In support of the placental programming hypothesis: Placental endocrine insufficiency programs atypical behaviour in mothers and their offspring

Prenatal adversity, which is estimated to impact more than half of all pregnancies in the UK, compromises fetal growth and increases the chances of stillbirth, prematurity and infant mortality. Beyond these immediate and highly visible problems, infants that survive carry the invisible burden of increased risk of some of the most common and pervasive diseases that impact human populations. In utero exposure to depression and anxiety is one adversity that has been linked to these poorer outcomes, suggesting that maternal mood disorders drive the outcomes. However, recent studies in animal models suggest that both the maternal mood disorders and the detrimental outcomes for children could be the result of the same underlying placental pathology. In these studies, genetically wild-type rodent mothers exposed to placental endocrine insufficiency engaged in less pup-focused behaviours and less self-care. Genetically wild-type rodent offspring raised in this abnormal environment exhibited increased anxiety-like behaviours, with male offspring additionally exhibiting deficits in cognition and atypical social behaviour, with some evidence of depressive-like symptoms. This work establishes experimentally that placental endocrine insufficiency alone is sufficient to drive atypical behaviour in both mothers and their offspring. Although there are some data to suggest that this phenomenon is relevant to human pregnancy, considerably more work is required

Prenatal adversity modulates the quality of maternal care via the exposed offspring

Adversities in pregnancy, including poor diet and stress, are associated with increased risk of developing both metabolic and mental health disorders later in life, a phenomenon described as fetal programming or developmental origins of disease. Predominant hypotheses proposed to explain this relationship suggest that the adversity imposes direct changes to the developing fetus which are maintained after birth resulting in an increased susceptibility to ill health. However, during pregnancy the mother, the developing fetus, and the placenta are all exposed to the adversity. The same adversities linked to altered offspring outcome can also result in suboptimal maternal care, which is considered an independent adverse exposure for the offspring. Recent key experiments in mice reveal the potential of prenatal adversity to drive alterations in maternal care through abnormal maternal–pup interactions and via alterations in placental signaling. Together, these data highlight the critical importance of viewing fetal programming holistically paying attention to the intimate, bidirectional, and reiterative relationship between mothers and their offspring

CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation

<p>Abstract</p> <p>Background</p> <p>CXCR4, the receptor for the chemokine stromal-derived factor 1 (SDF-1), has been shown to mediate many of the processes essential for cancer progression such as tumor cell proliferation, metastasis, and angiogenesis. To understand the role of CXCR4 in the biology of neuroblastoma, a disease that presents with wide spread metastases in over 50% of patients, we screened ten patient derived-neuroblastoma cell-lines for basal CXCR4 expression and sought to identify characteristics that correlate with tumor cell phenotype.</p> <p>Results</p> <p>All cell lines expressed <it>CXCR4 </it>mRNA at variable levels, that correlated well with three distinct classes of CXCR4 surface expression (low, moderate, or high) as defined by flow cytometry. Analysis of the kinetics of CXCR4 surface expression on moderate and high expressing cell lines showed a time-dependent down-regulation of the receptor that directly correlated with cell confluency, and was independent of SDF1. Cell lysates showed the presence of multiple CXCR4 isoforms with three major species of approximately 87, 67 and 55 kDa associating with high surface expression, and two distinct species of 45 and 38 kDa correlating with low to null surface expression. Western blot analysis of CXCR4 immunoprecipitates showed that the 87 and 67 kDa forms were ubiquitinated, while the others were not. Finally, treatment of cells with a proteasome inhibitor resulted in down regulation of CXCR4 surface expression.</p> <p>Conclusions</p> <p>Taken together, these data show that regulation of CXCR4 surface expression in neuroblastoma cells can occur independently of SDF-1 contribution arguing against an autocrine mechanism. Additionally these data suggest that post-translational modifications of CXCR4, in part through direct ubiquitination, can influence trafficking of CXCR4 to the surface of neuroblastoma cells in a ligand-independent manner.</p

Genomic imprinting and neurobehavioral programming by adverse early life environments: evidence from studying Cdkn1c

Imprinted genes are subject to epigenetic regulation that leads to monoallelic expression from one parental allele only. Brain expression of the imprinted gene Cdkn1c is sensitive to early life adversity, including exposure to maternal low protein diet (LPD) where increased expression of Cdkn1c is due to de-repression of the normally silent paternal allele. Maternal LPD also leads to changes in the dopamine system and reward related behaviours in offspring. We have recently demonstrated that these brain and behavioural phenotypes are recapitulated in a transgenic model in which Cdkn1c expressi alone is increased. Here we summarise these findings and suggest that the loss of imprinting of Cdkn1c in the offspring following maternal low protein diet is a key contributor to the associated changes in the dopamine system and behavior reported after early life adversity

Real-time forecasting of infectious disease dynamics with a stochastic semi-mechanistic model.

