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An initial concept of a resonance phase matched junction-loaded travelling wave parametric tripler
Get PDFIn this paper, we investigate the possibility of utilising a tunnel-junction loaded transmission line as high efficiency parametric frequency multiplier. Through the interaction between the injected primary tone and the nonlinear medium, higher harmonic tones can be generated through wave-mixing process. Here, we aim to maximise the third harmonic wave generation. We first establish a theoretical framework outlining the mechanism for generating the third harmonic component from a single pump wave propagating in a nonlinear transmission line. We begin by demonstrating that strong third harmonic generation is possible with the resonance phase matching technique, albeit with an extremely narrow operational bandwidth. To broaden the bandwidth, we modify the dispersion engineering element of our circuit and show that broadband operation is achievable, while preventing unwanted harmonic tone growth. We extend this calculation from the microwave to the millimetre and sub-millimetre regimes and demonstrate that by adjusting the parameters of the junctions and the dispersion engineering circuits, we can achieve high conversion efficiency close to 1 THz
On the decidability of Presburger arithmetic expanded with powers
Get PDFWe prove that for any integers α, β > 1, the existential fragment of the first-order theory of the structure ⟨Z; 0, 1, 1 would lead to mathematical breakthroughs regarding base-α and base-β expansions of certain transcendental numbers
Breaking up rationally
Get PDFThe end of a long-term romantic relationship ranks among the most stressful and momentous events in life. Thus, the decision of whether to break up with someone whom one has been with for many years should generally be made very carefully. Unfortunately, decision theory is often thought to be unable to provide rational guidance in such high-stake life choices due to the outcomes’ presumed transformative character. The present paper shows how agents can rationally decide whether to leave their romantic partner even if the decision is transformative. It does so by using a novel five-level account of transformative decision-making, which can also be used for other key life choices, and which is the first to integrate in a systematic way several approaches for making (certain types of) transformative decisions that have been proposed in recent years
Paradoxical parenting practices and Australian higher education
Get PDFWhile there is now a large literature on ‘intensive parenting’ practices, the majority of studies have focused on young children, rather than those in their early adulthood. This article draws on interviews with 30 Australian parents to explore parenting practices as they pertain to higher education. It argues that although parents tended to stress the importance of children achieving independence during their degree programmes, in other ways, their parenting practices were notably ‘intensive’ in nature. The research is significant in documenting both the extension of intensive parenting beyond the years of childhood and the associated dependencies that appear to continue to characterise family relationships in early adulthood. It also suggests that, politically, it may be harder to demonstrate the degree that responsibilities (particularly those that are financial in nature) have shifted from the state to families if parental contributions are masked by the discourse of ‘independence’
Convex co-design of control barrier functions and feedback controllers for linear systems
Get PDFControl Barrier Functions (CBFs) have been proposed as an efficient tool for safe control design. Given an initial
set, a safe set and system dynamics, designing a candidate CBF
is known to be NP-hard in general. In this paper, we propose
a convex design method for linear dynamical systems under
mild assumptions on the initial and the safe set. A CBF and
an associated safe feedback controller can be co-designed by
solving a single semi-definite program. Our method can handle
mixed- (high-) relative degree problems directly, without the
need to use backstepping or other methods. The efficacy of the
proposed method is demonstrated on two different numerical
examples
Low-rank approximation of parameter-dependent matrices via CUR decomposition
Get PDFA low-rank approximation of a parameter-dependent matrix A(t) is an important
task in the computational sciences appearing for example in dynamical systems and compression of
a series of images. In this work, we introduce AdaCUR, an efficient algorithm for computing a low-rank approximation of parameter-dependent matrices via CUR decompositions. The key idea for this
algorithm is that for nearby parameter values, the column and row indices for the CUR decomposition
can often be reused. AdaCUR is rank-adaptive, provides error control, and has complexity that
compares favorably against existing methods. A faster algorithm which we call FastAdaCUR that
