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Pain and touch differentially modulate corticospinal excitability, independent of afferent inhibition
No full textCharacterisation of the Enzymes Involved in the Anaerobic Biosynthesis of Benzimidazolylcobamides
No full textVitamin B12 is a complex metalloorganic cofactor involved in a variety of biochemical reactions that are essential for life. There are two routes by which its biosynthesis can be achieved: the oxygen independent (anaerobic) and oxygen dependent (aerobic), involving around 30 enzymatic steps. However, little biochemical characterisation has been conducted on the newly identified bza operon, which has been shown to encode enzymes capable of biosynthesising dimethylbenzamidizole (DMB), the α-ligand of vitamin B12. Furthermore, other bza-like operons have been linked to the production of cobamides with alternatively functionalised benzimidazole α-ligands (benzimidazolylcobamides). This thesis describes the biochemical investigation of the enzymes involved in these Bza and Bza-like pathways, aiming to provide insight into how they operate.
Three different BzaC enzymes identified in Bza and Bza-like pathways have been recombinantly produced, purified and biochemically characterised. This involved reconstitution of BzaCs activity with a benzimidazolylcobamide substrate, investigation of their reaction mechanisms, substrate specificity, inhibition and 3D structure. Furthermore, an interesting BzaE enzyme, which potentially belongs to the newly identified B12 dependent radical SAM family, identified in a Bza-like pathway has been investigated.
This work identified that BzaC can catalyse regioselective SAM dependent methyl transfer to 5(6)-hydroxybenzimidazolylcobamide with differences seen in percentage conversion of substrate to product across the BzaCs investigated. Assays containing 5(6)-hydroxybenzimidazole cobamides with differing upper ligands (cyano, hydroxo, adenosyl) identified that the enzymes prefer an adenosylated substrate. Furthermore, the highest performing BzaC, DtBzaC, was subject to kinetic analysis identifying a low micro molar affinity for its adenosylated substate (Km = 11 µM), together supporting BzaC's role in cobamide biosynthesis.
The 3D crystal structure of the DtBzaC dimer with SAH identified the SAM binding domain and in combination with substrate docking and structural comparison to similar enzymes allowed for a catalytic mechanism to be proposed, in which an active site histidine residue can deprotonate the substrate hydroxyl group, increasing its nucleophilicity, promoting SAM dependent methyltransfer.
In addition, biochemical analysis of DtBzaE identified that it can catalyse the radical rearrangement of adenosyl 5(6)-methoxybenzimidazolylcobamide likely forming a hydroxymethyl product (Ado[5(6)-CH2OH]Cba), deviating from the currently proposed reaction scheme for a BzaE enzyme.
Together the studies conducted in this thesis have contributed novel findings to the field, shifting the understanding of how these enzymes and pathway's function
Extended excitation backprop with gradient weighting: A general visualization solution for understanding heterogeneous face recognition
Get PDFVisualization methods have been used to reveal areas of images which influence the decision making of machine learning models, thereby helping to understand and diagnose the learned models and suggest ways to improve their performance. This concept is termed Explainable Artificial Intelligence. In this work, we focus on visualization methods for metric-learning based neural networks. We propose a gradient-weighted extended Excitation Back-Propagation (gweEBP) method that integrates the gradient information during its backpropagation for the accurate investigation of embedding networks. We perform an extensive evaluation of our gweEBP, and seven other visualization methods, on two neural networks, trained for heterogeneous face recognition. The evaluation is performed over two publicly available cross-modality datasets using two evaluation methods termed the “hiding game” and the “inpainting game”. Our experiments showed that the proposed method outperforms the competing methods in both games in most cases. Additionally, our comprehensive study also provides a benchmark for comparing visualization techniques, which may help other researchers develop new techniques and perform comparative studies on them
The importance of small-island populations for the long-term survival of endangered large-bodied insular mammals
