In vitro rescue of genital strains of Chlamydia trachomatis from interferon-γ and tryptophan depletion with indole-positive, but not indole-negative Prevotella spp.

© 2016 The Author(s). Background: The natural course of sexually transmitted infections caused by Chlamydia trachomatis varies between individuals. In addition to parasite and host effects, the vaginal microbiota might play a key role in the outcome of C. trachomatis infections. Interferon-gamma (IFN-γ), known for its anti-chlamydial properties, activates the expression of indoleamine 2,3-dioxygenase (IDO1) in epithelial cells, an enzyme that catabolizes the amino acid L- tryptophan into N-formylkynurenine, depleting the host cell's pool of tryptophan. Although C. trachomatis is a tryptophan auxotroph, urogenital strains (but not ocular strains) have been shown in vitro to have the ability to produce tryptophan from indole using the tryptophan synthase (trpBA) gene. It has been suggested that indole producing bacteria from the vaginal microbiota could influence the outcome of Chlamydia infection. Results: We used two in vitro models (treatment with IFN-γ or direct limitation of tryptophan), to study the effects of direct rescue by the addition of exogenous indole, or by the addition of culture supernatant from indole-positive versus indole-negative Prevotella strains, on the growth and infectivity of C. trachomatis. We found that only supernatants from the indole-positive strains, P. intermedia and P. nigrescens, were able to rescue tryptophan-starved C. trachomatis. In addition, we analyzed vaginal secretion samples to determine physiological indole concentrations. In spite of the complexity of vaginal secretions, we demonstrated that for some vaginal specimens with higher indole levels, there was a link to higher recovery of the Chlamydia under tryptophan-starved conditions, lending preliminary support to the critical role of the IFN-γ-tryptophan-indole axis in vivo. Conclusions: Our data provide evidence for the ability of both exogenous indole as well as supernatant from indole producing bacteria such as Prevotella, to rescue genital C. trachomatis from tryptophan starvation. This adds weight to the hypothesis that the vaginal microbiota (particularly from women with lower levels of lactobacilli and higher levels of indole producing anaerobes) may be intrinsically linked to the outcome of chlamydial infections in some women

Implementation of Pedestrian Meso Models in Portugal. VRU-TOO Deliverable 8.

DRIVE I Project "An Intelligent Traffic System for Vulnerable Road Users" created a computer model WLCAN1, which simulated the crossing behaviour of pedestrians on a length of urban street. Furthermore, a car-based assignment model SATURN was used to assess the effect on cars of pedestrian-friendly policies. The attitude towards this modelling work were very "Northern European" in four important senses: - The technical approach was based upon technology developed in Northern Europe for network models of cars, which are used widely throughout Northern Europe. - The behavioural sub-models used in WLCANl and SATURN were all taken from empirical results obtained in Northern Europe. - All data to feed and calibrate the models was collected at Northern European sites. - All the partners in the DRIVE I project were from Northern Europe, and so the model development automatically followed their way of thinking. The objectives of this deliverable are to assess the transferability of the modelling work of VULCANl (and subsequent updating in DRIVE 11) and SATURN to Portugal. These objectives cover both the transferability of empirically created behavioural sub-models as well as the usefulness of the technology to the practical end user

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

Background: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). Methods: Ovarian tumours from two independent data sets were characterised for defects in BRCA1,BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. Results: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10−11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10−5 and 10−29), and identified breast and pancreatic cell lines with BRCA defects. Conclusion: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers

Dynamic Bayesian belief network to model the development of walking and cycling schemes

This paper aims to describe a model which represents the formulation of decision-making processes (over a number of years) affecting the step-changes of walking and cycling (WaC) schemes. These processes can be seen as being driven by a number of causal factors, many of which are associated with the attitudes of a variety of factors, in terms of both determining whether any scheme will be implemented and, if it is implemented, the extent to which it is used. The outputs of the model are pathways as to how the future might unfold (in terms of a number of future time steps) with respect to specific pedestrian and cyclist schemes. The transitions of the decision making processes are formulated using a qualitative simulation method, which describes the step-changes of the WaC scheme development. In this article a Bayesian belief network (BBN) theory is extended to model the influence between and within factors in the dynamic decision making process

High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.

