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Shifting across internally and externally oriented cognition: behavioural and neural explorations using task-switching and resting-state paradigms
Get PDFThe human brain frequently shifts between internal and external monitoring, and these changes in cognitive content can occur spontaneously or intentionally both at rest as well as during task performance. Specific frontoparietal networks have been associated with internal and external cognition and were shown to often display anticorrelated activation. Despite this being a persistent feature of human cognition, the neuroscientific study of cognitive flexibility lacks proper investigation of the exchange between internal and external processes. Cognitive flexibility research commonly employs task-switching paradigms, which often demonstrated the presence of switch costs (decreased performance) and increased lateral frontoparietal activation in conditions where people switched between tasks as compared to repeating the same task. However, all these studies mainly focused on switching between tasks requiring attention to external stimulus features, and have not investigated switching across internal and external cognition. Specifically, no studies have ever explored task-switching involving self-referential processes. Therefore, it is of interest to the scientific community to expand our understanding of cognitive flexibility in relation to these prominent aspects of cognition. In addition to this, despite the great deal of attention towards the correlation patterns between frontoparietal networks, there is little neuroscientific research focusing on identifying specific points of change within and across these networks. Therefore, this thesis investigates the behavioural and neural correlates of cognitive shifts across self-referential and externally oriented processes using novel task-switching paradigms, and explores the changes in brain networks subserving internal and external cognition at rest using change-point detection. Chapter 3 finds significant behavioural switch costs both in the external and internal domain, as well as additional costs in switching between domains as compared to within each domain. Chapter 4 partly replicates these behavioural findings and finds domain-specific activation of dorsal attention and default mode network when preparing externally and internally oriented tasks, respectively, as well as domain-general preparatory control in lateral parietal regions and dorsal precuneus. Chapter 5 investigates the same task-switching dynamics with another paradigm using different tasks and stimuli, confirming the presence of switch costs in both domains, but not the presence of additional costs to between-domain switching. Finally, Chapter 6 investigates the brain activity around change points as found through change-point detection and reveals small clusters in mediodorsal thalamus and regions of salience and default mode networks. It also explores dynamic functional connectivity and graph measures after segmentation based on this novel approach. Moreover, it examines the differences in the above measures across chronotypes, probing the effects of arousal fluctuations on brain dynamics, as induced by circadian preferences. Together, these empirical chapters provide novel information regarding the cognitive control of domain switching when involving internally oriented versus externally oriented tasks, and regarding the resting-state dynamics of the networks underlying these processes. Due to COVID-19, the entire trajectory of the thesis was adapted to allow the conduction of online behavioural studies (Chapters 3 and 5) and the analysis of existing datasets (Chapter 6), while waiting for in-person testing to resume (Chapter 4)
Creating sacred space in First Century Corinth
No full textA long-held belief among New Testament scholarship is that first century followers of the Jesus movement met in domestic spaces to worship. Yet, demographic studies demonstrate many of the early believers were low on the socio-economic scale, so it was plausible they did not have access to a domestic space which could accommodate a believing community. This thesis examines the archaeological remains of Ancient Corinth to determine the potential worship places which could have been frequented by the first century believers. Using spatial theories from human and cultural geography, consideration is given to how space becomes place: a process by which significance is assigned to the space through three elements of place: history, identity, and behaviour. The original contribution of this thesis is applying these three elements to the Corinthian believers and their worship spaces. This thesis will answer the question, “what are the emerging senses of sacred space within the first century Corinthian ἐκκλησία which can be investigated by considering their spiritual history, identity, and behaviour?” In his correspondence, Paul declares the ἐκκλησία as God’s temple; they themselves are a sacred space in which they can interact with the divine. To retain their sacrality, it is necessary for the believers to remember their spiritual history, comprised of Jewish, Greco-Roman as well as early Jesus Movement beliefs. Paul also calls for the believers to remember their spiritual identity as being in Christ and Christ in them, and to enact the proper behaviours as the ἐκκλησία τοῦ Θεοῦ, whether they are assembled for worship or living their daily lives. Recognizing these three elements of place demonstrates how the ἐκκλησία τοῦ Θεοῦ can be the sacred space of God’s temple as well as creating sacred space in first century Corinth when they assembled for worship in mundane spaces
Doses and routes of administration for uterotonic agents to prevent postpartum haemorrhage
Get PDFBackground: Postpartum haemorrhage (PPH) is the most common cause of maternal mortality and serious morbidity after childbirth, worldwide. Inadequate uterine tone after the birth of the baby can lead to excessive bleeding from the open vessels on the placental bed. Therefore, the administration of drugs that increase uterine contractility is recommended for all births. However, there is still uncertainty about the best route and dose of administration for each of the available uterotonic drugs.
