title: Novel sulfonamides for the treatment of breast and cervical cancers

authors: Buckley, Nathaniel Thomas

subjects: Sulfonamide

abstract: A series of novel sulfonamides were studied computationally to identify a potential mechanism of action for the treatment of breast and cervical cancers. Previous in vivo testing demonstrated varying degrees of effectiveness, with seven molecules showing the highest cytotoxicity. Computational calculations were chosen as the means for determining the drug target. Previous studies indicated β-Tubulin and Carbonic Anhydrase IX as the most likely proteins of interest, so these were selected for study.
The computational methodology selected for this study follows that of Krzywik et al.¹ For this, conventional docking studies were undertaken using Autodock Vina, followed by more accurate and computationally demanding molecular dynamics simulations using the MM/PBSA procedures in AMBER. Docking studies for the seven active compounds were performed using Vina, and showed promising results. The three most effective compounds (5AP, 6AP and 7BP) were then utilised in a series of MM/PBSA calculations to determine strength of interaction between the sulfonamides and drug targets.
The results of the AMBER calculations determined β-Tubulin to be the more likely drug target, although this result did show 6AP (the most effective in vivo molecule) to have the weakest binding, which was an unexpected result. A LIGPLOT study was done to determine a potential cause for this, showing a heavy emphasis on non-polar interactions between the drug molecules and proteins. Drug-like comparisons and pKa calculations were also performed, showing all three molecules to have very similar acidity and hydrogen bond capabilities, but suggesting lipophilicity and molecule size to be possible determining factors in the overall effect of the compounds. Transport across the cell membrane and through the cytoplasm were also suggested as potential reasons for the differing results, and further studies into these were suggested for possible confirmation.

text: Novel sulfonamides for the treatment of breast and cervical cancers A series of novel sulfonamides were studied computationally to identify a potential mechanism of action for the treatment of breast and cervical cancers. Previous in vivo testing demonstrated varying degrees of effectiveness, with seven molecules showing the highest cytotoxicity. Computational calculations were chosen as the means for determining the drug target. Previous studies indicated β-Tubulin and Carbonic Anhydrase IX as the most likely proteins of interest, so these were selected for study.
The computational methodology selected for this study follows that of Krzywik et al.¹ For this, conventional docking studies were undertaken using Autodock Vina, followed by more accurate and computationally demanding molecular dynamics simulations using the MM/PBSA procedures in AMBER. Docking studies for the seven active compounds were performed using Vina, and showed promising results. The three most effective compounds (5AP, 6AP and 7BP) were then utilised in a series of MM/PBSA calculations to determine strength of interaction between the sulfonamides and drug targets.
The results of the AMBER calculations determined β-Tubulin to be the more likely drug target, although this result did show 6AP (the most effective in vivo molecule) to have the weakest binding, which was an unexpected result. A LIGPLOT study was done to determine a potential cause for this, showing a heavy emphasis on non-polar interactions between the drug molecules and proteins. Drug-like comparisons and pKa calculations were also performed, showing all three molecules to have very similar acidity and hydrogen bond capabilities, but suggesting lipophilicity and molecule size to be possible determining factors in the overall effect of the compounds. Transport across the cell membrane and through the cytoplasm were also suggested as potential reasons for the differing results, and further studies into these were suggested for possible confirmation.

year: 2022

title: An Investigation into Establishing (Motivating) Operations

authors: Jackson, Surrey Merryn Kate

subjects: establishing operations

abstract: Motivating Operations (MOs) are a fundamental concept in behavioural psychology. Despite this, empirical research into MOs is lacking. The overall aim of this thesis is to contribute to the experimental literature base for MOs.
Experiment 2.1 used an already published video analysis methodology to assess the morphology of food motivated pecks made to a computer screen by hens, after the hens had been trained to emit the peck using either an autoshaping or handshaping procedure. The intention of this was to then be able to use the video analysis to assess the effect of altering two MOs related to two different reinforcers (e.g., food and water) at one time, on morphology. The study showed that both methods produced similarly formed pecks despite the variability inherent in the handshaping procedure. It was then concluded it is the nature of the reinforcer that gives rise to morphology not the autoshaping procedure per se which gives rise to a particular form of elicited responses.
The aim of Experiment 3.1 and 3.2 was to develop a procedure for restricting access to water in laying hens, in order to motivate them sufficiently to respond for water reinforcers. Experiment 3.1 assessed the effect that gradually decreasing time and amount of water access had on food-restricted hens’ water consumption and health. It was found that hens could be restricted to one hr access of water (restricted to the maximum amount that hens would consume when access was ad libitum) without adverse effects to health being apparent. However, when the hens were subsequently exposed to FR schedules with a low response requirement in Experiment 3.2, they did not respond consistently. This indicated that the level of restriction was insufficient to motivate responding and this finding, combined with the difficulty of obtaining ethical approval, meant that the proposed experiments utilising water deprivation as an MO had to be abandoned.
Experiment 4.1 used the autoshaping paradigm to assess the acquisition of food motivated pecks to a stimulus, at two different levels of bodyweight (75% and 95%). An infra-red screen was used to analyse performance separately from learning effects by examining activity levels (location and amount of pecks). It was found that that higher numbers of effective pecks were made by hens maintained at 75% free-feeding bodyweight than hens maintained at 95% (different MO conditions). There were also higher levels of ineffective pecks in the 75% group.
Experiment 5.1 investigated relative preference for stimuli correlated with different MO conditions: high deprivation (no pre-feeding), or low deprivation (pre-feeding), when subjects were maintained at either 75% or 95% of free-feeding bodyweight. The results showed that 6/10 hens demonstrated an increased preference for the stimulus paired with high deprivation conditions (no pre-feeding) when measured by log ratios of responses, and had faster response rates on this stimulus. Overall, the 75% bodyweight hens had faster response rates than the 95% hens (as in Experiment 4.1), and 8/10 hens responded faster on the stimulus that was paired with no pre-feeding. It was also found, as per Experiment 4.1, that higher numbers of effective pecks were made by hens maintained at 75% free-feeding bodyweight than hens maintained at 95% (different MO conditions).
Experiments 6.1 and 6.2 extended the findings of the thesis thus far in that concurrent VI VI schedules were used to assess the effect of bodyweight and pre-feeding as MOs on steady state responding. In total 16 conditions were run exposing hens to three different VI pairs: VI-12, VI-60 (5:1); VI-20, VI-20 (1:1); and VI-60, VI-12 (1:5). Bodyweight values of 85%, 95%, 100%, and 85% with pre-feeding of 40 cc wheat delivered 40 minutes prior to experimental sessions were manipulated between hens finishing a series of the three VI pairs. It was found that 4/6 hens had higher absolute and relative response rates when bodyweight was made lower. For 3/6 of these hens, increasing bodyweight increased sensitivity as measured by the parameter a; this was more distinct when the Generalised Matching Law was applied to response rather than time locations for these hens. Frequency distributions of IRTs showed that for the hens that tended to show increasing sensitivity as bodyweights increased there were more IRTs in bins greater than 0.4 s. This was reflected on the log-survivor plots as the limbs were shallower when bodyweights were higher, indicating that more between-bout responses were occurring. It was also found that pre-feeding increased sensitivity as measured by the parameter a for all hens; this was more noticeable when the GML was applied to response rather than time allocations. Although overall response rates tended to resemble those for the 85% bodyweight condition and remain higher than the 95% and 100% bodyweight conditions, the distribution of left and right response rates showed that hens matched better to the prevailing reinforcer rates when they were pre-fed, than when they were not pre-fed.
Overall, the main findings were: (1) that reducing bodyweights increased amounts of species-specific behaviour; and (2) that reducing bodyweight causes increases in response rate. These findings could explain why changes in preference for stimuli paired with high levels of deprivation are observed during SDVL procedures, and why increased sensitivity to available reinforcement at lower levels of deprivation found in studies utilising the GML have been observed in previous studies. These findings contribute to the empirical data informing the behavioural treatment of motivation and have applied implications. Reinforcement and punishment procedures such as extinction or differential reinforcement of alternative behaviours may no longer be necessary when MOs are manipulated.

text: An Investigation into Establishing (Motivating) Operations Motivating Operations (MOs) are a fundamental concept in behavioural psychology. Despite this, empirical research into MOs is lacking. The overall aim of this thesis is to contribute to the experimental literature base for MOs.
Experiment 2.1 used an already published video analysis methodology to assess the morphology of food motivated pecks made to a computer screen by hens, after the hens had been trained to emit the peck using either an autoshaping or handshaping procedure. The intention of this was to then be able to use the video analysis to assess the effect of altering two MOs related to two different reinforcers (e.g., food and water) at one time, on morphology. The study showed that both methods produced similarly formed pecks despite the variability inherent in the handshaping procedure. It was then concluded it is the nature of the reinforcer that gives rise to morphology not the autoshaping procedure per se which gives rise to a particular form of elicited responses.
The aim of Experiment 3.1 and 3.2 was to develop a procedure for restricting access to water in laying hens, in order to motivate them sufficiently to respond for water reinforcers. Experiment 3.1 assessed the effect that gradually decreasing time and amount of water access had on food-restricted hens’ water consumption and health. It was found that hens could be restricted to one hr access of water (restricted to the maximum amount that hens would consume when access was ad libitum) without adverse effects to health being apparent. However, when the hens were subsequently exposed to FR schedules with a low response requirement in Experiment 3.2, they did not respond consistently. This indicated that the level of restriction was insufficient to motivate responding and this finding, combined with the difficulty of obtaining ethical approval, meant that the proposed experiments utilising water deprivation as an MO had to be abandoned.
Experiment 4.1 used the autoshaping paradigm to assess the acquisition of food motivated pecks to a stimulus, at two different levels of bodyweight (75% and 95%). An infra-red screen was used to analyse performance separately from learning effects by examining activity levels (location and amount of pecks). It was found that that higher numbers of effective pecks were made by hens maintained at 75% free-feeding bodyweight than hens maintained at 95% (different MO conditions). There were also higher levels of ineffective pecks in the 75% group.
Experiment 5.1 investigated relative preference for stimuli correlated with different MO conditions: high deprivation (no pre-feeding), or low deprivation (pre-feeding), when subjects were maintained at either 75% or 95% of free-feeding bodyweight. The results showed that 6/10 hens demonstrated an increased preference for the stimulus paired with high deprivation conditions (no pre-feeding) when measured by log ratios of responses, and had faster response rates on this stimulus. Overall, the 75% bodyweight hens had faster response rates than the 95% hens (as in Experiment 4.1), and 8/10 hens responded faster on the stimulus that was paired with no pre-feeding. It was also found, as per Experiment 4.1, that higher numbers of effective pecks were made by hens maintained at 75% free-feeding bodyweight than hens maintained at 95% (different MO conditions).
Experiments 6.1 and 6.2 extended the findings of the thesis thus far in that concurrent VI VI schedules were used to assess the effect of bodyweight and pre-feeding as MOs on steady state responding. In total 16 conditions were run exposing hens to three different VI pairs: VI-12, VI-60 (5:1); VI-20, VI-20 (1:1); and VI-60, VI-12 (1:5). Bodyweight values of 85%, 95%, 100%, and 85% with pre-feeding of 40 cc wheat delivered 40 minutes prior to experimental sessions were manipulated between hens finishing a series of the three VI pairs. It was found that 4/6 hens had higher absolute and relative response rates when bodyweight was made lower. For 3/6 of these hens, increasing bodyweight increased sensitivity as measured by the parameter a; this was more distinct when the Generalised Matching Law was applied to response rather than time locations for these hens. Frequency distributions of IRTs showed that for the hens that tended to show increasing sensitivity as bodyweights increased there were more IRTs in bins greater than 0.4 s. This was reflected on the log-survivor plots as the limbs were shallower when bodyweights were higher, indicating that more between-bout responses were occurring. It was also found that pre-feeding increased sensitivity as measured by the parameter a for all hens; this was more noticeable when the GML was applied to response rather than time allocations. Although overall response rates tended to resemble those for the 85% bodyweight condition and remain higher than the 95% and 100% bodyweight conditions, the distribution of left and right response rates showed that hens matched better to the prevailing reinforcer rates when they were pre-fed, than when they were not pre-fed.
Overall, the main findings were: (1) that reducing bodyweights increased amounts of species-specific behaviour; and (2) that reducing bodyweight causes increases in response rate. These findings could explain why changes in preference for stimuli paired with high levels of deprivation are observed during SDVL procedures, and why increased sensitivity to available reinforcement at lower levels of deprivation found in studies utilising the GML have been observed in previous studies. These findings contribute to the empirical data informing the behavioural treatment of motivation and have applied implications. Reinforcement and punishment procedures such as extinction or differential reinforcement of alternative behaviours may no longer be necessary when MOs are manipulated.

year: 2017

title: A Mana Wahine inquiry into indigenous governance

authors: Toi, Sharon Marjorie

subjects: Mana Wahine

abstract: This thesis investigates the question “How can indigenous women reinvigorate their role in tribal governance structures when many such structures continue to reinforce gendered colonial constructs within which women are marginalised?”  It is noted that contemporary tribal governance structures are often considered a site within which indigenous peoples can express cultural identity, however, when indigenous women are clearly under-represented in positions of power within those structures, this thesis questions why this situation continues. 
First, the thesis seeks to address the broad historical context within which indigenous women were subjected to colonial constructs of legislation, paternalistic government policies and the mechanisms of a euro-western court system policy. It is against this backdrop that comparisons are drawn that take into account the historical relationships between Māori, First Nations, Aboriginal, and Native American women and their respective colonising governments which bear alarming similarities in terms of the subjugation of these populations of women through colonisation. The significance of this historical-comparative lens is to illustrate how the status of women became seriously eroded within indigenous societies from traditional through to modern times. Consequently, this thesis goes on to explore the contemporary socio-political status of indigenous women as a result of their colonised history. 
From this broad historical context, the thesis narrows its view to examine commonalities and differences in relation to Māori and Native American women's experiences of tribal governance as tribal leaders and women of cultural significance and influence. The thesis changes tack to reflect the specific research intent of my Fulbright scholar experience to the University of Arizona, Tucson Arizona. Narrowing the focus of the research allowed me to analyse in more detail, beneficial comparisons of what was working for women tribal leaders under the auspices of the largely successful Native Nations Institute, Indigenous Governance Programme, in comparison to Māori women in tribal governance in Aotearoa, New Zealand. Importantly, this research synergises indigenous women’s shared knowledge in the reinvigoration of traditional tribal governance structures. The objective being to establish a body of knowledge that gives strength to a collective indigenous women's experience of governance from which normative propositions of indigenous governance based on western concepts can be examined, challenged and potentially transformed.  
It is noted that indigenous women have been included as essential decision-makers and leaders in traditional tribal governance systems; however, contemporary indigenous governance models do little to reflect this. The impact is that for indigenous women, tribal institutions and structures can themselves embed and reflect western colonial and patriarchal ideologies. Through our colonial experiences, indigenous peoples have inherited an oppressive gender legacy entrenched in policy and legislation that is socially constructed and instructed. To survive, indigenous women have to engage, challenge, resist and mitigate gendered spaces. This research highlights the extent to which indigenous women’s ways of leading or governing continue to be circumscribed in the on-going process of colonisation. Colonialism was a gendered process, and consequently, this thesis draws upon indigenous Feminist, Kaupapa Maori and Mana Wahine (Māori women’s) theoretical frameworks to analyse the complex ways that intersecting discourses of colonialism, race, gender and power continue to marginalise indigenous women within tribal governance. Indigenous Feminist theory also provides a framework for contextualising how First Nations, Aboriginal and Native American/American Indian women speak to these issues.  Importantly, how indigenous women are engaging in decolonising methodologies that impact the colonised practices, ways and attitudes they have or are currently experiencing in tribal governance, are also revealed.
Lastly, this thesis contributes to legal scholarship by contextualising the specific challenges of tribal governance for indigenous women. It addresses this by situating women’s experiences and ways of ‘being and doing’ within the micro tribal governance context while taking account of the macro realities of tribal governance politically, socially and more importantly, culturally.

