A Petri Net Model of Granulomatous Inflammation: Implications for IL-10 Mediated Control of Leishmania donovani Infection

Experimental visceral leishmaniasis, caused by infection of mice with the protozoan parasite Leishmania donovani, is characterized by focal accumulation of inflammatory cells in the liver, forming discrete “granulomas” within which the parasite is eventually eliminated. To shed new light on fundamental aspects of granuloma formation and function, we have developed an in silico Petri net model that simulates hepatic granuloma development throughout the course of infection. The model was extensively validated by comparison with data derived from experimental studies in mice, and the model robustness was assessed by a sensitivity analysis. The model recapitulated the progression of disease as seen during experimental infection and also faithfully predicted many of the changes in cellular composition seen within granulomas over time. By conducting in silico experiments, we have identified a previously unappreciated level of inter-granuloma diversity in terms of the development of anti-leishmanial activity. Furthermore, by simulating the impact of IL-10 gene deficiency in a variety of lymphocyte and myeloid cell populations, our data suggest a dominant local regulatory role for IL-10 produced by infected Kupffer cells at the core of the granuloma.     

Red Blood Cell Transfusion and Mortality in Trauma Patients: Risk-Stratified Analysis of an Observational Study

Background

Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.

Methods and Findings

A secondary analysis of the CRASH-2 trial (which originally evaluated the effect of tranexamic acid on mortality in trauma patients) was conducted. The trial included 20,127 trauma patients with significant bleeding from 274 hospitals in 40 countries. We evaluated the association of RBC transfusion with mortality in four strata of predicted risk of death: <6%, 6%–20%, 21%–50%, and >50%. For this analysis the exposure considered was RBC transfusion, and the main outcome was death from all causes at 28 days. A total of 10,227 patients (50.8%) received at least one transfusion. We found strong evidence that the association of transfusion with all-cause mortality varied according to the predicted risk of death (p-value for interaction <0.0001). Transfusion was associated with an increase in all-cause mortality among patients with <6% and 6%–20% predicted risk of death (odds ratio [OR] 5.40, 95% CI 4.08–7.13, p<0.0001, and OR 2.31, 95% CI 1.96–2.73, p<0.0001, respectively), but with a decrease in all-cause mortality in patients with >50% predicted risk of death (OR 0.59, 95% CI 0.47–0.74, p<0.0001). Transfusion was associated with an increase in fatal and non-fatal vascular events (OR 2.58, 95% CI 2.05–3.24, p<0.0001). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest (<6%) predicted risk of death (p-value for interaction <0.0001). As this was an observational study, the results could have been affected by different types of confounding. In addition, we could not consider haemoglobin in our analysis. In sensitivity analyses, excluding patients who died early; conducting propensity score analysis adjusting by use of platelets, fresh frozen plasma, and cryoprecipitate; and adjusting for country produced results that were similar.

Conclusions

The association of transfusion with all-cause mortality appears to vary according to the predicted risk of death. Transfusion may reduce mortality in patients at high risk of death but increase mortality in those at low risk. The effect of transfusion in low-risk patients should be further tested in a randomised trial.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01746953","term_id":"NCT01746953"}}NCT01746953 Please see later in the article for the Editors'' Summary     

When Is Visual Information Used to Control Locomotion When Descending a Kerb?

Background

Descending kerbs during locomotion involves the regulation of appropriate foot placement before the kerb-edge and foot clearance over it. It also involves the modulation of gait output to ensure the body-mass is safely and smoothly lowered to the new level. Previous research has shown that vision is used in such adaptive gait tasks for feedforward planning, with vision from the lower visual field (lvf) used for online updating. The present study determined when lvf information is used to control/update locomotion when stepping from a kerb.

Methodology/Principal Findings

12 young adults stepped down a kerb during ongoing gait. Force sensitive resistors (attached to participants'' feet) interfaced with an high-speed PDLC ‘smart glass’ sheet, allowed the lvf to be unpredictably occluded at either heel-contact of the penultimate or final step before the kerb-edge up to contact with the lower level. Analysis focussed on determining changes in foot placement distance before the kerb-edge, clearance over it, and in kinematic measures of the step down. Lvf occlusion from the instant of final step contact had no significant effect on any dependant variable (p>0.09). Occlusion of the lvf from the instant of penultimate step contact had a significant effect on foot clearance and on several kinematic measures, with findings consistent with participants becoming uncertain regarding relative horizontal location of the kerb-edge.

Conclusion/Significance

These findings suggest concurrent feedback of the lower limb, kerb-edge, and/or floor area immediately in front/below the kerb is not used when stepping from a kerb during ongoing gait. Instead heel-clearance and pre-landing-kinematic parameters are determined/planned using lvf information acquired in the penultimate step during the approach to the kerb-edge, with information related to foot placement before the kerb-edge being the most salient.     

