CORA
Cork Open Research Archive (CORA) is UCC’s Open Access institutional repository which enables UCC researchers to make their research outputs freely available and accessible.
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Gut-heart axis in a large animal model of metabolic syndrome and heart failure
(University College Cork, 2024) Cluzel, Gaston; Caplice, Noel M.; Stanton, Catherine; SFI Manufacturing
Background
The metabolic syndrome (MetS) is a pathological condition diagnosed as the combination of obesity with either hypertension, dyslipidaemia, or hyperglycaemia. MetS constitutes a deadly cocktail of cardiovascular risk factors that greatly increases patient mortality. Among the cardiovascular complications of MetS, heart failure with preserved ejection fraction (HFpEF) represents one of the greatest unmet clinical needs of the 21st century. Indeed, as HFpEF prevalence increases along with soaring MetS cases, current therapeutic strategies fail to prevent disease complications. Therefore, novel approaches are required.
MetS and HFpEF are accompanied by a low-grade inflammation (LGI) state. LGI is characterised as a steady but lingering increase in circulating inflammatory factors. Inflammatory signalling is known for promoting structural and functional changes in the myocardium that may contribute to HFpEF. Thus, decreasing LGI may reduce HFpEF progression.
While the precise origin of LGI is uncertain, the gut microbiome has recently emerged as a hidden organ with critical immune regulatory functions. Crucially, the gut microbiome is tightly connected to the intestinal barrier. In MetS and HFpEF, patients show alteration of the gut microbiome and of the intestinal barrier, a phenomenon called gut permeability. Gut permeability results in the translocation of bacterial antigens from the gut lumen to circulation. Circulating bacterial antigens are pro-inflammatory, that contributes to LGI and, indirectly, to cardiac structural changes and HFpEF. Therefore, therapeutic strategies aimed at the gut microbiome may effectively prevent HFpEF via reducing gut permeability and LGI. This concept is described as the “gut-heart” axis.
The gut-heart axis constitutes a novel field of investigation in cardiometabolic disorders and may answer the urgent need for novel therapeutic strategies directed against HFpEF. However, more research is needed to characterise the mechanisms involved in gut-heart signalling.
Aims of the project
This thesis aimed at characterising the cardiac pathological mechanisms involved in gut-heart signalling, and determining whether they can be modulated by a microbiota-targeted treatment.
Methodology
In this project, gut-heart axis pathological signalling was characterised using a porcine model of MetS and HFpEF induced by Western diet (WD) and hypertensive corticosteroid salts (desoxycorticosterone acetate, DOCA). Then, to investigate the effects of a gut microbiome-targeted intervention on MetS and HFpEF, this model was supplemented with a synbiotic product combining soluble corn fibre and Lactobacillus mucosae. Inflammatory signalling associated with HFpEF structural changes was investigated in the four cardiac chambers. In particular, the project focused on the roles of tumour necrosis factor (TNF)-α, lipopolysaccharide (LPS) and NOD-like receptor family, pyrin domain containing 3 (NLRP3). These central inflammatory pathways may be key in transducing gut-originating LGI into cardiac pathological signalling in HFpEF.
Results
Upon WD and DOCA challenge, the porcine model constituted a clinically-relevant reproduction of MetS and HFpEF. MetS was characterised by increased body weight, severe hypertension, hypercholesterolemia, and hypertriglyceridemia. HFpEF was characterised by left atrium enlargement (LAE) and left ventricle hypertrophy (LVH). LAE was associated with tissue apoptosis, and LVH was accompanied by cardiomyocyte hypertrophy. Left atrium (LA) and left ventricle (LV) also had increased inflammatory activity with cardiac macrophage (Mφ) expansion, and activation of TNF receptor 1 (TNFR1), toll-like receptor 4 (TLR4), and NLRP3 pathways. Moreover, the increase in TNFR1, TLR4, and NLRP3 activity was colocalised with cardiac Mφ, microvascular endothelial cells, and cardiomyocytes. While no structural or pressure-induced changes were observed in right heart chambers, the right atrium and the right ventricle also exhibited prominent inflammatory signalling. Data not reported in this thesis indicated that the model exhibited LGI and features of gut permeability. Overall, the porcine model of MetS and HFpEF was characterised by inflammatory cardiac changes along with systemic and intestinal alterations.