text: A Mana Wahine inquiry into indigenous governance This thesis investigates the question “How can indigenous women reinvigorate their role in tribal governance structures when many such structures continue to reinforce gendered colonial constructs within which women are marginalised?”  It is noted that contemporary tribal governance structures are often considered a site within which indigenous peoples can express cultural identity, however, when indigenous women are clearly under-represented in positions of power within those structures, this thesis questions why this situation continues. 
First, the thesis seeks to address the broad historical context within which indigenous women were subjected to colonial constructs of legislation, paternalistic government policies and the mechanisms of a euro-western court system policy. It is against this backdrop that comparisons are drawn that take into account the historical relationships between Māori, First Nations, Aboriginal, and Native American women and their respective colonising governments which bear alarming similarities in terms of the subjugation of these populations of women through colonisation. The significance of this historical-comparative lens is to illustrate how the status of women became seriously eroded within indigenous societies from traditional through to modern times. Consequently, this thesis goes on to explore the contemporary socio-political status of indigenous women as a result of their colonised history. 
From this broad historical context, the thesis narrows its view to examine commonalities and differences in relation to Māori and Native American women's experiences of tribal governance as tribal leaders and women of cultural significance and influence. The thesis changes tack to reflect the specific research intent of my Fulbright scholar experience to the University of Arizona, Tucson Arizona. Narrowing the focus of the research allowed me to analyse in more detail, beneficial comparisons of what was working for women tribal leaders under the auspices of the largely successful Native Nations Institute, Indigenous Governance Programme, in comparison to Māori women in tribal governance in Aotearoa, New Zealand. Importantly, this research synergises indigenous women’s shared knowledge in the reinvigoration of traditional tribal governance structures. The objective being to establish a body of knowledge that gives strength to a collective indigenous women's experience of governance from which normative propositions of indigenous governance based on western concepts can be examined, challenged and potentially transformed.  
It is noted that indigenous women have been included as essential decision-makers and leaders in traditional tribal governance systems; however, contemporary indigenous governance models do little to reflect this. The impact is that for indigenous women, tribal institutions and structures can themselves embed and reflect western colonial and patriarchal ideologies. Through our colonial experiences, indigenous peoples have inherited an oppressive gender legacy entrenched in policy and legislation that is socially constructed and instructed. To survive, indigenous women have to engage, challenge, resist and mitigate gendered spaces. This research highlights the extent to which indigenous women’s ways of leading or governing continue to be circumscribed in the on-going process of colonisation. Colonialism was a gendered process, and consequently, this thesis draws upon indigenous Feminist, Kaupapa Maori and Mana Wahine (Māori women’s) theoretical frameworks to analyse the complex ways that intersecting discourses of colonialism, race, gender and power continue to marginalise indigenous women within tribal governance. Indigenous Feminist theory also provides a framework for contextualising how First Nations, Aboriginal and Native American/American Indian women speak to these issues.  Importantly, how indigenous women are engaging in decolonising methodologies that impact the colonised practices, ways and attitudes they have or are currently experiencing in tribal governance, are also revealed.
Lastly, this thesis contributes to legal scholarship by contextualising the specific challenges of tribal governance for indigenous women. It addresses this by situating women’s experiences and ways of ‘being and doing’ within the micro tribal governance context while taking account of the macro realities of tribal governance politically, socially and more importantly, culturally.

year: 2019