prioritizes speed over accuracy is also given, which is rank-adaptive and has complexity which is at
most linear in the number of rows or columns, but without error control
De dialectica: Augustine's study of verba in dialectic
No full textThis thesis presents the first full-length analysis of the earliest treatise dedicated to dialectic to survive from classical antiquity: De dialectica by Augustine of Hippo. Previous studies have treated the work as a repository of earlier, mainly Stoic, material. I argue that De dialectica is a unique didactic work which repays close reading on the level of both form and content. In contrast with other ancient versions of dialectic, De dialectica characterises dialectic as entirely comprised of verba; the extant part of the text advances a distinctive account of the nature of an individual word (verbum simplex) via analyses of semantics, etymology, and ambiguity. I argue that De dialectica 1-4 present an account of the verbum simplex as that which signifies one specific thing, and that this ‘simple model of signification’ is reinforced by the methods of definition and division employed by the text itself. This theory and method may be influenced by Platonism’s use of individual names as tools of division or as imitations of their nominata, by theories of inference from signs, or by the common language of verba signifying in classical Latin. However, this first definition of the verbum simplex as signifying one specific thing is deconstructed in the remainder of the text. I show how De dialectica 5-10 challenges the simple model of signification, dismantles the Stoic theory of etymology, and develops a rich typology of obscurity and ambiguity to present a new account of the verbum not as a signum but as fundamentally ambiguum. As with De dialectica 1-4, I show that the didactic approach of the latter chapters also works to undermine the original picture of the verbum simplex by conditioning the reader to engage with ambiguities in the structure and wordplay of the text. This evidence invites a reconsideration of prevalent opinions on Augustine’s theory of dialectic and language.
Multiorgan imaging and multimorbidity prevention: evidence from the heart-brain-liver axis in UK Biobank
Get PDFAs populations age globally, multimorbidity (the coexistence of multiple chronic conditions) presents increasing challenges to clinicians, policymakers and patients. Despite widespread interest in addressing this issue, strategies for multimorbidity prevention are scarce, often targeting individual organ systems rather than considering the interconnections between them. This thesis uses the UK Biobank health research database to answer a series of questions regarding population-level multimorbidity prevention, expanding the traditional focus on atherosclerotic cardiovascular disease to include disease risk across the heart, brain, liver and kidneys. By taking an explicitly multiorgan approach, this research gathers evidence that could inform and elevate multi-disease prevention efforts.
We used multiorgan magnetic resonance imaging (MRI) in 30,444 participants to describe the significant cross-organ relationships between the heart, brain and liver. We found that liver impairment (in the form of elevated liver fat, fibrosis and liver iron) was linked to poorer cardiovascular function and adverse brain features (such as reduced brain volume and poorer white matter microstructure). Conversely, markers of healthy heart function were associated with larger brain volumes and fewer cerebrovascular plaques. Multiorgan modelling suggests that liver and heart health affect brain health directly and indirectly, in conjunction with common risk factors like diabetes, hypertension, and obesity.
Building on these findings, we evaluated the effectiveness of primary care health checks in preventing multiorgan disease. We analysed the multiorgan outcomes of 48,602 participants who received an NHS Health Check between 2009 and 2016, compared with extensively-matched controls, over an average follow-up of 9 years. Adjusted survival models demonstrated that NHS Health Check recipients experienced lower rates of heart, liver, and kidney disease, likely due to the earlier detection and management of risk factor conditions.
While the NHS Health Check showed benefits, our analysis also revealed limitations in its ability to predict, and therefore prevent, multimorbidity. Consequently, we explored the feasibility of expanding the NHS Health Check protocol to more effectively predict multiorgan risk. In a proof-of-concept analysis with 228,240 participants, we showed how the same information currently available as part of the NHS Health Check could be reconfigured to produce multiple risk estimates for diseases across the heart, brain, liver and kidneys. This approach places multiorgan risk information at the fingertips of primary care physicians, enhancing prevention efforts by targeting multiple diseases simultaneously.
