A goal programming network for linear programming

Tank and Hopfield have shown that networks of analog neurons can be used to solve linear programming (LP) problems. We have re-examined their approach and found that their network model frequently computes solutions that are only suboptimal or that violate the LP problem's constraints. As their approach has proven unreliable, we have developed a new network model: the goal programming network. To this end, a network model was first developed for goal programming problems, a particular type of LP problems. From the manner the network operates on such problems, it was concluded that overconstrainedness, which is possibly present in an LP formulation, should be removed, and we have provided a simple procedure to accomplish this.     

Fetal programming of hypertension

Numerous epidemiological studies suggest an inverse relationship between low birth weight (LBW) and hypertension, an observation now supported by numerous animal studies. The mechanisms linking LBW and hypertension appear to be multifactorial and involve alterations in the normal regulatory systems and renal functions involved in the long-term control of arterial pressure. Recent studies using animal models of fetal programming suggest that programming during fetal life occurs in response to an adverse fetal environment and results in permanent adaptive responses that lead to structural and physiological alterations and the subsequent development of hypertension. This review summarizes the adaptive responses observed in the different models used to induce a suboptimal fetal environment and discusses insights into the mechanisms mediating the fetal programming of hypertension.     

Intrauterine programming of ageing

Ageing is an unavoidable corollary to being alive; the most intuitive interpretation of ageing being that it is the consequence of progressive body degeneration. In agreement with this, current models propose that ageing occurs through a stepwise accumulation of DNA damage, which ultimately limits the regenerative capacity of tissues. On the other hand, there is increasing evidence that fetal distress can influence the development of disease in adult life, a phenomenon known as ‘intrauterine programming’. The extent to which an intrauterine exposure to DNA damage can compromise lifespan remains unclear. My group has recently generated a murine model of a human syndrome linked to defective DNA repair and observed that these animals age prematurely, but the accumulation of DNA damage is restricted mostly to the embryonic period. Here, I discuss the implications of this finding and propose that ageing can be influenced by fetal distress.     

Fetal programming of neuropsychiatric disorders

Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207–223, 2016. © 2016 Wiley Periodicals, Inc.     

Sex-specificity in transgenerational epigenetic programming

Prenatal programming of the epigenome is a critical determinant in offspring outcome and stands at the interface between environment and genetics. Maternal experiences such as stress and obesity are associated with a host of neurodevelopmental and metabolic diseases, some of which have been characterized into the second and third generations. The mechanism through which determinants such as maternal diet or stress contribute to disease development likely involves a complex interaction between the maternal environment, placental changes, and epigenetic programming of the embryo. While we have begun to more fully appreciate and explore the epigenome in determination of disease risk, we know little as to the contribution embryo sex makes in epigenetic regulation. This review discusses the importance of sex differences in the transmission and inheritance of traits that are generated in the prenatal environment using models of maternal stress and diet.     

Circadian programming in cyanobacteria.

Prokaryotic cyanobacteria express robust circadian (daily) rhythms under the control of a timing mechanism that is independent of the cell division cycle. This biological clock orchestrates global regulation of gene expression. Competition experiments demonstrate that fitness is enhanced when the circadian period is consonant with the period of the environmental cycle. Mutational analyses have identified three clock genes in the organism, one of which is related to DNA recombinases and helicases. We propose a new model for the core 'clockwork' that implicates rhythmic changes in the status of the chromosome that underly the rhythms of gene expression.     

Nutritional programming of adult disease

Intrauterine and early neonatal life is a period of physiological plasticity, during which environmental influences may produce long-term effects. Both undernutrition and overnutrition during this period have been shown to change disease risk in adulthood. These effects are influenced by the type, timing and duration of inappropriate nutrition and by the previous nutritional environment and may not be reflected in changes in body size. An understanding of the interaction between nutrient imbalance and alteration of gene expression is likely to be the key to optimising future health outcomes.     

