Domain knowledge, uncertainty, and parameter constraints

Ph.D.Committee Chair: Guy Lebanon; Committee Member: Alex Shapiro; Committee Member: Alexander Gray; Committee Member: Chin-Hui Lee; Committee Member: Hongyuan Zh

Regulation of intestinal regulatory T cells by prostaglandin E₂

Pathogenesis of autoimmune and auto-inflammatory diseases is induced by auto-aggressive helper T (Th) cells (i.e. Th1 and Th17 cells), and can be controlled by regulatory T cells (Tregs) characterized by expression of the transcription factor Foxp3. Thus, development of autoimmunity is regulated by the balance of Tregs and Th1/Th17 cells. Prostaglandin E₂ (PGE₂) is a bioactive lipid mediator with immune-modulatory potential that acts through 4 receptors (EP1-4). It has been shown that PGE₂ facilitates Th1 and Th17 cell development and expansion, therefore promoting autoimmune inflammation. However, the role of PGE₂ in Treg development and function is largely unclear. The aim of this PhD was to test the hypothesis that PGE₂ regulates Treg development, function and subsequent immune response. I observed that in vivo inhibition of endogenous PGE₂ biosynthesis using a COX inhibitor resulted in increased Foxp3+ Tregs in various lymphoid organs. This response was prevented by addition of an EP4 agonist. PGE₂-EP4 signalling particularly inhibits RORγt+ Tregs in the intestine. This was not observed in either antibiotic-treated mice or MyD88/TRIF double-knockout mice, suggesting gut commensal microbiota involvement. In addition, PGE₂ has a role in microbiota-dependent regulation of intestinal CD11c+MHCII+CD11b+CD103- mononuclear phagocytes (MNPs) which drive intestinal Treg expansion through production of type 1 interferons. Consistent with these in vivo observations, gut microbial metabolites from indomethacin treated mice enhanced in vitro RORγt+ Treg differentiation in the dendritic cell- T cell co-culture system. Adoptive transfer of caecal microbiota from COX inhibitor- treated mice into naïve mice also provided protective benefits in a chemical (DSS)-induced colitis disease model. In summary, this work has demonstrated that PGE₂ affects intestinal Tregs, indicating a novel mechanism for interaction of PGE₂, the adaptive immune system and the gut microbiota in homeostasis within this environment. These findings increase our understanding of the role of PGE₂ in development of inflammatory bowel disease and offer potential therapeutic strategies for treating this disease

Knowledge Reasoning with Graph Neural Networks

Knowledge reasoning is the process of drawing conclusions from existing facts and rules, which requires a range of capabilities including but not limited to understanding concepts, applying logic, and calibrating or validating architecture based on existing knowledge. With the explosive growth of communication techniques and mobile devices, much of collective human knowledge resides on the Internet today, in unstructured and semi-structured forms such as text, tables, images, videos, etc. It is overwhelmingly difficult for human to navigate the gigantic Internet knowledge without the help of intelligent systems such as search engines and question answering systems. To serve various information needs, in this thesis, we develop methods to perform knowledge reasoning over both structured and unstructured data. This thesis attempts to answer the following research questions on the topic of knowledge reasoning: (1) How to perform multi-hop reasoning over knowledge graphs? How should we leverage graph neural networks to learn graph-aware representations efficiently? And, how to systematically handle the noise in human questions? (2) How to combine deep learning and symbolic reasoning in a consistent probabilistic framework? How to make the inference efficient and scalable for large-scale knowledge graphs? Can we strike a balance between the representation power and the simplicity of the model? (3) What is the reasoning pattern of graph neural networks for knowledge-aware QA tasks? Can those elaborately designed GNN modules really perform complex reasoning process? Are they under- or over-complicated? Can we design a much simpler yet effective model to achieve comparable performance? (4) How to build an open-domain question answering system that can reason over multiple retrieved documents? How to efficiently rank and filter the retrieved documents to reduce the noise for the downstream answer prediction module? How to propagate and assemble the information among multiple retrieved documents? (5) How to answer the questions that require numerical reasoning over textual passages? How to enable pre-trained language models to perform numerical reasoning? We explored the research questions above and discovered that graph neural networks can be leveraged as a powerful tool for various knowledge reasoning tasks over both structured and unstructured knowledge sources. On structured graph-based knowledge source, we build graph neural networks on top of the graph structure to capture the topology information for downstream reasoning tasks. On unstructured text-based knowledge source, we first identify graph-structured information such as entity co-occurrence and entity-number binding, and then employ graph neural networks to reason over the constructed graphs, working together with pre-trained language models to handle unstructured part of the knowledge source.Ph.D

