Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease

Poor maternal nutrition during pregnancy can alter postnatal phenotype and increase susceptibility to adult cardiovascular and metabolic diseases. However, underlying mechanisms are largely unknown. Here, we show that maternal low protein diet (LPD), fed exclusively during mouse preimplantation development, leads to offspring with increased weight from birth, sustained hypertension, and abnormal anxiety-related behavior, especially in females. These adverse outcomes were interrelated with increased perinatal weight being predictive of later adult overweight and hypertension. Embryo transfer experiments revealed that the increase in perinatal weight was induced within blastocysts responding to preimplantation LPD, independent of subsequent maternal environment during later pregnancy. We further identified the embryo-derived visceral yolk sac endoderm (VYSE) as one mediator of this response. VYSE contributes to fetal growth through endocytosis of maternal proteins, mainly via the multiligand megalin (LRP2) receptor and supply of liberated amino acids. Thus, LPD maintained throughout gestation stimulated VYSE nutrient transport capacity and megalin expression in late pregnancy, with enhanced megalin expression evident even when LPD was limited to the preimplantation period. Our results demonstrate that in a nutrient-restricted environment, the preimplantation embryo activates physiological mechanisms of developmental plasticity to stablize conceptus growth and enhance postnatal fitness. However, activation of such responses may also lead to adult excess growth and cardiovascular and behavioral diseases. © 2008 by the Society for the Study of Reproduction, Inc.

Adaptive responses of the embryo to maternal diet and consequences for post-implantation development

Maternal periconceptional (PC) nutrition, coupled with maternal physiological condition, can impact on reproductive performance and potential across mammalian species. Oocyte quality and embryo development are affected adversely by either nutrient restriction or excess. Moreover, the quality of maternal PC nutrition can have lasting effects through fetal development and postnatally into adulthood. Chronic disease, notably cardiovascular and metabolic disease, and abnormal behaviour have been identified in adult offspring in small and large animal models of PC nutrient restriction. These long-term effects associate with compensatory responses that begin from the time of early embryo development. This review assesses the field of PC nutrition in vivo on short- and long-term developmental consequences in rodent and ruminant models and considers the implications for human health. © IETS 2012.

Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health

Previously, we have shown that a maternal low protein diet, fed exclusively during the preimplantation period of mouse development (Emb-LPD), is sufficient to induce by the blastocyst stage a compensatory growth phenotype in late gestation and postnatally, correlating with increased risk of adult onset cardiovascular disease and behavioural dysfunction. Here, we examine mechanisms of induction of maternal Emb-LPD programming and early compensatory responses by the embryo. Emb-LPD induced changes in maternal serum metabolites at the time of blastocyst formation (E3.5), notably reduced insulin and increased glucose, together with reduced levels of free amino acids (AAs) including branched chain AAs leucine, isoleucine and valine. Emb-LPD also caused reduction in the branched chain AAs within uterine fluid at the blastocyst stage. These maternal changes coincided with an altered content of blastocyst AAs and reduced mTORC1 signalling within blastocysts evident in reduced phosphorylation of effector S6 ribosomal protein and its ratio to total S6 protein but no change in effector 4E-BP1 phosphorylated and total pools. These changes were accompanied by increased proliferation of blastocyst trophectoderm and total cells and subsequent increased spreading of trophoblast cells in blastocyst outgrowths. We propose that induction of metabolic programming following Emb-LPD is achieved through mTORC1signalling which acts as a sensor for preimplantation embryos to detect maternal nutrient levels via branched chain AAs and/or insulin availability. Moreover, this induction step associates with changes in extra-embryonic trophectoderm behaviour occurring as early compensatory responses leading to later nutrient recovery. © 2012 Fleming et al.

