Interface Focus最新文献

To enable large in silico trials and personalized model predictions on clinical timescales, it is imperative that models can be constructed quickly and reproducibly. First, we aimed to overcome the challenges of constructing cardiac models at scale through developing a robust, open-source pipeline for bilayer and volumetric atrial models. Second, we aimed to investigate the effects of fibres, fibrosis and model representation on fibrillatory dynamics. To construct bilayer and volumetric models, we extended our previously developed coordinate system to incorporate transmurality, atrial regions and fibres (rule-based or data driven diffusion tensor magnetic resonance imaging (MRI)). We created a cohort of 1000 biatrial bilayer and volumetric models derived from computed tomography (CT) data, as well as models from MRI, and electroanatomical mapping. Fibrillatory dynamics diverged between bilayer and volumetric simulations across the CT cohort (correlation coefficient for phase singularity maps: left atrial (LA) 0.27 ± 0.19, right atrial (RA) 0.41 ± 0.14). Adding fibrotic remodelling stabilized re-entries and reduced the impact of model type (LA: 0.52 ± 0.20, RA: 0.36 ± 0.18). The choice of fibre field has a small effect on paced activation data (less than 12 ms), but a larger effect on fibrillatory dynamics. Overall, we developed an open-source user-friendly pipeline for generating atrial models from imaging or electroanatomical mapping data enabling in silico clinical trials at scale (https://github.com/pcmlab/atrialmtk).

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10^-2 µM in the RA versus 0.9 × 10^-3 µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: -0.5 m s^-1 in the RA versus -0.05 m s^-1 in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Fibrosis has been mechanistically linked to arrhythmogenesis in multiple cardiovascular conditions, including atrial fibrillation (AF). Previous studies have demonstrated that fibrosis can create functional barriers to conduction which may promote excitation wavebreak and the generation of re-entry, while also acting to pin re-entrant excitation in stable rotors during AF. However, few studies have investigated the role of fibrosis in the generation of AF triggers in detail. We apply our in-house computational framework to study the impact of fibrosis on the generation of AF triggers and trigger-substrate interactions in two- and three-dimensional atrial tissue models. Our models include a reduced and efficient description of stochastic, spontaneous cellular triggers as well as a simple model of heterogeneous inter-cellular coupling. Our results demonstrate that fibrosis promotes the emergence of focal excitations, primarily through reducing the electrotonic load on individual fibre strands. This enables excitation to robustly initiate within these single strands before spreading to neighbouring strands and inducing a full tissue focal excitation. Enhanced conduction block can allow trigger-substrate interactions that result in the emergence of complex, re-entrant excitation patterns. This study provides new insight into the mechanisms by which fibrosis promotes the triggers and substrate necessary to induce and sustain arrhythmia.

[This corrects the article DOI: 10.1098/rsfs.2022.0048.][This corrects the article DOI: 10.1098/rsfs.2022.0048.].

Living cells regulate many of their vital functions through dynamic, membraneless compartments that phase separate (condense) in response to different types of stimuli. In synthetic cells, responsive condensates could similarly play a crucial role in sustaining their operations. Here we use DNA nanotechnology to design and characterize artificial condensates that respond to light. These condensates form via the programmable interactions of star-shaped DNA subunits (nanostars), which are engineered to include photo-responsive protection domains. In the absence of UV irradiation, the nanostar interactions are not conducive to the formation of condensates. UV irradiation cleaves the protection domains, increases the nanostar valency and enables condensation. We demonstrate that this approach makes it possible to tune precisely the kinetics of condensate formation by dosing UV exposure time. Our experimental observations are complemented by a computational model that characterizes phase transitions of mixtures of particles of different valency, under changes in the mixture composition and bond interaction energy. In addition, we illustrate how UV activation is a useful tool to control the formation and size of DNA condensates in emulsion droplets, as a prototype organelle in a synthetic cell. This research expands our capacity to remotely control the dynamics of DNA-based components via physical stimuli and is particularly relevant to the development of minimal artificial cells and responsive biomaterials.

Hypothesis and theory-based studies in microbial ecology have been neglected in favour of those that are descriptive and aim for data-gathering of uncultured microbial species. This tendency limits our capacity to create new mechanistic explanations of microbial community dynamics, hampering the improvement of current environmental biotechnologies. We propose that a multiscale modelling bottom-up approach (piecing together sub-systems to give rise to more complex systems) can be used as a framework to generate mechanistic hypotheses and theories (in-silico bottom-up methodology). To accomplish this, formal comprehension of the mathematical model design is required together with a systematic procedure for the application of the in-silico bottom-up methodology. Ruling out the belief that experimentation before modelling is indispensable, we propose that mathematical modelling can be used as a tool to direct experimentation by validating theoretical principles of microbial ecology. Our goal is to develop methodologies that effectively integrate experimentation and modelling efforts to achieve superior levels of predictive capacity.

Engineered ecosystems span multiple volume scales, from a nano-scale to thousands of cubic metres. Even the largest industrial systems are tested in pilot scale facilities. But does scale affect outcomes? Here we look at comparing different size laboratory anaerobic fermentors to see if and how the volume of the community affects the outcome of community coalescence (combining multiple communities) on community composition and function. Our results show that there is an effect of scale on biogas production. Furthermore, we see a link between community evenness and volume, with smaller scale communities having higher evenness. Despite those differences, the overall patterns of community coalescence are very similar at all scales, with coalescence leading to levels of biogas production comparable with that of the best-performing component community. The increase in biogas with increasing volume plateaus, suggesting there is a volume where productivity stays stable over large volumes. Our findings are reassuring for ecologists studying large ecosystems and industries operating pilot scale facilities, as they support the validity of pilot scale studies in this field.