The local and systemic immune response to intrauterine LPS in the prepartum mouse

Inflammation plays a key role in human term and preterm labor (PTL). Intrauterine LPS has been widely used to model inflammation-induced complications of pregnancy, including PTL. It has been shown to induce an intense myometrial inflammatory cell infiltration, but the role of LPS-induced inflammatory cell activation in labor onset and fetal demise is unclear. We investigated this using a mouse model of PTL, where an intrauterine injection of 10 μg of LPS (serotype 0111:B4) was given at E16 of CD1 mouse pregnancy. This dose induced PTL at an average of 12.7 h postinjection in association with 85% fetal demise. Flow cytometry showed that LPS induced a dramatic systemic inflammatory response provoking a rapid and marked leucocyte infiltration into the maternal lung and liver in association with increased cytokine levels. Although there was acute placental inflammatory gene expression, there was no corresponding increase in fetal brain inflammatory gene expression until after fetal demise. There was marked myometrial activation of NFκB and MAPK/AP-1 systems in association with increased chemokine and cytokine levels, both of which peaked with the onset of parturition. Myometrial macrophage and neutrophil numbers were greater in the LPS-injected mice with labor onset only; prior to labor, myometrial neutrophils and monocytes numbers were greater in PBS-injected mice, but this was not associated with an earlier onset of labor. These data suggest that intrauterine LPS induces parturition directly, independent of myometrial inflammatory cell infiltration, and that fetal demise occurs without fetal inflammation. Intrauterine LPS provokes a marked local and systemic inflammatory response but with limited inflammatory cell infiltration into the myometrium or placenta

Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor.

Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at gestational day 16. Although control animals delivered at term 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 delivered 7 ± 2 hours p.i., O55:B5 delivered 10 ± 3 hours p.i., O127:B8 delivered 16 ± 10 hours p.i., and O128:B12 delivered 17 ± 2 hours p.i. (means ± SD). A correlation between the onset of preterm labor and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics

BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies

Is Acceleration Used for Ocular Pursuit and Spatial Estimation during Prediction Motion?

Here we examined ocular pursuit and spatial estimation in a linear prediction motion task that emphasized extrapolation of occluded accelerative object motion. Results from the ocular response up to occlusion showed that there was evidence in the eye position, velocity and acceleration data that participants were attempting to pursue the moving object in accord with the veridical motion properties. They then attempted to maintain ocular pursuit of the randomly-ordered accelerative object motion during occlusion but this was not ideal, and resulted in undershoot of eye position and velocity at the moment of object reappearance. In spatial estimation there was a general bias, with participants less likely to report object reappearance being behind than ahead of the expected position. In addition, participants’ spatial estimation did not take into account the effects of object acceleration. Logistic regression indicated that spatial estimation was best predicted for the majority of participants by the difference between actual object reappearance position and an extrapolation based on pre-occlusion velocity. In combination, and in light of previous work, we interpret these findings as showing that eye movements are scaled in accord with the effects of object acceleration but do not directly specify information for accurate spatial estimation in prediction motion

Progesterone, the maternal immune system and the onset of parturition in the mouse

The role of progesterone (P4) in the regulation of the local (uterine) and systemic innate immune system, myometrial expression of connexin 43 (Cx-43) and cyclooxygenase 2 (COX-2) and the onset of parturition was examined in: 1) naïve mice delivering at term; 2) E16 mice treated with RU486 (P4-antagonist) to induce preterm parturition; and 3) in mice treated with P4 to prevent term parturition.In naïve mice, myometrial neutrophil and monocyte numbers peaked at E18 and declined with the onset of parturition. In contrast, circulating monocytes did not change and although neutrophils were increased with pregnancy, they did not change across gestation. The myometrial mRNA and protein levels of most chemokines/cytokines, Cx-43 and COX-2 increased with, but not before, parturition.With RU486-induced parturition, myometrial and systemic neutrophil numbers increased before and myometrial monocyte numbers increased with parturition only. Myometrial chemokine/cytokine mRNA abundance increased with parturition, but protein levels peaked earlier at between 4.5 and 9h post RU486. Cx-43, but not COX-2, mRNA expression and protein levels increased prior to the onset of parturition.In mice treated with P4, the gestation-linked increase in myometrial monocyte, but not neutrophil, numbers was prevented and expression of Cx-43 and COX-2 was reduced. On E20 of P4 supplementation, myometrial chemokine/cytokine and leukocyte numbers, but not Cx-43 and COX-2 expression, increased.These data show that during pregnancy P4 controls myometrial monocyte infiltration, cytokine and prolabour factor synthesis via mRNA dependent and independent mechanisms and, with prolonged P4 supplementation, P4 action is repressed resulting in increased myometrial inflammation