Objectives: To perform two network meta-analyses, one to specify the route of administration, and one to specify the dose, that maximise the effectiveness of each of the available uterotonic drugs without increasing the risk for side effects. A ranking of the available options will be generated for all primary and secondary outcomes.
Selection criteria: Population: Randomised controlled trials involving women in the third stage of labour after a vaginal or caesarean delivery in hospital or community settings. Interventions: Systemically administered uterotonic drugs of any route and dose for PPH prevention. Comparison: Any other uterotonic drug, or a different route or dose of a given drug, or placebo, or no treatment. Outcomes (primary): PPH ≥500 mL and PPH ≥1000 mL.
Data collection and analysis: Data will be extracted from the eligible studies and entered on an electronic database. Risk of bias and trustworthiness assessments will be performed. Direct, indirect and network meta-analyses will be conducted, and results will be summarised as risk ratio with 95% confidence intervals (CI) for dichotomous outcomes and as mean difference with 95% CI for continuous outcomes. The certainty of generated evidence will be assessed according to the GRADE approach. Results with relative and absolute treatments effects will be summarised in Summary of Findings tables. Cumulative probabilities will be calculated and the surface under the cumulative ranking curve (SUCRA) will be used to create a ranking of the available drugs.
Main results: One hundred eighty-one studies involving 122,867 randomised women were included in the Routes-NMA. Results suggest that carbetocin IV(B), ergometrine plus oxytocin combination IM, oxytocin IV(B+I), and oxytocin IV(B) are probably more effective in preventing PPH and related morbidity outcomes, when compared with oxytocin IM. Intramuscularly administered oxytocin and carbetocin have a favourable side effects profile.
One hundred eighty-two studies with 132,593 randomised participants were included in the Doses-NMA. Carbetocin 100 mcg, ergometrine >200 mcg, and ergometrine plus oxytocin combination 500 mcg plus 5 IU rank among the best options for preventing excessive bleeding, use of additional uterotonics, and administration of a blood transfusion. However, when comparing these uterotonics against oxytocin 10 IU the generated evidence varies from very low to moderate certainty without statistically significant results, and thus findings are inconclusive. Carbetocin 100 mcg is associated with a favourable side effects profile.
Authors’ conclusions: Although carbetocin IV(B), ergometrine plus oxytocin combination IM, oxytocin IV(B+I), and oxytocin IV(B) are among the top uterotonics for PPH prevention, these uterotonics also increase the risk for side effects. In terms of which dose of administration maximises effectiveness results are unclear
Human lower limb movement prediction based on optimal control
Get PDFThe movement behaviour of the human body can be predicted by solving an optimal control problem, however, many limitations exist, for example, only certain movement behaviour such as level walking has been undertaken, and these predictions are often limited to able-bodied individuals. This thesis aims to advance existing predictive simulation studies, using optimal control theory to achieve prediction for both disabled individuals and able-bodied individuals.
There are significant technical challenges in predicting sit-to-stand motion for people with lower limb amputations, making it rare for researchers to delve into this field. The predictive study of sit-to-stand motion for the unilateral transtibial amputees completed in this thesis is the first in this field. This study not only modelled seat contact, but also created a novel "free fall method" to determine the initial and final postures of the motion, which is key for successful predictions. On this basis, using the established simulation framework, the motion behaviour under nominal prosthetic stiffness was first predicted, and then the effects of changing prosthetic stiffness were studied. Finally, several scientific conclusions were drawn.
Limited ankle dorsiflexion is a common problem due to ankle injuries and surgical operations, greatly affects our mobility. This thesis is the first to complete the predictive study on the sit-to-stand movement behaviour for people with ankle dorsiflexion limitations. The prediction of sit-to-stand motion was formulated as an optimal control problem and solved by the direct collocation method. Subsequently, the effects of different levels of ankle dorsiflexion limitation were studied, revealing the corresponding biomechanical compensation strategies. The nature of no experimental data required as input makes our predictive study eliminate the lengthy tests in the laboratory or clinical settings, with great potential to benefit the development of new interventional treatment for people with ankle joint impairments.
