An architecture of support - Investigating ways small insertions within the informal act as catalysts that support the existing practices and networks established by the residents of Imizamo Yethu

Informal ways of living have become the new norm in response to our rapidly urbanising world. The logic used in the making of self-built cities is poorly understood and therefore poorly supported. Many of the communities that live in these self-built cities face extreme hardship by having inadequate access to basic services, public space and educational support. As architects, our influence in the built environment is powerful and therefore these issues need to be challenged by using our skills to better the lives of the collective people. The architectural inquiry looks into how the theoretical ideas of informality can be implemented into a design which attempts to weave collaborative responses within an existing self-built environment. This metaphoric idea of weaving is used to guide my studies and test ideas through the design response research. The process of design is used to describe and analyse how the existing environment can be supported in ways which encourage positive change. This dissertation examines the need for sustainable and productive space for the youth of Imizamo Yethu as well as adequate service provision for the community at large. The project seeks to investigate ways small insertions within the existing environment of Imizamo Yethu act as catalysts that support the existing practices and networks established by its residents. The design proposes an architecture which offers support in terms of expression , play and learning as well as access to adequate service provisio

Psychometric attributes of the DISC Predictive Scales

Introduction: This study was designed to evaluate the psychometric attributes and screening efficiency of a Spanish version of the Children Predictive Scales (DPS) against the Spanish Diagnostic Interview Schedule for Children (DISC-IV). Method: This pilot cross-sectional study included 61 children aged 9 to 14 years in a mainstream school. The following psychometric attributes were analyzed: acceptability, scale assumptions, internal consistency, and precision, as well the predictive validity (AUC). Results: The scale did not show ceiling or floor effects (6.4%, 1.3%, respectively). The internal consistency was high (α±=0.92), and the standard error of measurement was adequate (SEM=1.54). The overall DPS AUC was 0.72 against DISC IV corresponding diagnosis. Conclusion: The Spanish version of the DPS-4.32 seems to be a reliable and precise tool for screening mental health disorders in a school-age population

The potential use of single-particle electron microscopy as a tool for structure-based inhibitor design

Recent developments in electron microscopy (EM) have led to a step change in our ability to solve the structures of previously intractable systems, especially membrane proteins and large protein complexes. This has provided new opportunities in the field of structure-based drug design, with a number of high-profile publications resolving the binding sites of small molecules and peptide inhibitors. There are a number of advantages of EM over the more traditional X-ray crystallographic approach, such as resolving different conformational states and permitting the dynamics of a system to be better resolved when not constrained by a crystal lattice. There are still significant challenges to be overcome using an EM approach, not least the speed of structure determination, difficulties with low-occupancy ligands and the modest resolution that is available. However, with the anticipated developments in the field of EM, the potential of EM to become a key tool for structure-based drug design, often complementing X-ray and NMR studies, seems promising

Metabolomics for bioactivity assessment of natural products.

Natural products historically have been a rich source of lead molecules in drug discovery, based on their capability to create unique and diverse chemical structures. However, it is also true that the vast number of metabolites typically present in natural products and their huge dynamic range results in the loss of many possibly bioactive natural compounds, becoming an inextricable obstacle for drug development. Recently, new strategies which favour a holistic approach as opposed to the traditional reductionist methods used previously, have been introduced with the purpose of overcoming the bottlenecks in natural product research. This approach is based on the application of new technologies, including metabolomics, for example. Metabolomics allows a systematic study of a complex mixture such as a phytochemical preparation, which can be linked to observations obtained through biological testing systems without the need for isolating active principles. This may put drug discovery from natural products back in the limelight again. In this review paper, the description of some examples of successful metabolomics applications in several important fields related to drug discovery from natural sources aims at raising the potential of metabolomics in reducing the gap between natural products (NP) and modern drug discovery demand

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns

A survey of across-target bioactivity results of small molecules in PubChem

This work provides an analysis of across-target bioactivity results in the screening data deposited in PubChem. Two alternative approaches for grouping-related targets are used to examine a compound's across-target bioactivity. This analysis identifies compounds that are selectively active against groups of protein targets that are identical or similar in sequence. This analysis also identifies compounds that are bioactive across unrelated targets. Statistical distributions of compound' across-target selectivity provide a survey to evaluate target specificity of compounds by deriving and analyzing bioactivity profile across a wide range of biological targets for tested small molecules in PubChem. This work enables one to select target specific inhibitors, identify promiscuous compounds and better understand the biological mechanisms of target-small molecule interactions

Automated radiofrequency-based US measurement of common carotid intima-media thickness in RA patients treated with synthetic vs synthetic and biologic DMARDs

Objective. To compare the carotid intima-media thickness (IMT) assessed with automated radiofrequency-based US in RA patients treated with synthetic vs synthetic and biologic DMARDs and controls. Methods. Ninety-four RA patients and 94 sex-and age-matched controls were prospectively recruited at seven centres. Cardiovascular (CV) risk factors and co-morbidities, RA characteristics and therapy were recorded. Common carotid artery (CCA)-IMT was assessed in RA patients and controls with automated radiofrequency-based US by the same investigator at each centre. Results. Forty-five (47.9%) RA patients had been treated with synthetic DMARDs and 49 (52.1%) with synthetic and biologic DMARDs. There were no significant differences between the RA patients and controls in demographics, CV co-morbidities and CV disease. There were significantly more smokers among RA patients treated with synthetic and biologic DMARDs (P = 0.036). Disease duration and duration of CS and synthetic DMARD therapy was significantly longer in RA patients treated with synthetic and biologic DMARDs (P<0.0005). The mean CCA-IMT was significantly greater in RA patients treated only with synthetic DMARDs than in controls [591.4 (98.6) vs 562.1 (85.8); P = 0.035] and in RA patients treated with synthetic and biologic DMARDs [591.4 (98.6) vs 558.8 (95.3); P = 0.040). There was no significant difference between the mean CCA-IMT in RA patients treated with synthetic and biologic DMARDs and controls (P = 0.997). Conclusion. Our results suggest that radiofrequency-based measurement of CCA-IMT can discriminate between RA patients treated with synthetic DMARDs vs RA patients treated with synthetic and biologic DMARDs