Get PDFIsland populations of large vertebrates have experienced higher extinction rates than mainland populations over long timescales due to demographic stochasticity, genetic drift, and inbreeding. While being more susceptible to extinction and as such potentially targeted for conservation interventions such as genetic rescue, small-island populations can experience relatively less anthropogenic habitat degradation than those on larger islands. Here, we determine the consequences and conservation implications of long-term isolation and recent human activities on genetic diversity of island populations of two forest-dependent mammals endemic to the Wallacea archipelago: the anoa (Bubalus spp.) and babirusa (Babyrousa spp.). Using genomic analyses and habitat suitability models, we show that, compared to closely related species, populations on mainland Sulawesi exhibit low heterozygosity, high inbreeding, a high proportion of deleterious alleles, and experience a high rate of anthropogenic disturbance. In contrast, populations on smaller islands occupy higher-quality habitats, possess fewer deleterious mutations despite exhibiting lower heterozygosity and higher inbreeding. Site frequency spectra indicate that these patterns reflect stronger, long-term purging in smaller-island populations. Our results thus suggest that conservation efforts should focus on protecting small-island high-quality habitats and avoiding translocations from mainland populations. This study highlights the crucial role of small offshore islands for the long-term survival of Wallacea’s iconic and indigenous mammals in the face of development on the mainland
Rapid changes in hydrostatic pressure as a probe for correlating function of purified proteins with their measured activity in living cells
Get PDFHydrostatic pressure (HP) has long been used to perturb protein and membrane structures and to alter their interactions with binding partners in a fully reversible manner. HP has also long been used to perturb molecular structures in living cells where it can alter cytoskeleton dynamics, cellular signalling pathways and to stall cell division in a wide variety of cells. HP can be applied and removed, in a fraction of a second and is transmitted through tissue at the speed of sound thus rapid changes in HP can be very useful to correlate the behaviour of isolated macromolecules with the same molecules within living cells. Despite its usefulness HP has not found wide use among researchers mainly because of the need for specialist equipment. This largely reflects the use of High HP (≥ 1000 atmospheres) by the majority of practitioners. While these high pressures have provided insights into protein denaturation, membrane reorganization, and sterilization of bacteria and viruses in medicine and food here we will focus on the uses of moderate HP (< 200 atmospheres) where the engineering and safety issues are less significant. At these lower pressures HP has its effect by altering the water shells at molecular interfaces. We outline here the background to the methods used, some of the simple adaptations required to laboratory equipment to allow HP studies and give some examples of its use for studying isolated proteins and the same proteins in living cells
Interoception in social cognition under uncertainty: a computational and psychophysiological approach
Get PDFInteroception - the perception and monitoring of physiological states - plays a critical role in affective processes, intuitive decision-making, and social interactions. However, how interoceptive processing influences emotional and social processes under uncertainty remains empirically underexplored. Within a predictive processing framework, this dissertation combined behavioural, computational, and electrophysiological methods to investigate how individuals integrated interoceptive and external cues to infer others' emotions and adapt empathic responses in dynamic and uncertain environments.
In the first study (Chapter 2), questionnaires and behavioural experiments were employed, along with Structural Equation Modelling and Diffusion Drift Modelling, to explore if intolerance of uncertainty (IU) and alexithymia mediated the relationship between interoceptive sensibility and anxiety, as well as empathic distress and emotion perception. The second study (Chapter 3) further investigated how emotion perception is influenced by interpersonal contextual uncertainty. Specifically, it explored how emotion egocentricity biases in emotion recognition are modulated by learned interpersonal emotion contingencies and perceptual ambiguity. Computational modelling using the Hierarchical Gaussian Filter (HGF) illustrated how individuals adapted their beliefs about interpersonal emotional congruency, with learning trajectories modulated by individual differences in interoceptive sensibility and physiological reactions.
In the third study (Chapter 4), we measured heart-evoked potentials (HEPs), a cortical index of cardiac interoceptive processing, to probe interoceptive predictive processing during an adaptive empathy task. Results indicated that HEP amplitudes tracked precision-weighted prediction errors during social feedback, while showing that interoceptive modulations were associated with autistic traits. HEPs also predicted empathic accuracy during decision-making in this task. Lastly, in chapter 5, transcutaneous vagus nerve stimulation was shown to modulate adaptive empathic learning, providing causal evidence for the role of afferent vagal input in social interactions.
