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Stability and gene strand bias of lambda prophages and chromosome organization in Escherichia coli
(2024-07) Li, Xintian; Gallardo, Oscar; August, Elias; Dassa, Bareket; Court, Donald L.; Stavans, Joel; Arbel-Goren, Rinat; Department of Engineering
Temperate phage-mediated horizontal gene transfer is a potent driver of genetic diversity in the evolution of bacteria. Most lambdoid prophages in Escherichia coli are integrated into the chromosome with the same orientation with respect to the direction of chromosomal replication, and their location on the chromosome is far from homogeneous. To better understand these features, we studied the interplay between lysogenic and lytic states of phage lambda in both native and inverted integration orientations at the wild-type integration site as well as at other sites on the bacterial chromosome. Measurements of free phage released by spontaneous induction showed that the stability of lysogenic states is affected by location and orientation along the chromosome, with stronger effects near the origin of replication. Competition experiments and range expansions between lysogenic strains with opposite orientations and insertion loci indicated that there are no major differences in growth. Moreover, measurements of the level of transcriptional bursts of the cI gene coding for the lambda phage repressor using single-molecule fluorescence in situ hybridization resulted in similar levels of transcription for both orientations and prophage location. We postulate that the preference for a given orientation and location is a result of a balance between the maintenance of lysogeny and the ability to lyse.
Verk
Comfortable sleep monitoring : using physiological process interconnectedness during sleep for novel software sensors
(2026) Bavarsad, Anna; August, Elias; Arnardóttir, Erna Sif; Department of Engineering
Introduction: Monitoring sleep-disordered breathing typically requires many sensors, including pneumoflow masks, measuring nasal and oral airflow, and esophageal pressure catheters. While these tools provide detailed information about airflow, effort, and respiratory mechanics, they can be uncomfortable, invasive, and less feasible for long-term, home-based, or large-scale sleep studies. In contrast, respiratory inductance plethysmography (RIP) belts offer a non-invasive and well-tolerated alternative. Methods: In this study, we introduce four models that estimate key physiological signals from either RIP-belt data or pneumoflow mask data. Specifically, we present a heart rate model based on the RIP-belt signal, a nasal pneumoflow model estimating airflow from the RIP-belt signal, and two esophageal pressure models – one based on the RIP-belt signal, and the other one based on pneumoflow mask data. Data from 55 participants with varying degrees of sleep-disordered breathing were analyzed. Results: When fitted to each participant individually, the heart rate model as well as the nasal pneumoflow model achieved a mean Pearson correlation of 0.60. The esophageal pressure model, using RIP-belt data, yielded a mean Pearson correlation of 0.65, while the model using pneumoflow mask data yielded a mean Pearson correlation of 0.52. Discussion: Although these models do not replace gold-standard instruments, they provide physiologically interpretable estimates from non-invasive inputs and demonstrate potential for scalable, lower-burden sleep monitoring, and highlight the potential of considering physiological interconnectedness to extract desired information. Future work will focus on further validation and clinical diagnostic utility.
Verk
Feedback Control Architecture and the Bacterial Chemotaxis Network
(2011-05) Hamadeh, Abdullah; Roberts, Mark A.J.; August, Elias; McSharry, Patrick E.; Maini, Philip K.; Armitage, Judith P.; Papachristodoulou, Antonis; Department of Engineering
Bacteria move towards favourable and away from toxic environments by changing their swimming pattern. This response is regulated by the chemotaxis signalling pathway, which has an important feature: it uses feedback to 'reset' (adapt) the bacterial sensing ability, which allows the bacteria to sense a range of background environmental changes. The role of this feedback has been studied extensively in the simple chemotaxis pathway of Escherichia coli. However it has been recently found that the majority of bacteria have multiple chemotaxis homologues of the E. coli proteins, resulting in more complex pathways. In this paper we investigate the configuration and role of feedback in Rhodobacter sphaeroides, a bacterium containing multiple homologues of the chemotaxis proteins found in E. coli. Multiple proteins could produce different possible feedback configurations, each having different chemotactic performance qualities and levels of robustness to variations and uncertainties in biological parameters and to intracellular noise. We develop four models corresponding to different feedback configurations. Using a series of carefully designed experiments we discriminate between these models and invalidate three of them. When these models are examined in terms of robustness to noise and parametric uncertainties, we find that the non-invalidated model is superior to the others. Moreover, it has a 'cascade control' feedback architecture which is used extensively in engineering to improve system performance, including robustness. Given that the majority of bacteria are known to have multiple chemotaxis pathways, in this paper we show that some feedback architectures allow them to have better performance than others. In particular, cascade control may be an important feature in achieving robust functionality in more complex signalling pathways and in improving their performance.
