Dynamic Euler Diagram Drawing

In this paper we describe a method to lay out a graph enhanced Euler diagram so that it looks similar to a previously drawn graph enhanced Euler diagram. This task is non-trivial when the underlying structures of the diagrams differ. In particular, if a structural change is made to an existing drawn diagram, our work enables the presentation of the new diagram with minor disruption to the user's mental map. As the new diagram can be generated from an abstract representation, its initial embedding may be very different from that of the original. We have developed comparison measures for Euler diagrams, integrated into a multicriteria optimizer, and applied a force model for associated graphs that attempts to move nodes towards their positions in the original layout. To further enhance the usability of the system, the transition between diagrams can be animated

Delineating neuroinflammation, parasite CNS invasion, and blood-brain barrier dysfunction in an experimental murine model of human African trypanosomiasis

Although Trypanosoma brucei spp. was first detected by Aldo Castellani in CSF samples taken from sleeping sickness patients over a century ago there is still a great deal of debate surrounding the timing, route and effects of transmigration of the parasite from the blood to the CNS. In this investigation, we have applied contrast-enhance magnetic resonance imaging (MRI) to study the effects of trypanosome infection on the blood-brain barrier (BBB) in the well-established GVR35 mouse model of sleeping sickness. In addition, we have measured the trypanosome load present in the brain using quantitative Taqman PCR and assessed the severity of the neuroinflammatory reaction at specific time points over the course of the infection. Contrast enhanced – MRI detected a significant degree of BBB impairment in mice at 14 days following trypanosome infection, which increased in a step-wise fashion as the disease progressed. Parasite DNA was present in the brain tissue on day 7 after infection. This increased significantly in quantity by day 14 post-infection and continued to rise as the infection advanced. A progressive increase in neuroinflammation was detected following trypanosome infection, reaching a significant level of severity on day 14 post-infection and rising further at later time-points. In this model stage-2 disease presents at 21 days post-infection. The combination of the three methodologies indicates that changes in the CNS become apparent prior to the onset of established stage-2 disease. This could in part account for the difficulties associated with defining specific criteria to distinguish stage-1 and stage-2 infections and highlights the need for improved staging diagnostics

Drawing Area-Proportional Euler Diagrams Representing Up To Three Sets

Area-proportional Euler diagrams representing three sets are commonly used to visualize the results of medical experiments, business data, and information from other applications where statistical results are best shown using interlinking curves. Currently, there is no tool that will reliably visualize exact area-proportional diagrams for up to three sets. Limited success, in terms of diagram accuracy, has been achieved for a small number of cases, such as Venn-2 and Venn-3 where all intersections between the sets must be represented. Euler diagrams do not have to include all intersections and so permit the visualization of cases where some intersections have a zero value. This paper describes a general, implemented, method for visualizing all 40 Euler-3 diagrams in an area-proportional manner. We provide techniques for generating the curves with circles and convex polygons, analyze the drawability of data with these shapes, and give a mechanism for deciding whether such data can be drawn with circles. For the cases where non-convex curves are necessary, our method draws an appropriate diagram using non-convex polygons. Thus, we are now always able to automatically visualize data for up to three sets

Some Results for Drawing Area Proportional Venn3 With Convex Curves

Many data sets are visualized effectively with area proportional Venn diagrams, where the area of the regions is in proportion to a defined specification. In particular, Venn diagrams with three intersecting curves are considered useful for visualizing data in many applications, including bioscience, ecology and medicine. To ease the understanding of such diagrams, using restricted nice shapes for the curves is considered beneficial. Many research questions on the use of such diagrams are still open. For instance, a general solution to the question of when given area specifications can be represented by Venn3 using convex curves is still unknown. In this paper we study symmetric Venn3 drawn with convex curves and show that there is a symmetric area specification that cannot be represented with such a diagram. In addition, by using symmetric diagrams drawn with polygons, we show that, if area specifications are restricted so that the double intersection areas are no greater than the triple intersection area then the specification can be drawn with convex curves. We also propose a construction that allows the representation of some area specifications when the double intersection areas are greater than the triple intersection area. Finally, we present some open questions on the topic

Probing Structure for Photophysical Properties Through Synthesis of Novel Nucleosides

