Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.

Body | Movement | Architecture

<p>Architecture is considered a permanent and solid structure incapable of responding and adapting to the constant changing needs of the user. This thesis questions the static nature of architecture and instead seeks to create a typology of flexible and dynamic architecture which engages the body with the built environment. The thesis focuses on the direct relationship between the body’s movement and architecture to understand how spatial experiences can be created in the built environment. In order to answer the thesis question how can movement be used to engage the body with architecture, investigations into architecture at the micro, medium and macro scale were completed. Two strategies of using movement; the physical and the contained (“conception/perception of movement in the architecture” ) have been explored to understand which strategies work best at what scale. This inquiry into how movement engages the body with architecture was investigated using a design through research methodology . An iterative design process including model making, photography and sketches was used to create a body of work that tests architecture and movement. The results of this inquiry into movement in architecture were three architectural outcomes at three scales. Firstly the design of a mobile installation tested the user’s personal engagement with architecture at a micro scale. Secondly a medium scale house was designed to test how movement could be used to create different experiences in one space. Finally the findings of these two outcomes were incorporated into the design of a macro scale transport hub that used movement to create spatial experiences and engagement for the user. The use of movement in architecture, enables user to have an engagement with architecture through the varying spatial experiences created in the space.</p>

Body | Movement | Architecture

<p>Architecture is considered a permanent and solid structure incapable of responding and adapting to the constant changing needs of the user. This thesis questions the static nature of architecture and instead seeks to create a typology of flexible and dynamic architecture which engages the body with the built environment. The thesis focuses on the direct relationship between the body’s movement and architecture to understand how spatial experiences can be created in the built environment. In order to answer the thesis question how can movement be used to engage the body with architecture, investigations into architecture at the micro, medium and macro scale were completed. Two strategies of using movement; the physical and the contained (“conception/perception of movement in the architecture” ) have been explored to understand which strategies work best at what scale. This inquiry into how movement engages the body with architecture was investigated using a design through research methodology . An iterative design process including model making, photography and sketches was used to create a body of work that tests architecture and movement. The results of this inquiry into movement in architecture were three architectural outcomes at three scales. Firstly the design of a mobile installation tested the user’s personal engagement with architecture at a micro scale. Secondly a medium scale house was designed to test how movement could be used to create different experiences in one space. Finally the findings of these two outcomes were incorporated into the design of a macro scale transport hub that used movement to create spatial experiences and engagement for the user. The use of movement in architecture, enables user to have an engagement with architecture through the varying spatial experiences created in the space.</p>

Inside / Outside and the [Inbetween]

<p>How can architecture overcome the traditional differentiation of inside and outside? Architects tend to associate our inhabitation and movement within two spatial realms, those being inside and outside. The connection between the two plays a fundamental role in our relationship and understanding of the environment in which we live in. The details of these connections are often neglected and standardised ideals and components are regularly implemented without much consideration in regards to the context in which they are being established. The fundamental act of architecture is to define one space from another. Primarily this means differentiating the inside from the outside (interactivearchitecture.org). Perceptually and practically the worlds of interior and exterior are mutually exclusive one cannot be in both at the same time, and yet traditionally they border directly on each other. (Lo, 1986) Through the exploration of the relationship between interior and exterior space a focus will be given to the boundary condition. Looking into the details and material expression which enable these connections and their ability and potential to blur the boundary. Along with material properties and capabilities aspects such as kinetic, interactive and dynamic architecture will be investigated and subsequently implemented as a response to the interior, exterior relationship established. Aim to achieve architecture, where one is able to interact with the structure and help to adapt the space surrounding in order to accommodate the activities and behaviour of the occupants whilst enabling a comfortable space in regards to the climatic conditions. With an objective to live with nature and the surrounding environment achieved through blurring the spatial boundaries, forcing one to acknowledge and establish a simultaneous relationship where one can interact and co-exist between the two realms. This will be enhanced through the integration of the building into the landscape enabling the opportunity for the building to work with the environment.</p>

Inside / Outside and the [Inbetween]

<p>How can architecture overcome the traditional differentiation of inside and outside? Architects tend to associate our inhabitation and movement within two spatial realms, those being inside and outside. The connection between the two plays a fundamental role in our relationship and understanding of the environment in which we live in. The details of these connections are often neglected and standardised ideals and components are regularly implemented without much consideration in regards to the context in which they are being established. The fundamental act of architecture is to define one space from another. Primarily this means differentiating the inside from the outside (interactivearchitecture.org). Perceptually and practically the worlds of interior and exterior are mutually exclusive one cannot be in both at the same time, and yet traditionally they border directly on each other. (Lo, 1986) Through the exploration of the relationship between interior and exterior space a focus will be given to the boundary condition. Looking into the details and material expression which enable these connections and their ability and potential to blur the boundary. Along with material properties and capabilities aspects such as kinetic, interactive and dynamic architecture will be investigated and subsequently implemented as a response to the interior, exterior relationship established. Aim to achieve architecture, where one is able to interact with the structure and help to adapt the space surrounding in order to accommodate the activities and behaviour of the occupants whilst enabling a comfortable space in regards to the climatic conditions. With an objective to live with nature and the surrounding environment achieved through blurring the spatial boundaries, forcing one to acknowledge and establish a simultaneous relationship where one can interact and co-exist between the two realms. This will be enhanced through the integration of the building into the landscape enabling the opportunity for the building to work with the environment.</p>

Reactivating Dynamic Architecture: A Strategy to Inject Relevant Bodily Imagery Back into Architecture

<p>The building-body analogy, which used to be crucial in the designing of buildings, to the exception of a few, is fading. This broken link leaves us with a melancholic yearning; a sense of loss. Reactivating Dynamic Architecture readdresses the use of the body in architecture by the application of an intervening design process. The processes we undertake in order to design architecture are too often assumed, and go unchallenged. In this thesis the design process is seen as a protagonist for change. Representation, both architectural and artistic, is a central theme as the thesis guides images of the human body through abstraction. Both the dynamic body and fragmented body are investigated for their potential to create a relevant expression for the human condition. Dalibor Vesely’s theory of the positive fragment is identified as a way forward for bodily fragmentation, and Analytical Cubism, which resonated with this theory, is explored. The thesis initially moves through the investigation of historical interpretations of the body before drawing on contemporary theory. Past depictions of the fragmented and dynamic body are assessed in order to establish what they can offer us for future analysis. A representational mode is established, based on Cubism’s methods, from here the transition from drawings to architecture begins. Rowe and Slutzky’s text Transparency: Literal and Phenomenal is used to unravel the intricacies of Le Corbusier’s Villa at Garches, and their reading of this building is used to channel a successful conversion process. The resulting architecture was created as a trial of the strategy and is posed as an expression, or speculation, for what can be achieved through this method. Three different scale interventions are explored within the chosen site of Ava Train Station, Wellington. Carlo Scarpa’s techniques guide the last transition to architecture, as his processes are recognised for their ability to fold meaning into design. The described design process gathers complexity as it gains momentum; there is much to negotiate through the realms of bodily perception, modern art and architectural representation. However, the architectural expression carries that density of meaning in a simple expression</p>

Reactivating Dynamic Architecture: A Strategy to Inject Relevant Bodily Imagery Back into Architecture

<p>The building-body analogy, which used to be crucial in the designing of buildings, to the exception of a few, is fading. This broken link leaves us with a melancholic yearning; a sense of loss. Reactivating Dynamic Architecture readdresses the use of the body in architecture by the application of an intervening design process. The processes we undertake in order to design architecture are too often assumed, and go unchallenged. In this thesis the design process is seen as a protagonist for change. Representation, both architectural and artistic, is a central theme as the thesis guides images of the human body through abstraction. Both the dynamic body and fragmented body are investigated for their potential to create a relevant expression for the human condition. Dalibor Vesely’s theory of the positive fragment is identified as a way forward for bodily fragmentation, and Analytical Cubism, which resonated with this theory, is explored. The thesis initially moves through the investigation of historical interpretations of the body before drawing on contemporary theory. Past depictions of the fragmented and dynamic body are assessed in order to establish what they can offer us for future analysis. A representational mode is established, based on Cubism’s methods, from here the transition from drawings to architecture begins. Rowe and Slutzky’s text Transparency: Literal and Phenomenal is used to unravel the intricacies of Le Corbusier’s Villa at Garches, and their reading of this building is used to channel a successful conversion process. The resulting architecture was created as a trial of the strategy and is posed as an expression, or speculation, for what can be achieved through this method. Three different scale interventions are explored within the chosen site of Ava Train Station, Wellington. Carlo Scarpa’s techniques guide the last transition to architecture, as his processes are recognised for their ability to fold meaning into design. The described design process gathers complexity as it gains momentum; there is much to negotiate through the realms of bodily perception, modern art and architectural representation. However, the architectural expression carries that density of meaning in a simple expression</p>

Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses

Viruses have evolved means to manipulate the host’s ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4DCAF1 specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infecting Cercopithecus cephus (SIVmus). X-ray crystallography reveals commonalities between SIVmus Vpr and other members of the Vpx/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIVmus Vpr exploits the dynamic architecture of the multi-subunit CRL4DCAF1 assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx/Vpr proteins.