Behavioral and epigenetic consequences of oxytocin treatment at birth.

Oxytocin is used in approximately half of all births in the United States during labor induction and/or augmentation. However, the effects of maternal oxytocin administration on offspring development have not been fully characterized. Here, we used the socially monogamous prairie vole to examine the hypothesis that oxytocin exposure at birth can have long-term developmental consequences. Maternally administered oxytocin increased methylation of the oxytocin receptor (Oxtr) in the fetal brain. As adults, oxytocin-exposed voles were more gregarious, with increased alloparental caregiving toward pups and increased close social contact with other adults. Cross-fostering indicated that these effects were the result of direct action on the offspring, rather than indirect effects via postnatal changes in maternal behavior. Male oxytocin-exposed offspring had increased oxytocin receptor density and expression in the brain as adults. These results show that long-term effects of perinatal oxytocin may be mediated by an epigenetic mechanism

Random Matrix Theory and Chiral Symmetry in QCD

Random matrix theory is a powerful way to describe universal correlations of eigenvalues of complex systems. It also may serve as a schematic model for disorder in quantum systems. In this review, we discuss both types of applications of chiral random matrix theory to the QCD partition function. We show that constraints imposed by chiral symmetry and its spontaneous breaking determine the structure of low-energy effective partition functions for the Dirac spectrum. We thus derive exact results for the low-lying eigenvalues of the QCD Dirac operator. We argue that the statistical properties of these eigenvalues are universal and can be described by a random matrix theory with the global symmetries of the QCD partition function. The total number of such eigenvalues increases with the square root of the Euclidean four-volume. The spectral density for larger eigenvalues (but still well below a typical hadronic mass scale) also follows from the same low-energy effective partition function. The validity of the random matrix approach has been confirmed by many lattice QCD simulations in a wide parameter range. Stimulated by the success of the chiral random matrix theory in the description of universal properties of the Dirac eigenvalues, the random matrix model is extended to nonzero temperature and chemical potential. In this way we obtain qualitative results for the QCD phase diagram and the spectrum of the QCD Dirac operator. We discuss the nature of the quenched approximation and analyze quenched Dirac spectra at nonzero baryon density in terms of an effective partition function. Relations with other fields are also discussed.Comment: invited review article for Ann. Rev. Nucl. Part. Sci., 61 pages, 11 figures, uses ar.sty (included); references added and typos correcte

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Does Uptake of Pharmaceuticals Vary Across Earthworm Species?

This study compared the uptake and depuration of four commonly used pharmaceuticals (carbamazepine, diclofenac, fluoxetine and orlistat) in two earthworm species (Lumbricus terrestris and Eisenia fetida). L. terrestris are a larger species and often found in deep burrows whereas E. fetida prefer to reside near the soil surface. Species burrowing habits and sizes may alter uptake by earthworms. All four pharmaceuticals were taken up into both L. terrestris and E. fetida tissue after 21 days exposure to spiked soil. Bioconcentration factors (BCFs) ranged between 1.72 and 29.83 for L. terrestris and 1.14 and 63.03 for E. fetida. For carbamazepine and diclofenac, BCFs were similar whereas for fluoxetine and orlistat, BCFs in E. fetida were more than double those seen in L. terrestris. Results indicate that uptake into earthworms cannot be generalised between species and that the influence of species traits can vary depending on the nature of the study chemical

Increased entropy of signal transduction in the cancer metastasis phenotype

Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis. Further exploration of such integrated cancer expression and protein interaction networks will therefore be a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table

Immunity against sexual stage Plasmodium falciparum and Plasmodium vivax parasites.

The efficient spread of malaria from infected humans to mosquitoes is a major challenge for malaria elimination initiatives. Gametocytes are the only Plasmodium life stage infectious to mosquitoes. Here, we summarize evidence for naturally acquired anti-gametocyte immunity and the current state of transmission blocking vaccines (TBV). Although gametocytes are intra-erythrocytic when present in infected humans, developing Plasmodium falciparum gametocytes may express proteins on the surface of red blood cells that elicit immune responses in naturally exposed individuals. This immune response may reduce the burden of circulating gametocytes. For both P. falciparum and Plasmodium vivax, there is a solid evidence that antibodies against antigens present on the gametocyte surface, when co-ingested with gametocytes, can influence transmission to mosquitoes. Transmission reducing immunity, reducing the burden of infection in mosquitoes, is a well-acknowledged but poorly quantified phenomenon that forms the basis for the development of TBV. Transmission enhancing immunity, increasing the likelihood or intensity of transmission to mosquitoes, is more speculative in nature but is convincingly demonstrated for P. vivax. With the increased interest in malaria elimination, TBV and monoclonal antibodies have moved to the center stage of malaria vaccine development. Methodologies to prioritize and evaluate products are urgently needed

An exploratory cluster randomised controlled trial of knowledge translation strategies to support evidence-informed decision-making in local governments (The KT4LG study)

