The validity of quasi steady-state approximations in discrete stochastic simulations

In biochemical networks, reactions often occur on disparate timescales and can be characterized as either "fast" or "slow." The quasi-steady state approximation (QSSA) utilizes timescale separation to project models of biochemical networks onto lower-dimensional slow manifolds. As a result, fast elementary reactions are not modeled explicitly, and their effect is captured by non-elementary reaction rate functions (e.g. Hill functions). The accuracy of the QSSA applied to deterministic systems depends on how well timescales are separated. Recently, it has been proposed to use the non-elementary rate functions obtained via the deterministic QSSA to define propensity functions in stochastic simulations of biochemical networks. In this approach, termed the stochastic QSSA, fast reactions that are part of non-elementary reactions are not simulated, greatly reducing computation time. However, it is unclear when the stochastic QSSA provides an accurate approximation of the original stochastic simulation. We show that, unlike the deterministic QSSA, the validity of the stochastic QSSA does not follow from timescale separation alone, but also depends on the sensitivity of the non-elementary reaction rate functions to changes in the slow species. The stochastic QSSA becomes more accurate when this sensitivity is small. Different types of QSSAs result in non-elementary functions with different sensitivities, and the total QSSA results in less sensitive functions than the standard or the pre-factor QSSA. We prove that, as a result, the stochastic QSSA becomes more accurate when non-elementary reaction functions are obtained using the total QSSA. Our work provides a novel condition for the validity of the QSSA in stochastic simulations of biochemical reaction networks with disparate timescales.Comment: 21 pages, 4 figure

Flexibility and development of mirroring mechanisms

The empirical support for the SCM is mixed. We review recent results from our own lab and others supporting a central claim of SCM that mirroring occurs at multiple levels of representation. By contrast, the model is silent as to why human infants are capable of showing imitative behaviours mediated by a mirror system. This limitation is a problem with formal models that address neither the neural correlates nor the behavioural evidence directly

Synthetic Biology and the Gut Microbiome

The gut microbiome plays a crucial role in maintaining human health. Functions performed by gastrointestinal microbes range from regulating metabolism to modulating immune and nervous system development. Scientists have attempted to exploit this importance through the development of engineered probiotics that are capable of producing and delivering small molecule therapeutics within the gut. However, existing synthetic probiotics are simplistic and fail to replicate the complexity and adaptability of native homeostatic mechanisms. In this review, the ways in which the tools and approaches of synthetic biology have been applied to improve the efficacy of therapeutic probiotics, and the ways in which they might be applied in the future is discussed. Simple devices, such as a bistable switches and integrase memory arrays, have been successfully implemented in the mammalian gut, and models for targeted delivery in this environment have also been developed. In the future, it will be necessary to introduce concepts such as logic-gating and biocontainment mechanisms into synthetic probiotics, as well as to expand the collection of relevant biosensors. Ideally, this will bring us closer to a reality in which engineered therapeutic microbes will be able to accurately diagnose and effectively respond to a variety of disease states

Transcriptional delay stabilizes bistable gene networks

Transcriptional delay can significantly impact the dynamics of gene networks. Here we examine how such delay affects bistable systems. We investigate several stochastic models of bistable gene networks and find that increasing delay dramatically increases the mean residence times near stable states. To explain this, we introduce a non-Markovian, analytically tractable reduced model. The model shows that stabilization is the consequence of an increased number of failed transitions between stable states. Each of the bistable systems that we simulate behaves in this manner

Valuing Carers 2021:England and Wales

This research, undertaken by Centre for Care colleagues Maria Petrillo and Matt Bennett, finds that the value of unpaid care in England and Wales is now estimated to be £162 billion, exceeding that of the entire NHS budget in England for health service spending.<br/

Insights Into Informal Caregivers’ Well-being:A Longitudinal Analysis of Care Intensity, Care Location, and Care Relationship

ObjectivesThis study investigates the psychological well-being of informal caregivers over time. It identifies the thresholds (or “tipping points”) of caring intensity at which caregiving is associated with lower psychological well-being, and how this varies by care location and caregiver–care recipient relationships. It also examines how caring location and relationship are linked to informal caregivers’ psychological well-being while controlling for caring intensity.MethodsWaves 1–18 (1991–2009) of the harmonized British Household Panel Survey and Waves 1–8 (2009–2017) of the U.K. Household Longitudinal Study were analyzed. Psychological well-being was measured using the General Health Questionnaire (GHQ)-12 score. Care intensity was measured by the weekly hours of care provided. Fixed-effects estimators were applied to the GHQ-12 score of caregivers across different care intensities, caring locations, and caring relationships.ResultsAll levels of informal care intensity are associated with lower psychological well-being among spousal caregivers. The thresholds to well-being are 5 hours per week when caring for a parent, and 50 hours per week when caring for a child (with a disability or long-term illness). Caring for “other relatives” or nonrelatives is not negatively associated with psychological well-being. The thresholds are 5 hours per week for both coresident and extraresident caregivers. Extraresident caregivers experience better psychological well-being compared to coresident caregivers, given relatively lower weekly care hours. Caring for primary kin (especially spouses) is linked to lower psychological well-being compared to other caregiving relationships, regardless of care intensity.DiscussionPolicy and practice responses should pay particular attention to spousal caregivers’ well-being. Caregiving relationship has a stronger association with the caregiver’s well-being than care location

Effects of cell cycle noise on excitable gene circuits

We assess the impact of cell cycle noise on gene circuit dynamics. For bistable genetic switches and excitable circuits, we find that transitions between metastable states most likely occur just after cell division and that this concentration effect intensifies in the presence of transcriptional delay. We explain this concentration effect with a 3-states stochastic model. For genetic oscillators, we quantify the temporal correlations between daughter cells induced by cell division. Temporal correlations must be captured properly in order to accurately quantify noise sources within gene networks.Comment: 15 pages, 8 figure

Stochastic Gene Expression in Single Gene Oscillator Variants

It is infeasible to understand all dynamics in cell, but we can aim to understand the impact of design choices under our control. Here we consider a single gene oscillator as a case study to understand the influence of DNA copy number and repressor choice on the resulting dynamics. We first switch the repressor in the oscillator from the originally published lacI to treRL, a chimeric repressor with a lacI DNA binding domain that is inducible by trehalose. This slightly modified system produces faster and more regular oscillations than the original lacI oscillator. We then compare the treRL oscillator at three different DNA copy numbers. The period and amplitude of oscillations increases as the copy number is decreased. We cannot explain the change in period with differential equation models without changing delays or degradation rates. The correlation and phase coherence between daughter cells after cell division also tend to fall off faster for the lower copy oscillator variants. These results suggest that lower copy number variants of our single gene oscillator produce more synchronized oscillations

Cycles of caring:transitions in and out of unpaid care

Our new research, undertaken by Centre for Care colleagues, Maria Petrillo, Matt Bennett and Gwilym Pryce, is released for Carers Rights Day (24th November 2022) and shows the astonishing numbers of people in the UK starting or ending an unpaid caring role each year