Abstract Introduction of synthetic circuits into microbes creates competition between circuit and host genes for shared cellular resources, such as ribosomes. This can lead to the emergence unwanted coupling expression different genes, complicating design process potentially leading failure. By expressing a 16S rRNA with altered specificity, we partition ribosome pool host-specific circuit-specific activities. We show mathematically experimentally that effects resource be alleviated by...

Abstract Background There is on-going controversy regarding the potential for increased respiratory effort to generate patient self-inflicted lung injury (P-SILI) in spontaneously breathing patients with COVID-19 acute hypoxaemic failure. However, direct clinical evidence linking inspiratory scarce. We adapted a computational simulator of cardiopulmonary pathophysiology quantify mechanical forces that could lead P-SILI at different levels effort. In accordance recent data, parameters were...

We show how an important class of nonlinear feedback controllers can be designed using idealized abstract chemical reactions and implemented via DNA strand displacement (DSD) reactions. Exploiting reaction networks (CRNs) as a programming language for the design complex circuits networks, we set unimolecular bimolecular used to realize input-output dynamics that produce quasi sliding mode (QSM) controller. The kinetics required then enzyme-free, enthalpy/entropy driven toehold mediated...

Nucleic acid-based chemistry is a strong candidate framework for the construction of future synthetic biomolecular control circuits. Previous work has demonstrated capacity circuits based on DNA strand displacement (DSD) reactions to implement digital and analogue signal processing in vivo, including mammalian cells. To date, however, feedback system designs attempted within this have been restricted extremely simple proportional or proportional-integral controller architectures. In letter,...

Biological systems that have been experimentally verified to be robust significant changes in their environments require mathematical models are themselves robust. In this context, a necessary condition for model robustness is the dynamics should not sensitive small variations model's parameters. Robustness analysis problems of type extensively studied field control theory and found very difficult solve general. The authors describe how some tools from nonlinear optimisation can used analyse...

Abstract A general anti‐windup (AW) compensation scheme is provided for a class of input constrained feedback‐linearizable nonlinear systems. The controller considered an inner‐loop dynamic inversion controller, augmented with outer‐loop linear arbitrary structure. For open‐loop globally exponentially stable plants, it shown that (i) there always exists stabilizing AW compensator corresponding to generalization the Internal‐Model‐Control (IMC) solution; (ii) important operator theoretic...

BackgroundPositive end-expiratory pressure (PEEP) is widely used to improve oxygenation and prevent alveolar collapse in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). Although PEEP improves arterial predictably, high-PEEP strategies have demonstrated equivocal improvements ARDS-related mortality. The effect of on tissue oxygen delivery poorly understood difficult quantify or investigate clinical environment.MethodsWe investigated effects ARDS using a...

Recent analyses of patient data in acute respiratory distress syndrome (ARDS) showed that a lower ventilator driving pressure was associated with reduced relative risk mortality. These findings await full validation prospective clinical trials.To investigate the association between pressures and induced lung injury (VILI), we calibrated high fidelity computational simulator cardiopulmonary pathophysiology against dataset, capturing responses to changes mechanical ventilation 25 adult ARDS...

Abstract Introduction and objectives High flow nasal cannula (HFNC) therapy is an increasingly popular mode of non-invasive respiratory support for the treatment patients with acute hypoxemic failure (AHRF). Previous experimental studies in healthy subjects have established that HFNC generates flow-dependent positive airway pressures, but no data available on levels mean pressure (mP aw ) or end-expiratory (PEEP) generated by AHRF patients. We aimed to estimate pressures at different rates...

Early identification of patients with acute hypoxemic respiratory failure (AHRF) who are at risk failing high-flow nasal cannula (HFNC) therapy could facilitate closer monitoring, and timely adjustment/escalation treatment. We aimed to establish whether machine learning (ML) models predict HFNC outcome, early in the course treatment, greater accuracy than currently used clinical indices. developed ML trained using measurements made within first 2 h treatment from 184 AHRF (37% failures)...

Clinical trials have, so far, failed to establish clear beneficial outcomes of recruitment maneuvers (RMs) on patient mortality in acute respiratory distress syndrome (ARDS), and the effects RMs cardiovascular system remain poorly understood. A computational model with highly integrated pulmonary systems was configured replicate static dynamic cardio-pulmonary data from clinical trials. Recruitment were executed 23 individual in-silico patients varying levels ARDS severity initial cardiac...

The application of two evolutionary optimization methods, namely, differential evolution and genetic algorithms, to the clearance nonlinear flight control laws for highly augmented aircraft is described. algorithms are applied problem evaluating a handling quality criterion simulation model high-performance with delta canard configuration full-authority law. Hybrid versions both incorporating local gradient-based optimization, also developed evaluated. Statistical comparisons computational...

The selection of mechanical ventilator settings that ensure adequate oxygenation and carbon dioxide clearance while minimizing the risk ventilator-associated lung injury (VALI) is a significant challenge for intensive-care clinicians. Current guidelines are largely based on previous experience combined with recommendations from limited number in vivo studies whose data typically more applicable to populations than individuals suffering particular diseases lung. By combining validated...

Mechanical power and driving pressure have been proposed as indicators, possibly drivers, of ventilator-induced lung injury. We tested the utility these different measures targets to derive maximally protective ventilator settings.A high-fidelity computational simulator was matched individual patient data used identify strategies that minimize pressure, mechanical power, a modified removes direct linear, positive dependence between end-expiratory pressure.Interdisciplinary Collaboration in...

Calmodulin is an important multifunctional molecule that regulates the activities of a large number proteins in cell. Calcium binding induces conformational transitions calmodulin make it specifically active to particular target proteins. The precise mechanisms underlying calcium are still, however, quite poorly understood. In this study, we adopt structural systems biology approach and develop mathematical model investigate various types cooperative calcium-calmodulin interactions. We...

The antizyme protein, Oaz1, regulates synthesis of the polyamines putrescine, spermidine and spermine by controlling stability polyamine biosynthetic enzyme, ornithine decarboxylase. Antizyme mRNA translation depends upon a polyamine-stimulated +1 ribosomal frameshift, forming complex negative feedback system in which translational frameshifting event may be viewed engineering terms as controller for intracellular concentrations. In this article, we present first systems level study...

Abstract Introduction Direct comparison of the relative efficacy different recruitment maneuvers (RMs) for patients with acute respiratory distress syndrome (ARDS) via clinical trials is difficult, due to heterogeneity patient populations and disease states, as well a variety practical issues. There also significant uncertainty regarding minimum values positive end-expiratory pressure (PEEP) required ensure maintenance effective lung using RMs. We used patient-specific computational...

The use of orthogonal ribosomes in combination with dynamic resource allocation controllers is a promising approach for relieving the negative effects cellular limitations on modularity synthetic gene circuits. Here, we develop detailed mechanistic model expression and allocation, which when simplified to tractable level complexity, allows rational design translational controllers. Analysis this reveals fundamental trade-off: that reducing coupling acts decrease expression. Through...