Finally, the thesis explores the role of imaging for multiorgan risk stratification. We showed that risk models incorporating imaging information were better at identifying people at risk for multiorgan disease than non-imaging methods. Cost-effectiveness analysis indicated that while imaging is expensive, there may be certain subgroups for whom such imaging could be cost effective. We develop and present a "first-in-line" methodology for modelling effectiveness scenarios of this type.
Altogether, these findings highlight the importance of a multiorgan awareness in healthcare delivery and prevention of disease in the heart-brain-liver-kidney cluster. We provide large-scale evidence and actionable recommendations for expanding existing preventive frameworks to better preserve multiorgan health. Further research is needed to refine these strategies and facilitate their practical implementation within the National Health Service
Engineering of a third-generation chimeric antigen receptor with specificity for HLA-A2 for use in regulatory T cell therapy
Get PDFBackground:
Current pharmacologic regimes of immunosuppression for allogeneic transplant recipients increase vulnerability to cancers and infections due to their systemic mode of action, in addition to side effects such as organ toxicity. Furthermore, daily medication regimes pose a significant burden to the patient. Cellular therapy has been proposed as an alternative, and clinical trials have shown promising results for the efficacy of regulatory T cells – a naturally-occurring subset of T cells responsible for maintaining immune homeostasis – for preventing graft rejection in kidney patients. Genetic engineering has led to the development of Chimeric Antigen Receptors (CARs); these are customizable receptors that can be expressed in therapeutic cells to confer specificity for an antigen of choice. Pre-clinical models have shown the superiority of CAR-expressing Tregs over polyclonal Tregs at preventing allograft rejection, as well as their preferential homing towards the target antigen, and it is envisaged that CAR-Tregs could replace standard drugs in the clinic.
Objectives:
1. To critically review current applications of Green Fluorescent Protein (GFP) expression induction in cell therapies, with a focus on Tregs.
2. To evaluate induction of Green Fluorescent Protein expression in human Tregs on their function and molecular phenotype.
3. To critically review current approaches and outcomes of CAR-Treg adoptive therapy in pre-clinical and clinical studies.
4. To design and create a third-generation CAR with specificity for Human Leukocyte Antigen HLA-A2.
Findings:
CRISPR-Cas9 mediated genome editing was used to insert a GFP homology-directed repair template into the RAB11A locus of sorted and ex vivo-expanded human Tregs, and proof-of-concept experiments with bulk CD4+ T cells illustrated the longevity of GFP expression using this method. Editing efficiency was between 30 and 40%, and GFP-expressing Tregs were capable of suppressing effector CD8+ T cells almost completely when delivered in ratios of 1:2 or 1:4. In addition, their gene expression and cytokine production (notably the anti-inflammatory cytokine IL-10) was comparable to that of unmodified Tregs.
Simultaneously, a Chimeric Antigen Receptor construct was designed and synthesized with an antigen-binding region specific to HLA-A2, then inserted into a pIRES2-eGFP expression vector.
Conclusion:
Human Tregs do not lose their suppressive function upon the induction of GFP expression, and CARs hold potential for preventing allograft rejection in allogeneic transplantation
Robust gradient descent for phase retrieval
Get PDFRecent progress in robust statistical learning has mainly tackled convex problems, like
mean estimation or linear regression, with
non-convex challenges receiving less attention. Phase retrieval exemplifies such a nonconvex problem, requiring the recovery of a
signal from only the magnitudes of its linear
measurements, without phase (sign) information. While several non-convex methods, especially those involving the Wirtinger Flow
algorithm, have been proposed for noiseless
or mild noise settings, developing solutions
for heavy-tailed noise and adversarial corruption remains an open challenge. In this paper, we investigate an approach that leverages robust gradient descent techniques to
improve the Wirtinger Flow algorithm’s ability to simultaneously cope with fourth moment bounded noise and adversarial contamination in both the inputs (covariates) and
outputs (responses). We address two scenarios: known zero-mean noise and completely
unknown noise. For the latter, we propose
a preprocessing step that alters the problem
into a new format that does not fit traditional
phase retrieval approaches but can still be
resolved with a tailored version of the algorithm for the zero-mean noise context