The objective function is the important component of the optimal control problem. However, the weights of different terms in the objective function are often adjusted manually, imposing a substantial burden in terms of time and labour. To address this problem, this thesis integrated the inverse optimal control method with the muscle-driven musculoskeletal dynamics model to investigate muscle coordination during the transition from squatting to standing. A nested bilevel optimisation algorithm was proposed to solve the inverse optimal control problem. The proposed bilevel optimisation algorithm effectively addressed the complex muscle coordination problem during human motion, providing a new approach for studying muscle coordination patterns.
The new model and algorithm proposed in this thesis effectively fill various gaps in the existing human lower limb predictive simulation studies and have great potential in the customisation of rehabilitation programs, design of assistive devices and development of bionic robots. In addition, the achievements in this thesis have important reference significance for predicting movements in other scenarios
Shakespeare's Cupio Dissolvi: desire, death and renewal
Get PDFThis thesis draws attention to the theme of destructive renewal in Shakespeare’s plays and narrative poems. Scholarship to date has explored Shakespeare’s destructive acts and frequently attributed them to a crisis of character: a result of shame, melancholy or hubris. Little attention has been given to the notion that these destructive, often self-destructive, acts are motivated by a desire to die. This thesis focuses on these moments of desiring death and reveals them to be expressions of faith, love, power and renewal. Many plays and other texts are discussed, but a particular focus is placed on three of Shakespeare's plays, Hamlet, Romeo and Juliet, and Timon Athens, and his narrative poem The Rape of Lucrece. In these works, I find persistent, if varied, manifestations of a sentiment found in St Paul's epistle to the Philippians, 'desiderium habens dissolvi, et esse cum Christo' [I desire to dissolve, and be with Christ]. This Pauline sentiment, abbreviated to cupio dissolvi and invoked in sermons, religious treatises and emblem books in late medieval and early modern Europe, had become, by the late sixteenth century, a powerful expression of faith in the resurrection, and a belief in the soul’s priority over the flesh.
I intend to follow the early modern users of cupio dissolvi, employing the sentiment as a shorthand for a desire for destructive renewal. In the first four chapters, the analysis remains tethered to its Christian inception, which is important to the context of early modern literature and allows a roving freedom to articulate a broader paradigm of desiring violent renewal. In some texts, such as Hamlet, the paradigmatic use of cupio dissolvi intersects with a strong allusion to the original Pauline desire; in others, such as Romeo and Juliet, the paradigm is stretched in its application to notions of a secular union in death; and in the final chapter, which explores Shakespeare’s epic poem The Rape of Lucrece, cupio dissolvi is used alongside twentieth-century literary theory, ostensibly removed from its Christian origin
Idiopathic intracranial hypertension: empowering patients and physicians to advance patient care through research
Get PDFIdiopathic Intracranial Hypertension (IIH) is a condition characterised by raised intracranial pressure (ICP), papilloedema, with risk of permanent visual loss and chronic headaches. It predominately affects young women and is associated with obesity. The incidence of IIH is increasing as obesity rates increase, as confirmed in England analysing the Hospital Episode Statistic dataset.
Both physicians and patients are central to improving care and advancing knowledge. The first IIH consensus guidelines brought together a multidisciplinary group. A priority setting partnership was subsequently conducted and found a key knowledge gap that the Idiopathic Intracranial Hypertension Weight Trial (IIHWT) aimed to address.
The IIHWT found that bariatric surgery provided sustained ICP reduction and weight loss for up to two years. The per protocol analysis determined how much body weight should be lost to ensure disease remission. The IIHWT headache analysis uniquely found that ICP was correlated with headache outcomes. The pointwise visual field analysis demonstrated what could be a meaningful change in an IIH trial population.
The direct impact of this work has afforded a change in national guidelines for people living with obesity and IIH. The cumulative knowledge gained has now delivered the first international multidisciplinary research guideline for IIH
Searching for Charged Lepton Flavour Violation at LHCb and Long-Lived Particles with CODEX-b
Get PDFThe CODEX-b detector is an RPC-based experiment proposed to search for long-lived particles that may be produced in \proton\proton collisions at the LHC. The first comprehensive investigation on the impact of misalignments of CODEX-b are presented alongside reports of hardware quality assurance tests of the readout electronics for this detector.