Synbiotic treatment of MetS pigs reduced LAE, LA cardiomyocyte apoptosis, and LVH, but did not affect MetS core parameters. These improvements in cardiac structural changes were associated with a reduction in cardiac Mφ expansion and in TNFR1, TLR4, and NLRP3 activity in all four cardiac chambers. Reductions in TNFR1, TLR4, and NLRP3 activity were colocalised within the cardiac Mφ, microvascular endothelial cells, and cardiomyocytes populations. Data not reported in this thesis also indicated that synbiotic treatment reduced LGI and gut permeability. Therefore, synbiotic treatment targeted at the gut microbiome reduced pathological signalling along the gut-heart axis, and effectively reduced cardiac structural changes associated with HFpEF.
Discussion
The porcine model of MetS and HFpEF stood out as a robust model for investigating gut-heart axis inflammatory signalling. The study also highlighted the central role of TNFR1, TLR4, and NLRP3 in driving structural changes in HFpEF through pro-apoptotic and pro-hypertrophic signalling. Crucially, synbiotic treatment targeted at the gut microbiota effectively reduced HFpEF-associated structural changes via reducing cardiac inflammatory signalling. Finally, while exempt of structural changes, the right heart reflected accurately and dynamically the systemic changes in gut-heart axis pathology and treatment.
Conclusions
Synbiotic targeting of the gut microbiome resulted in cardiac structural improvements in a clinically-relevant porcine model of MetS and HFpEF. This study demonstrates the critical role of gut-heart inflammatory signalling cardiometabolic disease progression.
Working relationships in family business: a psychological contract theory perspective
(University College Cork, 2024) O'Leary, Olivia; Murphy, Linda; Sherman, Ultan; Duggan, James
Family businesses have long been recognised as pillars of economies worldwide, with Ireland boasting a rich history of such enterprises dating back centuries. Despite their prevalence, the distinct characteristics of family businesses present challenges, with their unique dynamics and working relationships often shaping their success or failure. Drawing upon psychological contract theory, this study investigates the formation and content dimensions of psychological contracts among family and non-family employees in family businesses. By comparing and contrasting these perspectives, this study uncovers the underlying processes and implications for the working relationship within family businesses.
Conducted through an exploratory qualitative study with four independent family-owned retailers in Ireland, the study revealed distinct patterns in the formation of the psychological contract and illustrated that both family and non-family employees’ psychological contract formation is influenced by critical factors such as pre-entry and post-entry episodes, information sources, and agency relationships. However, family members have a protracted psychological contract formation process rooted in early organic experiences through their family membership. Non-family employees experience psychological formation through recruitment and standardised organisational entry processes. The research uncovers distinctive terms in the psychological contract with family employees, often emphasising familial obligations and legacy preservation, while non-family employees prioritise career development and stable employment. Both family and non-family employees feel obligated to the community in which the business operates. These findings shed light on the unique dynamics at play within family businesses, highlighting the importance of understanding and addressing the diverse needs and expectations of employees.
This study contributes to both psychological contract theory and the unique context of family businesses. Furthermore, this thesis deepens our understanding of psychological contract theory by introducing novel concepts such as dormant psychological contracts and the influence of family relationships on employment arrangements. It advances psychological contract theory by demonstrating how early experiences shape working relationships in family businesses. It contributes to the family business domain by illuminating the role of HRM processes and co-workers in constructing psychological contracts in working relationships.
Practically, this research offers valuable insights for organisational leaders and HR practitioners in managing working relationships within family businesses. By recognising and addressing the distinct dimensions of psychological contracts, family businesses can build positive employee-organisation relationships, enhance employee engagement, and ultimately improve organisational outcomes. Overall, this thesis comprehensively explores the formation of psychological contracts in family businesses, offering theoretical contributions and practical implications for organisational practice.
A model of SPRY3 - VGCC interactions relating to autism
(University College Cork, 2023) Bharatham Vijayaraghavan, Sashank; Moore, Thomas F.; Burk, Katja
Autism Spectrum Disorder (ASD) is a neurobehavioral condition characterized by impaired social interaction and communication resulting from irregular brain development during infancy and adolescence. Globally, over 168 million cases of ASD have been diagnosed, with Ireland ranking sixth in prevalence (583.69 cases per 100,000 people). Heritability, estimated between 40% and 80% in twin and family studies, underscores the importance of identifying susceptibility genes in ASD research. The ASD susceptibility candidate gene SPRY3 encodes a receptor tyrosine kinase inhibitor and plays a regulatory role in branching morphogenesis. SPRY3 is highly expressed in cerebellar Purkinje cells. Spry3 and p75NTR have opposite expression patterns in the cerebellar vermis of the mouse and it has been hypothesized that reactivation of the epigenetically silenced Y-linked SPRY3 copy in the human might interact with the TrkB and p75NTR signaling pathways to cause Purkinje cell pathology.