BACKGROUND: Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. METHODS: We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3). This trial is registered with ClinicalTrials.gov number NCT00419068. FINDINGS: 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6-88·2; p<0·0001). INTERPRETATION: Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. FUNDING: British Lung Foundation

Watermelon-derived extracellular vesicles influence human ex vivo placental cell behavior by altering intestinal secretions

Scope During pregnancy, mother-to-fetus transfer of nutrients is mediated by the placenta; sub-optimal placental development and/or function results in fetal growth restriction (FGR), and the attendant risk of stillbirth, neurodevelopmental delay, and non-communicable diseases in adulthood. A maternal diet high in fruit and vegetables lowers the risk of FGR but the association cannot be explained fully by known macro- and micronutrients. Methods and results This study investigates if dietary-derived extracellular vesicles (EVs) can regulate placental function. The study characterizes the microRNA and protein cargo of EVs isolated from watermelon, show they are actively internalized by human intestinal epithelial cells in vitro, use mass spectrometry to demonstrate that they alter the intestinal secretome and bioinformatic analyses to predict the likely affected pathways in cells/tissues distal to gut. Application of the watermelon EV-modified intestinal secretome to human placental trophoblast cells and ex vivo tissue explants affects the trophoblast proteome and key aspects of trophoblast behavior, including migration and syncytialization. Conclusion Dietary-derived plant EVs can modify intestinal communication with distal tissues, including the placenta. Harnessing the beneficial properties of dietary-derived plant EVs and/or exploiting their potential as natural delivery agents may provide new ways to improve placental function and reduce rates of FGR

Kinetic energy of solid neon by Monte Carlo with improved Trotter- and finite-size extrapolation

The kinetic energy of solid neon is calculated by a path-integral Monte Carlo approach with a refined Trotter- and finite-size extrapolation. These accurate data present significant quantum effects up to temperature T=20 K. They confirm previous simulations and are consistent with recent experiments.Comment: Text and figures revised for minor corrections (4 pages, 3 figures included by psfig

Timing of crystallization of the lunar magma ocean constrained by the oldest zircon

The Moon is thought to have formed through the consolidationof debris from the collision of a Mars-sized body with the Earthmore than 4,500 million years ago. The primitive Moon wascovered with a thick layer of melt known as the lunar magmaocean1, the crystallization of which resulted in the Moon?ssurface as it is observed today. There is considerable debate,however, over the precise timing and duration of the processof magma ocean crystallization. Here we date a zircon fromlunar breccias to an age of 4,4176 million years. This dateprovides a precise younger age limit for the solidification ofthe lunar magma ocean. We propose a model that suggestsan exponential rate of lunar crystallization, based on acombination of this oldest known lunar zircon and the age of theMoon-forming giant impact. We conclude that the formationof the Moon?s anorthositic crust followed the solidification of80?85% of the original melt, within about 100 million years ofthe collision. The existence of younger zircons2 is indicative ofthe continued solidification of a small percentage of melt for anextra 200?400 million years

A Cognitive Model of an Epistemic Community: Mapping the Dynamics of Shallow Lake Ecosystems

We used fuzzy cognitive mapping (FCM) to develop a generic shallow lake ecosystem model by augmenting the individual cognitive maps drawn by 8 scientists working in the area of shallow lake ecology. We calculated graph theoretical indices of the individual cognitive maps and the collective cognitive map produced by augmentation. The graph theoretical indices revealed internal cycles showing non-linear dynamics in the shallow lake ecosystem. The ecological processes were organized democratically without a top-down hierarchical structure. The steady state condition of the generic model was a characteristic turbid shallow lake ecosystem since there were no dynamic environmental changes that could cause shifts between a turbid and a clearwater state, and the generic model indicated that only a dynamic disturbance regime could maintain the clearwater state. The model developed herein captured the empirical behavior of shallow lakes, and contained the basic model of the Alternative Stable States Theory. In addition, our model expanded the basic model by quantifying the relative effects of connections and by extending it. In our expanded model we ran 4 simulations: harvesting submerged plants, nutrient reduction, fish removal without nutrient reduction, and biomanipulation. Only biomanipulation, which included fish removal and nutrient reduction, had the potential to shift the turbid state into clearwater state. The structure and relationships in the generic model as well as the outcomes of the management simulations were supported by actual field studies in shallow lake ecosystems. Thus, fuzzy cognitive mapping methodology enabled us to understand the complex structure of shallow lake ecosystems as a whole and obtain a valid generic model based on tacit knowledge of experts in the field.Comment: 24 pages, 5 Figure