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The multifaceted nature of human interaction
Get PDFIn everyday life, we engage in interactions with others to express our thoughts and desires, employing verbal and non-verbal communication methods. This thesis examined the multifaceted nature of effective communication and joint action. Chapter 1 provides an overview of relevant literature related to language, cooperation, and joint action as well as relevant background information about the electroencephalography (EEG) method used in my thesis. In Chapter 2, using EEG and a minimal two-word paradigm, we investigated age-related oscillatory mechanisms of lexical retrieval and semantic binding. Results reported a different and delayed age-related oscillatory signature for semantic binding, suggesting that older adults rely on different mechanisms and take longer to integrate the word meaning into the semantic context. Chapter 3 examined the brain-to-brain neural coupling that underlie the mechanisms of developing shared representations of a specific task goal in response to feedback. We utilised EEG hyperscanning and a newly developed non-verbal cooperation paradigm. We found that an anti-correlation of theta power between two individuals following negative feedback forecasted successful convergence of the representation of the task goal and thus successful cooperation. Conversely, correlated activity in the theta band forecasted a lack of convergence and subsequent cooperative failure. Lastly, Chapter 4 considered the impact of theory of mind (i.e. ToM) abilities on verbal cooperation in a novel verbal two-player paradigm. We found that pairs featuring two individuals with high ToM abilities committed less cooperative errors and subsequently cooperated better compared to pairs where both individuals have low ToM abilities. Overall, the findings from this thesis highlight the complex nature of human interaction and offer new perspectives on its study
Three essays in empirical corporate finance
Get PDFThis thesis comprises three empirical essays in the field of corporate finance, all of which utilize the difference-in-differences methodology to mitigate potential endogeneity issues. The first essay within this thesis focuses on examining the influence of pay transparency on employee productivity. I introduce the staggered adoption of pay secrecy laws at the state level to measure the state pay transparency level. Pay secrecy laws were initially introduced to address gender and race pay gaps by promoting transparency and prohibiting pay secrecy practices (Kim, 2013, 2015). These laws aim to empower employees by providing information on salary and enabling them to address and potentially reduce pay disparities (Cullen and Perez-Truglia, 2018b; Cullen and Pakzad-Hurson, 2019).
Employers implement pay secrecy policies to prevent wage comparisons and employee dissatisfaction (Colella et al., 2007; Kim, 2015). However, some argue that pay secrecy contributes to pay discrimination (Kim, 2013, 2015; Baker et al., 2019). Therefore, in the United States, there is an increasing emphasis on pay transparency to narrow gender and ethnicity pay gaps (Trotter et al., 2017; Heisler, 2021). The impact of increased pay transparency on employee productivity is ambiguous. On one hand, it can improve morale by addressing issues of prejudice and favoritism (Cullen and Perez-Truglia, 2018), and reduce uncertainty regarding compensation employees expect for their efforts (Hsieh et al., 2019). It can also promote gender equality and lead to increased productivity and retention (Bennedsen et al., 2019). In summary, increased pay transparency can have a positive effect on employee productivity.
On the other hand, increased pay transparency may reduce job satisfaction and result in complaints or resignations due to wage comparisons. This is because individuals not only care about absolute income but also their relative income (Colella et al., 2007). Lower-paid employees may be dissatisfied, while higher-paid employees may perceive efforts to mitigate inequality as threats (Card et al., 2012; Breza et al., 2018). Dissatisfied employees may engage in destructive behaviors, and highly valued employees may leave for better opportunities elsewhere (Hitz and Werner, 2012; Kim and Marschke, 2005), which aligns with "Inequity Aversion Theory" (Adams, 1965; Cowherd and Levine, 1992) and "Relative Deprivation Theory" (Martin, 1981). Therefore, increased pay transparency could also have a negative effect on employee productivity.
To enhance precision and minimize confounding factors, this essay introduces a novel measure to proxy employee productivity. It divides EBITDA, excluding incomes and incorporating expenses unrelated to employees or dominated by managers, by the number of employees. This essay stands as the first to uncover a significant correlation between heightened pay transparency and diminished employee productivity across a substantial and diverse sample of U.S. firms. This finding lends support to the notion that wage comparisons can erode job satisfaction. On average, firms headquartered in states where pay secrecy laws have been implemented experience a 1.58% decline in employee productivity compared to the overall sample mean.
