title: Heat capacity changes for transition-state analogue binding and catalysis with human 5 '-methylthioadenosine phosphorylase

authors: Firestone, Ross S.

subjects: Science & Technology

abstract: Human 5′-methylthioadenosine phosphorylase (MTAP) catalyzes the phosphorolysis of 5′-methylthioadenosine (MTA). Its action regulates cellular MTA and links polyamine synthesis to S-adenosylmethionine (AdoMet) salvage. Transition state analogues with picomolar dissociation constants bind to MTAP in an entropically driven process at physiological temperatures, suggesting increased hydrophobic character or dynamic structure for the complexes. Inhibitor binding exhibits a negative heat capacity change (−ΔCₚ), and thus the changes in enthalpy and entropy upon binding are strongly temperature-dependent. The ΔCₚ of inhibitor binding by isothermal titration calorimetry does not follow conventional trends and is contrary to that expected from the hydrophobic effect. Thus, ligands of increasing hydrophobicity bind with increasing values of ΔCₚ. Crystal structures of MTAP complexed to transition-state analogues MT-DADMe-ImmA, BT-DADMe-ImmA, PrT-ImmA, and a substrate analogue, MT-tubercidin, reveal similar active site contacts and overall protein structural parameters, despite large differences in ΔCₚ for binding. In addition, ΔCₚ values are not correlated with Kd values. Temperature dependence of presteady state kinetics revealed the chemical step for the MTAP reaction to have a negative heat capacity for transition state formation (−ΔCₚ‡). A comparison of the ΔCₚ‡ for MTAP presteady state chemistry and ΔCₚ for inhibitor binding revealed those transition-state analogues most structurally and thermodynamically similar to the transition state. Molecular dynamics simulations of MTAP apoenzyme and complexes with MT-DADMe-ImmA and MT-tubercidin show small, but increased dynamic motion in the inhibited complexes. Variable temperature CD spectroscopy studies for MTAP–inhibitor complexes indicate remarkable protein thermal stability (to Tₘ = 99 °C) in complexes with transition-state analogues.

text: Heat capacity changes for transition-state analogue binding and catalysis with human 5 '-methylthioadenosine phosphorylase Human 5′-methylthioadenosine phosphorylase (MTAP) catalyzes the phosphorolysis of 5′-methylthioadenosine (MTA). Its action regulates cellular MTA and links polyamine synthesis to S-adenosylmethionine (AdoMet) salvage. Transition state analogues with picomolar dissociation constants bind to MTAP in an entropically driven process at physiological temperatures, suggesting increased hydrophobic character or dynamic structure for the complexes. Inhibitor binding exhibits a negative heat capacity change (−ΔCₚ), and thus the changes in enthalpy and entropy upon binding are strongly temperature-dependent. The ΔCₚ of inhibitor binding by isothermal titration calorimetry does not follow conventional trends and is contrary to that expected from the hydrophobic effect. Thus, ligands of increasing hydrophobicity bind with increasing values of ΔCₚ. Crystal structures of MTAP complexed to transition-state analogues MT-DADMe-ImmA, BT-DADMe-ImmA, PrT-ImmA, and a substrate analogue, MT-tubercidin, reveal similar active site contacts and overall protein structural parameters, despite large differences in ΔCₚ for binding. In addition, ΔCₚ values are not correlated with Kd values. Temperature dependence of presteady state kinetics revealed the chemical step for the MTAP reaction to have a negative heat capacity for transition state formation (−ΔCₚ‡). A comparison of the ΔCₚ‡ for MTAP presteady state chemistry and ΔCₚ for inhibitor binding revealed those transition-state analogues most structurally and thermodynamically similar to the transition state. Molecular dynamics simulations of MTAP apoenzyme and complexes with MT-DADMe-ImmA and MT-tubercidin show small, but increased dynamic motion in the inhibited complexes. Variable temperature CD spectroscopy studies for MTAP–inhibitor complexes indicate remarkable protein thermal stability (to Tₘ = 99 °C) in complexes with transition-state analogues.

year: 2017

title: Chinese clientele at Chinese hotels—Preferences and satisfaction

authors: Gu, Huimin

subjects: Chinese hotels

abstract: The paper examines the proposal that levels of satisfaction with mainland Chinese hotels by the domestic market are related to performance in core services to which clients attribute high levels of importance. Regression analysis indicates that the main determinants of satisfaction are the external environment, reputation and cleanliness of the bedroom. It is suggested that key components of the hotel product such as a comfortable bed are akin to hygiene factors in Herzberg's theory of human relations, that is, their absence causes dissatisfaction, but their presence is insufficient to generate high levels of satisfaction. The sample comprises 941 Chinese respondents.

text: Chinese clientele at Chinese hotels—Preferences and satisfaction The paper examines the proposal that levels of satisfaction with mainland Chinese hotels by the domestic market are related to performance in core services to which clients attribute high levels of importance. Regression analysis indicates that the main determinants of satisfaction are the external environment, reputation and cleanliness of the bedroom. It is suggested that key components of the hotel product such as a comfortable bed are akin to hygiene factors in Herzberg's theory of human relations, that is, their absence causes dissatisfaction, but their presence is insufficient to generate high levels of satisfaction. The sample comprises 941 Chinese respondents.