This research advances the understanding of how interoception shapes social and emotional functioning. It uncovers neural, cognitive, and physiological mechanisms underlying empathy and interoceptive processing using computational approaches. These findings have significant implications for our understanding of the role of interoceptive processing on social perception under uncertainty and, potentially, for the development of targeted interventions to improve emotional resilience and social functioning in clinical and non-clinical populations. This thesis enriches emerging perspectives of social cognition as an embodied anticipatory process, where interoception and uncertainty dynamically shape how we perceive, learn, and adapt to the social world
Infinite dimensional symmetric cones and gauge-reversing maps
Get PDFThe famous Koecher-Vinberg theorem characterises the finite dimensional formally real Jordan algebras among the finite dimensional order unit spaces as the ones that have a symmetric cone. An alternative characterisation of symmetric cones was obtained by Walsh who showed that the symmetric cones correspond exactly to the finite dimensional order unit spaces for which there exists a gauge-reversing map from the interior of the cone to itself. In this paper we prove an infinite dimensional version of this characterisation of symmetric cones
AI-driven advancements in orthodontics for precision and patient outcomes
Get PDFArtificial Intelligence (AI) is rapidly transforming orthodontic care by providing personalized treatment plans that enhance precision and efficiency. This narrative review explores the current applications of AI in orthodontics, particularly its role in predicting tooth movement, fabricating custom aligners, optimizing treatment times, and offering real-time patient monitoring. AI’s ability to analyze large datasets of dental records, X-rays, and 3D scans allows for highly individualized treatment plans, improving both clinical outcomes and patient satisfaction. AI-driven aligners and braces are designed to apply optimal forces to teeth, reducing treatment time and discomfort. Additionally, AI-powered remote monitoring tools enable patients to check their progress from home, decreasing the need for in-person visits and making orthodontic care more accessible. The review also highlights future prospects, such as the integration of AI with robotics for performing orthodontic procedures, predictive orthodontics for early intervention, and the use of 3D printing technologies to fabricate orthodontic devices in real-time. While AI offers tremendous potential, challenges remain in areas such as data privacy, algorithmic bias, and the cost of adopting AI technologies. However, as AI continues to evolve, its capacity to revolutionize orthodontic care will likely lead to more streamlined, patient-centered, and effective treatments. This review underscores the transformative role of AI in modern orthodontics and its promising future in advancing dental care
Complex grammar in English: A snapshot of comprehension in children aged 5 to 8
Get PDFOur study makes an empirical contribution to questions relating to the developmental trajectory of four examples of English complex grammar: subject and object control, subject and object relative clauses, long passives, and seem-raising constructions with and without an overt experiencer argument. We tested children’s comprehension of all seven sentence sets at the same point in time using a picture-selection task. 45 children (20 girls) from three Year groups (1, 2, and 3) with a mean age of 6.3, 7.4, and 8.3 years participated. The three groups scored at ceiling on subject relatives and on raising without an experiencer, and there were Year differences in order of age for object and subject control. Subject control showed a predictably delayed pattern and success with it correlated positively with verb-knowledge scores. However, all Year groups performed less well – with no differences between Years – on passives, object relatives, and raising with an experiencer, suggesting that even at age 8, these constructions were not fully comprehended. The most problematic construction was raising with an experiencer, where all Years achieved a mean score of 3/6 or below. We discuss this data pattern in relation to four grammatical properties (empty categories, displacement, intervention, word order), frequency and the lexical idiosyncrasies of some of the verbs. With respect to the grammatical properties, we ask whether certain combinations are more difficult for children to navigate than others
Mayan Bees and their Keepers: An abductive analysis of the revival of stingless beekeeping in the Yucatán Peninsula
No full textMelipona beecheii is a domesticated eusocial bee of the stingless Meliponini tribe. Known as Xunan kab, the Royal Lady Bee, M. beecheii has been cultivated by the Yucatec Maya of Mexico for more than 3,000 years. In the early 21st century, scientists recorded a steep decline in traditional beekeeping, with the number of domesticated hives falling as much as 93% over a 25-year period (Villanueva Gutierrez et al, 2005). To try to arrest the extinction of Yucatec meliponiculture, universities, civil society and government agencies collaborated in the design and implementation of new beekeeping training courses. Their efforts appear to have been successful, and scholars recently heralded a ‘resurgence’ in stingless beekeeping (Bratman, 2020). However, there is limited research explaining exactly how and why Xunan kab came back from the brink. The financial return for many stingless beekeepers is negligible, suggesting that utilitarian factors may not be foremost. The reproduction of traditional culture is a possible motive, but meliponiculture in the 21st century has undergone such a transformation that the meaning of tradition is hardly certain. Stingless beekeeping in the Yucatan Peninsula now includes innovative techniques and technologies developed in modern scientific contexts. Younger generations of Maya farmers do not appear to be much interested in old fashioned customs. And Maya women, who were traditionally prohibited from practicing meliponiculture, are now the most ardent defenders of stingless bees. Given the changing face of meliponiculture, this master’s thesis seeks to explain why people start, continue and stop keeping stingless bees. It used a critical realist framework and abductive methodology (Walters and Vayda, 2009) to identify working hypotheses and potential causative factors. To learn more about those factors, 14 beekeepers in the states of Yucatan and Quintana Roo in Mexico were recruited to participate in semi-structured life history interviews. 3 interviews from a previous journalism project in 2018 were added to the data (Kennedy and Arghiris, 2019). The resultant transcripts were translated and analysed thematically using NVivo. The analysis yielded rich data on a wide variety of factors and events. The family, educational networks, traditional culture, conservation ethics, spirituality, emotion, aesthetics and other themes were found to be implicated in beekeeping practices. The results were collated and written up as an ethnographic ‘thick description’. They were then discussed with reference to the literature, answering the research questions and generating new directions for future research
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