Modular self-assembling and self-reconfiguring e-pucks

In this paper, we present the design of a new structural extension for the e-puck mobile robot. The extension may be used to transform what is traditionally a swarm robotics platform into a self-reconfigurable modular robotic system. We introduce a modified version of a previously developed collective locomotion algorithm and present new experimental results across three different themes. We begin by investigating how the performance of the collective locomotion algorithm is affected by the size and shape of the robotic structures involved, examining structures containing up to nine modules. Without alteration to the underlying algorithm, we then analyse the implicit self-assembling and self-reconfiguring capabilities of the system and show that the novel use of ‘virtual sensors’ can significantly improve performance. Finally, by examining a form of environment driven self-reconfiguration, we observe the behaviour of the system in a more complex environment. We conclude that the modular e-puck extension represents a viable platform for investigating collective locomotion, self-assembly and self-reconfiguration.     

The origin and characterization of new nuclear genes originating from a cytoplasmic organellar genome

Endosymbiotic transfer of DNA and functional genes from the cytoplasmic organelles (mitochondria and chloroplasts) to the nucleus has been a major factor driving the origin of new nuclear genes, a process central to eukaryote evolution. Although organelle DNA transfers very frequently to the nucleus, most is quickly deleted, decays, or is alternatively scrapped. However, a very small proportion of it gives rise, immediately or eventually, to functional genes. To simulate the process of functional transfer, we screened for nuclear activation of a chloroplast reporter gene aadA, which had been transferred from the chloroplast to independent nuclear loci in 16 different plant lines. Cryptic nuclear activity of the chloroplast promoter was revealed, which became conspicuous when present in multiple nuclear copies. We screened ～50 million cells of each line and retrieved three plants in which aadA showed strong nuclear activation. Activation occurred by acquisition of the CaMV 35S nuclear promoter or by nuclear activation of the native chloroplast promoter. Two fortuitous sites within the 3' UTR of aadA mRNA both promoted polyadenylation without any sequence change. Complete characterization of one nuclear sequence before and after gene transfer demonstrated integration by nonhomologous end joining involving simultaneous insertion of multiple chloroplast DNA fragments. The real-time observation of three different means by which a chloroplast gene can become expressed in the nucleus suggests that the process, though rare, may be more readily achieved than previously envisaged.     

Conservation of plastid sequences in the plant nuclear genome for millions of years facilitates endosymbiotic evolution

The nuclear genome of eukaryotes contains large amounts of cytoplasmic organelle DNA (nuclear integrants of organelle DNA [norgs]). The recent sequencing of many mitochondrial and chloroplast genomes has enabled investigation of the potential role of norgs in endosymbiotic evolution. In this article, we describe a new polymerase chain reaction-based method that allows the identification and evolutionary study of recent and older norgs in a range of eukaryotes. We tested this method in the genus Nicotiana and obtained sequences from seven nuclear integrants of plastid DNA (nupts) totaling 25 kb in length. These nupts were estimated to have been transferred 0.033 to 5.81 million years ago. The spectrum of mutations present in the potential protein-coding sequences compared with the noncoding sequences of each nupt revealed that nupts evolve in a nuclear-specific manner and are under neutral evolution. Indels were more frequent in noncoding regions than in potential coding sequences of former chloroplastic DNA, most probably due to the presence of a higher number of homopolymeric sequences. Unexpectedly, some potential protein-coding sequences within the nupts still contained intact open reading frames for up to 5.81 million years. These results suggest that chloroplast genes transferred to the nucleus have in some cases several millions of years to acquire nuclear regulatory elements and become functional. The different factors influencing this time frame and the potential role of nupts in endosymbiotic gene transfer are discussed.     

Late immature mortality is the major influence on reproductive success of African black beetle, Heteronychus arator (Fabricius) (Coleoptera: Scarabaeidae), in a Mediterranean-climate region of Australia

In field and laboratory studies, mortality of African black beetle, Heteronychus arator, in the winter-rainfall, Mediterranean-type climate region of south-western Australia was higher in the late immature stages during summer than in the early immature stages that occur during spring, a contrast to summer-rainfall climatic regions. Greatest mortality occurred around the pupal stage in contrasting soil types, despite drying differences in summer and supplementary watering in some plots. Sampling of natural populations confirmed experimental results that mortality in late immature stages is the major factor limiting H. arator populations under a Mediterranean-type climate. Inter-generation increase in H. arator abundance was uncommon, explaining the consistent abundance typically observed between years in south-western Australia. Random dispersal of newly emerged adults in autumn was inferred to restore uniformity in adult abundance between areas of varying favourability for immature survival.