A brief history of nucleosides and their photophysics provides the background information for the discussion of synthesis, photophysics and incorporation of fluorescent nucleotide analogs during enzymatic DNA synthesis. Through the use of nucleoside starting material, it is possible to synthesize a number of modified nucleotides for use as fluorescent probes in biochemical research. Synthetic endeavors into the synthesis of these and related molecules from nucleobase starting materials are also presented. The synthesis of these molecules involved re-development of the synthetic routes to broaden substrate scope by overcoming the changed reactivity resulting from the presence of additional functionality. While many highly useful fluorescent probes exist today, there remains to be filled significant gaps in performance. Brighter probes, probes that emit at various wavelengths while maintaining fluorescence when present in folded biomolecules (proteins, nucleic acids), and probes that work together as a nucleic acid FRET pairs are still needed. In the work described in this thesis, a series of cytidine analogs that are closely related have been synthesized and investigated to elucidate trends in effects on photophysical properties by the electronic character and position of substituents. The location of substitution as well as the surrounding environment has an influence on how the introduction of new functionality affects the photophysical properties of the chromophore. Tricyclic cytosine skeletons have been substituted to produce analogs that are brighter, and more or less sensitive to their environment. These substitutions affect not only the photophysical properties of the compound but also the tautomeric equilibrium between cytosine and tyrosine-like hydrogen bonding patterns. This equilibrium between hydrogen positions controls the base pairing properties of the compound and how it is treated by cellular machinery during incorporation in nascent nucleic acids. Incorporation studies reveal that the substitution affects the incorporation efficiency for templates containing different hydrogen bonding partners

Clinical and neuropathogenetic aspects of human African trypanosomiasis

Trypanosomiasis has been recognized as a scourge in sub-Saharan Africa for centuries. The disease, caused by protozoan parasites of the Trypanosoma genus, is a major cause of mortality and morbidity in animals and man. Human African trypanosomiasis (HAT), or sleeping sickness, results from infections with T. brucei (b.) gambiense or T. b. rhodesiense with T. b. gambiense accounting for over 95% of infections. Historically there have been major epidemics of the infection, followed by periods of relative disease control. As a result of concerted disease surveillance and treatment programmes, implemented over the last two decades, there has been a significant reduction in the number of cases of human disease reported. However, the recent identification of asymptomatic disease carriers gives cause for some concern. The parasites evade the host immune system by switching their surface coat, comprised of variable surface glycoprotein (VSG). In addition, they have evolved a variety of strategies, including the production of serum resistance associated protein (SRA) and T. b. gambiense-specific glycoprotein (TgsGP) to counter host defense molecules. Infection with either disease variant results in an early haemolymphatic-stage followed by a late encephalitic-stage when the parasites migrate into the CNS. The clinical features of HAT are diverse and non-specific with early-stage symptoms common to several infections endemic within sub-Saharan Africa which may result in a delayed or mistaken diagnosis. Migration of the parasites into the CNS marks the onset of late-stage disease. Diverse neurological manifestations can develop accompanied by a neuroinflammatory response, comprised of astrocyte activation, and inflammatory cell infiltration. However, the transition between the early and late-stage is insidious and accurate disease staging, although crucial to optimize chemotherapy, remains problematic with neurological symptoms and neuroinflammatory changes recorded in early-stage infections. Further research is required to develop better diagnostic and staging techniques as well as safer more efficacious drug regimens. Clearer information is also required concerning disease pathogenesis, specifically regarding asymptomatic carriers and the mechanisms employed by the trypanosomes to facilitate progression to the CNS and precipitate late-stage disease. Without progress in these areas it may prove difficult to maintain current control over this historically episodic disease

Neuropathogenesis of African trypanosomiasis: The use of a mouse model system to elucidate likely mechanisms of the disease process and to design potential therapeutic strategies in man