Secreted Proteins, Infectivity and Immunity to the Parasitic Nematode Nippostrongylus brasiliensis

Comparative analysis of a recent isolate (J) and a laboratory-adapted strain (W) of the parasitic nematode Nippostrongylus brasiliensis found that the former had higher fecundity and gave rise to more persistent infections, although these traits were partially abolished after three years of laboratory passage, suggesting that infection dynamics can be modified by continuous high-dose propagation. Host immune responses to the two strains were similar in mode and magnitude. Proteins secreted by infective larvae (L3) and adult parasites showed some subtle differences between strains, although the activity of enzymes which might impact on persistence such as acetylcholinesterases and nucleotide metabolising enzymes were similar. Activation of N. brasiliensis L3 was not influenced by host serum, but a 37°C temperature cue was sufficient to induce feeding and protein secretion. Rat skin extracts induced chemotaxis of L3 and also induced the secretion of pre-synthesised proteins, although feeding and subsequent protein secretion were unaffected. Analysis of L3 secreted products by two-dimensional immunoblotting revealed differential immune recognition of specific proteins. Analysis of host resistin-like molecules showed that they had no effect on parasite chemotaxis and feeding activities, in contrast to published data. The venom-allergen homologue/ASP-like (VAL) proteins are important therapeutic targets found in all parasitic nematodes studied to date, and eight secreted variants of VALs have been discovered in N. brasiliensis. Although N. brasiliensis VALs (NbVALs) were found to be immunogenic during natural infection, immunisation with recombinant NbVAL-7 did not protect mice against challenge. Moreover, natural infection induced antigen-specific IgE and Type I hypersensitivity reactions to NbVALs, suggesting that this may be an intrinsic property of these proteins which limits their use in immunoprophylaxis of nematode infection

History and Mathematics: Political Demography and Global Ageing

Among different important issues, which are discussed in Political Demography the issue of global ageing becomes more and more pressing every year. It is sufficient to take into account the point that within two forthcoming decades a rapid global increase in the number of retirement-age persons will lead to its doubling within this fairly small historical period. The concerns about population ageing apply to both developed and many developing countries and it has turned into a global issue. In forthcoming decades the population ageing is likely to become one of the most important processes determining the future society characteristics and the direction of technological development. The present volume of the Yearbook (which is the fifth in the series) is subtitled ‘Political Demography & Global Ageing’. It brings together a number of interesting articles by scholars from Europe, Asia, and America. They examine global ageing from a variety of perspectives. This issue of the Yearbook consists of two main sections: (I) Aspects of Political Demography; (II) Facing Population Ageing. We hope that this issue will be interesting and useful both for historians and mathematicians, as well as for all those dealing with various social and natural sciences

Investigating Inflammatory Pathways as Therapeutic Targets and Biomarkers using Functional Imaging and Pharmacological Interventions in Epilepsy Models.