Glucocorticoid programming of adult disease

Fetal exposure to elevated levels of glucocorticoids can occur naturally when maternal glucocorticoids are elevated in times of stress or when exogenous glucocorticoids are administered. Epidemiological studies and animal models have shown that, whereas short-term benefits may be associated with fetal glucocorticoid exposure, long-term deleterious effects may arise. This review compares the effects of exposure to natural versus synthetic glucocorticoids and considers the ways in which the timing of the exposure and the sex of the fetus may influence outcomes. Some of the long-term effects of glucocorticoid exposure may be explained by epigenetic mechanisms.     

Predicting metabolic pathways by logic programming

This paper discusses logic programming and its application for the expert system I use to simulate the metabolic fate of substances. An expert system called Metabolexpert accepts the formula of the compound to be metabolized and produces a treelike picture of the metabolites generated together with the formula of the compounds. On request, three-dimensional (3D) pictures of the metabolites are also displayed and hydrophobicity (logP) values of the compounds calculated. A retrospective investigation of Metabolexpert's achievement showed that the expert system can reproduce almost all primary, secondary and tertiary metabolites of amphetamine. A compound series has been suggested for benchmark testing of metabolic transformation knowledge bases.     

Automated programming for bioinformatics algorithm deployment

Many bioinformatics solutions suffer from the lack of usable interface/platform from which results can be analyzed and visualized. Overcoming this hurdle would allow for more widespread dissemination of bioinformatics algorithms within the biological and medical communities. The algorithms should be accessible without extensive technical support or programming knowledge. Here, we propose a dynamic wizard platform that provides users with a Graphical User Interface (GUI) for most Java bioinformatics library toolkits. The application interface is generated in real-time based on the original source code. This platform lets developers focus on designing algorithms and biologists/physicians on testing hypotheses and analyzing results. AVAILABILITY: The open source code can be downloaded from: http://bcl.med.harvard.edu/proteomics/proj/APBA/.     

An application programming interface for CellNetAnalyzer

CellNetAnalyzer (CNA) is a MATLAB toolbox providing computational methods for studying structure and function of metabolic and cellular signaling networks. In order to allow non-experts to use these methods easily, CNA provides GUI-based interactive network maps as a means of parameter input and result visualization. However, with the availability of high-throughput data, there is a need to make CNA's functionality also accessible in batch mode for automatic data processing. Furthermore, as some algorithms of CNA are of general relevance for network analysis it would be desirable if they could be called as sub-routines by other applications. For this purpose, we developed an API (application programming interface) for CNA allowing users (i) to access the content of network models in CNA, (ii) to use CNA's network analysis capabilities independent of the GUI, and (iii) to interact with the GUI to facilitate the development of graphical plugins.Here we describe the organization of network projects in CNA and the application of the new API functions to these projects. This includes the creation of network projects from scratch, loading and saving of projects and scenarios, and the application of the actual analysis methods. Furthermore, API functions for the import/export of metabolic models in SBML format and for accessing the GUI are described. Lastly, two example applications demonstrate the use and versatile applicability of CNA's API. CNA is freely available for academic use and can be downloaded from http://www.mpi-magdeburg.mpg.de/projects/cna/cna.html.     

Neonatal programming of innate immune function

The early life environment can be crucial in influencing the development of an animal's long-term physiology. There is now much evidence to suggest that perinatal challenges to an animal's immune system will result in changes in adult rat behavior, physiology, and molecular pathways following a single inflammatory event during development caused by the bacterial endotoxin lipopolysaccharide (LPS). In particular, it is now apparent that neonatal LPS administration can influence the adult neuroimmune response to a second LPS challenge through hypothalamic-pituitary-adrenal axis modifications, some of which are caused by alterations in peripheral prostaglandin synthesis. These pronounced changes are accompanied by a variety of alterations in a number of disparate aspects of endocrine physiology, with significant implications for the health and well-being of the adult animal. In this review, we discuss the newly elucidated mechanisms by which neonatal immune challenge can permanently alter an animal's endocrine and metabolic physiology and the implications this has for various disease states.     

Mining parasite data using genetic programming

Genetic programming is a technique that can be used to tackle the hugely demanding data-processing problems encountered in the natural sciences. Application of genetic programming to a problem using parasites as biological tags demonstrates its potential for developing explanatory models using data that are both complex and noisy.