IDO1 is an Integral Mediator of Inflammatory Neovascularization.

The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects neovascularization in mouse models of oxygen-induced retinopathy and lung metastasis. Neovascularization in both models was significantly reduced in mice lacking IDO1, was similarly reduced with loss of IL6, and was restored in both cases by concomitant loss of IFNγ. Likewise, the lack of IDO1 or IL6 resulted in reduced metastatic tumor burden and increased survival, which the concomitant loss of IFNγ abrogated. This insight into IDO1\u27s involvement in pro-tumorigenic inflammatory neovascularization may have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications associated with neovascularization as well

Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

Background: There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon. Methods: Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth. Results: Neither genetic measure was associated with season or month of birth within the UKBB sample. Conclusions: As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure

Modeling current and potential distributions of mammal species using presence?only data: a case study on British deer

Aim: Decisions on wildlife conservation, management, and epidemiological risk are best based on robust evidence. The continual improvement of species distributions, such that they can be relied upon in decision?making, is important. Here we seek to refine aspects of a generic modelling approach and improve the utility of speciesdistribution maps.Location: Great Britain (GB).Methods: We applied a modeling framework based on hierarchical Bayesian species distribution models exploiting opportunistic occurrence records from citizen science datasets to predict both current and potential distributions for each of the six deerspecies known to be present in GB. Using the resulting maps, we performed a simple analysis of the overlap between species to illustrate possible contact, which we interpret as the relative risk of potential disease spread given an introduction.Results: Predicted distribution maps showed good agreement with the broader scale occurrence reported by a recent national deer survey with an average True Skill Statistics and AUC of 0.69 and 0.89, respectively. Aggregation of the maps for all species highlighted regions of central and eastern England as well as parts of Scotlandwhere extensive areas of range overlap could result in interspecific contact with consequences for risk assessments for diseases of deer. However, if populations are allowed to expand to their predicted potential, then areas of overlap, and therefore disease interspecific transmission risk, will become extensive and widespread across all of mainland Britain.Main conclusions: The generic modeling approach outlined performed well across all of the deer species tested, offering a robust and reliable tool through which current and potential animal distributions can be estimated and presented. Our application,intended to inform quantitative risk assessments, demonstrates the practical use of such outputs to generate the valuable evidence required to inform policy decisions on issues such as management strategy

Network Hawkes Process Models for Exploring Latent Hierarchy in Social Animal Interactions

Group-based social dominance hierarchies are of essential interest in animal behavior research. Studies often record aggressive interactions observed over time, and models that can capture such dynamic hierarchy are therefore crucial. Traditional ranking methods summarize interactions across time, using only aggregate counts. Instead, we take advantage of the interaction timestamps, proposing a series of network point process models with latent ranks. We carefully design these models to incorporate important characteristics of animal interaction data, including the winner effect, bursting and pair-flip phenomena. Through iteratively constructing and evaluating these models we arrive at the final cohort Markov-Modulated Hawkes process (C-MMHP), which best characterizes all aforementioned patterns observed in interaction data. We compare all models using simulated and real data. Using statistically developed diagnostic perspectives, we demonstrate that the C-MMHP model outperforms other methods, capturing relevant latent ranking structures that lead to meaningful predictions for real data

Asset Accumulation and Family Size

Utilizing panel data on families, estimates are made of the effects of children on asset accululation, asset composition, consumption, and family income. Young children are found to depress savings for young families but to increase savings for marriages of duration greater than five years. The principal channel through which children act to reduce savings is the decline in female earnings associated with the child- induced withdrawal of wives from the labor force. Family consumption actually decreases with the birth of a child, but this reduction is insufficient, for young families, to offset the fall in income. For families in which the wife does not work the estimates suggest that savings may actually increase with children.

Circulating microRNAs as biomarkers to assist the management of the malignant germ-cell-tumour subtype choriocarcinoma.

Germ-cell-tumours (GCTs) are heterogeneous and management is complex. The current conventional biomarkers, alpha-fetoprotein and human-chorionic-gonadotropin (HCG), have limited utility for diagnosis/follow-up as secretion is restricted to specific malignant-GCT subtypes and long half-life can make interpretation and clinical decision-making challenging. We sought to identify circulating microRNAs that reflected choriocarcinoma disease activity more accurately than HCG in a metastatic primary mediastinal nonseminomatous-GCT (PMNSGCT) case with elevated diagnostic serum HCG (>250,000U/L), consistent with pure choriocarcinoma. We undertook comprehensive microRNA profiling (n=754 microRNAs) using two 384-well TaqMan Low-Density-Array cards in 16 serum samples; 10 from PMNSGCT diagnosis/follow-up and six controls. Key findings underwent confirmatory qRT-PCR. We identified a serum panel of choriocarcinoma-specific ‘chromosome-19-microRNA-cluster’ (C19MC) microRNAs that were highly elevated at diagnosis but fell rapidly on treatment and normalised before the second full chemotherapy course. We also re-confirmed serum elevation of the previously identified malignant-GCT marker miR-371a-3p at diagnosis. These circulating microRNA markers reflected choriocarcinoma disease activity more accurately than serum HCG and real-time knowledge would have assisted clinical decision-making. With further study, these microRNA markers will facilitate future management of such patients and are likely to result in improved outcomes.Acknowledgment of research support: The authors acknowledge grant funding from the St. Baldrick’s Foundation [reference 358099], the Isaac Newton Trust [reference 15.40f], the Medical Research Council [reference MR/R001146/1] and Addenbrooke’s Charitable Trust [reference 23/17 B (iv)]. We are grateful for support from the Max Williamson Fund and from Christiane and Alan Hodson, in memory of their daughter Olivia. The funders were not involved in study design, data collection or interpretation, or decision to submit for publication

Vru (Sub0144) controls expression of proven and putative virulence determinants and alters the ability of Streptococcus uberis to cause disease in dairy cattle

The regulation and control of gene expression in response to differing environmental stimuli is crucial for successful pathogen adaptation and persistence. The regulatory gene vru of Streptococcus uberis encodes a stand-alone response regulator with similarity to the Mga of group A Streptococcus. Mga controls expression of a number of important virulence determinants. Experimental intramammary challenge of dairy cattle with a mutant of S. uberis carrying an inactivating lesion in vru showed reduced ability to colonize the mammary gland and an inability to induce clinical signs of mastitis compared with the wild-type strain. Analysis of transcriptional differences of gene expression in the mutant, determined by microarray analysis, identified a number of coding sequences with altered expression in the absence of Vru. These consisted of known and putative virulence determinants, including Lbp (Sub0145), SclB (Sub1095), PauA (Sub1785) and hasA (Sub1696)