Epilepsy is a neurological disorder that is characterised by spontaneous seizures. After various epileptogenic injuries, astrocytes become dysfunctional and experimental evidence indicates that these cells contribute to seizure mechanisms. The generation of inflammatory molecules in astrocytes appears to play a key pathogenic role in seizures. However, astrocytes may also contribute to repair the hyperexcitable neuronal networks underlying seizures. We focused our studies on understanding the role of astrocytes in epilepsy by (1) developing a new in vivo imaging method to monitor astrocytic cell activation during epileptogenesis and coupled this with their phenotypic characterization; (2) studying the role of Toll-like receptor 3 (TLR3) signaling in seizure mechanisms. We report that in vivo bioluminescence imaging is a powerful tool for monitoring astrocytic activation in diseased conditions. Characterization of astrocytic activation during epileptogenesis showed a rapid cell activation corresponding to their inflammatory phenotype while homeostatic (neuroprotective) mechanisms were activated with a delay. Moreover, we demonstrate that in vivo imaging of astrocyte activation allows to study the potential involvement of these cells in the therapeutic effects of anti-inflammatory drugs. We also show that priming TLR3 activation in astrocytes with the use of a synthetic agonist results in remarkable anti-inflammatory and anti-ictogenic effects. Mechanistic studies revealed that interferon regulatory factor (IRF)-3/Interferon-β mediated cascade is likely responsible for the inhibitory effects of TLR3 priming on seizures and neuronal excitability. In summary, astroglia activation during the critical epileptogenesis phase provides a potential target for interfering in a timely manner with the inflammatory phenotype of these cells contributing to seizures. Importantly, there are astrocytic cell functions that mediate decreased neuronal excitability and they should be carefully considered when developing treatments targeting these cells for therapeutic purposes

Globalistics and Globalization Studies: Global Transformations and Global Future

The present volume is the fifth in the series of yearbooks with the title Globalistics and Globalization Studies. The subtitle of the present volume is Global Transformations and Global Future. We become more and more accustomed to think globally and to see global processes. And our future can all means be global. However, is this statement justified? Indeed, in recent years, many have begun to claim that globalization has stalled, that we are rather dealing with the process of anti-globalization. Will not we find ourselves at some point again in an edifice spanning across the globe, but divided into national apartments, separated by walls of high tariffs and mutual suspicion? Of course, some setbacks are always possible, because the process of globalization cannot develop smoothly. It is a process which is itself emerging from contradictions and is shaped by a new contradiction. They often go much further than underlying systemic changes allow. They break forward, as the vanguard of a victorious army, and then often meet resistance of various social and political forces and may suddenly start to roll back just at the moment when everyone expects their further offensive. We believe that this is what is happening with globalization at present. The yearbook will be interesting to a wide range of researchers, teachers, students and all those who are concerned about global issues

Detecting Events and Patterns in Large-Scale User Generated Textual Streams with Statistical Learning Methods

A vast amount of textual web streams is influenced by events or phenomena emerging in the real world. The social web forms an excellent modern paradigm, where unstructured user generated content is published on a regular basis and in most occasions is freely distributed. The present Ph.D. Thesis deals with the problem of inferring information - or patterns in general - about events emerging in real life based on the contents of this textual stream. We show that it is possible to extract valuable information about social phenomena, such as an epidemic or even rainfall rates, by automatic analysis of the content published in Social Media, and in particular Twitter, using Statistical Machine Learning methods. An important intermediate task regards the formation and identification of features which characterise a target event; we select and use those textual features in several linear, non-linear and hybrid inference approaches achieving a significantly good performance in terms of the applied loss function. By examining further this rich data set, we also propose methods for extracting various types of mood signals revealing how affective norms - at least within the social web's population - evolve during the day and how significant events emerging in the real world are influencing them. Lastly, we present some preliminary findings showing several spatiotemporal characteristics of this textual information as well as the potential of using it to tackle tasks such as the prediction of voting intentions.Comment: PhD thesis, 238 pages, 9 chapters, 2 appendices, 58 figures, 49 table

In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.

Regulatory T cells (Tregs) have been shown to be critical in the balance between autoimmunity and tolerance and have been implicated in several human autoimmune diseases. However, the small number of Tregs in peripheral blood limits their therapeutic potential. Therefore, we developed a protocol that would allow for the expansion of Tregs while retaining their suppressive activity. We isolated CD4+CD25 hi cells from human peripheral blood and expanded them in vitro in the presence of anti-CD3 and anti-CD28 magnetic Xcyte Dynabeads and high concentrations of exogenous Interleukin (IL)-2. Tregs were effectively expanded up to 200-fold while maintaining surface expression of CD25 and other markers of Tregs: CD62L, HLA-DR, CCR6, and FOXP3. The expanded Tregs suppressed proliferation and cytokine secretion of responder PBMCs in co-cultures stimulated with anti-CD3 or alloantigen. Treg expansion is a critical first step before consideration of Tregs as a therapeutic intervention in patients with autoimmune or graft-versus-host disease