The mechanical precision <5 mm when constructing the RPC modules will be more than sufficient to ensure track reconstruction is unaffected by misalignments. The first major quality control process for the evaluation of CODEX-b’s RPC readout boards and its results are also presented, with more than 95% of the 440 tested boards validated for installation.
The first experimental upper limits of the branching fraction of the rare decay, \Lambda_b^0\rightarrow\Lambda e^\mp \mu^\pm, are presented based on analysis of data taken by the LHCb experiment between 2011 and 2018 (Run 1 & 2), corresponding to an integrated luminosity of 9 fb^{-1}.
Although the dataset remains blinded, estimated upper limits of the branching fraction of \Lambda_b^0\rightarrow\Lambda e^\mp \mu^\pm assuming no signal is present were obtained using a background-only proxy dataset derived from the data sidebands. This is evaluated for two scenarios, one with higher efficiency and one with lower background contributions (including a \Lambda_c decay veto), leading to results of
B(\Lambda_b^0\rightarrow\Lambda e^\mp \mu^\pm)_{std}\buildrel{\sim}\under< 2.09\times10^{-7} @ 95% CL,
B(\Lambda_b^0\rightarrow\Lambda e^\mp \mu^\pm)_{veto}\buildrel{\sim}\under< 6.45\times10^{-8} @ 95% CL,
respectively. These limits are comparable to that from a theoretical analysis of a proposed model-independent limit
Investigating how adenovirus E1A oncoproteins regulate host cell signalling pathways
Get PDFThe adenovirus E1A 13S and 12S transcripts give rise to protein products of 289 and 243 amino acids, respectively, in Ad2/5, and differ by conserved region 3 which is present only in the 289-residue protein. These proteins are, functionally, well characterised: the CR3 region of the 13S gene product is essential for transactivation of other viral early promoters through interaction with the cellular basal transcriptional machinery, transcription factors and transcriptional regulators; whilst the 12S gene product also regulates transcription through interaction with an overlapping set of transcriptional regulators, which can bind to other regions of the E1A protein, as well as CR3, to regulate cellular transcription programmes.
To study cellular functions of the Ad5 and Ad12 13S gene product, in the absence of 12S and other E1A gene products, we have made clonal, tetracycline (doxycycline)-inducible Ad5 and Ad12 13S E1A U2OS cell lines. In this regard, we have also made tetracycline-inducible Ad5 13S E1A L1920A and Ad12 13S E1A RG2 U2OS cell lines where the function of the N-terminal region has been inactivated through mutation. Co-immunoprecipitation/Western blot studies with these cell lines revealed that E1A expressed in response to doxycycline was functional as it was able to bind known E1A-binding proteins, CBP/p300, the pRB family of proteins as well as CtBP, although we were unable to confirm the ability of potential E1A-interacting proteins, identified by mass spectrometry, to interact with the 13S E1A gene product. These cell lines do have the potential, however, to study 13S E1A function in greater detail.
In order to study the function of the 9S E1A gene product we similarly attempted to make tetracycline-inducible Ad5 and Ad12 9S E1A U2OS cell lines, though such attempts were unsuccessful. We therefore utilised GFP-tagged Ad2 and Ad12 9S E1A constructs that could be expressed transiently to study their function. GFP pulldowns from U2OS cells expressing either GFP alone or GFP-tagged Ad12 9S E1A, coupled to mass spectrometry identified a number of cellular proteins that isolated specifically with the Ad12 9S gene product. Conventional IP-Western blot studies will need to be performed however, to identify bona fide 9S-interacting proteins before functional assays can be employed to determine the consequences of 9S interactions with these proteins.
Very little is known about the structure of E1A proteins other than that E1A function is dictated by molecular recognition features that interact with partner proteins. The 13S and 12S E1A gene products, are thought to be largely intrinsically-disordered proteins that assume structure on binding to partner proteins. We therefore utilised Alphafold 2 to determine putative structures for Ad2, Ad5 and Ad12 13S gene products. Consistent with the idea that E1A is mostly unstructured, large regions of the E1A were deemed not to have structural integrity. Interestingly, however, the proposed Zn-finger component of CR3 from these Ad species are predicted to form finger like projections, with an α-helical region separated by a short unstructured region that runs into a smaller α-helix, with the 4 Cys residues, responsible for coordinating Zn2+ binding, forming the base of the finger. These data suggest that CR3 from different adenovirus types are very well conserved at the structural level.