Human African trypanosomiasis (HAT), also known as sleeping sickness, is prevalent in sub-Saharan Africa. The illness results from infection with the protozoan parasites Trypanosoma brucei (T.b.) gambiense in West and Central Africa and T.b.rhodesiense in East and Central Africa and is spread through the bite of the insect vector of the parasite, the tsetse fly. Both forms of the disease are invariably fatal if not diagnosed and drug treated. During the acute-stage of the infection the trypanosomes spread from the site of the tsetse fly bite, via the lymphatics and bloodstream to invade most of the organs and tissues of the body. As the disease progresses the parasites enter the brain tissue and become established within the CNS and a neuroinflammatory reaction develops. Treatment of the infection once it has reached the CNS-stage is problematic since few trypanocidal drugs can cross the blood-brain barrier (BBB) to clear' the parasites that are sequestered in the brain. The only drug commonly available to treat this stage of the disease is the arsenical derivative melarsoprol but its use is associated with the development of a post-treatment reactive encephalopathy (PTRE) that can in itself prove fatal. The PTRE is characterised by a severe meningoencephalitic reaction with the presence of reactive astrocytes, macrophages, T-cells, B-cells and plasma cells. The pathogenesis of this adverse reaction remains unclear. Since brain tissue can only be obtained from post-mortem cases of HAT, there is a paucity of information regarding the early changes that occur within the CNS following infection and during the development of the PTRE. Therefore, a well-established and highly reproducible murine model, which closely mimics the human disease, was used in the current investigation to elucidate the kinetics of cellular reactivity and the expression of cytokines and chemokines following trypanosome-infection and induction of the PTRE. The mode of action of the ornithine decarboxylase inhibitor, efiornithine, a typanostatic drug used in the treatment of trypanosome infections, was also examined in the possible prevention and amelioration of the severe meningoencephalitic reaction, In addition, the role of the neuropeptide Substance P (SP) in the modulation of the inflammatory response associated with the disease was investigated. In this study eflornithine resistant trypanosomes were used in the infections to isolate the anti-inflammatory effects of the drug treatment from those that arise due to the clearance of the parasites. Therefore, the value of eflornithine treatment as an anti-inflammatory agent, even in cases where trypanosome resistance to the drug is suspected was demonstrated. The identification of the key cellular and functional events resulting in the neuroinflammatory reaction associated with trypanosome infection have allowed a further degree of understanding regarding the mechanisms involved in the development of the CNS inflammation in human disease. Without the existence of the murine model the above conclusions could not have been reached. Furthermore, it is now possible to consider application of the potential novel therapeutic approaches indicated by this study, to prevent and ameliorate the development of the CNS inflammatory reaction, in the management of this devastating disease condition in man. (Abstract shortened by ProQuest.)

Trypanosoma brucei brucei invasion and T-cell infiltration of the brain parenchyma in experimental sleeping sickness: timing and correlation with functional changes

Background: The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications. Methodology: Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses. Principal findings: Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion. Conclusion: These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging

Safety and efficacy of three trypanocides in confirmed field cases of trypanosomiasis in working equines in The Gambia: a prospective, randomised, non-inferiority trial

Background: Globally, working equines have a continued and growing socioeconomic role in supporting the livelihoods of between 300–600 million people in low income countries which is rarely recognised at a national or international level. Infectious diseases have significant impact on welfare and productivity in this population and equine trypanosomiasis is a priority disease due to its severity and prevalence. Strategies are required to improve the prevention, diagnosis, management and treatment of trypanosomiasis in equines and more data are required on the efficacy and safety of current trypanocidal drugs. Methods: A prospective randomised, open-label non-inferiority trial was performed in The Gambia on horses and donkeys that fulfilled 2/5 clinical inclusion criteria (anaemia, poor body condition, pyrexia, history of abortion, oedema). Following randomised trypanocidal treatment (diminazene diaceturate, melarsomine dihydrochloride or isometamidium chloride), animals were observed for immediate adverse drug reactions and follow-up assessment was performed at 1 and 2 weeks. Blood samples underwent PCR analysis with specific Trypanosoma sp. primers. Treatment efficacy was assessed by measuring changes in clinical parameters, clinicopathological results and PCR-status post-treatment after evaluating for bias. Using PCR status as the outcome variable, non-inferiority of isometamidium treatment was determined if the upper bound limit of a 2-sided 95% CI was less than 10%. Results: There was a significant beneficial effect upon the Trypanosoma sp. PCR positive population following trypanocidal treatment for all groups. The findings of clinical evaluation and PCR status supported a superior treatment effect for isometamidium. Melarsomine dihydrochloride efficacy was inferior to isometamidium. There were immediate, self-limiting side effects to isometamidium in donkeys (26%). Diminazene had the longest duration of action as judged by PCR status. Conclusions: The data support the continued use of isometamidium following careful dose titration in donkeys and diminazene for trypanosomiasis in equines using the doses and routes of administration reported