The nature of data in early modern architectural practice

In contemporary data-driven society, forces of capital increasingly seek risk-averse decision making through data and digital calculation, aligned to this the discourse around design intelligence in architecture has begun to embrace the role of data and the technical non-human as much as the human. In parallel, the cultural understanding of data, in technologically mediated societies, has become tied to the digital representation of information experienced in everyday life, which in turn influences human practices. A problem exists in the dominance of scientific thought around data in architecture that exerts disciplinary bias towards quantity rather than quality. In contemporary digital practice, data is assumed to offer an objective characterisation of the world and have faithful representation through the mechanisms of the computer. From this shift, a macro question exists concerning the influence of data’s conceptualisation on the physical products of architecture. To contribute to this overall question this paper considers the register of data in early modernism identified as a moment when scientific abstraction and the mapping capacity of the machine combine to afford recognisable data practices and infrastructure

Running out of STE(A)M: A critical perspective on the political rhetoric of innovation.

The frequent use of the acronym STEM (Science, Technology, Engineering, Maths) within the rhetoric of the National Innovation and Science Agenda should immediately sound alarm bells for the field of architecture. While some, now and then, include the A (Art), there is a bias toward these four core disciplines and a perception that they provide a means towards “innovation”, and with it “progress” and “growth” through new technology. In Australia the socially facing practice of architecture has found itself navigating the territories of service and construction economies through technologies of shelter, in doing so it is complicit in serving mainly the wealthy, and assisting in the political control of resources. As we enter a post-resource era is the architectural profession making the same mistake by adopting the rhetoric of another capitalist profit driven economic paradigm? In this paper, I wish to assess the political rhetoric behind the innovation economy critically to highlight the assumptions contained within. In response, I will offer alternative approaches based on social use-value and a focus away from consumption and labour as means of value exchange. Through considering peer to peer production, and associated cultures of making, hacking and re-use, as alternative frameworks for political economy, the question is proposed whether architecture should seek to create its own agenda for innovation, rather than adopt the dominant economic model? The paper aims to address the assumptions that surround the rhetoric of innovation in Australian political discourse, question the motivations of this focus, and assess its benefit for architecture

A Comparative Study of Two Methods of Teaching Arithmetic

It was the purpose of this study to (1) compare the achievement gained by youngsters being taught by two different methods of arithmetic; (2) find, for the benefit of the district, whether the children receive a better concept of numbers and processes through the Scott, Foresman method; and (3) determine whether the Scott, Foresman method makes the teaching of problem solving more efficient

Transcatheter Aortic Valve Implantation for Severe Pure Aortic Regurgitation with Dedicated Devices

Aortic regurgitation (AR) is not the most common valvular disease; however, its prevalence increases with age, with more than 2% of those aged >70 years having at least moderate AR. Once symptoms related to AR develop, the prognosis becomes poor. Transcatheter aortic valve implantation for patients with pure severe AR and at prohibitive surgical risk is occasionally performed, but remains a clinical challenge due to absence of valvular calcium, large aortic root and increased stroke volume. These issues make the positioning and deployment of transcatheter aortic valve implantation devices unpredictable, with a tendency to prosthesis embolisation or malposition. To date, the only two dedicated transcatheter valves for AR are the J-Valve (JC Medical) and the JenaValve (JenaValve Technology). Both devices have been used successfully via the transapical approach. The transfemoral experience is limited to first-in-human publications and to a clinical trial dedicated to AR, for which the completion date is still pending

Optimization of a “Bump-and-Hole” Approach to Allele-Selective BET Bromodomain Inhibition

Allele-specific chemical genetics enables selective inhibition within families of highly-conserved proteins. The four BET (bromodomain & extra-terminal domain) proteins – BRD2, BRD3, BRD4 and BRDT bind acetylated chromatin via their bromodomains and regulate processes such as cell proliferation and inflammation. BET bromodomains are of particular interest, as they are attractive therapeutic targets but existing inhibitors are pan-selective. We previously established a bump-&-hole system for the BET bromodomains, pairing a leucine/alanine mutation with an ethyl-derived analogue of an established benzodiazepine scaffold. Here we optimize upon this system with the introduction of a more conservative and less disruptive leucine/valine mutation. Extensive structure-activity-relationships of diverse benzodiazepine analogues guided the development of potent, mutant-selective inhibitors with desirable physiochemical properties. The active enantiomer of our best compound – 9-ME-1 – shows ~200 nM potency, >100-fold selectivity for the L/V mutant over wild-type and excellent DMPK properties. Through a variety of in vitro and cellular assays we validate the capabilities of our optimized system, and then utilize it to compare the relative importance of the first and second bromodomains to chromatin binding. These experiments confirm the primacy of the first bromodomain in all BET proteins, but also significant variation in the importance of the second bromodomain. We also show that, despite having a minor role in chromatin recognition, BRD4 BD2 is still essential for gene expression , likely through the recruitment of non-histone proteins. The disclosed inhibitor:mutant pair provides a powerful tool for future cellular and in vivo target validation studies

PhotoAffinity bits : a photoaffinity-based fragment screening platform for efficient identification of protein ligands

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutic

Progress in the development of non-​BET bromodomain chemical probes

The bromodomain and extra terminal (BET) family of bromodomains have been the focus of extensive research, leading to the development of many potent, selective chem. probes and recent clinical assets. The profound biol. associated with BET bromodomain inhibition has provided a convincing rationale for targeting bromodomains for the treatment of disease. However, the BET family represents just eight of the at least 56 human bromodomains identified to date. Until recently, there has been significantly less interest in non-​BET bromodomains, leaving a vast area of research and the majority of this new target class yet to be thoroughly investigated. It has been widely reported that several non-​BET bromodomain containing. proteins are associated with various diseases including cancer and HIV. Therefore, the development of chem. probes for non-​BET bromodomains will facilitate elucidation of their precise biol. roles and potentially lead to the development of new medicines. This review summarises the progress made towards the development of non-​BET bromodomain chem. probes to date. In addn., we highlight the potential for future work in this new and exciting area

A Cell-Based Small Molecule Screening Method for Identifying Inhibitors of Epithelial-Mesenchymal Transition in Carcinoma

Epithelial Mesenchymal Transition (EMT) is a crucial mechanism for carcinoma progression, as it provides routes for in situ carcinoma cells to dissociate and become motile, leading to localized invasion and metastatic spread. Targeting EMT therefore represents an important therapeutic strategy for cancer treatment. The discovery of oncogene addiction in sustaining tumor growth has led to the rapid development of targeted therapeutics. Whilst initially optimized as anti-proliferative agents, it is likely that some of these compounds may inhibit EMT initiation or sustenance, since EMT is also modulated by similar signaling pathways that these compounds were designed to target. We have developed a novel screening assay that can lead to the identification of compounds that can inhibit EMT initiated by growth factor signaling. This assay is designed as a high-content screening assay where both cell growth and cell migration can be analyzed simultaneously via time-course imaging in multi-well plates. Using this assay, we have validated several compounds as viable EMT inhibitors. In particular, we have identified compounds targeting ALK5, MEK, and SRC as potent inhibitors that can interfere with EGF, HGF, and IGF-1 induced EMT signaling. Overall, this EMT screening method provides a foundation for improving the therapeutic value of recently developed compounds in advanced stage carcinoma

The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition