Elasticity sampling links thermodynamics to metabolic control

Metabolic networks can be turned into kinetic models in a predefined steady state by sampling the reaction elasticities in this state. Elasticities for many reversible rate laws can be computed from the reaction Gibbs free energies, which are determined by the state, and from physically unconstrained saturation values. Starting from a network structure with allosteric regulation and consistent metabolic fluxes and concentrations, one can sample the elasticities, compute the control coefficients, and reconstruct a kinetic model with consistent reversible rate laws. Some of the model variables are manually chosen, fitted to data, or optimised, while the others are computed from them. The resulting model ensemble allows for probabilistic predictions, for instance, about possible dynamic behaviour. By adding more data or tighter constraints, the predictions can be made more precise. Model variants differing in network structure, flux distributions, thermodynamic forces, regulation, or rate laws can be realised by different model ensembles and compared by significance tests. The thermodynamic forces have specific effects on flux control, on the synergisms between enzymes, and on the emergence and propagation of metabolite fluctuations. Large kinetic models could help to simulate global metabolic dynamics and to predict the effects of enzyme inhibition, differential expression, genetic modifications, and their combinations on metabolic fluxes. MATLAB code for elasticity sampling is freely available

The role of the translator’s personality in the process of self-revision

Wydział AnglistykiW rozprawie doktorskiej pojęcie autokorekty jest zdefiniowane jako etap decyzyjny w procesie tłumaczenia oraz jako „procedura zapewniania jakości” (Mossop 2014) powstającego produktu − tłumaczenia. Takie podejście do autokorekty pozwala na połączenie ilościowych danych z procesu tłumaczenia oraz jakościowych danych z ocenionego produktu tłumaczenia. Podobnie, pojęcie osobowości jest postrzegane w kontekście takich jego składników jak cechy osobowości (charakterystyki ilościowe) oraz funkcje psychologiczne (opis jakościowy). Cechy procesu autokorekty wykonywanej przez tłumacza, takie jak: czas poświęcony na korektę końcową, ilość i typ wprowadzonych poprawek, często były uznawane jako składniki „indywidualnego stylu pracy” tłumacza (Jakobsen 2003; Carl i in. 2011), lub jego „profilu” (Dragsted i Carl 2012). Przedstawione w pracy badanie empiryczne miało na celu ujawnić rolę preferowanych funkcji psychologicznych w podejściu tłumaczy do procesu autokorekty oraz formowaniu „indywidualnego stylu pracy”. Również badanie miało pokazać, jakie dominujące cechy osobowości najlepiej opisują profil psychologiczny tłumaczy oraz odróżniają ich od przedstawicieli innych zawodów. Psychologiczne profile autorów najlepiej ocenionych tłumaczeń zostały zanalizowane w celu wyjaśnienia, czy pewne „style pracy” oraz dominujące cechy osobowości korelują z jakością tłumaczenia. Wyniki badania mogą pomóc nauczycielom tłumaczenia uświadomić rolę, jaką cechy osobowości odgrywają w zawodzie tłumacza, oraz jak studenci rozwijają swoje podejście do aspektów decyzyjnych w procesie autokorekty tłumaczenia.In the dissertation, self-revision is viewed as both the decision-related stage of the translation process and the “quality-assurance procedure” (Mossop 2014) of the emerging translation product. Such a view of self-revision allows combining the quantitative translation process data and qualitative translation product assessment data using multi-method approaches. Similarly, the concept of personality is referred to as a set of its quantitative characteristics, personality traits, and qualitative characteristics, personality types. The process characteristics of the translator’s self-revision behaviour, such as the duration of the end revision and the number and the type of corrections introduced, have often been found to form the translators’ “individual working styles” (Jakobsen 2003; Carl et al. 2011) or “profiles” (Dragsted and Carl 2012). The aim of the empirical study was to identify the role of the preferred psychological functions in the translator’s approach to self-revision and the formulation of their “individual working styles”. The experiment also sought to determine the translator’s dominant psychological traits that make translators differ from the representatives of the other professions. The psychological profiles of the authors of the best translations were analysed so as to establish if certain “working styles” and dominant personality traits correlate with translation quality. The results of the study may help translation teachers understand the role that individual personality characteristics play in the translator’s professional life, and in their approach to the decisional aspects of the translation process reflected in self-revision