A role for 3′-O-β-D-ribofuranosyladenosine in altering plant immunity

This is the final version. Available on open access from Elsevier via the DOI in this recordOur understanding of how, and the extent to which, phytopathogens reconfigure host metabolic pathways to enhance virulence is remarkably limited. Here we investigate the dynamics of the natural disaccharide nucleoside, 3′-O-β-D-ribofuranosyladenosine, in leaves of Arabidopsis thaliana infected with virulent Pseudomonas syringae pv. tomato strain DC3000. 3′-O-β-D-ribofuranosyladenosine is a plant derived molecule that rapidly accumulates following delivery of P. syringae type III effectors to represent a major component of the infected leaf metabolome. We report the first synthesis of 3′-O-β-D-ribofuranosyladenosine using a method involving the condensation of a small excess of 1-O-acetyl-2,3,5-three-O-benzoyl-β-ribofuranose activated with tin tetrachloride with 2′,5′-di-O-tert-butyldimethylsilyladenosine in 1,2-dichloroethane with further removal of silyl and benzoyl protecting groups. Interestingly, application of synthetic 3′-O-β-D-ribofuranosyladenosine did not affect either bacterial multiplication or infection dynamics suggesting a major reconfiguration of metabolism during pathogenesis and a heavy metabolic burden on the infected plant.Russian Science FoundationBiotechnology and Biological Sciences Research Council (BBSRC

High-resolution patterns and inequalities in ambient fine particle mass (PM2.5) and black carbon (BC) in the Greater Accra Metropolis, Ghana.

Growing cities in sub-Saharan Africa (SSA) experience high levels of ambient air pollution. However, sparse long-term city-wide air pollution exposure data limits policy mitigation efforts and assessment of the health and climate effects in growing cities. In the first study of its kind in West Africa, we developed high resolution spatiotemporal land use regression (LUR) models to map fine particulate matter (PM2.5) and black carbon (BC) concentrations in the Greater Accra Metropolitan Area (GAMA), one of the fastest sprawling metropolises in SSA. We conducted a one-year measurement campaign covering 146 sites and combined these data with geospatial and meteorological predictors to develop separate Harmattan and non-Harmattan season PM2.5 and BC models at 100 m resolution. The final models were selected with a forward stepwise procedure and performance was evaluated with 10-fold cross-validation. Model predictions were overlayed with the most recent census data to estimate the population distribution of exposure and socioeconomic inequalities in exposure at the census enumeration area level. The fixed effects components of the models explained 48-69 % and 63-71 % of the variance in PM2.5 and BC concentrations, respectively. Spatial variables related to road traffic and vegetation variables explained the most variability in the non-Harmattan models, while temporal variables were dominant in the Harmattan models. The entire GAMA population is exposed to PM2.5 levels above the World Health Organization guideline, including even the Interim Target 3 (15 μg/m3), with the highest exposures in poorer neighborhoods. The models can be used to support air pollution mitigation policies, health, and climate impact assessments. The measurement and modelling approach used in this study can be adapted to other African cities to bridge the air pollution data gap in the region

Who should be prioritized for renal transplantation?: Analysis of key stakeholder preferences using discrete choice experiments

Background Policies for allocating deceased donor kidneys have recently shifted from allocation based on Human Leucocyte Antigen (HLA) tissue matching in the UK and USA. Newer allocation algorithms incorporate waiting time as a primary factor, and in the UK, young adults are also favoured. However, there is little contemporary UK research on the views of stakeholders in the transplant process to inform future allocation policy. This research project aimed to address this issue. Methods Discrete Choice Experiment (DCE) questionnaires were used to establish priorities for kidney transplantation among different stakeholder groups in the UK. Questionnaires were targeted at patients, carers, donors / relatives of deceased donors, and healthcare professionals. Attributes considered included: waiting time; donor-recipient HLA match; whether a recipient had dependents; diseases affecting life expectancy; and diseases affecting quality of life. Results Responses were obtained from 908 patients (including 98 ethnic minorities); 41 carers; 48 donors / relatives of deceased donors; and 113 healthcare professionals. The patient group demonstrated statistically different preferences for every attribute (i.e. significantly different from zero) so implying that changes in given attributes affected preferences, except when prioritizing those with no rather than moderate diseases affecting quality of life. The attributes valued highly related to waiting time, tissue match, prioritizing those with dependents, and prioritizing those with moderate rather than severe diseases affecting life expectancy. Some preferences differed between healthcare professionals and patients, and ethnic minority and non-ethnic minority patients. Only non-ethnic minority patients and healthcare professionals clearly prioritized those with better tissue matches. Conclusions Our econometric results are broadly supportive of the 2006 shift in UK transplant policy which emphasized prioritizing the young and long waiters. However, our findings suggest the need for a further review in the light of observed differences in preferences amongst ethnic minorities, and also because those with dependents may be a further priority.</p