Furthermore, this analysis reveals that the impact of pay secrecy laws is more significant in companies based in states characterized by lower levels of social capital. This finding underscores the heterogeneous nature of the effects and provides valuable insights into the mechanisms through which these laws operate. Moreover, this essay uncovers a compelling relationship between increased pay transparency resulting from the implementation of pay secrecy laws and a decrease in employee salaries. This discovery offers a potential explanation for the observed decline in productivity.
This essay makes the following contributions. First, in response to concerns regarding pay secrecy practices and their potential for pay discrimination (Kim, 2013, 2015; Cullen and Perez-Truglia, 2018; Baker et al., 2019), my empirical research aims to investigate the causal effects of pay transparency on employee productivity. To address endogeneity concerns and isolate exogenous variation in peer group pay (Gao et al., 2021), I employ a difference-in-differences framework using the staggered adoption of pay secrecy laws and incorporate high-dimensional fixed effects. This study extends the existing literature on pay secrecy law adoption and salary transparency, contributing to a broader understanding of the topic. Previous research by Kim (2013, 2015), Baker et al., (2019), Bennedsen et al., (2019), Mas (2017), Duchini et al., (2020), and Gao et al. (2021) sheds light on pay inequality and gender pay gaps. However, the effects of pay secrecy laws on firm-level outcomes and generalized employee productivity have not been thoroughly explored.
Second, to accurately capture employee productivity, I draw inspiration from previous studies and utilize individual profits as a proxy, constructing a less noisy and more accurate measure of broader employee output. My findings are consistent with alternative measures used in previous studies (Kale et al., 2016; Lins et al., 2017; Gao et al., 2018), enhancing my confidence in this novel proxy.
Third, my analysis reveals that increased pay transparency is associated with lower employee productivity, providing empirical evidence supporting the notion that wage comparisons can reduce job satisfaction (Card et al., 2012). This finding contrasts with the positive influence of pay transparency on innovation found by Gao et al. (2021), which focused on patents and citations for minority inventors. This is because my study focuses on a broader measure encompassing all employees instead of only innovators, which enables a comprehensive evaluation of employee incentives and behaviors that plausibly have direct effects on productivity (Faleye et al., 2013).
The second essay in the thesis examines the effects of restricted executive mobility on institutional shareholding. It introduces the concept of the Inevitable Disclosure Doctrine (IDD), which imposes stricter restrictions on managerial mobility to protect trade secrets. Restricted executive mobility imposes higher costs on managers whose current positions are at risk. This situation leads to increased career concerns and a stronger inclination to engage in opportunistic behaviors that can improve their current employer's perception of their abilities (Kothari et al., 2009; Gao et al., 2018; Ali and Li, 2019). Additionally, limitations on external employment opportunities for managers reduce the pool of potential replacement CEOs, making it difficult for companies to identify and recruit qualified successors, thus necessitating the retention of the current CEO (Grande-Herrera, 2019). As a result, this disruption in the labor market's disciplinary mechanism enables the occurrence of executive opportunistic behaviors (Li et al., 2017; Kim et al., 2020; Ali and Li, 2019; Li et al., 2018; Gao et al., 2018; Islam et al., 2020; Na, 2020). Consequently, it can be argued that restricted executive mobility undermines the quality of corporate governance.
To address the challenges posed by restricted executive mobility and enhance corporate governance, companies may choose to increase institutional shareholding (Chung and Zhang, 2011). This is based on the recognition of the monitoring role played by institutional investors. Therefore, it can be inferred that following restricted executive mobility, institutional shareholding may increase. However, institutional investors need to carefully evaluate the costs and benefits associated with monitoring, and exercise prudence in their actions. Thus, the quality of corporate governance, which is influenced by opportunistic behaviors, becomes a significant factor in the decision-making process of institutional investors. This suggests that, following restricted executive mobility, institutional shareholding may decrease.