Verk
Dynamically induced spatial segregation in multispecies bacterial bioconvection
(2025-12) Gallardo-Navarro, Oscar; Arbel-Goren, Rinat; August, Elias; Olmedo-Alvarez, Gabriela; Stavans, Joel; Department of Engineering
Active matter, from motile bacteria to animals, can exhibit striking collective and coherent behavior. Despite significant advances in understanding the behavior of homogeneous systems, little is known about the self-organization and dynamics of heterogeneous active matter, such as complex and diverse bacterial communities. Under oxygen gradients, many bacterial species swim towards air-liquid interfaces in auto-organized, directional bioconvective flows, whose spatial scales exceed the cell size by orders of magnitude. Here we show that multispecies bacterial suspensions undergoing oxytactic-driven bioconvection exhibit dynamically driven spatial segregation, despite the enhanced mixing of bioconvective flows, and the fact that these species coexist in their natural habitat. Segregation is observed as patterns of spatially interlocked domains, with local dominance of one of the constituent species in the suspension. Our findings suggest that segregation mechanisms are driven by species-specific motile behaviors under conditions of hydrodynamic flow, rather than biochemical repulsion. Thus, species with different motile characteristics in the same ecological context can enhance their access to limiting resources. This work provides novel insights on the role of heterogeneity in active matter, as well as on the dynamics of complex microbial communities, their spatial organization and their collective behavior.
Verk
Discriminating between rival biochemical network models : Three approaches to optimal experiment design
(2010-04-01) Mélykúti, Bence; August, Elias; Papachristodoulou, Antonis; El-Samad, Hana; Department of Engineering
Background: The success of molecular systems biology hinges on the ability to use computational models to design predictive experiments, and ultimately unravel underlying biological mechanisms. A problem commonly encountered in the computational modelling of biological networks is that alternative, structurally different models of similar complexity fit a set of experimental data equally well. In this case, more than one molecular mechanism can explain available data. In order to rule out the incorrect mechanisms, one needs to invalidate incorrect models. At this point, new experiments maximizing the difference between the measured values of alternative models should be proposed and conducted. Such experiments should be optimally designed to produce data that are most likely to invalidate incorrect model structures.Results: In this paper we develop methodologies for the optimal design of experiments with the aim of discriminating between different mathematical models of the same biological system. The first approach determines the 'best' initial condition that maximizes the L2 (energy) distance between the outputs of the rival models. In the second approach, we maximize the L2-distance of the outputs by designing the optimal external stimulus (input) profile of unit L2-norm. Our third method uses optimized structural changes (corresponding, for example, to parameter value changes reflecting gene knock-outs) to achieve the same goal. The numerical implementation of each method is considered in an example, signal processing in starving Dictyostelium amœbæ.Conclusions: Model-based design of experiments improves both the reliability and the efficiency of biochemical network model discrimination. This opens the way to model invalidation, which can be used to perfect our understanding of biochemical networks. Our general problem formulation together with the three proposed experiment design methods give the practitioner new tools for a systems biology approach to experiment design.

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