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

Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.

BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types. RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs. CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism. TRIAL REGISTRATION: Trial registration number NCT01701869

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

No Detectable Fertility Benefit from a Single Additional Mating in Wild Stalk-Eyed Flies

Background: Multiple mating by female insects is widespread, and the explanation(s) for repeated mating by females has been the subject of much discussion. Females may profit from mating multiply through direct material benefits that increase their own reproductive output, or indirect genetic benefits that increase offspring fitness. One particular direct benefit that has attracted significant attention is that of fertility assurance, as females often need to mate multiply to achieve high fertility. This hypothesis has never been tested in a wild insect population.Methodology/Principal Findings: Female Malaysian stalk-eyed flies (Teleopsis dalmanni) mate repeatedly during their lifetime, and have been shown to be sperm limited under both laboratory and field conditions. Here we ask whether receiving an additional mating alleviates sperm limitation in wild females. In our experiment one group of females received a single additional mating, while a control group received an interrupted, and therefore unsuccessful, mating. Females that received an additional mating did not lay more fertilised eggs in total, nor did they lay proportionately more fertilised eggs. Female fertility declined significantly through time, demonstrating that females were sperm limited. However, receipt of an additional mating did not significantly alter the rate of this decline.Conclusions/Significance: Our data suggest that the fertility consequences of a single additional mating were small. We discuss this effect (or lack thereof), and suggest that it is likely to be attributed to small ejaculate size, a high proportion of failed copulations, and the presence of X-linked meiotic drive in this species

Four patients with a history of acute exacerbations of COPD: implementing the CHEST/Canadian Thoracic Society guidelines for preventing exacerbations

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/ by/4.0

Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors

Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme

Spectral Pattern Recognition by a Two-Layer Perceptron: Effects of Training Set Size

Pattern recognition in urban areas is one of the most challenging issues in classifying satellite remote sensing data. Parametric pixel-by-pixel classification algorithms tend to perform poorly in this context. This is because urban areas comprise a complex spatial assemblage of disparate land cover types - including built structures, numerous vegetation types, bare soil and water bodies. Thus, there is a need for more powerful spectral pattern recognition techniques, utilizing pixel-by-pixel spectral information as the basis for automated urban land cover detection. This paper adopts the multi-layer perceptron classifier suggested and implemented in [5]. The objective of this study is to analyse the performance and stability of this classifier - trained and tested for supervised classification (8 a priori given land use classes) of a Landsat-5 TM image (270 x 360 pixels) from the city of Vienna and its northern surroundings - along with varying the training data set in the single-training-site case. The performance is measured in terms of total classification, map user's and map producer's accuracies. In addition, the stability with initial parameter conditions, classification error matrices, and error curves are analysed in some detail. (authors' abstract)Series: Discussion Papers of the Institute for Economic Geography and GIScienc

Optimising EEG-fMRI for Localisation of Focal Epilepsy in Children

BACKGROUND: Early surgical intervention in children with drug resistant epilepsy has benefits but requires using tolerable and minimally invasive tests. EEG-fMRI studies have demonstrated good sensitivity for the localization of epileptic focus but a poor yield although the reasons for this have not been systematically addressed. While adults EEG-fMRI studies are performed in the "resting state"; children are commonly sedated however, this has associated risks and potential confounds. In this study, we assessed the impact of the following factors on the tolerability and results of EEG-fMRI in children: viewing a movie inside the scanner; movement; occurrence of interictal epileptiform discharges (IED); scan duration and design efficiency. This work's motivation is to optimize EEG-fMRI parameters to make this test widely available to paediatric population. METHODS: Forty-six children with focal epilepsy and 20 controls (6-18) underwent EEG-fMRI. For two 10 minutes sessions subjects were told to lie still with eyes closed, as it is classically performed in adult studies ("rest sessions"), for another two sessions, subjects watched a child friendly stimulation i.e. movie ("movie sessions"). IED were mapped with EEG-fMRI for each session and across sessions. The resulting maps were classified as concordant/discordant with the presumed epileptogenic focus for each subject. FINDINGS: Movement increased with scan duration, but the movie reduced movement by ~40% when played within the first 20 minutes. There was no effect of movie on the occurrence of IED, nor in the concordance of the test. Ability of EEG-fMRI to map the epileptogenic region was similar for the 20 and 40 minute scan durations. Design efficiency was predictive of concordance. CONCLUSIONS: A child friendly natural stimulus improves the tolerability of EEG-fMRI and reduces in-scanner movement without having an effect on IED occurrence and quality of EEG-fMRI maps. This allowed us to scan children as young as 6 and obtain localising information without sedation. Our data suggest that ~20 minutes is the optimal length of scanning for EEG-fMRI studies in children with frequent IED. The efficiency of the fMRI design derived from spontaneous IED generation is an important factor for producing concordant results

Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza virus that expresses an altered nucleoprotein sequence

Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes

Mass distribution in our Galaxy

This article summarizes recent work on the luminosity and mass distribution of the Galactic bulge and disk, and on the mass of the Milky Way's dark halo. A new luminosity model consistent with the COBE NIR data and the apparent magnitude distributions of bulge clump giant stars has bulge/bar length of \simeq 3.5\kpc, axis ratios of 1:(0.3-0.4):0.3, and short disk scale-length (\simeq 2.1\kpc). Gas-dynamical flows in the potential of this model with constant M/L fit the terminal velocities in $10\deg\le |l| \le 50\deg$ very well. The luminous mass distribution with this M/L is consistent with the surface density of known matter near the Sun, but still underpredicts the microlensing optical depth towards the bulge. Together, these facts argue strongly for a massive, near-maximal disk in our $\sim L^\ast$, Sbc spiral Galaxy. While the outer rotation curve and global mass distribution are not as readily measured as in similar spiral galaxies, the dark halo mass estimated from satellite velocities is consistent with a flat rotation curve continuing on from the luminous mass distribution