Specific lipidome signatures in central nervous system from methionine-restricted mice

Membrane lipid composition is an important correlate of the rate of aging of animals. Dietary methionine restriction (MetR) increases lifespan in rodents. The underlying mechanisms have not been elucidated but could include changes in tissue lipidomes. In this work, we demonstrate that 80% MetR in mice induces marked changes in the brain, spinal cord, and liver lipidomes. Further, at least 50% of the lipids changed are common in the brain and spinal cord but not in the liver, suggesting a nervous system-specific lipidomic profile of MetR. The differentially expressed lipids includes (a) specific phospholipid species, which could reflect adaptive membrane responses, (b) sphingolipids, which could lead to changes in ceramide signaling pathways, and (c) the physiologically redox-relevant ubiquinone 9, indicating adaptations in phase II antioxidant response metabolism. In addition, specific oxidation products derived from cholesterol, phosphatidylcholine, and phosphatidylethanolamine were significantly decreased in the brain, spinal cord, and liver from MetR mice. These results demonstrate the importance of adaptive responses of membrane lipids leading to increased stress resistance as a major mechanistic contributor to the lowered rate of aging in MetR mice. © 2013 American Chemical Society.

A study of adaptive load balancing algorithms for distributed systems

With the advent of distributed computer systems with a largely transparent user interface, new questions have arisen regarding the management of such an environment by an operating system. One fertile area of research is that of load balancing, which attempts to improve system performance by redistributing the workload submitted to the system by the users. Early work in this field concentrated on static placement of computational objects to improve performance, given prior knowledge of process behaviour. More recently this has evolved into studying dynamic load balancing with process migration, thus allowing the system to adapt to varying loads. In this thesis, we describe a simulated system which facilitates experimentation with various load balancing algorithms. The system runs under UNIX and provides functions for user processes to communicate through software ports; processes reside on simulated homogeneous processors, connected by a user-specified topology, and a mechanism is included to allow migration of a process from one processor to another. We present the results of a study of adaptive load balancing algorithms, conducted using the aforementioned simulated system, under varying conditions; these results show the relative merits of different approaches to the load balancing problem, and we analyse the trade-offs between them. Following from this study, we present further novel modifications to suggested algorithms, and show their effects on system performance.

Early visual detection of oriented line targets: spatial characteristics,and reference frames of early visual orientation-processing

The orientations of lines and edges are important in defining the structure of the visual environment, and observers can detect differences in line orientation within the first few hundred milliseconds of scene viewing. The present work is a psychophysical investigation of the mechanisms of early visual orientation-processing. In experiments with briefly presented displays of line elements, observers indicated whether all the elements were uniformly oriented or whether a uniquely oriented target was present among uniformly oriented nontargets. The minimum difference between nontarget and target orientations that was required for effective target-detection (the orientation increment threshold) varied little with the number of elements and their spatial density, but the percentage of correct responses in detection of a large orientation-difference increased with increasing element density. The differing variations with element density of thresholds and percent-correct scores may indicate the operation of more than one mechanism in early visual orientation-processIng. Reducing element length caused threshold to increase with increasing number of elements, showing that the effectiveness of rapid, spatially parallel orientation-processing depends on element length. Orientational anisotropy in line-target detection has been reported previously: a coarse periodic variation and some finer variations in orientation increment threshold with nontarget orientation have been found. In the present work, the prominence of the coarse variation in relation to finer variations decreased with increasing effective viewing duration, as if the operation of coarse orientation-processing mechanisms precedes the operation of finer ones. Orientational anisotropy was prominent even when observers lay horizontally and viewed displays by looking upwards through a black cylinder that excluded all possible visual references for orientation. So, gravitational and visual cues are not essential to the definition of an orientational reference frame for early vision, and such a reference can be well defined by retinocentric neural coding, awareness of body-axis orientation, or both.

The development of calibration and adaptive filtering procedures for neuromagnetic studies of human visual function

This thesis first considers the calibration and signal processing requirements of a neuromagnetometer for the measurement of human visual function. Gradiometer calibration using straight wire grids is examined and optimal grid configurations determined, given realistic constructional tolerances. Simulations show that for gradiometer balance of 1:104 and wire spacing error of 0.25mm the achievable calibration accuracy of gain is 0.3%, of position is 0.3mm and of orientation is 0.6°. Practical results with a 19-channel 2nd-order gradiometer based system exceed this performance. The real-time application of adaptive reference noise cancellation filtering to running-average evoked response data is examined. In the steady state, the filter can be assumed to be driven by a non-stationary step input arising at epoch boundaries. Based on empirical measures of this driving step an optimal progression for the filter time constant is proposed which improves upon fixed time constant filter performance. The incorporation of the time-derivatives of the reference channels was found to improve the performance of the adaptive filtering algorithm by 15-20% for unaveraged data, falling to 5% with averaging. The thesis concludes with a neuromagnetic investigation of evoked cortical responses to chromatic and luminance grating stimuli. The global magnetic field power of evoked responses to the onset of sinusoidal gratings was shown to have distinct chromatic and luminance sensitive components. Analysis of the results, using a single equivalent current dipole model, shows that these components arise from activity within two distinct cortical locations. Co-registration of the resulting current source localisations with MRI shows a chromatically responsive area lying along the midline within the calcarine fissure, possibly extending onto the lingual and cuneal gyri. It is postulated that this area is the human homologue of the primate cortical area V4.

Oculomotor responses in emmetropia and myopia

It has been proposed that early-onset myopia (EOM) i.e. myopia onset before the age of 15 is primarily inherited whereas late-onset myopia (LOM) i.e. myopia onset after the age of 16 is induced by environmental factors, principally sustained near vision. No consensus exists as to which aspect of the near vision response; accommodation, vergence or their synergistic cross links promotes LOM development. Furthermore, the mechanism by which near vision could induce elongation of posterior chamber is obscure although there is evidence to show that ciliary muscle tone plays an important role. By comparing accommodation and vergence responses of emmetropes (EMMs), EOMs and LOMs under both open- and closed-loop conditions, this thesis aims to define further the oculomotor correlates of myopic development. A Canon Autoref R-1 optometer was used to measure accommodation responses while an Apple IIe controlled the flashed Maddox Rod sequence used when measuring vergence. Both techniques permitted open- and closed-loop measures to be obtained. The results presented demonstrate that it is unlikely that those individuals susceptible to LOM can be distinguished with regard to oculomotor responses or innervational characteristics of the ciliary muscle. The aetiology of LOM may be associated with ciliary muscle function but account needs to be taken of interactions between the ciliary muscle, choriod, sclera and introcular pressure and further research is necessary before those EMMs susceptible to LOM can be identified.

Synkinesis of accommodation and vergence during sustained rear vision

It is well established that a synkinetic relationship exists between the accommodation and vergence components of the oculomotor near response such that increased accommodation will initiate a vergence response (i.e. accommodative convergence) and conversely increased vergence will drive accommodation (i.e. convergent accommodation) . The synkinesis associated with sustained near-vision was examined in a student population consisting of emmetropes, late-onset myopes (LOMs) i.e. myopia onset at 15 years of age or later and early-onset myopes (EOMs) i.e. myopia onset prior to 15 years of age. Oculomotor synkinesis was investigated both under closed-loop conditions and with either accommodation or vergence open-loop. Objective measures of the accommodative response were made using an infra-red optometer. Differences in near-response characteristics were observed between LOMs and EOMs under both open- and closed-loop conditions. LOMs exhibit significantly higher levels of disparity-induced accommodation (accommodation driven by vergence under closed-loop conditions) and lower response accommodative convergence/accommodation (AC/A) ratios when compared with EOMs. However no difference in convergent accommodation/convergence (CA/C) ratios were found between the three refractive groups. Accommodative adaptation was examined by comparing the pre- to post-task shift in dark focus (DF) following near-vision tasks. Accommodative adaptation was observed following tasks as brief as 15s. Following a 45s near-vision task, subjects having pre-task DF greater than +0.750 exhibited a marked negative shift in post-task DF which was shown to be induced by beta-adrenergic innervation to the ciliary muscle. However no evidence was found to support the proposal of reduced adrenergic innervation to the ciliary muscle in LOMs. Disparity-vergence produced a reduction in accommodative adaptation suggesting that oculomotor adaptation was not driven by the output of the near-response crosslinks. In order to verify this proposition, the effect of vergence adaptation on CA/C was investigated and it was observed that prism adaptation produced no significant change in the CA/C ratio. This would indicate that in a model of accommodation-vergence interaction, the near response cross-links occur after the input to the adaptive components of the oculomotor response rather than before the adaptive elements as reported in previous literature. The findings of this thesis indicate differences in the relative composition of the aggregate accommodation and vergence responses in the three refractive groups examined. They may also have implications with regard to the aetiology of late-onset myopia.

Leadership through intellect:the meaning of leadership in the intellectual history of nineteenth and early twentieth century Germany

This study examines the understanding of leadership in Germany, as it developed throughout the nineteenth and early twentieth century. The investigation is based on the work of contemporary writers and thinkers, as well as on the leadership styles of key political figures. Given the ideological connotations of the term "Führung" in post-war Germany, the aim is to reconsider the meaning of leadership, with particular reference to the alternative notion of spiritual guidance. The rise to power of Napoleon I fundamentally influenced the understanding of leadership in Germany, as is demonstrated through an analysis of the Napoleonic reception in contemporary literature. Despite polarised responses, the formation of the heroic ideal may be identified, the quest for spiritual guidance having become subordinate to the charismatic legitimisation of political authority. As advocated by Thomas Carlyle, the mid to late nineteenth century witnessed the realisation of this ideal through Bismarck. The intellectual response to this development is characterised by the work of Wagner, Burckhardt and Nietzsche. In different ways each figure emphasised the need to redefine greatness and to seek spiritual guidance from alternative sources. The reflection on leadership in the early twentieth century is traced through the work of Harry Graf Kessler and the circles around Stefan George. Hitherto unpublished material is examined, revealing both the influences of nineteenth century thought and reactions to the "persönliches Regiment" of Wilhelm II. The intellectual debate culminates in Max Kommerell's 1928 study Der Dichter als Führer. Read in conjunction with unpublished notes and correspondence, this provides new insights into Kommerell's thought. The concept of poetic leadership constitutes a potential spiritual and intellectual alternative to the ideal of the political "Führer" which dominated the forthcoming era. It therefore remains of contemporary significance and may contribute to a broader discussion of the leadership dilemma in modern Germany.

Anatomical correlates of dynamic auditory processing:relationship to literacy during early adolescence

Adults show great variation in their auditory skills, such as being able to discriminate between foreign speech-sounds. Previous research has demonstrated that structural features of auditory cortex can predict auditory abilities; here we are interested in the maturation of 2-Hz frequency-modulation (FM) detection, a task thought to tap into mechanisms underlying language abilities. We hypothesized that an individual's FM threshold will correlate with gray-matter density in left Heschl's gyrus, and that this function-structure relationship will change through adolescence. To test this hypothesis, we collected anatomical magnetic resonance imaging data from participants who were tested and scanned at three time points: at 10, 11.5 and 13 years of age. Participants judged which of two tones contained FM; the modulation depth was adjusted using an adaptive staircase procedure and their threshold was calculated based on the geometric mean of the last eight reversals. Using voxel-based morphometry, we found that FM threshold was significantly correlated with gray-matter density in left Heschl's gyrus at the age of 10 years, but that this correlation weakened with age. While there were no differences between girls and boys at Times 1 and 2, at Time 3 there was a relationship between gray-matter density in left Heschl's gyrus in boys but not in girls. Taken together, our results confirm that the structure of the auditory cortex can predict temporal processing abilities, namely that gray-matter density in left Heschl's gyrus can predict 2-Hz FM detection threshold. This ability is dependent on the processing of sounds changing over time, a skill believed necessary for speech processing. We tested this assumption and found that FM threshold significantly correlated with spelling abilities at Time 1, but that this correlation was found only in boys. This correlation decreased at Time 2, and at Time 3 we found a significant correlation between reading and FM threshold, but again, only in boys. We examined the sex differences in both the imaging and behavioral data taking into account pubertal stages, and found that the correlation between FM threshold and spelling was strongest pre-pubertally, and the correlation between FM threshold and gray-matter density in left Heschl's gyrus was strongest mid-pubertally.

Supporting decision-making for self-adaptive systems:from goal models to dynamic decision networks

Context/Motivation - Different modeling techniques have been used to model requirements and decision-making of self-adaptive systems (SASs). Specifically, goal models have been prolific in supporting decision-making depending on partial and total fulfilment of functional (goals) and non-functional requirements (softgoals). Different goalrealization strategies can have different effects on softgoals which are specified with weighted contribution-links. The final decision about what strategy to use is based, among other reasons, on a utility function that takes into account the weighted sum of the different effects on softgoals. Questions/Problems - One of the main challenges about decisionmaking in self-adaptive systems is to deal with uncertainty during runtime. New techniques are needed to systematically revise the current model when empirical evidence becomes available from the deployment. Principal ideas/results - In this paper we enrich the decision-making supported by goal models by using Dynamic Decision Networks (DDNs). Goal realization strategies and their impact on softgoals have a correspondence with decision alternatives and conditional probabilities and expected utilities in the DDNs respectively. Our novel approach allows the specification of preferences over the softgoals and supports reasoning about partial satisfaction of softgoals using probabilities. We report results of the application of the approach on two different cases. Our early results suggest the decision-making process of SASs can be improved by using DDNs. © 2013 Springer-Verlag.

Self-explanation in adaptive systems

The behaviour of self adaptive systems can be emergent. The difficulty in predicting the system's behaviour means that there is scope for the system to surprise its customers and its developers. Because its behaviour is emergent, a self-adaptive system needs to garner confidence in its customers and it needs to resolve any surprise on the part of the developer during testing and mainteinance. We believe that these two functions can only be achieved if a self-adaptive system is also capable of self-explanation. We argue a self-adaptive system's behaviour needs to be explained in terms of satisfaction of its requirements. Since self-adaptive system requirements may themselves be emergent, a means needs to be found to explain the current behaviour of the system and the reasons that brought that behaviour about. We propose the use of goal-based models during runtime to offer self-explanation of how a system is meeting its requirements, and why the means of meeting these were chosen. We discuss the results of early experiments in self-explanation, and set out future work. © 2012 C.E.S.A.M.E.S.

Th1 immune responses can be modulated by varying dimethyldioctadecylammonium and distearoyl-sn-glycero-3-phosphocholine content in liposomal adjuvants

Objectives - Cationic liposomes of dimethyldioctadecylammonium bromide (DDA) combined with trehalose 6,6'-dibehenate (TDB) elicit strong cell-mediated and antibody immune responses; DDA facilitates antigen adsorption and presentation while TDB potentiates the immune response. To further investigate the role of DDA, DDA was replaced with the neutral lipid of distearoyl-sn-glycero-3-phosphocholine (DSPC) over a series of concentrations and these systems investigated as adjuvants for the delivery of Ag85B–ESAT-6-Rv2660c, a multistage tuberculosis vaccine. Methods - Liposomal were prepared at a 5?:?1 DDA–TDB weight ratio and DDA content incrementally replaced with DSPC. The physicochemical characteristics were assessed (vesicle size, zeta potential and antigen loading), and the ability of these systems to act as adjuvants was considered. Key findings - As DDA was replaced with DSPC within the liposomal formulation, the cationic nature of the vesicles decreases as does electrostatically binding of the anionic H56 antigen (Hybrid56; Ag85B-ESAT6-Rv2660c); however, only when DDA was completed replaced with DSPC did vesicle size increase significantly. T-helper 1 (Th1)-type cell-mediated immune responses reduced. This reduction in responses was attributed to the replacement of DDA with DSPC rather than the reduction in DDA dose concentration within the formulation. Conclusion - These results suggest Th1 responses can be controlled by tailoring the DDA/DSPC ratio within the liposomal adjuvant system.

Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on Bilayer properties, biodistribution, and immune responses

Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses. © 2013 American Chemical Society.