Explicit kinetic heterogeneity: mechanistic models for interpretation of labeling data of heterogeneous cell populations

Estimation of division and death rates of lymphocytes in different conditions is vital for quantitative understanding of the immune system. Deuterium, in the form of deuterated glucose or heavy water, can be used to measure rates of proliferation and death of lymphocytes in vivo. Inferring these rates from labeling and delabeling curves has been subject to considerable debate with different groups suggesting different mathematical models for that purpose. We show that the three models that are most commonly used are in fact mathematically identical and differ only in their interpretation of the estimated parameters. By extending these previous models, we here propose a more mechanistic approach for the analysis of data from deuterium labeling experiments. We construct a model of "kinetic heterogeneity" in which the total cell population consists of many sub-populations with different rates of cell turnover. In this model, for a given distribution of the rates of turnover, the predicted fraction of labeled DNA accumulated and lost can be calculated. Our model reproduces several previously made experimental observations, such as a negative correlation between the length of the labeling period and the rate at which labeled DNA is lost after label cessation. We demonstrate the reliability of the new explicit kinetic heterogeneity model by applying it to artificially generated datasets, and illustrate its usefulness by fitting experimental data. In contrast to previous models, the explicit kinetic heterogeneity model 1) provides a mechanistic way of interpreting labeling data; 2) allows for a non-exponential loss of labeled cells during delabeling, and 3) can be used to describe data with variable labeling length

Reconciling Estimates of Cell Proliferation from Stable Isotope Labeling Experiments.

Stable isotope labeling is the state of the art technique for in vivo quantification of lymphocyte kinetics in humans. It has been central to a number of seminal studies, particularly in the context of HIV-1 and leukemia. However, there is a significant discrepancy between lymphocyte proliferation rates estimated in different studies. Notably, deuterated (2)H2-glucose (D2-glucose) labeling studies consistently yield higher estimates of proliferation than deuterated water (D2O) labeling studies. This hampers our understanding of immune function and undermines our confidence in this important technique. Whether these differences are caused by fundamental biochemical differences between the two compounds and/or by methodological differences in the studies is unknown. D2-glucose and D2O labeling experiments have never been performed by the same group under the same experimental conditions; consequently a direct comparison of these two techniques has not been possible. We sought to address this problem. We performed both in vitro and murine in vivo labeling experiments using identical protocols with both D2-glucose and D2O. This showed that intrinsic differences between the two compounds do not cause differences in the proliferation rate estimates, but that estimates made using D2-glucose in vivo were susceptible to difficulties in normalization due to highly variable blood glucose enrichment. Analysis of three published human studies made using D2-glucose and D2O confirmed this problem, particularly in the case of short term D2-glucose labeling. Correcting for these inaccuracies in normalization decreased proliferation rate estimates made using D2-glucose and slightly increased estimates made using D2O; thus bringing the estimates from the two methods significantly closer and highlighting the importance of reliable normalization when using this technique

Direct generation of photon triplets using cascaded photon-pair sources

Non-classical states of light, such as entangled photon pairs and number states, are essential for fundamental tests of quantum mechanics and optical quantum technologies. The most widespread technique for creating these quantum resources is the spontaneous parametric down-conversion (SPDC) of laser light into photon pairs. Conservation of energy and momentum in this process, known as phase-matching, gives rise to strong correlations which are used to produce two-photon entanglement in various degrees of freedom. It has been a longstanding goal of the quantum optics community to realise a source that can produce analogous correlations in photon triplets, but of the many approaches considered, none have been technically feasible. In this paper we report the observation of photon triplets generated by cascaded down-conversion. Here each triplet originates from a single pump photon, and therefore quantum correlations will extend over all three photons in a way not achievable with independently created photon pairs. We expect our photon-triplet source to open up new avenues of quantum optics and become an important tool in quantum technologies. Our source will allow experimental interrogation of novel quantum correlations, the post-selection free generation of tripartite entanglement without post- selection and the generation of heralded entangled-photon pairs suitable for linear optical quantum computing. Two of the triplet photons have a wavelength matched for optimal transmission in optical fibres, ideally suited for three-party quantum communication. Furthermore, our results open interesting regimes of non-linear optics, as we observe spontaneous down-conversion pumped by single photons, an interaction also highly relevant to optical quantum computing.Comment: 7 pages, 3 figures, 1 table; accepted by Natur

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

The flight feather moult pattern of the bearded vulture (Gypaetus barbatus).