The current work evaluates the potential that SPRY3-GFP colocalizes with neurotropic receptors in HEK293 cell line model and found that SPRY3-GFP colocalizes with TrkB-RFP and p75NTR-RFP. Significant colocalization of SPRY3 with EGFR-GFP and TrkA-RFP was also observed. This investigation detected no colocalization between SPRY3-RFP and CasR-GFP, which is a G-protein-coupled extracellular calcium-sensing receptor. The involvement of voltage-gated calcium channels (Cav) have been implicated in ASD and their role in the regulation of branching morphogenesis in the brain and lung, and the fact that calcium acts as a secondary messenger to modulate various signaling pathways involved in branching morphogenesis, we hypothesized a functional relationship between SPRY3 and calcium signaling mediated through Cav receptors. SPRY3 plays an important role in regulating axon branching of motor neurons. Similarly, growth cones rely on calcium signaling to respond to guidance cues and adjust their behavior accordingly and it is critical for proper axon extension and guidance. Using calcium imaging in SH-SY5Y cells, we found that adding KCl to SH-SY5Y cells expressing SPRY3-GFP significantly altered the function of Cav 1.2, Cav 1.3, and Cav 2.2. SPRY3-GFP did not alter the levels of calcium when the L-type inhibitor nifedipine was added to SH-SY5Y cells, shows that SPRY3 interacts with Cav 1.2 and Cav 1.3. Cav2.2 is a prominent VGCC in IMR-32 cells, where calcium levels are not altered. Also, we found that adding BDNF to SH-SY5Y cells transfected with SPRY3-GFP shown no changes in intracellular calcium levels. Overall, this study suggests an interaction between SPRY3 and L-type VGCCs, which may be relevant to ASD pathogenesis. In a pilot study, there was no significant difference in the mRNA expression of FMR1-, a known ASD gene in SPRY3-GFP transfected SH-SY5Y cells compared to GFP transfected SH-SY5Y cells.
Childhood trauma and trauma-informed care in early intervention in psychosis
(University College Cork, 2024) Hunt, Evan; Lambert, Sharon; Murphy, Mike; Lonergan, Edgar; O'Connor, Karen; Health Service Executive
This doctoral thesis explores the integration of Trauma-Informed Care (TIC) within Mental Health Services (MHS) and examines the prevalence and impact of childhood trauma in individuals experiencing First-Episode Psychosis (FEP). Through a systematic review, the research identifies core principles and practices of TIC in MHS, leading to the development of a framework that encompasses therapeutic environment, sociocultural responsiveness, and workforce development, providing a blueprint for operationalising TIC within mental healthcare.
Building on this foundation, an empirical study establishes the demographic and clinical profile of service users accessing an Early Intervention in Psychosis (EIP) service in Ireland. Findings reveal the complex and diverse needs of the population, including significant gender differences in age of onset, substance use, and functional impairments, emphasising the necessity for tailored interventions in EIP services.
Further research investigates the prevalence of childhood trauma among FEP service users, revealing a high rate of trauma exposure (78%), with emotional abuse and neglect being most common. Gender differences were also found, with females reporting higher severity and cumulative trauma. These findings highlight the importance of integrating trauma-informed approaches into EIP services to address the multifaceted needs of individuals with psychosis.
Finally, the thesis examines the longitudinal impact of childhood trauma on clinical outcomes in FEP. While trauma severity was linked to self-harm, it did not significantly affect other baseline clinical characteristics. Over the course of 12 months of treatment, significant improvements in symptomatology and functioning were observed, regardless of trauma history, highlighting the effectiveness of EIP services in supporting individuals with FEP. This research collectively emphasises the need for trauma-informed, individualised care to optimise outcomes for individuals with early psychosis.
Dynamics of adaptive recurrent neural networks
(University College Cork, 2023) Fox, David; Amann, Andreas; Keane, Andrew; University College Cork
In this thesis a simple, phenomenological model of a neural network with plasticity is presented in the form of a slow-fast adaptive dynamical recurrent neural network. The plasticity rule is chosen from the class of Hebbian learning rules, in which the synaptic connection between two neurons evolves continuously as a function of their correlation in the recent past. Initially an analysis of networks of two neurons is presented, which exhibit relaxation oscillations in which one neuron switches between an ’off’ state, where it takes a negative value, and an ’on’ state, where it takes a positive value, while the other neuron stays in one on/off state. Then, by means of an example with a nine neuron network, the system is shown to exhibit both stable frequency cluster synchronization and transient frequency cluster synchronization.