Doctor of Philosophy

dissertationThis dissertation studies how heterogeneous opinions affect financial market outcomes, including price informativeness and trading volume. The dissertation contains two chapters. In both chapters, theoretical models are developed and then supportive empirical evidence is provided. In the chapter ""Index Trading and Its Effects on the Underlying Assets'' (Chapter 2), I present a rational expectation model of index trading. The key finding is that the efficiency of each of the underlying stocks decreases as the proportion of index traders increases, while the efficiency of the index itself is unchanged. This result is achieved despite the fact that no arbitrage opportunities exist, i.e., the price of the basket (index) is the sum of its components. Using S&P 500 ETFs data, I show that the index contributes to price discovery in its underlying stocks. In addition, the regression analysis is consistent with the model predictions: index trading impairs efficiency of the component securities but does not have effects on the index itself. In the chapter ""News, Influence, and Evolution of Prices in Financial Markets'' (Chapter 2), we study the influence of published views on the evolution of prices by constructing a theoretical model and using empirical work to test the model. Our sequential trade model demonstrates how the influence of published views creates patterns in prices and volume. Still, a ""wisdom of the crowds'' effect emerges endogenously in our framework and helps expunge such shared errors from the price, thus setting the paper apart from the information cascades literature. We use the timing of earnings announcements to test our model, and find evidence consistent with the theoretical predictions. The magnitude of the empirical effects is then used to calibrate the model, and our calibration exercise suggests that patterns in the evolution of prices are affected more strongly by the extent of the influence of the published view than by its accuracy

Optimization with pattern-avoiding input

Permutation pattern-avoidance is a central concept of both enumerative and extremal combinatorics. In this paper we study the effect of permutation pattern-avoidance on the complexity of optimization problems. In the context of the dynamic optimality conjecture (Sleator, Tarjan, STOC 1983), Chalermsook, Goswami, Kozma, Mehlhorn, and Saranurak (FOCS 2015) conjectured that the amortized access cost of an optimal binary search tree (BST) is $O(1)$ whenever the access sequence avoids some fixed pattern. They showed a bound of $2^{\alpha{(n)}^{O(1)}}$, which was recently improved to $2^{\alpha{(n)}(1+o(1))}$ by Chalermsook, Pettie, and Yingchareonthawornchai (2023); here $n$ is the BST size and $\alpha(\cdot)$ the inverse-Ackermann function. In this paper we resolve the conjecture, showing a tight $O(1)$ bound. This indicates a barrier to dynamic optimality: any candidate online BST (e.g., splay trees or greedy trees) must match this optimum, but current analysis techniques only give superconstant bounds. More broadly, we argue that the easiness of pattern-avoiding input is a general phenomenon, not limited to BSTs or even to data structures. To illustrate this, we show that when the input avoids an arbitrary, fixed, a priori unknown pattern, one can efficiently compute a $k$-server solution of $n$ requests from a unit interval, with total cost $n^{O(1/\log k)}$, in contrast to the worst-case $\Theta(n/k)$ bound; and a traveling salesman tour of $n$ points from a unit box, of length $O(\log{n})$, in contrast to the worst-case $\Theta(\sqrt{n})$ bound; similar results hold for the euclidean minimum spanning tree, Steiner tree, and nearest-neighbor graphs. We show both results to be tight. Our techniques build on the Marcus-Tardos proof of the Stanley-Wilf conjecture, and on the recently emerging concept of twin-width; we believe our techniques to be more generally applicable

Investigating the functional consequences of expanded triplet repeat sequence in a mouse model of Huntington's Disease (HD)

