Intrinsic noise profoundly alters the dynamics and steady state of morphogen-controlled bistable genetic switches

During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signaling molecules - morphogens - guide this process. The continuous positional information provided by the gradient is converted into discrete cell types by the downstream transcriptional network that responds to the morphogen. A mechanism commonly used to implement a sharp transition between two adjacent cell fates is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses emphasize the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, stochastic switching introduces differences in patterning time along the morphogen gradient that result in a patterning wave propagating away from the morphogen source. The velocity of this wave is influenced by noise; the wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively alter developmental patterning

The Accidental Archivists: Lessons Learned from a Digital Archive Project

This article tells the story of the University of Colorado Law Library’s successful effort to develop its first digital archive. The sudden death of the Law School’s Dean was the catalyst for this project, with a goal to unveil the archive at a memorial symposium scheduled nine months in the future. The Law Library staff had never tackled a project of this type or scale before. This article discusses the technological, cataloging and management issues which were encountered during the project. It also provides advice and tips on how librarians in their own institutions can accomplish such a project

The Accidental Archivists: Lessons Learned from a Digital Archive Project

This article tells the story of the University of Colorado Law Library’s successful effort to develop its first digital archive. The sudden death of the Law School’s Dean was the catalyst for this project, with a goal to unveil the archive at a memorial symposium scheduled nine months in the future. The Law Library staff had never tackled a project of this type or scale before. This article discusses the technological, cataloging and management issues which were encountered during the project. It also provides advice and tips on how librarians in their own institutions can accomplish such a project

Interventions to minimise doctors’ mental ill-health and its impacts on the workforce and patient care: the Care Under Pressure realist review

BackgroundThe growing incidence of mental ill-health in health professionals, including doctors, is a global concern. Although a large body of literature exists on interventions that offer support, advice and/or treatment to sick doctors, it has not yet been synthesised in a way that takes account of the complexity and heterogeneity of the interventions, and the many dimensions (e.g. individual, organisational, sociocultural) of the problem.ObjectivesOur aim was to improve understanding of how, why and in what contexts mental health services and support interventions can be designed to minimise the incidence of doctors’ mental ill-health. The objectives were to review interventions to tackle doctors’ mental ill-health and its impact on the clinical workforce and patient care, drawing on diverse literature sources and engaging iteratively with diverse stakeholder perspectives to produce actionable theory; and recommendations that support the tailoring, implementation, monitoring and evaluation of contextually sensitive strategies to tackle mental ill-health and its impacts.DesignRealist literature review consistent with the Realist And Meta-narrative Evidence Syntheses: Evolving Standards quality and reporting standards.Data sourcesBibliographic database searches were developed and conducted using MEDLINE (1946 to November week 4 2017), MEDLINE In-Process and Other Non-indexed Citations (1946 to 6 December 2017) and PsycINFO (1806 to November week 2 2017) (all via Ovid) and Applied Social Sciences Index and Abstracts (1987 to 6 December 2017) (via ProQuest) on 6 December 2017. Further UK-based studies were identified by forwards and author citation searches, manual backwards citation searching and hand-searching relevant journal websites.Review methodsWe included all studies that focused on mental ill-health; all study designs; all health-care settings; all studies that included medical doctors/medical students; descriptions of interventions or resources that focus on improving mental ill-health and minimising its impacts; all mental health outcome measures, including absenteeism (doctors taking short-/long-term sick leave); presenteeism (doctors working despite being unwell); and workforce retention (doctors leaving the profession temporarily/permanently). Data were extracted from included articles and the data set was subjected to realist analysis to identify context–mechanism–outcome configurations.ResultsA total of 179 out of 3069 records were included. Most were from the USA (45%) and had been published since 2009 (74%). More included articles focused on structural-level interventions (33%) than individual-level interventions (21%), but most articles (46%) considered both levels. Most interventions focused on prevention, rather than treatment/screening, and most studies referred to doctors/physicians in general, rather than to specific specialties or career stages. Nineteen per cent of the included sources provided cost information and none reported a health economic analysis. The 19 context–mechanism–outcome configurations demonstrated that doctors were more likely to experience mental ill-health when they felt isolated or unable to do their job, and when they feared repercussions of help-seeking. Healthy staff were necessary for excellent patient care. Interventions emphasising relationships and belonging were more likely to promote well-being. Interventions creating a people-focused working culture, balancing positive/negative performance and acknowledging positive/negative aspects of a medical career helped doctors to thrive. The way that interventions were implemented seemed critically important. Doctors needed to have confidence in an intervention for the intervention to be effective.LimitationsVariable quality of included literature; limited UK-based studies.Future workUse this evidence synthesis to refine, implement and evaluate interventions

‘Care Under Pressure’: a realist review of interventions to tackle doctors’ mental ill-health and its impacts on the clinical workforce and patient care