This study provides the first empirical evidence on the impact of recognizing the IDD on institutional investors' equity holdings. Firms in states acknowledging the IDD experience an average 2% decrease in institutional shareholding compared to the sample period mean. This decline primarily stems from reduced corporate governance indicated by agency costs. Notably, activist and long-term institutional investors exhibit sensitivity to executive mobility constraints, reinforcing their monitoring incentives. Additionally, the study demonstrates that IDD recognition's influence on institutions is more pronounced in knowledge-intensive industries, highlighting the impact of executive mobility on institutional shareholding due to trade secret protection. These findings shed light on institutional investors' motivations to target portfolio companies, aiming to mitigate monitoring costs and fulfill fiduciary responsibilities. The study contributes to the related literature by examining the outcomes associated with restricted executive mobility. It also expands understanding of the IDD's economic effects, particularly on ownership structure, and complements existing research on institutional investor engagement in corporate governance strategies.
The third essay of the thesis revisits the causal link between takeover threats and corporate default risk, incorporating a fresh perspective by examining the implementation of Second-Generation State-level Antitakeover Laws alongside traditional proxies for takeover threat. An active takeover market serves as an external disciplinary mechanism for managers, promoting managerial replacements in cases of poor performance (Manne, 1965; Fama and Jensen, 1983; Jensen and Ruback, 1983; Scharfstein, 1988; Lel and Miller, 2015). However, anti-takeover protections weaken this mechanism by shielding managers and increasing their managerial entrenchment, resulting in heightened agency costs of equity. Balachandran et al. (2022) argue that reduced takeover likelihood, caused by weakened disciplining mechanisms, exacerbates agency conflicts, leading to diminished cash flows for debt payments and increased default risk (Driss et al., 2021).
Conversely, takeover threats can have a negative impact on default risk. Garvey and Hanka (1999) find that companies influenced by second-generation state-level anti-takeover laws exhibit a reduction in reliance on debt. The decreased likelihood of hostile takeovers diminishes managerial career concerns and allows managers greater discretion in capital structure decisions, leading to a decrease in debt issuance (Grossman and Hart, 1980; Knoeber, 1986; Scherer, 1988; Stein, 1988; Jung et al., 1996). Furthermore, the financial leverage ratio can serve as an indicator of default risk (Traczynski, 2017; Cathcart et al., 2019), as default occurs when a company's asset value falls below its debt face value (Merton, 1974). Strengthened anti-takeover protection can potentially reduce default risk, benefiting debtholders, in line with the trade-off theory of capital structure (Kraus and Litzenberger, 1973).
This study is the first to show that firms incorporated in states influenced by Control Share Acquisition (CS) laws experience a decrease in default probability. Specifically, I find that these firms reduce their default risk by 18.2% on average compared to the mean default risk during the sample period. Additionally, I observe an increase in agency costs of equity, indicating that weakened external monitoring mechanisms prompt managers to exercise discretion in reducing debt usage. I suggest that agency costs of equity may serve as the possible link between takeover threats and default risk. This effect is particularly prominent in companies with high institutional shareholding, indicating that the decline in default risk for affected firms is a result of deteriorated corporate governance and heightened agency conflicts. Moreover, I report that the reduced default risk following the adoption of CS laws undermines shareholder interests, and managers' tendency to underinvest following the adoption of these laws suggests a preference for a "enjoy a quiet life" among executives.
This study contributes to the existing literature by expanding the research on determinants of corporate default risk. While previous studies have examined factors such as stock liquidity (Brogaard et al., 2017; Nadarajah et al., 2020), innovation performance (Hsu et al., 2015), and incentive structure (Bennett et al., 2015), I focus on the effects of anti-takeover protection on default risk. My findings differ from Balachandran et al. (2022) who argue that anti-takeover protection increases default likelihood derived from managerial opportunistic activities, which harms shareholder. In contrast, I conclude that decreased takeover threats are associated with a lower probability of default. Furthermore, I find that the reduced default risk resulting from the adoption of CS laws negatively affects shareholder benefits as well, contradicting Balachandran et al. (2022). I propose an alternative perspective that increased usage of anti-takeover provisions leads managers to prioritize their own well-being “enjoy a quiet life”, harming shareholders but benefiting debtholders (Bertrand and Mullainathan, 2003; Klock et al., 2005; Chava et al., 2009; Qiu and Yu, 2009; Gormley and Matsa, 2016). To support my hypothesis, I find evidence of managers' underinvestment following the adoption of CS laws. Therefore, my study contributes to understanding how managers' risk exposure influences their decisions and highlights that traditional agency conflicts related to "private benefits" may not be the primary driver of activities deviating from shareholders' interests.
Finally, this study extends the investigation into the effects of CS laws, which have received limited attention thus far. I demonstrate that CS laws, along with business combination laws, contribute to variations in corporate governance and have a negative impact on default risk.
In the three essays presented, I employ the difference-in-differences methodology, utilizing staggered treatments as natural experiments to facilitate causal investigations. By employing a difference-in-differences design, I take advantage of the occurrence of multiple shocks that affect different firms at various time points. Specifically, I compare the effects before and after the implementation of legislation changes in states where such changes were implemented (the treatment group), contrasting them with the effects observed in states where no such changes occurred (the control group) (Gormley and Matsa, 2016; Klasa et al., 2018; Ali et al., 2019). This methodology enables me to address potential biases related to the timing of the laws (Bertrand and Mullainathan, 2003) and overcome alternative explanations that may arise in settings with a single shock, where contemporaneous events could influence my findings (Roberts and Whited, 2013). Additionally, I introduce a one-year lag for the state-level laws and doctrines, allowing sufficient time for affected companies to adjust their firm-level outcomes and further mitigating concerns of reverse causality.
It is noteworthy that these laws were not primarily designed to impact my variable of interest, thus suggesting that this effect is likely an unintended consequence, rendering my utilization of these laws particularly valuable. My analysis incorporates state-by-year and industry-by-year fixed effects, which enhances the robustness of my findings. Specifically, since numerous companies are headquartered in states that differ from the ones in which they are incorporated, I have the opportunity to include the state-by-year fixed effect. In summary, by incorporating these high-dimensional fixed effects, I can alleviate concerns pertaining to unobserved heterogeneity associated with the industry, state, or observation year of the firms (Gormley and Matsa, 2016).
In order to ensure the validity of my analysis, I employ a comprehensive set of diagnostic or robustness tests. The foundational assumption of the difference-in-differences methodology is that, in the absence of the law or doctrine, the treatment group and control group would exhibit similar trends. I demonstrate that the trends in dependent variables prior to the treatment are indeed comparable between the two groups of firms. Moreover, I conduct a placebo test by randomly assigning states to adopt the law or doctrine, ensuring equal probabilities of adoption across all states. This guarantees that any observed differences between and within states are not systematic. My results reveal that the actual coefficient estimate from the baseline regression lies comfortably in the tail of the distribution of coefficient estimates derived from 1,000 simulated placebo tests. This finding eliminates the possibility that my results are merely due to chance.
To address potential self-selection bias arising from firm-specific characteristics that could influence my results, I perform a Propensity Score Matching (PSM) test. For each year, I match treatment firms with control firms based on the firm characteristics used as control variables in my baseline regression. I estimate the probability of being assigned to the treatment or control group using a logit regression that incorporates all control variables, year, state, and industry fixed effects. Utilizing the propensity scores obtained from this logit estimation, I conduct matching within a caliper of 0.01 without replacement. The results, after controlling for sample selection bias through the PSM method, support my baseline findings, emphasizing that my conclusions are not driven by systematic differences.
Cengiz et al. (2019) have highlighted potential econometric concerns related to the aggregation of discrete difference-in-differences (DiD) estimates using ordinary least squares (OLS). These concerns include heterogeneous treatment effects and the possibility of negative weights assigned to specific treatments. To ensure a more precise examination of the relationship, I employ stacked difference-in-differences (DID) estimates as an additional robustness check. The stacked DID method aims to transform the staggered adoption setting into a two-group, two-period design. In this transformed design, the difference-in-differences estimate captures the average effect of the treatment on the treated, while taking into account the relative sizes of the group-specific datasets and the variance of treatment status within those datasets. This approach uses more stringent criteria for admissible, clean control groups. And separate datasets are stacked in event-time, which is equivalent to a setting where the events happen contemporaneously. Finally, I find consistent results, which confirms that my difference-in-differences estimates are not sensitive to heterogeneous treatment effects.
The subsequent sections of this thesis are structured as follows. The first essay examines the impact of state-level pay secrecy laws on employee productivity and is titled "Pay Transparency and Employee Productivity: Evidence from State-level Pay Secrecy Laws." The second essay investigates the relationship between executive mobility and institutional ownership, drawing evidence from the Inevitable Disclosure Doctrine, and is titled "Executive Mobility and Institutional Ownership: Evidence from the Inevitable Disclosure Doctrine." The final essay critically evaluates the causal link between takeover threats and default risk and is titled "Takeover Threat and Default Risk: A Causal Re-evaluation.