Moult is an extremely time-consuming and energy-demanding task for large birds. In addition, there is a trade-off between the time devoted to moulting and that invested in other activities such as breeding and/or territory exploration. Moreover, it takes a long time to grow a long feather in large birds, and large birds that need to fly while moulting cannot tolerate large gaps in the wing, but only one or two simultaneously growing feathers. As a consequence, large birds take several years to complete a full moult cycle, and they resume the moult process during suboptimal conditions. A clear example of this pattern is the Bearded Vulture (Gypaetus barbatus), which needs 2-3 years for changing all flight feathers. Here we describe the sequence, extent, and timing of moult of 124 Bearded Vultures in detail for the first time. We found that extent and timing of flight feather moult was different between age classes. Subadults (from 3rd to 5th calendar year) started moult, on average, in early March, whereas adults only started moult, on average, in late April, possibly due to breeding requirements. Second calendar year individuals delayed onset of moult until the middle of May. In general, the moult lasted until November, and although adults started to moult later than subadults, they moulted more feathers. Subadults needed 3 years for moulting all flight feathers, whereas adults normally completed it in 2 years

Spatial heterogeneity of habitat suitability for Rift Valley fever occurrence in Tanzania: an ecological niche modelling approach

Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics

Effects of Grassland Management Practices on Ant Functional Groups in Central North America

Tallgrass prairies of central North America have experienced disturbances including fire and grazing for millennia. Little is known about the effects of these disturbances on prairie ants, even though ants are thought to play major roles in ecosystem maintenance. We implemented three management treatments on remnant and restored grassland tracts in the central U.S., and compared the effects of treatment on abundance of ant functional groups. Management treatments were: (1) patch-burn graze—rotational burning of three spatially distinct patches within a fenced tract, and growing-season cattle grazing; (2) graze-and-burn—burning entire tract every 3 years, and growing-season cattle grazing, and (3) burn-only—burning entire tract every 3 years, but no cattle grazing. Ant species were classified into one of four functional groups. Opportunist ants and the dominant ant species, Formica montana, were more abundant in burn-only tracts than tracts managed with either of the grazing treatments. Generalists were more abundant in graze-and-burn tracts than in burn-only tracts. Abundance of F. montana was negatively associated with pre-treatment time since fire, whereas generalist ant abundance was positively associated. F. montanawere more abundant in restored tracts than remnants, whereas the opposite was true for subdominants and opportunists. In summary, abundance of the dominant F. montana increased in response to intense disturbances that were followed by quick recovery of plant biomass. Generalist ant abundance decreased in response to those disturbances, which we attribute to the effects of competitive dominance of F. montana upon the generalists

Use of anthropogenic material affects bird nest arthropod community structure: influence of urbanisation, and consequences for ectoparasites and fledging success

Nests are a critically important factor in determining the breeding success of many species of birds. Nevertheless, we have surprisingly little understanding of how local environment helps shape materials used in construction, how this differs among related species using similar nest sites, or if materials used directly or indirectly influence the numbers of offspring successfully reared. We also have little understanding of any potential links between nest construction and the assemblage of invertebrates which inhabit the nest and in particular, with ectoparasites. We addressed these questions by monitoring the success rates of nest-box using Blue Tits Cyanistes caeruleus and Great Tits Parus major, from rural, urban greenspace and urban garden settings. We collected used nests, identified arthropods present, and measured the proportions of highly processed anthropogenic materials used in their construction. Some 25% of Great Tit nest materials were of an anthropogenic source and this was consistent across habitats, while Blue Tits used little (1-2%) except in gardens (~16%), suggesting that Great Tits preferentially sought out these materials. In fledged nests, increasing use of anthropogenic material was associated with lower general arthropod diversity and ectoparasite predator abundance (Blue Tits only) but higher levels of Siphonapterans (fleas). Higher arthropod diversity was associated with lower flea numbers, suggesting that increased diversity played a role in limiting flea numbers. No direct link was found between breeding success and either anthropogenic material usage, or arthropod diversity and abundance. However, breeding success declined with increasing urbanisation in both species and increased with nest weight in Blue Tits. The interplay between urbanisation and bird ecology is complex; our work shows that subtle anthropogenic influences may have indirect and unexpected consequences for urban birds