Introduction Mental ill-health is prevalent across all groups of health professionals and this is of great concern in many countries. In the UK, the mental health of the National Health Service (NHS) workforce is a major healthcare issue, leading to presenteeism, absenteeism and loss of staff from the workforce. Most interventions targeting doctors aim to increase their 'productivity' and 'resilience', placing responsibility for good mental health with doctors themselves and neglecting the organisational and structural contexts that may have a detrimental effect on doctors' well-being. There is a need for approaches that are sensitive to the contextual complexities of mental ill-health in doctors, and that do not treat doctors as a uniform body, but allow distinctions to account for particular characteristics, such as specialty, career stage and different working environments. Methods and analysis Our project aims to understand how, why and in what contexts support interventions can be designed to minimise the incidence of doctors' mental ill-health. We will conduct a realist review-A form of theory-driven interpretative systematic review-of interventions, drawing on diverse literature sources. The review will iteratively progress through five steps: (1) locate existing theories; (2) search for evidence; (3) select articles; (4) extract and organise data and (5) synthesise evidence and draw conclusions. The analysis will summarise how, why and in what circumstances doctors' mental ill-health is likely to develop and what can remediate the situation. Throughout the project, we will also engage iteratively with diverse stakeholders in order to produce actionable theory. Ethics and dissemination Ethical approval is not required for our review. Our dissemination strategy will be participatory. Tailored outputs will be targeted to: policy makers; NHS employers and healthcare leaders; team leaders; support organisations; doctors experiencing mental ill-health, their families and colleagues

Optimising strategies to address mental ill-health in doctors and medical students: 'Care under Pressure' realist review and implementation guidance

© 2020 The Author(s). Background: Mental ill-health in health professionals, including doctors, is a global and growing concern. The existing literature on interventions that offer support, advice and/or treatment to sick doctors has not yet been synthesised in a way that considers the complexity and heterogeneity of the interventions, and the many dimensions of the problem. We (1) reviewed interventions to tackle doctors' and medical students' mental ill-health and its impacts on the clinical workforce and patient care - drawing on diverse literature sources and engaging iteratively with diverse stakeholder perspectives - and (2) produced recommendations that support the tailoring, implementation, monitoring and evaluation of contextually sensitive strategies to tackle mental ill-health and its impacts. Methods: Realist literature review consistent with the RAMESES quality and reporting standards. Sources for inclusion were identified through bibliographic database searches supplemented by purposive searches - resulting also from engagement with stakeholders. Data were extracted from included articles and subjected to realist analysis to identify (i) mechanisms causing mental ill-health in doctors and medical students and relevant contexts or circumstances when these mechanisms were likely to be 'triggered' and (ii) 'guiding principles' and features underpinning the interventions and recommendations discussed mostly in policy document, reviews and commentaries. Results: One hundred seventy-nine records were included. Most were from the USA (45%) and were published since 2009 (74%). The analysis showed that doctors were more likely to experience mental ill-health when they felt isolated or unable to do their job and when they feared repercussions of help-seeking. Healthy staff were necessary for excellent patient care. Interventions emphasising relationships and belonging were more likely to promote wellbeing. Interventions creating a people-focussed working culture, balancing positive/negative performance and acknowledging positive/negative aspects of a medical career helped doctors to thrive. The way that interventions were implemented seemed critically important. Doctors and medical students needed to have confidence in an intervention for the intervention to be effective. Conclusions: Successful interventions to tackle doctors' and students' mental ill-health are likely to be multidimensional and multilevel and involve multiple stakeholders. Evaluating and improving existing interventions is likely to be more effective than developing new ones. Our evidence synthesis provides a basis on which to do this. Study registration: PROSPERO CRD42017069870. Research project webpage http://sites.exeter.ac.uk/cup

Neuronal differentiation influences progenitor arrangement in the vertebrate neuroepithelium

Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube, in which neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we used experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates the effect of interkinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube

A gene regulatory motif that generates oscillatory or multiway switch outputs.

The pattern of gene expression in a developing tissue determines the spatial organization of cell type generation. We previously defined regulatory interactions between a set of transcription factors that specify the pattern of gene expression in progenitors of different neuronal subtypes of the vertebrate neural tube. These transcription factors form a circuit that acts as a multistate switch, patterning the tissue in response to a gradient of Sonic Hedgehog. Here, by simplifying aspects of the regulatory interactions, we found that the topology of the circuit allows either switch-like or oscillatory behaviour depending on parameter values. The qualitative dynamics appear to be controlled by a simpler sub-circuit, which we term the AC-DC motif. We argue that its topology provides a natural way to implement a multistate gene expression switch and we show that the circuit is readily extendable to produce more distinct stripes of gene expression. Our analysis also suggests that AC-DC motifs could be deployed in tissues patterned by oscillatory mechanisms, thus blurring the distinction between pattern-formation mechanisms relying on temporal oscillations or graded signals. Furthermore, during evolution, mechanisms of gradient interpretation might have arisen from oscillatory circuits, or vice versa

Insights into the influence of solvent polarity on the crystallization of poly(ethylene oxide) spin-coated thin films via in situ grazing incidence wide-angle X-ray scattering

Controlling polymer thin-film morphology and crystallinity is crucial for a wide range of applications, particularly in thin-film organic electronic devices. In this work, the crystallization behavior of a model polymer, poly(ethylene oxide) (PEO), during spin-coating is studied. PEO films were spun-cast from solvents possessing different polarities (chloroform, THF, and methanol) and probed via in situ grazing incidence wide-angle X-ray scattering. The crystallization behavior was found to follow the solvent polarity order (where chloroform chloroform > methanol). When spun-cast from nonpolar chloroform, crystallization largely followed Avrami kinetics, resulting in the formation of morphologies comprising large spherulites. PEO solutions cast from more polar solvents (THF and methanol) do not form well-defined highly crystalline morphologies and are largely amorphous with the presence of small crystalline regions. The difference in morphological development of PEO spun-cast from polar solvents is attributed to clustering phenomena that inhibit polymer crystallization. This work highlights the importance of considering individual components of polymer solubility, rather than simple total solubility, when designing processing routes for the generation of morphologies with optimum crystallinities or morphologies