Gaian bottlenecks and planetary habitability maintained by evolving model biospheres: The ExoGaia model

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The search for habitable exoplanets inspires the question - how do habitable planets form? Planet habitability models traditionally focus on abiotic processes and neglect a biotic response to changing conditions on an inhabited planet. The Gaia hypothesis postulates that life influences the Earth's feedback mechanisms to form a self-regulating system, and hence that life can maintain habitable conditions on its host planet. If life has a strong influence, it will have a role in determining a planet's habitability over time. We present the ExoGaia model - a model of simple 'planets' host to evolving microbial biospheres. Microbes interact with their host planet via consumption and excretion of atmospheric chemicals. Model planets orbit a 'star' which provides incoming radiation, and atmospheric chemicals have either an albedo, or a heat-trapping property. Planetary temperatures can therefore be altered by microbes via their metabolisms. We seed multiple model planets with life while their atmospheres are still forming and find that the microbial biospheres are, under suitable conditions, generally able to prevent the host planets from reaching inhospitable temperatures, as would happen on a lifeless planet. We find that the underlying geochemistry plays a strong role in determining long-term habitability prospects of a planet. We find five distinct classes of model planets, including clear examples of 'Gaian bottlenecks' - a phenomenon whereby life either rapidly goes extinct leaving an inhospitable planet, or survives indefinitely maintaining planetary habitability. These results suggest that life might play a crucial role in determining the long-term habitability of planets.We thank the Gaia Charity and the University of Exeter for their support of this work

Alternative mechanisms for Gaia

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordA long-standing objection to the Gaia hypothesis has been a perceived lack of plausible mechanisms by which life on Earth could come to regulate its abiotic environment. A null hypothesis is survival by pure chance, by which any appearance of regulation on Earth is illusory and the persistence of life simply reflects the weak anthropic principle - it must have occurred for intelligent observers to ask the question. Recent work has proposed that persistence alone increases the chance that a biosphere will acquire further persistence-enhancing properties. Here we use a simple quantitative model to show that such ‘selection by survival alone’ can indeed increase the probability that a biosphere will persist in the future, relative to a baseline of pure chance. Adding environmental feedback to this model shows either an increased or decreased survival probability depending on the initial conditions. Feedback can hinder early life becoming established if initial conditions are poor, but feedback can also prevent systems from diverging too far from optimum environmental conditions and thus increase survival rates. The outstanding question remains the relative importance of each mechanism for the historical and continued persistence of life on Earth.Gaia CharityUniversity of Exete

Multiple states of environmental regulation in well-mixed model biospheres.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.The Gaia hypothesis postulates that life influences Earth's feedback mechanisms to form a self regulating system. This provokes the question: how can global self-regulation evolve? Most models demonstrating environmental regulation involving life have relied on alignment between local selection and global regulation. In these models environment-improving individuals or communities spread to outcompete environment degrading individuals/communities, leading to global regulation, but this depends on local differences in environmental conditions. In contrast, well-mixed components of the Earth system, such as the atmosphere, lack local environmental differentiation. These previous models do not explain how global regulation can emerge in a system with no well defined local environment, or where the local environment is overwhelmed by global effects. We present a model of self-regulation by 'microbes' in an environment with no spatial structure. These microbes affect an abiotic 'temperature' as a byproduct of metabolism. We demonstrate that global self-regulation can arise in the absence of spatial structure in a diverse ecosystem without localised environmental effects. We find that systems can exhibit nutrient limitation and two temperature limitation regimes where the temperature is maintained at a near constant value. During temperature regulation, the total temperature change caused by the microbes is kept near constant by the total population expanding or contracting to absorb the impacts of new mutants on the average affect on the temperature per microbe. Dramatic shifts between low temperature regulation and high temperature regulation can occur when a mutant arises that causes the sign of the temperature effect to change. This result implies that self-regulating feedback loops can arise without the need for spatial structure, weakening criticisms of the Gaia hypothesis that state that with just one Earth, global regulation has no mechanism for developing because natural selection requires selection between multiple entities.We thank the Gaia Charity and the University of Exeter for their support of this work

Multiple states of environmental regulation in well-mixed modle biospheres.

The Gaia hypothesis postulates that life influences Earth’s feedback mechanisms to form a self-regulating system. This provokes the question: how can global self-regulation evolve? Most models demonstrating environmental regulation involving life have relied on alignment between local selection and global regulation. In these models environment-improving individuals or communities spread to outcompete environment degrading individuals / communities, leading to global regulation, but this depends on local differences in environmental conditions. In contrast, well-mixed components of the Earth system, such as the atmosphere, lack local environmental differentiation. These previous models do not explain how global regulation can emerge in a system with no well-defined local environment, or where the local environment is overwhelmed by global effects. We present a model of self-regulation by ‘microbes’ in an environment with no spatial structure. These microbes affect an abiotic ‘temperature’ as a byproduct of metabolism. We demonstrate that global self-regulation can arise in the absence of spatial structure in a diverse ecosystem without localised environmental effects. We find that systems can exhibit nutrient limitation and two temperature limitation regimes where the temperature is maintained at a near constant value. During temperature regulation, the total temperature change caused by the microbes is kept near constant by the total population expanding or contracting to absorb the impacts of new mutants on the average affect on the temperature per microbe. Dramatic shifts between low temperature regulation and high temperature regulation can occur when a mutant arises that causes the sign of the temperature effect to change. This result implies that self-regulating feedback loops can arise without the need for spatial structure, weakening criticisms of the Gaia hypothesis that state that with just one Earth, global regulation has no mechanism for developing because natural selection requires selection between multiple entitie

Selection for Gaia across multiple scales

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Recently postulated mechanisms and models can help explain the enduring ‘Gaia’ puzzle of environmental regulation mediated by life. Natural selection can produce nutrient recycling at local scales and regulation of heterogeneous environmental variables at ecosystem scales. However, global-scale environmental regulation involves a temporal and spatial decoupling of effects from actors that makes conventional evolutionary explanations problematic. Instead, global regulation can emerge by a process of ‘sequential selection’ in which systems that destabilize their environment are short-lived and result in extinctions and reorganizations until a stable attractor is found. Such persistence-enhancing properties can in turn increase the likelihood of acquiring further persistence-enhancing properties through ‘selection by survival alone’. Thus, Earth system feedbacks provide a filter for persistent combinations of macroevolutionary innovations.T.M.L. was supported by a Royal Society Wolfson Research Merit Award. A.E.N. was supported by Gaia Charity and the University of Exeter

Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF

© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Rationale Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose. Methods We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung. Results We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF. Conclusions Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-ofmechanism trial of this agent is currently underway. Trial registration number NCT01725139, pre-clinical

Combining sport and conventional military training provides superior improvements in physical test performance

Training for both sporting and military performance is common practice within army trainee populations, although it is currently unknown what effect this combination of training methods may have on the physical attributes required for overall physical preparedness. This study examined the effects of sport-specific training on general fitness in a professional military population. Four hundred and twenty-three Greek male army cadets completed a 12-week training regimen involving standard physical training (callisthenics, strength and endurance running exercises) and either general military training (GMT) or sport military training (SMT). A series of physical tests took place before and after the training period: a mile run, pull-ups, 50 m swim and an obstacle course run. Both the GMT and SMT groups showed significant (p < 0.001) improvements in all physical tests. However, the SMT group produced significantly greater improvements in all four tests (pull-ups [p < 0.001], 50 m swim [p < 0.05], obstacle course [p < 0.01] and mile run [p < 0.01]) compared to the GMT group. Furthermore, different types of SMT (e.g. rock climbing and track sprinting) achieved greater improvements (p < 0.001–0.01) in certain physical tests when compared to other forms of SMT (e.g. Pankration, Fencing). These results indicate that cadets undertaking concurrent participation in general and sport military training are overall better prepared for physical performance than their counterparts who undertake only general military training. Military conditioning personnel should be aware of the positive interplay between general and sports specific training in forming a preparation strategy designed for physical performance

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

PURPOSE: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. METHODS: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti‐inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. RESULTS: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. CONCLUSIONS: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching