MODBASE, a database of annotated comparative protein structure models and associated resources.

MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by MODPIPE, an automated modeling pipeline that relies primarily on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE currently contains 5,152,695 reliable models for domains in 1,593,209 unique protein sequences; only models based on statistically significant alignments and/or models assessed to have the correct fold are included. MODBASE also allows users to calculate comparative models on demand, through an interface to the MODWEB modeling server (http://salilab.org/modweb). Other resources integrated with MODBASE include databases of multiple protein structure alignments (DBAli), structurally defined ligand binding sites (LIGBASE), predicted ligand binding sites (AnnoLyze), structurally defined binary domain interfaces (PIBASE) and annotated single nucleotide polymorphisms and somatic mutations found in human proteins (LS-SNP, LS-Mut). MODBASE models are also available through the Protein Model Portal (http://www.proteinmodelportal.org/)

Racial segregation in London.

Some ethnic minority groups are segregated in London, and face both direct and indirect discrimination. The thesis explores the extent to which there is institutional discrimination in the planning system, and what local planning authorities are, and could be doing, to prevent themselves from unintentionally discriminating against ethnic minorities. Immigration and race relations legislation has shaped the history of twentieth century immigration and the current distribution of ethnic minorities in London. The theory and debates surrounding the segregation and integration of ethnic minorities are summarised, as are as ways of measuring degrees of segregation. Four areas of ethnic minority concentration in London, Waxlow in Ealing, Roundwood in Brent, St Peter's in Tower Hamlets and Dalston in Hackney are described in terms of their populations, the problems facing them, and the local policies which affect ethnic minorities in housing, employment, education and land use. It is important to establish to what extent ethnic minorities (particularly non-white ethnic minorities) are still discriminated against in housing, employment and education, (through the "colour bar"), and how this affects the process of ethnic segregation. Ethnic minorities are discriminated against (usually unintentionally) by the planning system, simply by it taking a "colour-blind" approach, treating all groups' needs as the same. To some extent planning authorities are now seeking to take account of the needs of ethnic minorities, although it is still a low priority for most. Recommendations are made for better practice by the DoE, CRE, RTPI, and local authorities, affecting plan-making, monitoring, and development control procedures

A Historical Sociology of Teargas in Britain and the Empire, 1925-1965

Teargas has followed a markedly different trajectory to its chemical weapons (CW) counterparts over the twentieth century. While the Geneva Protocol of 1925 and the 1993 Chemical Weapons Convention prohibited chemical agents as means of warfare, from the early interwar period teargas gained legitimacy as a technology for domestic policing across the world. Moreover, this role in domestic riot control later became a means for some states to justify its use in military operations. This PhD therefore asks: how did teargas, in the case of British policy, become associated with riot control and policing in the twentieth century, yet prohibited as a means of warfare? Drawing from key concepts in STS and related social sciences, I argue that we can take the technical characteristics of ‘teargas’ (its ‘non-lethality’ or low toxicity) as being co-produced with its social role as a crowd control agent. Furthermore, I argue that by doing so we gain insight into how the ‘non-lethal’ status of teargas was situated within a ‘civilising’ governmentality in Britain. This governmentality both legitimated, and was legitimated by, the authority of scientific expertise. The thesis makes this argument by tracing a historical sociology of teargas in Britain and the empire from 1925 to 1965. Using declassified records from the UK National Archives and sources from newspaper archives, it examines three significant moments in Britain’s construction of teargas as a domestic technology. The first addresses the initial transition from military to colonial policing contexts that teargas made in British policy during the interwar period; the second focuses on Britain’s first use of teargas on populations within the UK during civil defence gas tests during WWII; the third traces the widespread use of teargas throughout the empire from WWII until 1965, examining the emergence of CS gas with the conception of riot control later in this period. Ultimately, I contend that CS, the ‘teargas’ of our contemporary moment, emerged from a sociotechnical imaginary of non-lethal chemical control grounded in ‘civilising’ modes of techno-politics

High Quality Genomic Copy Number Data from Archival Formalin-Fixed Paraffin-Embedded Leiomyosarcoma: Optimisation of Universal Linkage System Labelling

Most soft tissue sarcomas are characterized by genetic instability and frequent genomic copy number aberrations that are not subtype-specific. Oligonucleotide microarray-based Comparative Genomic Hybridisation (array CGH) is an important technique used to map genome-wide copy number aberrations, but the traditional requirement for high-quality DNA typically obtained from fresh tissue has limited its use in sarcomas. Although large archives of Formalin-fixed Paraffin-embedded (FFPE) tumour samples are available for research, the degradative effects of formalin on DNA from these tissues has made labelling and analysis by array CGH technically challenging. The Universal Linkage System (ULS) may be used for a one-step chemical labelling of such degraded DNA. We have optimised the ULS labelling protocol to perform aCGH on archived FFPE leiomyosarcoma tissues using the 180k Agilent platform. Preservation age of samples ranged from a few months to seventeen years and the DNA showed a wide range of degradation (when visualised on agarose gels). Consistently high DNA labelling efficiency and low microarray probe-to-probe variation (as measured by the derivative log ratio spread) was seen. Comparison of paired fresh and FFPE samples from identical tumours showed good correlation of CNAs detected. Furthermore, the ability to macro-dissect FFPE samples permitted the detection of CNAs that were masked in fresh tissue. Aberrations were visually confirmed using Fluorescence in situ Hybridisation. These results suggest that archival FFPE tissue, with its relative abundance and attendant clinical data may be used for effective mapping for genomic copy number aberrations in such rare tumours as leiomyosarcoma and potentially unravel clues to tumour origins, progression and ultimately, targeted treatment