Real-time forecasts of infectious diseases can help public health planning, especially during outbreaks. If forecasts are generated from mechanistic models, they can be further used to target resources or to compare the impact of possible interventions. However, paremeterising such models is often difficult in real time, when information on behavioural changes, interventions and routes of transmission are not readily available. Here, we present a semi-mechanistic model of infectious disease dynamics that was used in real time during the 2013-2016 West African Ebola epidemic, and show fits to a Ebola Forecasting Challenge conducted in late 2015 with simulated data mimicking the true epidemic. We assess the performance of the model in different situations and identify strengths and shortcomings of our approach. Models such as the one presented here which combine the power of mechanistic models with the flexibility to include uncertainty about the precise outbreak dynamics may be an important tool in combating future outbreaks

Factors associated with dog ownership and contact with dogs in a UK community

BACKGROUND: Dogs are popular pets in many countries. Identifying differences between those who own dogs or have contact with dogs, and those who do not, is useful to those interested in the human-animal bond, human health and for provision of veterinary services. This census-based, epidemiological study aimed to investigate factors associated with dog ownership and contact with dogs, in a semi-rural community of 1278 households in Cheshire, UK. RESULTS: Twenty-four percent of households were identified as dog-owning and 52% owned a pet of some type. Multivariable logistic regression suggested that households were more likely to own a dog if they had more occupants (five or more); if they had an adult female household member; or if they owned a horse. The age structure of the households was also associated with dog ownership, with households containing older children (between six and 19 years of age) and young adults (between 20 and 29 years of age), more likely to own dogs. We also found that dog owning households were more likely to be multi-dog households than single-dog if they also owned a cat or a bird, or if the household contained a person of 20–29 years old. Dog owners reported increased contact with dogs, other than their own, compared to those that did not own dogs and this contact appeared to be mainly through walking. CONCLUSION: Some household types are more likely to own a dog than others. This study supports the suggestion that dogs are more common in families who have older children (6–19 years), as has been generally observed in other countries. Dog owners are also more likely to have contact with dogs other than their own, compared with those not owning a dog

Behavioural abnormalities in a novel mouse model for Silver Russell Syndrome

Silver Russell Syndrome (SRS) syndrome is an imprinting disorder involving low birth weight with complex genetics and diagnostics. Some rare SRS patients carry maternally inherited microduplications spanning the imprinted genes CDKN1C, PHLDA2, SLC22A18 and KCNQ1, suggesting that overexpression of one of more of these genes contributes to the SRS phenotype. While this molecular alteration is very rare, feeding difficulties are a very common feature of this condition. Given that SRS children also have very low body mass index, understanding the underpinning biology of the eating disorder is important, as well as potential co-occurring behavioural alterations. Here, we report that a mouse model of this microduplication exhibits a number of behavioural deficits. The mice had a blunted perception of the palatability of a given foodstuff. This perception may underpin the fussiness with food. We additionally report hypoactivity, unrelated to anxiety or motoric function, and a deficit in appropriate integration of incoming sensory information. Importantly, using a second genetic model, we were able to attribute all altered behaviours to elevated expression of a single gene, Cdkn1c. This is the first report linking elevated Cdkn1c to altered behaviour in mice. Importantly, the findings from our study may have relevance for SRS and highlight a potentially underreported aspect of this disorder

Assessing the performance of real-time epidemic forecasts: A case study of Ebola in the Western Area Region of Sierra Leone, 2014–15

AbstractReal-time forecasts based on mathematical models can inform critical decision-making during infectious disease outbreaks. Yet, epidemic forecasts are rarely evaluated during or after the event, and there is little guidance on the best metrics for assessment. Here, we propose an evaluation approach that disentangles different components of forecasting ability using metrics that separately assess the calibration, sharpness and unbiasedness of forecasts. This makes it possible to assess not just how close a forecast was to reality but also how well uncertainty has been quantified. We used this approach to analyse the performance of weekly forecasts we generated in real time in Western Area, Sierra Leone, during the 2013–16 Ebola epidemic in West Africa. We investigated a range of forecast model variants based on the model fits generated at the time with a semi-mechanistic model, and found that good probabilistic calibration was achievable at short time horizons of one or two weeks ahead but models were increasingly inaccurate at longer forecasting horizons. This suggests that forecasts may have been of good enough quality to inform decision making requiring predictions a few weeks ahead of time but not longer, reflecting the high level of uncertainty in the processes driving the trajectory of the epidemic. Comparing forecasts based on the semi-mechanistic model to simpler null models showed that the best semi-mechanistic model variant performed better than the null models with respect to probabilistic calibration, and that this would have been identified from the earliest stages of the outbreak. As forecasts become a routine part of the toolkit in public health, standards for evaluation of performance will be important for assessing quality and improving credibility of mathematical models, and for elucidating difficulties and trade-offs when aiming to make the most useful and reliable forecasts.</jats:p