Exploring the roles of CASK and calcium signalling in apoptosis-induced proliferation
No full textApoptosis is one of the most characterised forms of programmed cell death, heavily reliant on caspases. Interestingly, many non-apoptotic functions of caspases have been reported recently. Among these functions is their capacity to elicit proliferation in neighbouring cells upon activation in stress or damaged cells, giving rise to a phenomenon known as apoptosis-induced proliferation (AiP) which is relevant to regeneration and tumourigenesis. The elucidation of regulatory mechanisms governing AiP has greatly benefited from studies conducted on the model organism Drosophila melanogaster. Notably, Dronc, an orthologue of the mammalian caspase-9, plays a pivotal role in activating the c-Jun N-terminal kinase (JNK) pathway, which leads to the release of multiple mitogenic factors including the Wnt orthologue Wingless (Wg), the TGF-β orthologue Decapentaplegic (Dpp) and the EGF orthologue Spitz (Spi), facilitating growth in the surrounding tissue. However, our knowledge of the molecular mechanisms underlying AiP remains quite limited. Recent work on AiP regulation has revealed F-actin polymerisation as a key event for the activation of JNK downstream of Dronc. In this PhD project, I have discovered a novel role of Calcium-calmodulin dependent serine protein kinase (CASK), a multidomain scaffold protein, in mediating F-actin polymerisation hence regulating AiP. Additionally, I have identified its potential interacting partners that have crucial roles in this process. Furthermore, I have explored the roles of calcium signalling in this process. Therefore, this study has unveiled novel functions of CASK, CASK-interacting proteins, and calcium signalling in the regulation of F-actin dynamics required for AiP
'She didn't get justice': Analysing barriers to post-rape medico-legal service provision in Kenya
Get PDFSexual and gender-based violence (SGBV) is a significant public health issue that affects millions of people around the world, especially women and girls. SGBV can have significant physical, mental, and social impacts, and victim/survivors rely on medico-legal professionals to provide medical care and pursue justice. Even though medico-legal services are essential for the wellbeing of victims, research indicates that service provision is lacking worldwide, but especially in East Africa, a region with higher-than-average rates of SGBV and significant resource constraints.
In this thesis I aim to explore the barriers faced both by rape survivors in accessing medico-legal services and medico-legal professionals in providing these services in urban and rural settings in Kenya. Further, I examine the lived experiences of my participants during the COVID-19 pandemic as well as during times of normalcy, while also situating the findings within a larger East-African context.
To begin my research and familiarise myself with medico-legal service provision in the East African context, I undertook a scoping literature review of 54 papers to synthesise the existing models of service provision in the region surrounding Kenya. I then conducted a prospective cross-sectional study on 541 case records held by the Wangu Kanja Foundation to evaluate patterns of violence in Kenya during the COVID-19 pandemic, research that was not in the original design of my PhD, but which emerged as a result of the ongoing worldwide pandemic. Following this study, I conducted a secondary data analysis on case records of 514 survivors engaged with the Wangu Kanja Foundation to evaluate patterns that might predict how far a victim moves through the case referral pathway in Kenya. Finally, I worked closely with my partner organisation to conduct my qualitative research.
The Wangu Kanja Foundation (WKF), which is based in Nairobi, Kenya, was a critical partner for this work, providing links to survivors on the ground, a library of data on previous violence in Kenya, and networking opportunities that were crucial when interviewing medico-legal service providers for this work. Due to the COVID-19 pandemic, I had to significantly postpone my fieldwork and the plan for this research was altered to accommodate travel restrictions. I conducted online interviews with medico-legal service providers between January and October 2021 with five medical professionals and six legal professionals. During this time, two in-person focus group discussions were also conducted by members of the WKF using interview guides I designed and based on an online training I conducted with Kenyan facilitators to ensure that the focus group discussions were moderated appropriately. One focus group discussion had eight participants, and the other had nine. In April 2022 I was able to travel to three cities in Kenya, where I conducted three focus group discussions with survivors with the help of UK and Kenyan-based researchers, and a further 10 semi-structured interviews with professionals, five medical and five legal. Each focus group I conducted in person had ten participants. In exploring the potential reasons behind the challenges encountered by both providers and survivors attempting to access medico-legal services, I identified shared barriers, including financial constraints, insufficient understanding of correct procedures, sociocultural prejudices, and ineffective implementation of policies and guidelines.
Results indicated that barriers to post-rape medico-legal service provision were prominent, and that there was a sense of resignation amongst survivors concerning how their cases would (or would not) move through the case referral pathway. In my scoping review (Chapter 2), I found a dearth of literature on sexual violence policies in East Africa and highlighted a disproportionate focus on Kenya compared to the other countries in the region. In a prospective cross-sectional study (Chapter 3), I identified new patterns of violence that emerged during COVID-19, which have implications for safeguarding in case of future humanitarian crises, including the need for plans to protect children when guardians are absent and schools are closed. My secondary data analysis (Chapter 4) revealed that certain case characteristics, such as the age of the survivor and the presence of forensic evidence, helped cases progress through each stage of the care-seeking process, yet ultimately very few cases advanced through to the sentencing phase. In the qualitative research presented in Chapters 5 and 6, I conducted an in-depth analysis of the lived experiences of survivors in accessing care, as well as the experiences of professionals in providing care. The research on providers appears before the research on survivors in this thesis to ensure that the survivors have the final say on this topic.
The findings revealed a consensus among both providers and survivors that financial barriers constitute the primary impediment, followed by the need for formal training for providers in caring for survivors. Notably, provider bias (i.e., disbelieving a victim’s rape story because of her physical appearance) remains a significant issue, despite the implementation of interventions in Kenya several years prior to the commencement of my research. My thesis findings have implications for future research, policy, and practice, and provide evidence for how the Kenyan government and international non-governmental organisations (NGOs) can better respond to the needs of both the victims and the practitioners delivering post-sexual violence medico-legal services
Exact Real Search: Formalised Optimisation and Regression in Constructive Univalent Mathematics
Get PDFThe real numbers are important in both mathematics and computation theory. Computationally, real numbers can be represented in several ways; most commonly using inexact floating-point data-types, but also using exact arbitrary-precision data-types which satisfy the expected mathematical properties of the reals. This thesis is concerned with formalising properties of certain types for exact real arithmetic, as well as utilising them computationally for the purposes of search, optimisation and regression.
We develop, in a constructive and univalent type-theoretic foundation of mathematics, a formalised framework for performing search, optimisation and regression on a wide class of types. This framework utilises Martín Escardó's prior work on searchable types, along with a convenient version of ultrametric spaces -- which we call closeness spaces -- in order to consistently search certain infinite types using the functional programming language and proof assistant Agda.
We formally define and prove the convergence properties of type-theoretic variants of global optimisation and parametric regression, problems related to search from the literature of analysis. As we work in a constructive setting, these convergence theorems yield computational algorithms for correct optimisation and regression on the types of our framework.
Importantly, we can instantiate our framework on data-types from the literature of exact real arithmetic, allowing us to perform our variants of search, optimisation and regression on ternary signed-digit encodings of the real numbers, as well as a simplified version of Hans-J. Boehm's functional encodings of real numbers. Furthermore, we contribute to the extensive work on ternary signed-digits by formally verifying the definition of certain exact real arithmetic operations using the Escardó-Simpson interval object specification of compact intervals
GDAHA representations with Teichmüller, Stokes, and Painlevé
Get PDFThe Painlevé VI equation governs the isomonodromic deformation problem of both 2-dimensional Fuchsian and 3-dimensional irregular types of linear systems of ODEs. Through Harnad duality, this feature turns into a map between the two systems, which translates to monodromy as a middle convolution operation. This thesis studies the quantum algebraic manifestation of the systems’ monodromy data by introducing a noncommutative analogue of the middle convolution functor. The Fuchsian data are known to quantize as the DAHA; we construct a quantization of the irregular ones that match the -type GDAHA, provided a specialization of the algebra parameters. Both quantum data are then shown to exhibit an alternative realization in higher Teichmüller terms. In particular, this framework advances the GDAHA representation theory by providing the first explicit representation of the universal GDAHA of type , which can be reduced to the quantum irregular monodromy data by a new quiver-theoretical operation
Regulatory roles of MarA in flagellar biosynthesis in Escherichia coli: a novel mechanism for transcription initiation
Get PDFMultiple antibiotic resistance is one of the main threats to human health in the modern world. Multiple antibiotic resistance (mar) locus provides resistance to a wide range of antibiotics and phenolic compounds in gram-negative bacteria Escherichia coli. The transcription factor MarA encoded in this locus is mainly required for activation and expression of the AcrAB- TolC encoded efflux pump, which plays a primary role in active antibiotic transport out of the cell. However, recent studies suggest that MarA is also involved in lipid trafficking, DNA repair and biofilm formation in E. coli.
The current work shows that MarA can also regulate flagellar gene expression, suggesting an interplay between flagellar biosynthesis and intrinsic response to antibiotics. New σ28- dependent promoter regions were found upstream of the flgBCDEFGHIJ/KL and flgAMN operons, which were known as σ70- and FlhDC-dependent only. Both operons are located in close proximity to each other on opposite DNA strands, and share an FlhDC binding site. Another σ28-dependent promoter was also found upstream of the flgJ gene, which is a part of the flgBCDEFGHIJ/KL operon. A new σ70-dependent promoter was found upstream of the flgM gene, which also has a σ28-dependent promoter, and can also be transcribed as part of the flgAMN operon. Marboxes were identified upstream of the flgA, flgB, flgJ and flgM genes.
MarA has been known as an activator that assists only σ70-dependent transcription in a Class I or Class II manner. In the current study, MarA activates both flgA and flgB σ70-dependent promoters in an FlhDC-dependent manner in vivo via an unknown indirect mechanism. However, in vitro MarA assists the novel σ28-dependent flgB promoter in a Class III manner. MarA binds between the -10 and -35 elements of σ28-dependent flgB promoter, and distort conserved -11A base, where unwinding of the open complex nucleates. At the same time, MarA represses open complex formation on flgA promoter.
This regulatory mechanism suggests that MarA plays a role in redirecting transcription to favor partial flagellar biosynthesis during antibiotic stress, potentially enabling E. coli to escape hazardous environments. The novel finding that MarA can assist RNAPσ28 expands our understanding of transcription regulation and suggests a broader regulatory interactions in bacterial adaptive responses
Immunomodulatory effects of distinct bioactive lipid groups on T lymphocytes within the obesity-induced inflammatory microenvironment
Get PDFDiet-induced obesity (DIO) is a global pandemic with an increasing trend in all age groups around the world. Overconsumption of energy dense obesogenic diets, with a high fat content, induce and escalate obesity-linked low grade chronic inflammatory microenvironment (OIIM). The OIIM is one of the main immune dysfunctions which induces and contributes to many obesity-associated diseases such as cardiovascular diseases, type-II diabetes and autoimmune diseases. Distinct bioactive fatty acids (FAs): palmitate and stearic acid, found within the high fat diet, augment the OIIM via their pro-inflammatory immunomodulatory effects. This pro-inflammatory biasing immunomodulation by bioactive FAs can lead to functional, epigenetic, developmental and migratory cellular modulations. Considering the critical contributions of T cells to OIIM, we have investigated the OIIM at two different stages by using early-DIO (3-weeks) and fully established-DIO (14-weeks) models. The aim of this thesis was to investigate the critical immunomodulatory potential of bioactive lipid groups that could potentially both alleviate or aggravate the OIIM.
WD-feeding in early-DIO model illustrated a profound bias towards pro-inflammatory Th17 phenotype with a codominant reduction of anti-inflammatory regulatory T cells which are key modulators of OIIM. Importantly, omega-3 supplementation into obesogenic WD significantly reverted the obesity-induced distortion in Th17/Treg balance and alleviated the OIIM.
