Ageing: a Multi-Scale Perspective
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In a growing and increasingly older population, we are progressively challenged by the impact of ageing on individuals and society. The UN declared the years 2021-2030 as the Decade of Healthy Ageing, highlighting the efforts to minimise the burden of ageing and age-related diseases. A crucial step towards this goal is to elucidate basic underlying mechanisms on a molecular and cellular level. While much is known about individual hallmarks of cellular ageing, their interactive and multi-scale nature hinders the progress in gaining deeper insights into the emergent effects on an organism. In the five papers underlying this thesis, we aimed to study protein damage accumulation over successive cell divisions (replicative ageing), as one emergent factor defining ageing. We combined experimental data in the unicellular model organism yeast Saccharomyces cerevisiae with mathematical modelling, which offers systematic and formal ways of analysing the complexity that arises from the interplay between processes on different time and length scales. In that way, we showed how interconnections in the cellular signalling network are essential to ensure a robust adaption to stress on a short time scale, being crucial for preventing and handling protein damage. By linking different models for cellular signalling, metabolism and protein damage accumulation, we provided one of the most comprehensive mathematical models of replicative ageing to date. The model allowed us to map metabolic changes during ageing to a dynamic trade-off between protein availability and energy demand, and to investigate global metabolic strategies underlying cellular ageing. Going beyond single-cell models, we examined the synergy between processes that create, retain and repair protein damage, balancing the health of individual cells with the viability of the cell population. Taken together, by constructing, validating and using mathematical models, we unified different scales of protein damage accumulation and explored its causes and consequences. Thus, this thesis contributes to a more comprehensive understanding of cellular ageing, taking a step further towards healthy ageing.
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| 5. |
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| 6. |
- Schnitzer, Barbara, et al.
(författare)
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Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing
- 2022
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 18:7
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of protein damage is one of the major drivers of replicative ageing, describing a cell’s reduced ability to reproduce over time even under optimal conditions. Reactive oxygen and nitrogen species are precursors of protein damage and therefore tightly linked to ageing. At the same time, they are an inevitable by-product of the cell’s metabolism. Cells are able to sense high levels of reactive oxygen and nitrogen species and can subsequently adapt their metabolism through gene regulation to slow down damage accumulation. However, the older or damaged a cell is the less flexibility it has to allocate enzymes across the metabolic network, forcing further adaptions in the metabolism. To investigate changes in the metabolism during replicative ageing, we developed an multi-scale mathematical model using budding yeast as a model organism. The model consists of three interconnected modules: a Boolean model of the signalling network, an enzyme-constrained flux balance model of the central carbon metabolism and a dynamic model of growth and protein damage accumulation with discrete cell divisions. The model can explain known features of replicative ageing, like average lifespan and increase in generation time during successive division, in yeast wildtype cells by a decreasing pool of functional enzymes and an increasing energy demand for maintenance. We further used the model to identify three consecutive metabolic phases, that a cell can undergo during its life, and their influence on the replicative potential, and proposed an intervention span for lifespan control. © 2022 Schnitzer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 7. |
- Schnitzer, Barbara, et al.
(författare)
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The choice of the objective function in flux balance analysis is crucial for predicting replicative lifespans in yeast
- 2022
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- Flux balance analysis (FBA) is a powerful tool to study genome-scale models of the cellular metabolism, based on finding the optimal flux distributions over the network. While the objective function is crucial for the outcome, its choice, even though motivated by evolutionary arguments, has not been directly connected to related measures. Here, we used an available multi-scale mathematical model of yeast replicative ageing, integrating cellular metabolism, nutrient sensing and damage accumulation, to systematically test the effect of commonly used objective functions on features of replicative ageing in budding yeast, such as the number of cell divisions and the corresponding time between divisions. The simulations confirmed that assuming maximal growth is essential for reaching realistic lifespans. The usage of the parsimonious solution or the additional maximisation of a growth-independent energy cost can improve lifespan predictions, explained by either increased respiratory activity using resources otherwise allocated to cellular growth or by enhancing antioxidative activity, specifically in early life. Our work provides a new perspective on choosing the objective function in FBA by connecting it to replicative ageing.
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| 8. |
- Welkenhuysen, Niek, 1988, et al.
(författare)
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Robustness of Nutrient Signaling Is Maintained by Interconnectivity Between Signal Transduction Pathways
- 2019
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Systems biology approaches provide means to study the interplay between biological processes leading to the mechanistic understanding of the properties of complex biological systems. Here, we developed a vector format rule-based Boolean logic model of the yeast S. cerevisiae cAMP-PKA, Snf1, and the Snf3-Rgt2 pathway to better understand the role of crosstalk on network robustness and function. We identified that phosphatases are the common unknown components of the network and that crosstalk from the cAMP-PKA pathway to other pathways plays a critical role in nutrient sensing events. The model was simulated with known crosstalk combinations and subsequent analysis led to the identification of characteristics and impact of pathway interconnections. Our results revealed that the interconnections between the Snf1 and Snf3-Rgt2 pathway led to increased robustness in these signaling pathways. Overall, our approach contributes to the understanding of the function and importance of crosstalk in nutrient signaling.
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