Microbial regulation of the soil carbon cycle: evidence from gene-enzyme relationships.

A lack of empirical evidence for the microbial regulation of ecosystem processes, including carbon (C) degradation, hinders our ability to develop a framework to directly incorporate the genetic composition of microbial communities in the enzyme-driven Earth system models. Herein we evaluated the linkage between microbial functional genes and extracellular enzyme activity in soil samples collected across three geographical regions of Australia. We found a strong relationship between different functional genes and their corresponding enzyme activities. This relationship was maintained after considering microbial community structure, total C and soil pH using structural equation modelling. Results showed that the variations in the activity of enzymes involved in C degradation were predicted by the functional gene abundance of the soil microbial community (R2&gt;0.90 in all cases). Our findings provide a strong framework for improved predictions on soil C dynamics that could be achieved by adopting a gene-centric approach incorporating the abundance of functional genes into process models

A multi-scale modelling framework to guide management of plant invasions in a transboundary context

Background Attention has recently been drawn to the issue of transboundary invasions, where species introduced and naturalized in one country cross international borders and become problematic in neighbouring countries. Robust modelling frameworks, able to identify the environmental drivers of invasion and forecast the current and future potential distribution of invasive species, are needed to study and manage invasions. Limitations due to the lack of species distribution and environmental data, or assumptions of modelling tools, often constrain the reliability of model predictions. Methods We present a multiscale spatial modelling framework for transboundary invasions, incorporating robust modelling frameworks (Multimodel Inference and Ensemble Modelling) to overcome some of the limitations. The framework is illustrated using Hakea sericea Schrad. (Proteaceae), a shrub or small tree native to Australia and invasive in several regions of the world, including the Iberian Peninsula. Two study scales were considered: regional scale (western Iberia, including mainland Portugal and Galicia) and local scale (northwest Portugal). At the regional scale, the relative importance of environmental predictors sets was evaluated and ranked to determine the main general drivers for the species distribution, while the importance of each environmental predictor was assessed at the local scale. The potential distribution of H. sericea was spatially projected for both scale areas. Results Model projections for western Iberia suggest that a large area is environmentally suitable in both Portugal and Spain. Climate and landscape composition sets were the most important determinants of this regional distribution of the species. Conversely, a geological predictor (schist lithology) was more important in explaining its local-scale distribution. Conclusions After being introduced to Portugal, H. sericea has become a transboundary invader by expanding in parts of Galicia (Spain). The fact that a larger area is predicted as environmentally suitable in Spain raises concerns regarding its potential continued expansion. This highlights the importance of transboundary cooperation in the early management of invasions. By reliably identifying drivers and providing spatial projections of invasion at multiple scales, this framework provides insights for the study and management of biological invasions, including the assessment of transboundary invasion risk.This work was funded by FEDER funds through the Operational Programme for Competitiveness Factors - COMPETE and by National Funds through FCT - Foundation for Science and Technology under the project PTDC/AAGMAA/4539/2012 / FCOMP-01-0124-FEDER-027863 (IND_CHANGE). J. Vicente is supported by POPH/FSE funds and by National Funds through FCT - Foundation for Science and Technology through Post-doctoral grant SFRH/BPD/84044/2012. D.M. Richardson acknowledges support from the DST-NRF Centre of Excellence for Invasion Biology and the National Research Foundation (grant 85417).info:eu-repo/semantics/publishedVersio