We also determined putative structures for the Ad2, Ad5 and Ad12 9S gene products, which have not been considered previously. Interestingly, 9S gene products were proposed to be highly structured, although structures generated were different for the 3 adenovirus types. Ad2 9S E1A was proposed to form a loop composed of 2 α-helices that ran parallel to each other, whilst Ad5 9S was also composed of 2 α-helices, though were proposed to be arranged perpendicular to one another. Ad12 9S was also composed of 2 α-helices that ran in series. Although these species might adopt similar structure when in association with partner proteins these data suggest that 9S from different Ad types might possess different functions.
Taken together, these studies have been useful in generating cell lines that can be used to probe E1A function in more detail and identifying putative 9S E1A-interacting proteins. It will be useful in the future to consider E1A function and interaction with cellular partner proteins in relation to specific amino acids within its predicted structure
Essays on the payment system in Indonesia: macroeconomics, behaviour analysis and policy implication
Get PDFThe use of non-cash payment instruments in developing nations, particularly Indonesia, has changed significantly compared to conventional payment instruments such as cash and coins. This rapid increase of non-cash payment instruments was made possible not only by the rapid development of the financial and payment system and telecommunications technology but also by government and central bank support, as well as unprecedented events such as pandemics and economic crises. This thesis comprises four articles with intertwined general purposes to present empirical evidence of economic analysis of payment system data, analysis of people’s behaviour in adopting a new payment instrument and policy impact analysis, as well as an examination of contemporary methodology to forecast inflation using payment system data. The first essay examines the determinants of money demand in Indonesia. This study examines the stability of money demand by incorporating the payment system innovation variable and the possibility of a structural break related to central bank policies. The second and third essays analyse the behaviour of consumers and merchants in adopting a new payment platform in the presence of a new central bank policy that was hindered by the COVID-19 pandemic. These studies use an online survey with self-administered questionnaires to obtain data from 31 Indonesian provinces. We introduced additional exogenous latent variables embedded inside the unified technology adoption theory; our research successfully unravels and distinguishes the effects of central bank policies and the pandemic. Finally, the fourth study explores payment system data to forecast inflation using various machine learning (ML) techniques and compares it to that of the univariate time series ARIMA and SARIMA models. We also perform various out-of-bag sample periods in each ML model to determine the appropriate data-splitting ratios for the regression case study. The study reveals that the ML models outperformed the ARIMA benchmark in terms of prediction accuracy and discovered that numerous payment system factors were highly predictive of inflation. We demonstrate the interpretation of ML forecast results that complement the causal inference of the more established econometric method
Non-linear quotient mappings of the plane and inscribed equilateral polygons in centrally symmetric convex bodies
Get PDFIn the present work, we are concerned with two underlying topics, which at first seem inherently disjoint, but are connected in a non-obvious way.
The first topic we study is the behaviour of non-linear quotient mappings whose domain is the plane; we pay particular attention to Lipschitz quotient mappings of the plane. This forms the underlying material in Chapters 2 and 3.
In Chapter 2 we correct a mistake from Johnson et al. Namely, we give a valid proof of the statement that for a fixed complex polynomial in one complex variable there exists a homeomorphism of the plane such that is a Lipschitz quotient mapping of the plane. Further, we introduce the notion of strong co-Lipschitzness, and prove the logical equivalence between the long standing conjecture that all Lipschitz quotient mappings from to itself are discrete and the necessity for every Lipschitz quotient mapping from to itself, , to be strongly co-Lipschitz.
Chapter 3 is dedicated to improving the lower estimates for the ratio of constants for any -fold planar Lipschitz quotient mappings in polygonal norms.
Chapters 4 and 5 concern the existence of inscribed equilateral polygons in centrally symmetric convex bodies. We investigate the extremal inscribed equilateral polygons and determine, for a large class of norms, when such polygons are essentially equivalent.
Finally, we consider the level sets of uniformly continuous, co-Lipschitz mappings defined on the plane; this forms Chapter 6. We show for any uniformly continuous, co-Lipschitz mapping , where is any norm of the plane, that the maximal number of components of the level sets of is intimately related to weak Lipschitz and co-Lipschitz constants of as well as the maximal possible edge length, in terms of , over all inscribed equilateral polygons. Further, we obtain a sharp bound for a certain class of norms which possess a particular separation property
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