Research Theses Submission
Permanent URI for this collection
Browse
Recent Submissions
Item PiRAMiD: predicting early onset autism through maternal immune activation and proteomic discovery(University College Cork, 2023) Carter, Michael; Murray, Deirdre M.; Gibson, Louise; O'Keeffe, Gerard W.; English, Jane; National Children's Research CentreAutism spectrum disorder (ASD) is a heterogeneous developmental disorder arising early in life. ASD is composed of a wide variety of clinical characteristics, neuropsychological impairments and complex phenotypes. The classical triad of ASD symptoms includes disrupted social function, atypical verbal and non-verbal communication skills, and restricted interests with repetitive behaviours. These core symptoms often coexist with other psychiatric and neurological comorbidities. Attention Deficit Hyperactivity Disorder (ADHD), epilepsy, migraine, and anxiety are much commoner in children with ASD. Children and adults with ASD often encounter difficulties with emotional and behavioural problems (EBPs) such as emotional reactivity, aggression, and depression. Up to 50% of those affected can have intellectual disability (ID) and limited verbal communication. Social, emotional and behavioural deficits in children with ASD are also important modifiers of outcome and are linked to elevated stress, mental and physical health problems, and lower overall family and caregiver well-being. We know that early intervention can be effective, and may be parent or therapist delivered. Pharmacological treatment of ASD can be successful insofar as it is useful for symptomatic management of some ASD comorbidities such as ADHD, and depression. Although genetic susceptibilities are increasingly recognised, the mechanism of disease development in ASD remains unknown. We are aware of both common and rare genetic risk factors with more than four hundred diverse high confidence genes now linked to ASD (https://www.sfari.org/resource/sfari-gene/). Singly, these genetic factors each convey only a modest increase in ASD risk (~1%), however collectively they can contribute to a far greater risk. Both de novo and inherited genetic defects are recognised but ASD risk in progeny does not follow a clear pattern of inheritance. Estimates of heritability of ASD in twin pairs vary widely between 50 – 90%. The apparent male preponderance in ASD persists with a clear bias towards males. Rates of ASD among males exceed those of females by three or fourfold hinting at a possible sex differential genetic foundation. Up to 20% of individuals with ASD may possess copy number variants (CNV) and de novo loss of function single nucleotide variants (SNV) that are individually rare but in combination, increase an individual’s overall ASD risk. While newer methods of genetic analysis (such as whole genome sequencing) are uncovering new candidate genes with regularity, the heterogeneity of the clinical and phenotypic groups within ASD strongly suggest that in those with a genetic predisposition, environmental factors may act in concert to bring about a multisystem dysfunction leading to ASD. Despite recent advances in gene analysis, we are yet to discover a single gene determinant that can account for more than a small percent of ASD cases. The current ASD literature suggests that mutations occurring in genes involved in synapse formation, cell adhesion molecule production (Cadherin), scaffolding proteins (SHANK proteins), ion channels (sodium, calcium, and potassium channels), and signaling molecules can disrupt regulatory or coding regions and affect synapse formation, plasticity and synaptic transmission. All this suggests that we cannot explain many cases of ASD by genetic factors alone, or at least we cannot explain them using our current understanding of ASD genetics or our current techniques of genetic analysis. The flawed picture of ASD genetics has led some to investigate the role of environmental exposures in the aetiology of ASD. Researchers have identified many environmental risks in ASD. Advanced parental age, foetal environmental exposures, perinatal and obstetric events, maternal medication use, smoking and alcohol use, psychosocial hardship, nutrition and toxic exposures have all been implicated as risks in the pathogenesis of ASD. While authors attribute between 17 - 41% of ASD risk to non-genetic or environmental exposures, the exact balance between genetic and environmental determinants and their roles in aetiology remains disputed. Multiple mechanisms have been proposed through which each of these exposures may exert an influence on genetic and epigenetic risk in ASD , but there are only a handful that are likely to effect abnormal neurodevelopment. Animal models of inflammation and maternal immune activation are particularly well characterised, and have successfully modelled ASD type behaviours and social difficulties in mice, rats and non-human primates. Maternal immune activation (MIA) is defined as an increase in measured levels of inflammatory markers