Background: Childhood overweight and obesity is the most prevalent and, arguably, politically complex child health problem internationally. Governments, communities and industry have important roles to play, and are increasingly expected to deliver an evidence-informed system-wide prevention program. However, efforts are impeded by a lack of organisational access to and use of research evidence. This study aims to identify feasible, acceptable and ideally, effective knowledge translation (KT) strategies to increase evidence-informed decision making in local governments, within the context of childhood obesity prevention as a national policy priority.Methods/Design: This paper describes the methods for KT4LG, a cluster randomised controlled trial which is exploratory in nature, given the limited evidence base and methodological advances. KT4LG aims to examine a program of KT strategies to increase the use of research evidence in informing public health decisions in local governments. KT4LG will also assess the feasibility and acceptability of the intervention. The intervention program comprises a facilitated program of evidence awareness, access to tailored research evidence, critical appraisal skills development, networking and evidence summaries and will be compared to provision of evidence summaries alone in the control program. 28 local governments were randomised to intervention or control, using computer generated numbers, stratified by budget tertile (high, medium or low). Questionnaires will be used to measure impact, costs, and outcomes, and key informant interviews will be used to examine processes, feasibility, and experiences. Policy tracer studies will be included to examine impact of intervention on policies within relevant government policy documents.Discussion: Knowledge translation intervention studies with a focus on public health and prevention are very few in number. Thus, this study will provide essential data on the experience of program implementation and evaluation of a system-integrated intervention program employed within the local government public health context. Standardised programs of system, organisational and individual KT strategies have not been described or rigorously evaluated. As such, the findings will make a significant contribution to understanding whether a facilitated program of KT strategies hold promise for facilitating evidence-informed public health decision making within complex multisectoral government organisations.<br /

Genomic Analysis of Salmonella enterica Serovar Typhimurium DT160 Associated with a 14-Year Outbreak, New Zealand, 1998–2012

During 1998–2012, an extended outbreak of Salmonella enterica serovar Typhimurium definitive type 160 (DT160) affected >3,000 humans and killed wild birds in New Zealand. However, the relationship between DT160 within these 2 host groups and the origin of the outbreak are unknown. Whole-genome sequencing was used to compare 109 Salmonella Typhimurium DT160 isolates from sources throughout New Zealand. We provide evidence that DT160 was introduced into New Zealand around 1997 and rapidly propagated throughout the country, becoming more genetically diverse over time. The genetic heterogeneity was evenly distributed across multiple predicted functional protein groups, and we found no evidence of host group differentiation between isolates collected from human, poultry, bovid, and wild bird sources, indicating ongoing transmission between these host groups. Our findings demonstrate how a comparative genomic approach can be used to gain insight into outbreaks, disease transmission, and the evolution of a multihost pathogen after a probable point-source introduction

Under pressure: Response urgency modulates striatal and insula activity during decision-making under risk

When deciding whether to bet in situations that involve potential monetary loss or gain (mixed gambles), a subjective sense of pressure can influence the evaluation of the expected utility associated with each choice option. Here, we explored how gambling decisions, their psychophysiological and neural counterparts are modulated by an induced sense of urgency to respond. Urgency influenced decision times and evoked heart rate responses, interacting with the expected value of each gamble. Using functional MRI, we observed that this interaction was associated with changes in the activity of the striatum, a critical region for both reward and choice selection, and within the insula, a region implicated as the substrate of affective feelings arising from interoceptive signals which influence motivational behavior. Our findings bridge current psychophysiological and neurobiological models of value representation and action-programming, identifying the striatum and insular cortex as the key substrates of decision-making under risk and urgency

Neural Circuitry of Emotional and Cognitive Conflict Revealed through Facial Expressions

Neural systems underlying conflict processing have been well studied in the cognitive realm, but the extent to which these overlap with those underlying emotional conflict processing remains unclear. A novel adaptation of the AX Continuous Performance Task (AX-CPT), a stimulus-response incompatibility paradigm, was examined that permits close comparison of emotional and cognitive conflict conditions, through the use of affectively-valenced facial expressions as the response modality.Brain activity was monitored with functional magnetic resonance imaging (fMRI) during performance of the emotional AX-CPT. Emotional conflict was manipulated on a trial-by-trial basis, by requiring contextually pre-cued facial expressions to emotional probe stimuli (IAPS images) that were either affectively compatible (low-conflict) or incompatible (high-conflict). The emotion condition was contrasted against a matched cognitive condition that was identical in all respects, except that probe stimuli were emotionally neutral. Components of the brain cognitive control network, including dorsal anterior cingulate cortex (ACC) and lateral prefrontal cortex (PFC), showed conflict-related activation increases in both conditions, but with higher activity during emotion conditions. In contrast, emotion conflict effects were not found in regions associated with affective processing, such as rostral ACC.These activation patterns provide evidence for a domain-general neural system that is active for both emotional and cognitive conflict processing. In line with previous behavioural evidence, greatest activity in these brain regions occurred when both emotional and cognitive influences additively combined to produce increased interference