Fetal programming of schizophrenia: select mechanisms

Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia.

Endurance training in early life results in long-term programming of heart mass in rats

Being born small for gestational age increases the risk of developing adult cardiovascular and metabolic diseases. This study aimed to examine if early-life exercise could increase heart mass in the adult hearts from growth restricted rats. Bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction in the offspring (Restricted) or sham surgery (Control) was performed on day 18 of gestation in WKY rats. A separate group of sham litters had litter size reduced to five pups at birth (Reduced litter), which restricted postnatal growth. Male offspring remained sedentary or underwent treadmill running from 5 to 9 weeks (early exercise) or 20 to 24 weeks of age (later exercise). Remarkably, in Control, Restricted, and Reduced litter groups, early exercise increased (P < 0.05) absolute and relative (to body mass) heart mass in adulthood. This was despite the animals being sedentary for ~4 months after exercise. Later exercise also increased adult absolute and relative heart mass (P < 0.05). Blood pressure was not significantly altered between groups or by early or later exercise. Phosphorylation of Akt Ser(473) in adulthood was increased in the early exercise groups but not the later exercise groups. Microarray gene analysis and validation by real-time PCR did not reveal any long-term effects of early exercise on the expression of any individual genes. In summary, early exercise programs the heart for increased mass into adulthood, perhaps by an upregulation of protein synthesis based on greater phosphorylation of Akt Ser(473).

Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats

Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1α levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction.

Maternal prenatal mental health and placental 11β-HSD2 gene expression: initial findings from the mercy pregnancy and emotional wellbeing study

High intrauterine cortisol exposure can inhibit fetal growth and have programming effects for the child's subsequent stress reactivity. Placental 11beta-hydroxysteroid dehydrogenase (11β-HSD2) limits the amount of maternal cortisol transferred to the fetus. However, the relationship between maternal psychopathology and 11β-HSD2 remains poorly defined. This study examined the effect of maternal depressive disorder, antidepressant use and symptoms of depression and anxiety in pregnancy on placental 11β-HSD2 gene (HSD11B2) expression. Drawing on data from the Mercy Pregnancy and Emotional Wellbeing Study, placental HSD11B2 expression was compared among 33 pregnant women, who were selected based on membership of three groups; depressed (untreated), taking antidepressants and controls. Furthermore, associations between placental HSD11B2 and scores on the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) during 12-18 and 28-34 weeks gestation were examined. Findings revealed negative correlations between HSD11B2 and both the EPDS and STAI (r = -0.11 to -0.28), with associations being particularly prominent during late gestation. Depressed and antidepressant exposed groups also displayed markedly lower placental HSD11B2 expression levels than controls. These findings suggest that maternal depression and anxiety may impact on fetal programming by down-regulating HSD11B2, and antidepressant treatment alone is unlikely to protect against this effect.

Epigenetic regulation of neurodevelopmental genes in response to in utero exposure to phthalate plastic chemicals: how can we delineate causal effects?

Accumulating evidence, from animal models and human observational studies, implicates the in utero (and early postnatal) environment in the 'programming' of risk for a variety of adverse outcomes and health trajectories. The modern environment is replete with man-made compounds such as plastic product chemicals (PPC), including phenols and phthalates. Evidence from several human cohorts implicates exposure to these chemicals in adverse offspring neurodevelopment, though a direct causal relationship has not been firmly established. In this review we consider a potential causal pathway that encompasses epigenetic human variation, and how we might test this mechanistic hypothesis in human studies. In the first part of this report we outline how PPCs induce epigenetic change, focusing on the brain derived neurotrophic factor (BDNF) gene, a key regulator of neurodevelopment. Further, we discuss the role of the epigenetics of BDNF and other genes in neurodevelopment and the emerging human evidence of an association between phthalate exposure and adverse offspring neurodevelopment. We discuss aspects of epidemiological and molecular study design and analysis that could be employed to strengthen the level of human evidence to infer causality. We undertake this using an exemplar recent research example: maternal prenatal smoking, linked to methylation change at the aryl hydrocarbon receptor repressor (AHRR) gene at birth, now shown to mediate some of the effects of maternal smoking on birth weight. Characterizing the relationship between the modern environment and the human molecular pathways underpinning its impact on early development is paramount to understanding the public health significance of modern day chemical exposures.

Combining extension matrix and integer programming for optimal concept learning

This paper proposes two integer programming models and their GA-based solutions for optimal concept learning. The models are built to obtain the optimal concept description in the form of propositional logic formulas from examples based on completeness, consistency and simplicity. The simplicity of the propositional rules is selected as the objective function of the integer programming models, and the completeness and consistency of the concept are used as the constraints. Considering the real-world problems that certain level of noise is contained in data set, the constraints in model 11 are slacked by adding slack-variables. To solve the integer programming models, genetic algorithm is employed to search the global solution space. We call our approach IP-AE. Its effectiveness is verified by comparing the experimental results with other well- known concept learning algorithms: AQ15 and C4.5.

Achieving behaviour change: three generations of HIV/AIDS programming and jargon in Thailand

NGOs have played an important role worldwide in the fight to prevent the spread of HIV/AIDS through achieving behaviour change. NGOs have often been at the forefront of innovative changes, influencing government and international programming activities. This paper identifies and analyses the evolution of the HIV/AIDS programmes of one NGO in Thailand over a period of ten years. Three generations of programming are identified both through distinct approaches to this area of work and through the changing jargon used to describe the people the programmes are aimed at.

Design guidelines for children programming in school environment

This paper describes design guidelines of a programming environment for children, aiming to lower the barriers for children to learn programming. Our model called GBuilder has been developed on the basis of guidelines, with the express purpose of enabling and empowering the students to develop their own learning programs in survival literacy within enjoyable and fun environment.

Implementation of novel methods of global and nonsmooth optimization : GANSO programming library

We discuss the implementation of a number of modern methods of global and nonsmooth continuous optimization, based on the ideas of Rubinov, in a programming library GANSO. GANSO implements the derivative-free bundle method, the extended cutting angle method, dynamical system-based optimization and their various combinations and heuristics. We outline the main ideas behind each method, and report on the interfacing with Matlab and Maple packages.

Opportunities and challenges with J2SE 5 for introductory programming teaching

The recent release of the Java version 5.0 "Tiger" introduces some significant language changes. For educators, some of these changes provide opportunities to improve teaching, while others pose additional problems that require awareness to avoid them. The authors have recently completed the inclusion of support for all new language features into a wellknown educational IDE for Java – BlueJ – and in the course of doing so evaluated each of them for usefulness in education, and developed pedagogic strategies to handle the inherent opportunities and challenges. This has formed the basis of the design of the features in BlueJ which support the language changes. In this paper, we describe the results of our evaluation, provide recommendations on treatment of the new features in introductory courses and discuss how BlueJ may be used to illustrate important aspects.

Programming your - objects (turtles, textboxes, sliders and buttons) in microworlds

This article outlines some new-object commands of Logo Microworlds and includes the use of buttons, sliders and programmable colours. The ability to assign object properties including font, colour and frames are discussed. As is assigning object-instructions and commands such as click on and clickoff, launch and cancel. Programming the turtle, making a new turtle, running simultaneous turtles, programming graphic colours and sliders as well as understanding dotimes are explored.