year: 2008

title: "Ko au te whenua, ko te whenua ko au:" A Māori housing development process

authors: Fletcher, Marcus Anzac Kewene

subjects: Māori

abstract: Tangata whenua (People of the land/Indigenous people of Aotearoa) are being recognised as emerging property and land developers in Aotearoa New Zealand (hereafter, Aotearoa). Literature and practice demonstrates how Māori are developing housing in different ways than traditional developers, supporting the wellbeing of whānau (families), hapū (sub-tribes) and iwi (tribes), while contributing to addressing the national housing crisis. The distinctiveness of these approaches are important to understand if we want to deepen our knowledge of urban development and the modelling of housing markets in Aotearoa. This thesis aims to reveal, codify and examine Māori decision-making processes relating to how and why we develop housing in Aotearoa and the values and principles that inform these approaches. Utilising Kaupapa Māori Theory and taking an insider/whānaunga (relatives) approach to the research, four whakawhiti kōrero sessions with Waikato whānau and kaimahi (workers) were undertaken to better understand how and why Māori develop housing and the processes and rationalities at play. The thesis has three contributions for academia, environmental planning and the housing sector in Aotearoa: insights into the values and rationalities that influence Māori urban development; the introduction of a Māori housing development framework; and insights into how the framework may be utilised to contribute towards more accurate and sophisticated agent-based modelling (ABM) or urban growth modelling.  

The findings and discussion identified six prominent values that Māori utilise to develop housing: kaitiakitanga, manaakitanga, orangatanga, whānaungatanga, ūkaipōtanga and rangatiratanga. Being rooted in Māori knowledge and epistemology essentially demands differing rationalities for when Māori undertake housing development, which are placed within an overarching framework. The framework represents a new tool to disrupt the current understanding of ‘developers’ as a single entity with a defined pathway that influences all development behaviour. Moreover, it demonstrates how whānau, hapū and iwi draw on the established learning and guidance of our tūpuna (ancestors) and the strides taken to reclaim tino rangatiratanga (self-determination). The thesis argues that academics, environmental practitioners and the housing sector should re-examine their understanding of developers in Aotearoa to become more pluralistic, which may present new challenges and opportunities for ABM and urban growth modelling. This framework argues some aspects may have potential to be incorporated into these technical analyses, while other aspects should be considered in the context of Māori and Indigenous Data Sovereignty to protect the contributions and mana of the participants within this thesis, or resist the ability to be captured altogether.

text: "Ko au te whenua, ko te whenua ko au:" A Māori housing development process Tangata whenua (People of the land/Indigenous people of Aotearoa) are being recognised as emerging property and land developers in Aotearoa New Zealand (hereafter, Aotearoa). Literature and practice demonstrates how Māori are developing housing in different ways than traditional developers, supporting the wellbeing of whānau (families), hapū (sub-tribes) and iwi (tribes), while contributing to addressing the national housing crisis. The distinctiveness of these approaches are important to understand if we want to deepen our knowledge of urban development and the modelling of housing markets in Aotearoa. This thesis aims to reveal, codify and examine Māori decision-making processes relating to how and why we develop housing in Aotearoa and the values and principles that inform these approaches. Utilising Kaupapa Māori Theory and taking an insider/whānaunga (relatives) approach to the research, four whakawhiti kōrero sessions with Waikato whānau and kaimahi (workers) were undertaken to better understand how and why Māori develop housing and the processes and rationalities at play. The thesis has three contributions for academia, environmental planning and the housing sector in Aotearoa: insights into the values and rationalities that influence Māori urban development; the introduction of a Māori housing development framework; and insights into how the framework may be utilised to contribute towards more accurate and sophisticated agent-based modelling (ABM) or urban growth modelling.  

The findings and discussion identified six prominent values that Māori utilise to develop housing: kaitiakitanga, manaakitanga, orangatanga, whānaungatanga, ūkaipōtanga and rangatiratanga. Being rooted in Māori knowledge and epistemology essentially demands differing rationalities for when Māori undertake housing development, which are placed within an overarching framework. The framework represents a new tool to disrupt the current understanding of ‘developers’ as a single entity with a defined pathway that influences all development behaviour. Moreover, it demonstrates how whānau, hapū and iwi draw on the established learning and guidance of our tūpuna (ancestors) and the strides taken to reclaim tino rangatiratanga (self-determination). The thesis argues that academics, environmental practitioners and the housing sector should re-examine their understanding of developers in Aotearoa to become more pluralistic, which may present new challenges and opportunities for ABM and urban growth modelling. This framework argues some aspects may have potential to be incorporated into these technical analyses, while other aspects should be considered in the context of Māori and Indigenous Data Sovereignty to protect the contributions and mana of the participants within this thesis, or resist the ability to be captured altogether.

year: 2025