Analysis and modeling of GaAs MESFET's for linear integrated circuit design

A complete Gallium Arsenide Metal Semiconconductor Field Effect Transistor (GaAs MESFET) model including deep-level trap effects has been developed, which is far more accurate than previous equivalent circuit models, for high-speed applications in linear integrated circuit design. A new self-backgating GaAs MESFET model, which can simulate low frequency anomalies, is presented by including deep-level trap effects which cause transconductance reduction and the output conductance and the saturation drain current to increase with the applied signal frequency. This model has been incorporated into PSPICE and includes a time dependent I-V curve model, a capacitance model, a subthreshold current model, an RC network describing the effective substrate-induced capacitance and resistance, and a switching resistance providing device symmetry. An analytical approach is used to derive capacitances which depend on Vgs and Vds and is one which also includes the channel/substrate junction modulation by the self backgating effect. A subthreshold current model is analytically derived by the mobile charge density from the parabolic potential distribution in the cut-off region. Sparameter errors between previous models and measured data in conventional GaAs MESFET's have been reduced by including a transit time delay in the transconductances, gm and gds, by the second order Bessel polynomial approximation. As a convenient extraction method, a new circuit configuration is also proposed for extracting simulated S-parameters which accurately predict measured data. Also, a large-signal GaAs MESFET model for performing nonlinear microwave circuit simulations is described. As a linear IC design vehicle for demonstrating the utility of the model, a 3-stage GaAs operational amplifier has been designed and also has been fabricated with results of a 35 dB open-loop gain at high frequencies and a 4 GHz gain bandwidth product by a conventional half micron MESFET technology. Using this new model, the low frequency anomalies of the GaAs amplifier such as a gain roll-off, a phase notch, and an output current lag are more accurately predicted than with any other previous model. This new self-backgating GaAs MESFET model, which provides accurate voltage dependent capacitances, frequency dependent output conductance, and transit time delay dependent transconductances, can be used to simulate low frequency effects in GaAs linear integrated circuit design

Developmental regulation of MURF E3 ubiquitin ligases in skeletal muscle

The striated muscle-specific tripartite motif (TRIM) proteins TRIM63/MURF1, TRIM55/MURF2 and TRIM54/MURF3 can function as E3 ubiquitin ligases in ubiquitin-mediated muscle protein turnover. Despite the well-characterised role of MURF1 in skeletal muscle atrophy, the dynamics of MURF isogene expression in the development and early postnatal adaptation of skeletal muscle is unknown. Here, we show that MURF2 is the isogene most highly expressed in embryonic skeletal muscle at E15.5, with the 50 kDa A isoform predominantly expressed. MURF1 and MURF3 are upregulated only postnatally. Knockdown of MURF2 p50A by isoform-specific siRNA results in delayed myogenic differentiation and myotube formation in vitro, with perturbation of the stable, glutamylated microtubule population. This underscores that MURF2 plays an important role in the earliest stages of skeletal muscle differentiation and myofibrillogenesis. During further development, there is a shift towards the 60 kDa A isoform, which dominates postnatally. Analysis of the fibre-type expression shows that MURF2 A isoforms are predominantly slow-fibre associated, whilst MURF1 is largely excluded from these fibres, and MURF3 is ubiquitously distributed in both type I and II fibres.</p

Integrated genomic analyses of ovarian carcinoma

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.National Institutes of Health (U.S.) (Grant U54HG003067)National Institutes of Health (U.S.) (Grant U54HG003273)National Institutes of Health (U.S.) (Grant U54HG003079)National Institutes of Health (U.S.) (Grant U24CA126543)National Institutes of Health (U.S.) (Grant U24CA126544)National Institutes of Health (U.S.) (Grant U24CA126546)National Institutes of Health (U.S.) (Grant U24CA126551)National Institutes of Health (U.S.) (Grant U24CA126554)National Institutes of Health (U.S.) (Grant U24CA126561)National Institutes of Health (U.S.) (Grant U24CA126563)National Institutes of Health (U.S.) (Grant U24CA143882)National Institutes of Health (U.S.) (Grant U24CA143731)National Institutes of Health (U.S.) (Grant U24CA143835)National Institutes of Health (U.S.) (Grant U24CA143845)National Institutes of Health (U.S.) (Grant U24CA143858)National Institutes of Health (U.S.) (Grant U24CA144025)National Institutes of Health (U.S.) (Grant U24CA143866)National Institutes of Health (U.S.) (Grant U24CA143867)National Institutes of Health (U.S.) (Grant U24CA143848)National Institutes of Health (U.S.) (Grant U24CA143843)National Institutes of Health (U.S.) (Grant R21CA135877

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4(−/−) and Dchs1(−/−) mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae