Later Life Consequences of Subteratogenic Exposure to a Complex PAH Mixture in the Atlantic Killifish (Fundulus heteroclitus)

Subteratogenic and other low-level chronic exposures to toxicant mixtures are an understudied threat to environmental and human health. It is especially important to understand the effects of these exposures for contaminants, such as polycyclic aromatic hydrocarbons (PAHs) a large group of more than 100 individual compounds, which are important environmental (including aquatic) contaminants. Aquatic sediments constitute a major sink for hydrophobic pollutants, and studies show PAHs can persist in sediments over time. Furthermore, estuarine systems (namely breeding grounds) are of particular concern, as they are highly impacted by a wide variety of pollutants, and estuarine fishes are often exposed to some of the highest levels of contaminants of any vertebrate taxon. Acute embryonic exposure to PAHs results in cardiac teratogenesis in fish, and early life exposure to certain individual PAHs and PAH mixtures cause heart alterations with decreased swimming capacity in adult fish. Consequently, the heart and cardiorespiratory system are thought to be targets of PAH mixture exposure. While many studies have investigated acute, teratogenic PAH exposures, few studies have longitudinally examined the impacts of subtle, subteratogenic PAH mixture exposures, which are arguably more broadly applicable to environmental contamination scenarios. The goal of this dissertation was to highlight the later-life consequences of early-life exposure to subteratogenic concentrations of a complex, environmentally relevant PAH mixture.

A unique population of Fundulus heteroclitus (the Atlantic killifish or mummichog, hereafter referred to as killifish), has adapted to creosote-based polycyclic aromatic hydrocarbons (PAHs) found at the Atlantic Wood Industries (AW) Superfund site in the southern branch of the Elizabeth River, VA, USA. This killifish population survives in a site heavily contaminated with a mixture of PAHs from former creosote operations. They have developed resistance to the acute toxicity and teratogenic effects caused by the mixture of PAHs in sediment from the site. The primary goal of this dissertation was to compare and contrast later-life outcomes of early-life, subteratogenic PAH mixture exposure in both the Atlantic Wood killifish (AW) and a naïve reference population of killifish from King’s Creek (KC; a relatively uncontaminated tributary of the Severn River, VA). Killifish from both populations were exposed to subteratogenic concentrations of a complex PAH-sediment extract, Elizabeth River Sediment Extract (ERSE), made by collecting sediment from the AW site. Fish were reared over a 5-month period in the laboratory, during which they were examined for a variety of molecular, physiological and behavioral responses.

The central aims of my dissertation were to determine alterations to embryonic gene expression, larval swimming activity, adult behavior, heart structure, enzyme activity, and swimming/cardiorespiratory performance following subteratogenic exposure to ERSE. I hypothesized that subteratogenic exposure to ERSE would impair cardiac ontogenic processes in a way that would be detectable via gene expression in embryos, and that the misregulation of cardiac genes would help to explain activity changes, behavioral deficits, and later-life swimming deficiencies. I also hypothesized that fish heart structure would be altered. In addition, I hypothesized that the AW killifish population would be resistant to developmental exposures and perform normally in later life challenges. To investigate these hypotheses, a series of experiments were carried out in PAH-adapted killifish from Elizabeth River and in reference killifish. As an ancillary project to the primary aims of the dissertation, I examined the toxicity of weaker aryl hydrocarbon receptor (AHR) agonists in combination with fluoranthene (FL), an inhibitor of cytochrome P4501A1 (CYP1A1). This side project was conducted in both Danio rerio (zebrafish) and the KC and AW killifish.

Embryonic gene expression was measured in both killifish populations over an ERSE dose response with multiple time points (12, 24, 48, and 144 hours post exposure). Genes known to play critical roles in cardiac structure/development, cardiac function, and angiogenesis were elevated, indicating cardiac damage and activation of cardiovascular repair mechanisms. These data helped to inform later-life swimming performance and cardiac histology studies. Behavior was assessed during light and dark cycles in larvae of both populations following developmental exposure to ERSE. While KC killifish showed activity differences following exposure, AW killifish showed no significant changes even at concentrations that would cause overt cardiac toxicity in KC killifish. Juvenile behavior experiments demonstrated hyperactivity following ERSE exposure in KC killifish, but no significant behavioral changes in AW killifish. Adult swimming performance via prolonged critical swimming capacity (Ucrit) demonstrated performance costs in the AW killifish. Furthermore, swimming performance decline was observed in KC killifish following exposure to increasing dilutions of ERSE. Lastly, cardiac histology suggested that early-life exposure to ERSE could result in cardiac structural alteration and extravasation of blood into the pericardial cavity.

Responses to AHR agonists resulted in a ranking of relative potency for agonists, and determined which agonists, when combined with FL, caused cardiac teratogenesis. These experiments showed interesting species differences for zebrafish and killifish. To probe mechanisms responsible for cardiotoxicity, a CYP1A-morpholino and a AHR2-morpholino were used to mimic FL effects or attempt to rescue cardiac deformities respectively. Findings suggested that the cardiac toxicity elicited by weak agonist + FL exposure was likely driven by AHR-independent mechanisms. These studies stand in contrast to previous research from our lab showing that moderate AHR agonist + FL caused cardiac toxicity that can be partially rescued by AHR-morpholino knockdown.

My findings will form better characterization of mechanisms of PAH toxicity, and advance our understanding of how subteratogenic mixtures of PAHs exert their toxic action in naïve killifish. Furthermore, these studies will provide a framework for investigating how subteratogenic exposures to PAH mixtures can impact aquatic organismal health and performance. Most importantly, these experiments have the potential to help inform risk assessment in fish, mammals, and potentially humans. Ultimately, this research will help protect populations exposed to subtle PAH-contamination.

Interception of host angiogenic signalling limits mycobacterial growth.

Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis. Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis. Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations. Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.

Neurology and psychiatry: waking up to opportunities of sleep. State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Advanced occupant behavioural features of the building-EXODUS evacuation model

The purpose of this paper is to describe and demonstrate some of the advanced behavioral features currently being developed for the building-EXODUS evacuation model. These advanced features involve the ability to specify roles for particular individuals during the evacuation. With these enhancements to the Behavioral Sub model of building-EXODUS, it is possible to include a number of procedural and behavioral aspects previously ignored in evacuation simulations. These include the behavioral aspect of group bonding, the procedural aspects involved with the role of the fire warden and rescue operations undertaken by the fire services. The importance of these enhancements are discussed and demonstrated through three simple simulations.

Models and tools for an integrated European environmental management and decision support system, (IEEMDSS)

This work proceeds from the assumption that a European environmental information and communication system (EEICS) is already established. In the context of primary users (land-use planners, conservationists, and environmental researchers) we ask what use may be made of the EEICS for building models and tools which is of use in building decision support systems for the land-use planner. The complex task facing the next generation of environmental and forest modellers is described, and a range of relevant modelling approaches are reviewed. These include visualization and GIS; statistical tabulation and database SQL, MDA and OLAP methods. The major problem of noncomparability of the definitions and measures of forest area and timber volume is introduced and the possibility of a model-based solution is considered. The possibility of using an ambitious and challenging biogeochemical modelling approach to understanding and managing European forests sustainably is discussed. It is emphasised that all modern methodological disciplines must be brought to bear, and a heuristic hybrid modelling approach should be used so as to ensure that the benefits of practical empirical modelling approaches are utilised in addition to the scientifically well-founded and holistic ecosystem and environmental modelling. The data and information system required is likely to end up as a grid-based-framework because of the heavy use of computationally intensive model-based facilities.

Computational fluid dynamics: advancements in technology for modeling iron and steelmaking processes

Computational fluid dynamics (CFD) software technology has formed the basis of many investigations into the behavior and optimization of primary iron and steelmaking processes for the last 25+ years. The objective of this contribution is to review the progress in CFD technologies over the last decade or so and how this can be brought to bear in advancing the process analysis capability of primary ferrous operations. In particular, progress on key challenges such as compute performance, fluid-structure transformation and interaction, and increasingly complex geometries are highlighted.

The phenomenology of religious life: Nietzsche and Bergson

In this paper I identify and discuss some themes in the thought of Nietzsche and Bergson respectively as these bear upon the wider project to which the paper contributes – the articulation of a philosophical naturalism which offers a non-reductive account of the origin and nature of religion on the basis that the real is 'religious' in essence. Implicitly, an alternative is thereby proposed to the approaches and presuppositions of the 'theological turn' perspective within contemporary 'continental philosophy of religion'. [PROVIDED BY THE AUTHOR]

Second language processing: an analysis of theory, problems and possible solutions

Second Language Processing examines the problems facing learners in the second language classroom from the theoretical perspectives of Processing Instruction (structured input) and Enhanced Input. These two theories are brought to bear on a variety of processing problems, such as the difficulty of connecting second language grammatical forms encoding tense and mood as well as noun-adjective agreement with their meaning. Empirical studies examine a range of languages including Japanese, Italian and Spanish, through which the authors suggest practical solutions to these processing problems.

Legal myth-making: Medea and the legal representation of the feminine ‘other'

The Law operates by, and through, the creation of ideal benchmarks of conduct that are deemed to be representative of the behavioural norm. It is in this sense that it could be contended that the Law utilises, and relies on, myths in the same way as do other disciplines, notably psycho-analysis. It is possible to go even further and argue that the use of a created narrative mythology is essential to the establishment of a defined legal benchmark of behaviour by which the female defendant is assessed, judged and punished. While mythology expresses and symbolizes cultural and political behaviour, it is the Law that embodies and prescribes punitive sanctions. This element represents a powerful literary strand in classical mythology. This may be seen, for instance, in Antigone’s appeal to the Law as justification for her conduct, as much as in Medea’s challenge to the Law though her desire for vengeance. Despite its image of neutral, objective rationality, the Law, in creating and sustaining the ideals of legally-sanctioned conduct, engages in the same literary processes of imagination, reason and emotion that are central to the creation and re-creation of myth. The (re-)presentation of the Medea myth in literature (especially in theatre) and in art, finds its echo in the theatre of the courtroom where wronged women who have refused to passively accept their place, have instead responded with violence. Consequently, the Medea myth, in its depiction of the (un)feminine, serves as a template for the Law’s judgment of ‘conventional’ feminine conduct in the roles of wife and mother. Medea is an image of deviant femininity, as is Lady Macbeth and the countless other un-feminine literary and mythological women who challenge the power of the dominant culture and its ally, the Law. These women stand opposed to the other dominant theme of both literature and Law: the conformist woman, the passive dupe, who are victims of male oppression – women such as Ariadne of Naxos and Tess of the D’Ubervilles – and who are subsequently consumed by the Law, much as Semele is consumed by the fire of Jupiter’s gaze upon her. All of these women, the former as well as the latter, have their real-life counterparts in the pages of the Law Reports. As Fox puts it, “these women have come to bear the weight of the cultural stereotypes and preconceptions about women who kill.”

Human respiration rate estimation using ultra-wideband distributed cognitive radar system

It has been shown that remote monitoring of pulmonary activity can be achieved using ultra-wideband (UWB) systems, which shows promise in home healthcare, rescue, and security applications. In this paper, we first present a multi-ray propagation model for UWB signal, which is traveling through the human thorax and is reflected on the air/dry-skin/fat/muscle interfaces. A geometry-based statistical channel model is then developed for simulating the reception of UWB signals in the indoor propagation environment. This model enables replication of time-varying multipath profiles due to the displacement of a human chest. Subsequently, a UWB distributed cognitive radar system (UWB-DCRS) is developed for the robust detection of chest cavity motion and the accurate estimation of respiration rate. The analytical framework can serve as a basis in the planning and evaluation of future measurement programs. We also provide a case study on how the antenna beamwidth affects the estimation of respiration rate based on the proposed propagation models and system architecture

Accelerating innovation in the built environment by research and education

Awareness of climate change and adaptations of building stock play a key role in the UK government’s environmental agenda. While some European countries and countries like Japan move forward by bringing their sustainability agenda to the public sector, the UK seems to be slow in embracing these ideas and long term sustainability in improved products and processes for better performance, efficiency and innovative application of renewable technology is yet to come. While funding remains a major constraint research show that a number of detrimental issues including; organisation, risk, mind sets of the stakeholders, planning constraints, reluctance to accept change and the unexploited markets are major contributing factors. Most of these barriers can be overcome with research, development and information and knowledge transfer techniques. Educating all stakeholders can act as an accelerator for innovation. This paper examines innovation in the built environment and how research and education can stimulate this process. It explores drivers and barriers for innovation and how research and education in construction, design, engineering and project management can enhance this process. It presents and discusses lessons learnt from two action research projects in relation to innovation.

Twenty years of schooling: student reflections on their educational journeys

[From cover and SRHE website] Nearly half of young people go into higher education today compared with around one in five 20 years ago. What do those who have grown up during this time make of their educational experiences? These chapters give an insight into how one group of students at the University of Greenwich experienced the 'education, education, education' stressed so much throughout their lives at school, college and university as the most tested and intensively taught generation in history. They bring sociological ideas to bear on their personal reflections, which are written in a lively style accessible to other students elsewhere, whether in higher education or thinking of going there. They will also be revealing for their teachers and parents. These reflections are a starting point for comparisons across the new system of 'lifelong learning'.

The Atlantic Meridional Transect (AMT) data management experience

As the UK's national marine data centre, a key responsibility of the British Oceanographic Data Centre (BODC) is to provide data management support for the scientific activities of complex multi-disciplinary long-term research programmes. Since the initial cruise in 1995, the NERC funded Atlantic Meridional Transect (AMT) project has undertaken 18 north–south transects of the Atlantic Ocean. As the project has evolved there has been a steady growth in the number of participants, the volume of data, its complexity and the demand for data. BODC became involved in AMT in 2002 at the beginning of phase II of this programme and since then has provided continuous support to the AMT and the wider scientific community through the rescue, quality control, processing and access to the data. The data management is carried out by a team of specialists using a sophisticated infrastructure and hardware to manage, integrate and serve physical, biological and chemical data. Here, we discuss the approach adopted, techniques applied and some guiding principles for management of large multi-disciplinary programmes.

Art, adolescence and Social Work: Anja, the invisible manager

This article has been written with the intention of being able to analyse the contributions of art —theatre, in this case— to the practice of social work. For this purpose, we have chosen to read the social reality in which we intervene through the lens of social constructionism. This helps us to rescue the social and subjective side of art, and, moreover, to recover the depathologization of the subject in professional intervention. Thus, using a practical case taken from work with adolescents in the German FSJ programme, hand-in-hand with a young girl called Anja we trace the developmental and sociological aspects of adolescence in order to later address certain common points of art and psychosocial work. Art will hence be redefined as a transitional object allowing questions to be addressed relating to (self-) perception, attachment, communication and changes in conduct as the ultimate goal of professional action. Lastly, we note the limitations and risks of art-based intervention, in order to conclude with a final synopsis.

Creación de una filmoteca de prácticas para la Facultad de Ciencias de la Información de la UCM: Adecuación de espacio y estrategias de catalogación

En el presente trabajo se da el primer paso para la creación de una Filmoteca de Prácticas en la facultad de Ciencias de la Información de la Universidad Complutense de Madrid. El Patrimonio Fílmico se ve gravemente expuesto al paso del tiempo y el abandono por lo que se necesita un rescate urgente. Mediante un riguroso trabajo de investigación, en el que se estudian diferentes propuestas y normativas expuestas por organismos especializados, se redacta un manual de inicio. Se han investigado, diseñado y propuesto las herramientas básicas y útiles para poner en funcionamiento la primera Filmoteca de Prácticas en el ámbito universitario español.