A PCR strategy showed that a number of total mtDNA molecules was significantly decreased (~30%) in the striatum (no reduction in the cortex and cerebellum) of 24-month old HD mice, but not a 15 months of age, when compared to wild-type mice, suggesting mtDNA depletion is a progressive rather than a developmental phenomenon. In light of the ~30% reduction of total mtDNA in the striatum, expression levels of the mitochondrial DNA-encoded respiratory complex enzymes, cytochrome b(Cytb), cytochrome c oxidase I (COI) and cytochrome c oxidase II (COII) were investigated in different brain regions of HD mice. At ~25 months of age, there were no significant differences in mRNA levels of CoII and Cytb in any brain region (striatum, cortex and cerebellum) studied when compared to normal littermates. However, HD mice showed significantly decreased CO-I protein levels and marginally decreased CoI mRNA levels in the striatum. Reduced levels of mtDNA may be caused by decreased replication of mtDNA or increased oxidative damage of mtDNA. Increased levels of 8-OHdG, a marker of increased oxidative stress, were detected in the dorsomedial, dorsolateral and ventromedial striatum, but not in the cortex of 24-month old HD mice providing direct evidence that increased oxidative stress specifically occurs in the striatum of HD mice. As no alterations in the mitochondrial transcription factor (mtTFA) in the striatum of HD mice could be detected, it is likely that mtDNA depletion in the HD mice is caused by increased levels of oxidative stress rather than decreased replication. The results provide a basis for further studies investigating how mutant huntingtin causes increased levels of oxidative stress and for identifying novel therapeutic targets

Biomarkers of mismatch repair deficiency in colorectal cancer and cancer predisposition syndromes

PhD ThesisColorectal cancer (CRC) is the third most common cancer in Western societies and approximately 15% are mismatch repair deficient (MMRd). MMRd CRCs have a distinct prognosis, respond to immunotherapy, and occur at a high rate in patients with Lynch syndrome or constitutional mismatch repair deficiency (CMMRD). Detection of MMR deficiency, therefore, guides treatment and identification of associated cancerpredisposition syndromes. However, there is a need for novel biomarkers to detect MMRd CRC, and innovative assays to improve Lynch syndrome and CMMRD diagnosis. I assessed autoantibodies generated against MMRd CRCs as a liquid-biopsy biomarker for cancer detection, by analysing the sera of 464 Lynch syndrome gene carriers using a recently published, multiplex method. Although autoantibodies correlated with a history of CRC, a lack of signal from patients who developed CRC shortly after sampling suggests the method has poor sensitivity. Microsatellite instability (MSI) is an established biomarker of MMR deficiency. I used single molecule molecular inversion probes to develop a sequencing-based MSI assay with an automated results analysis, suitable as a companion diagnostic for immunotherapy, and for streamlined Lynch syndrome screening. The assay achieved 100% accuracy in 197 CRCs, and was robust to sample variables, including quantity, quality, and tumour cell content. Subsequently, I adapted the MSI assay to detect low-level MSI in non-neoplastic tissues of CMMRD patients. The assay separated all 32 CMMRD patients from 94 controls. For both CRC and CMMRD diagnostics, the MSI assay is cheaper and faster than current methods, and is scalable to large cohorts. These results suggest that the humoral immune response to MMRd CRCs cannot readily be used as a biomarker to detect disease, and that alternatives should be sought. However, the MSI assay could be deployed into clinical practice to meet the high demand for MMR deficiency testing of CRCs and to improve CMMRD diagnostics.the Barbour Foundatio