in mothers during pregnancy. Through this process, a cytokine cascade transmits to the foetus, resulting in adverse neurodevelopmental phenotypes and even remodelling of the immature foetal brain. Many studies have profiled cytokine, chemokine, immune cell and inflammatory signatures in ASD affected individuals. Only a much smaller number have characterised cytokine profiles in expectant mothers who progressed to birth children who develop ASD. The few previous studies, which have examined gestational serum, have indicated mid-gestational upregulation in specific pro-inflammatory cytokines or indeed down-regulation in anti-inflammatory cytokines. Metabolomic analysis refers to the systematic identification and quantitation of all metabolites in a given biological sample. This collection of metabolites, known as the metabolome, is thought to directly reflect the biochemical activity of the studied system at a specific point in time. The metabolome has become an area of interest, as some inborn errors of metabolism (IEM) are clearly linked to ASD phenotypes. Phenylketonuria (PKU) and Smith-Lemli-Opitz syndrome (SLOS) are disorders of amino acid and cholesterol metabolism respectively. Untreated PKU is associated with strongly autistic phenotypes, while SLOS is phenotypically heterogeneous, but autism remains a common feature in these children. Similarly, proteomics is defined as the study of the complete protein profile in a given tissue, cell or biological sample. Proteomic studies of human sera have so far noted altered levels of proteins involved in inflammation or immune system regulation, including acute phase reactants and interleukins. Abnormalities of the complement system have also been found in ASD and other psychopathologies such as schizophrenia. Recent works demonstrate that the complement pathway can affect synaptic remodelling and has roles in neurodevelopmental processes. The initial focus of ASD research on genomics has largely failed to result in the much-hoped-for silver bullet of ASD aetiology, i.e. a common genetic cause. Instead, the genetic landscape has proven to be exceedingly complex and interdependent on a multitude of factors, including environmental exposures and other modifiers of genetic risk. Research examining the aetiology of ASD has shifted focus from genetics to a multimodal approach. In recent years, funding has become available for a far wider variety of ASD aligned research topics, beyond those with a focus on genetics. Opportunities now exist to adopt a multifaceted approach to ASD aetiology, shifting the focus from a narrow genetic base, to a broader multimodal approach to examine other potential mechanistic players. While this adds further complexity to what is already a complicated picture, the strived for parsimonious answer is simply never likely to materialise. Newer fields and modalities such as proteomics, metabolomics and machine learning will help to further refine and untangle the complicated web of ASD, and this variety of granular detail is what is likely to result in a practicable biomarker or effective therapy in the future. In this thesis using a multimodal approach (ELISA, metabolome and proteome analysis) we aim to explore further the role of MIA and alterations of the proteome and metabolome in the pathophysiology of ASD. We hope that our findings may ultimately help to identify a potential gestational biomarker of ASD, which will improve access to early diagnosis and treatment. We also aim to characterise co-morbid emotional and behavioural problems, which arise early in children with ASD and are pervasive throughout all spheres of life. Early recognition and intervention with these co-morbidities can improve treatment outcomes, patient, and family wellbeing.Item The gut microbiome of the wild great tit (Parus major): drivers and fitness consequences(University College Cork, 2023) Somers, Shane Edmond; Quinn, John; Ross, R. Paul; Stanton, Catherine; Irish Research Council for Science, Engineering and Technology; European Research Council; Science Foundation IrelandThe gut microbiome plays a vital role in its host’s ecology. Clinical studies have shown gut microbes increase host health and fitness by providing digestive and immune functions, as well as aiding development. Natural variation in the microbiome is widely believed to affect host fitness in the wild but we are lacking experimental studies to test this. The microbiome varies with both host and environmental factors but most studies to date have focussed on individual factors and not adequately addressed the multiple overlapping and hierarchical drivers of microbiome variation working at environmental, host and microbial scales. This thesis investigates the role of the gut microbiota in host fitness, and how this is affected by and varies across contexts. Additionally, we address sources of variation in the gut microbiota at a host and environmental level, accounting for host ecology and drivers at different scales. We find that the host’s