Furthermore, consistent with the background literature, 14-week HFD-feeding in an fully-established DIO model was shown to induce a profound elevation towards pro- inflammatory CXCR3+ and LFA-1+ CD44+ EM CD4+ T populations compared to CD control. Interestingly, introduction of dieting and weight loss (WGWL model), illustrated the same exacerbated potential for the expansion of pro-inflammatory EM populations even after the weight loss. This preserved HFD-driven priming phenotype was further associated with epigenetic alterations driven by bioactive saturated-FAs. Importantly, utilisation of in vitro experiments further identified the potential functional alterations including autophagy and senescence which are associated with the epigenetically modified genes STK26 and CDKN1C. Altogether this work identified various obesogenic diet-derived bioactive lipid inducing DIO- linked alterations on distinct T cell populations that prone a persistent pro-inflammatory phenotype inducing the OIIM pathophysiology
Understanding self-restraint and self-injurious behaviour in children with autism and/or intellectual disability
Get PDFBackground: Self-restraint, the self-initiated restriction of one’s own body movements, is observed alongside self-injurious behaviour in populations with neurodevelopmental conditions. Self-restraint behaviours are understood through mechanisms of operant learning, however a purely operant account cannot adequately account for the presence of both self-injury and self-restraint. To bridge this theoretical gap, two complementary hypotheses have been proposed: the compulsivity and inhibitory control accounts. Thus far, these accounts are limited by a paucity of research, lack of focus on self-restraint measurement and reliance on indirect measures of inhibitory control. Therefore, this thesis aimed to describe self-restraint in high-risk groups, and test prevailing theoretical accounts of this behaviour across different parameters of self-restraint.
Method: A comprehensive systematic review of the existing literature provided meta-analytic estimates of the prevalence of self-restraint, self-restraint topographies, and quantified the size of association between self-restraint and putative correlates, including self-injury. A large-scale cross-syndrome survey examined transdiagnostic correlates of self-restraint, including compulsivity and anxiety, using a dimensional measurement approach. The presence and intensity of self-restraint displayed by autistic children with intellectual disability was assessed using naturalistic observational techniques. Finally, the feasibility of a novel battery of direct executive function tasks was assessed, and tasks were administered alongside indirect measures to examine the compulsivity and inhibitory control accounts.
Results: The pooled prevalence estimate of self-restraint in autistic individuals and/or those with intellectual disability was 39%, and self-restraint and self-injury shared a significant moderate association. Compulsivity and anxiety were unique predictors of self-restraint across neurodevelopmental conditions, over-and-above confounding variables. Autistic children with intellectual disability displayed a high prevalence of self-restraint, with intensity of self-restraint varying both between and within topographies. The direct executive function tasks were deemed developmentally-appropriate for autistic children with varying degrees of intellectual disability. Indirect measures of executive function more closely associated with self-restraint than direct measures, with self-injury severity moderating the relation between poor executive function and greater self-restraint intensity.
Conclusions: The prevalence of self-restraint within populations who self-injure was consistently high, however the presence of ‘multi-parameter’ self-restraint was lower. Younger age, greater autism characteristics and lower adaptive functioning were important demographic factors associated with presence, topographies and intensity of self-restraint. Findings of impulsivity uniquely predicting self-restraint at high levels of self-injury, and of compulsivity and anxiety predicting self-restraint after accounting for covariates, allowed for proposal of a novel, integrated compulsivity/inhibitory control account. This suggests that ‘impulsive’ self-injury increases anxiety/arousal, leading to the emergence of habitual
‘compulsive’ self-restraint. Future research is required to examine this integrated theory
Biofortification of wheat using different molecular breeding techniques
Get PDFWheat grains are a poor source of iron and zinc, and identifying genetic ways to improve these through breeding could improve human health. In this thesis, we aimed to characterise the ZIP (zinc-regulated, iron-regulated transporter-like protein) family in wheat and identify novel variation for Fe content using an EMS population. In our first project, we identified and functionally characterised the ZIP genes in wheat, identifying 15 TaZIP genes in total. Using publicly available RNA-seq data, we found that in both wheat and rice, TaZIP11, TaZIP13, and TaZIP14 showed the highest
expression in most tissues. We functionally characterised these three ZIPs. We found that TaZIP11 could transport Fe and Zn in a yeast complementation assay but did not observe consistent effects on micronutrients in any wheat mutant lines. Although TaZIP13 did not transport Fe and Zn in yeast complementation assay, our TILLING mutants showed altered Fe contents, while these were inconsistent between different
crosses. TaZIP14 showed no effect in yeast or in planta. Secondly, we screened a hundred EMS lines cv. Cadenza using Perls staining and
selected three high Fe lines to develop the mapping populations. For Fe phenotyping in mapping population, we developed a computational method to quantify the Fe levels.
Additionally, this method also localized the Fe contents in grain tissues. Bulk segregant analysis of F2 lines identified significant QTL for Fe content in one population, including a highly significant QTL on Chromosome 3B. In summary, we identified and characterised three ZIP genes in wheat, found that EMS mutagenesis can increase grain iron content and found a novel QTL for Fe content
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