Bursa Malaysia index series revision effects on market microstructure

This thesis presents three interrelated empirical chapters on the Bursa Malaysia index series revisions effects on market microstructure. In the first empirical chapter, “The Effect of Changes in the Composition of the FTSE Bursa Malaysia Indices on Stock Price and Volume", the effect of re-constituents of the main indices (Big Cap, Mid Cap and Small Cap) on stock price and trade volume is investigated, using a data sample which comprises information dated from the time period between 2005 and 2012. An event-study methodology is employed to evaluate the effects of stock market reactions to extraneous event. I employ short term and long term event-window analysis for abnormal returns using cumulative abnormal return (CAR) and Buy and Hold Abnormal Return (BHAR). Harris and Gurel (1986) Volume Ratio (VR) methodology is used to test for abnormal trade volume. The results provide new empirical evidence supporting several hypotheses as previously studied in the literature. Empirical evidence supporting the Price Pressure Hypotheses (PPH) is found for both additions to and deletions from the Blue Chip Index, KLCI 30. There are positive abnormal returns for stocks added to the Mid Cap Index, KLCI 70 with a persistent increase in volume in the post event-window are observed, which supports the Information Cost Liquidity Hypotheses (ICLH) and results for the deletions support the Information Hypotheses (IH). The results support the Imperfect Substitute Hypotheses in the case of stocks added to the Small Cap index.The second empirical chapter studies “The Effect of the FTSE Bursa Malaysia Index Series Changes on Stocks Liquidity”. In this chapter, the effect of index revision on stock liquidity is investigated. This investigation is important particularly with regard to stocks added to the Mid Cap Index in order to assert my previous results regarding the ICLH as some researchers consider trade volume as an unsuitable liquidity proxy due to the double counting. Instead, a variety of liquidity measures are employed to capture multi-dimensional liquidity aspects. Specifically the study focuses on trading cost and price impact ratio as two different liquidity dimensions. Liquidity changes adapting Hedge and McDermott’s (2003) methodology is used; a pooled time series cross-sectional multivariate analysis of bid-ask spreads and also price impact ratios. Bid-ask spread (quoted), bid-ask spread (effective), Amihud’s (2002) RtoV, Florackis et al.’s (2011) RtoTR and a new price impact ratio, the RtoTRF (free float adjusted) are employed. The study is extended by examining the investability weight change in order to identify the type of shareholders that contribute more to the liquidity improvement. Evidence that supports the ICLH for stocks added to the KLCI 70 is found which confirms the earlier investigation using trade volume. More importantly, the finding support Florackis et al.’s (2011) argument on the advantages of their price impact ratio over Amihud’s (2002) liquidity ratio in terms of market capitalisation bias. Furthermore, the new liquidity measure, RtoTRF, prove to have better “encapsulation power” (at least for the Malaysian stock market) when compare to the Amihud’s (2002) liquidity measure, RtoV.The third empirical chapter investigates the effect of liquidity improvements on investment opportunities, entitled: “Does Liquidity Increase Investment Opportunity? Evidence from the Bursa Malaysia KLCI 70”. In this chapter, the relationship between improved stock liquidity and investment opportunity is investigated in light of the firms added to the Mid Cap Index. The liquidity premium hypotheses (LPH) is examined by testing whether investment opportunities increase with stock liquidity. Tobin’s Q, capital expenditures, Return on Assets (ROA) and Price Earnings (PE) ratio are used for growth opportunities and find a statistical significant increase in those depended variables after the stocks being added to the index. Amihud’s (2002) RtoV, Florackis et al.’s (2011) RtoTR and the RtoTRF ratios are proxied as liquidity measures and find that the firms whose stocks were added to the KLCI 70 had a significant increase in capital expenditures and PE ratio. The findings are consistent with those of Becker-Blease and Paul (2006). Therefore, it shows that the stock liquidity improvements associated with additions to the KLCI 70 affects firm’s investment decisions. For the LPH, it shows that investors demand lower returns on more liquid stocks and, which reduces the cost of capital and enhances growth opportunities

The unresolved role of mitochondrial DNA in Parkinson's disease: an overview of published studies, their limitations, and future prospects

Parkinson's disease (PD), a progressive neurodegenerative disorder, has long been associated with mitochondrial dysfunction in both sporadic and familial forms of the disease. Mitochondria are crucial for maintaining cellular homeostasis, and their dysfunction is detrimental to dopaminergic neurons. These neurons are highly dependent on mitochondrial adenosine triphosphate (ATP) and degenerate in PD. Mitochondria contain their own genomes (mtDNA). The role of mtDNA has been investigated in PD on the premise that it encodes vital components of the ATP-generating oxidative phosphorylation (OXPHOS) complexes and accumulates somatic variation with age. However, the association between mtDNA variation and PD remains controversial. Herein, we provide an overview of previously published studies on the role of inherited as well as somatic (acquired) mtDNA changes in PD including point mutations, deletions and depletion. We outline limitations of previous investigations and the difficulties associated with studying mtDNA, which have left its role unresolved in the context of PD. Lastly, we highlight the potential for further research in this field and provide suggestions for future studies. Overall, the mitochondrial genome is indispensable for proper cellular function and its contribution to PD requires further, more extensive investigation