weight is correlated with microbiome diversity during development but that the direction of this relationship is context dependent. This shows that the microbiome interacts with the environment to determine host fitness and is important because it helps explain the contradictory findings linking diversity to weight. We also show that the interaction between the host, its microbiome and environment change with developmental stage. Specifically, we found that the microbiome of developed individuals is remarkably resilient to environmental perturbation, while developing individuals are much more sensitive, with important implications for future experiments. We developed a novel method for experimentally perturbing the microbiome that will allow microbiome researchers to begin testing hypotheses linking the microbiome to host ecology and evolution in natural settings. Finally, we show that welfare measures, such as environmental enrichment may interact with the gut microbiota to impact on host health and behaviour. In summary, I show that variation in the microbiome is linked to host ecology and that this variation is linked to host fitness.Item Reforming mental condition defences and procedures in the criminal justice system in light of the Convention on the Rights of Persons with Disabilities(University College Cork, 2023) Noonan, Michael Luke; O'Sullivan, Catherine; Whelan, Darius; Irish Research CouncilThe United Nations Convention on the Rights of Persons with Disabilities (C.R.P.D.) is the first human rights treaty of this century. It aims to ensure that persons with disabilities have full and effective inclusion in society and are not the subjects of discrimination. Support for the C.R.P.D. was unprecedented, attracting widespread approval from states in all regions, and achieving the highest number of signatories to a U.N. Convention on its opening day. Whilst most of its provisions have been welcomed, the interpretation of several key articles by U.N. bodies has led to some unanticipated issues of compliance with areas of the criminal justice system. It has been argued that the C.R.P.D. requires the abolition of any criminal defence which relieves or mitigates liability because of a disability, and any procedures that declare an accused unfit to be tried based on mental impairment. The relevant mental condition defences for this study provide a defence based on a mental condition caused by an internal factor (insanity, diminished responsibility, and infanticide). No State Party to the C.R.P.D. has shown any inclination to abolish mental condition defences or procedures due to a perception that the interpretations advanced by the U.N. bodies are flawed and unworkable. The summary documents of the drafting process of the treaty show that the potential impact of the C.R.P.D. on criminal justice issues received almost no consideration during negotiations. This means that there has been very little consideration of how criminal law could be reformed in a way that is compliant with the C.R.P.D. As Ireland plans to ratify the Optional Protocol, which permits individuals to complain to the Committee about a C.R.P.D. violation, it is important to conduct a review of domestic law to identify what changes are required. This study establishes that mental condition defences and procedures can be reformed in a way that is C.R.P.D. compliant without the necessity of abolition. To identify whether the existing law requires reform, a normative framework is constructed from principles derived from the C.R.P.D. and used throughout the thesis to improve compliance. The normative framework’s key principle is the prohibition of the deprivation of legal capacity based on a defect in mental capacity. It also provides that determinations of criminal liability which fail to treat persons with disabilities as equals to others are discriminatory and must be abolished. It is determined that the insanity defence could be made compliant with the C.R.P.D. by the creation of several new mental condition defences. It is proposed that the cognitive limb of insanity should be replaced by a legal rule which allows for evidence of a psychosocial disability to negate mens rea. The evaluative and volitional limbs should be replaced with a new defence which focuses on the defendant’s ability to generate alternative choices. The third new defence is for crimes without a subjective mens rea. These offences pose a particular challenge as they do not require moral fault. It is identified that, in exceptional circumstances, other human rights need to take priority and defendants who are incapable of receiving notice about the law because of a psychosocial disability should not be found liable. It is also found that the partial defences of diminished responsibility and infanticide infringe an offender’s right to legal capacity by holding them to a lesser standard of behaviour because of a disability. It is recommended that both defences should be abolished and replaced by discretionary sentencing for murder. Fitness to be tried hearings should be replaced with an assessment of what support is necessary for the accused to participate effectively in the trial.Item L’infante, la donna, la bestia: un’analisi ecocritica degli incontri non umani in Federigo Tozzi, Dino Buzzati, Anna Maria Ortese(University College Cork, 2023) Ceravolo, Marco; Ross, Silvia; Irish Research Council for Science, Engineering and TechnologyThe authorial connections between Federigo Tozzi, Dino Buzzati and Anna Maria Ortese are notable and varied. Linked by a fervent animalistic and, in the case of the latter two, also environmentalist spirit, the non-human plays a central role in the works of the authors, who represent natural entities, animals, or fantastic creatures as narrative archetypes of universal pain. This thesis investigates the encounters between the human and the nonhuman in the works of Tozzi, Buzzati, and Ortese with the aim of answering the questions “what does otherness represent for the authors?”, and “how is this 'other' portrayed in their novels, short stories, and journalistic writings?”. To tackle these issues, my analysis considers three thematic areas, namely the representation of the child, the woman, and the beast, categories united by a perception of inferiority, and thus of marginalization, in a purely patriarchal social context. In the three chapters, one per individual author, the investigation of the three principal thematic areas makes use of a range of critical theories such as Ecocriticism (Garrard, Buell, Wolfe, Iovino), Animal Studies (Derrida, Cimatti, Regan, Singer), Ecofeminism (Warren, Adams, Plumwood, Ruether) and Children's Studies (Freud, Joosen, Khan, Kellert). In the works of the three authors, the animal is portrayed as abused, castrated, and killed, and this confirms how, due to a lack of logos, the nonhuman can be easily subjugated in human society. On other occasions, the animal, as a model of otherness, is acknowledged by the authors as a fragile entity, and thus in need of protection or defense. However, animality also serves the function of representing human figures through animalistic characteristics, or portraying characters who are placed on the same social scale as beasts enslaved to man: namely, women and children. Therefore, after having traced the narrative archetypes and symbolic connections between the child, the woman, and the animal in selected works of Tozzi, Buzzati and Ortese, the last part of the respective chapters addresses the salient themes of the three authors' attitude towards animals from an ethical-moral perspective. In the case of Tozzi, I analyze texts that draw upon his strong influence by nonhuman agents. For Ortese and Buzzati, I consider a selection of the authors’ militant journalistic production which advocates for the protection of those who have no voice to denounce their own oppression, existential imperatives of an ethical-moral order which constitute the critical building blocks of their animalist spirit. The conclusions highlight the connections between the authors through the three thematic cores examined (child, woman, and beast), and trace the positioning of the nonhuman in the authorial imaginary of Tozzi, Buzzati and Ortese, authors who are only seemingly dissimilar, but who are linked, instead, by a profound, indissoluble interest in the other.Item The socio-cultural terroir of Irish craft brewing(University College Cork, 2024) Day, Shawn; Crowley, John; O'Connor, Ray; Murphy, OrlaThis thesis provides a rich and unique exploration of the world of craft brewing in Ireland. One of the key concepts underpinning the research is that of socio-cultural terroir, which captures the all-important nexus between craft, practice, and place. Cultural geography provides a way of seeing and understanding the craft of brewing in all its richness, diversity and complexity. Foregrounding the brewers’ own experiences reveals how the craft is learned, affirmed and sustained. Applying emerging digital humanities methodologies such as textual analysis, information and knowledge visualisation to more conventional cultural geographic approaches allows for an exploration of how the journeys and values of Irish craft brewers emerge from, shape and (re)create meaning, identity and place in a rapidly growing and evolving community. Consisting of two parts, this thesis first seeks to bring a cultural geographic lens to bear on the craft brewing trade while carefully detailing the historical tradition from which it emerged, and secondly, it demonstrates how digital humanities practice can be employed to expand, augment, amplify, and enhance that exploration. The design, development, and deployment of an exploratory interactive platform to disseminate the findings facilitates an open sharing of the data, inviting further exploration, interpretation, and engagement with the research by a wider network of interested parties, including most importantly, the brewers themselves who have been a central focus of this research.