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This paper reflects on our mapping and database project britishmonumentsrelatedtoslavery.net, the first and currently most complete account of British representational public monuments related to British transatlantic slavery. It reproduces our headline findings and presents some new maps of the data. However, our main focus in this paper is on placing our project in a wider context of emergent practices and methods that inspired us. First, we note the exponential historical emergence of three connected critical, grassroots ‘counter’ practices across different institutions: of mapping, curating, and ethnography. We frame their critical commonality in their ‘counter’ approach to the nexus of what Benedict Anderson identified as three key ‘institutions of power … census, map, museum’, which have been central to conceiving and executing policy. Second, we prospectively identify some of the common structural causes that underlie this emergent assembly of instituent knowledge‐making practices from below. [ABSTRACT FROM AUTHOR]

This article is a product of the first complete survey of British public representational monuments in the U.K. related to transatlantic slavery, available online at . Identifying over 900 monuments, it brings this survey to bear on current public and policy debates about such monuments' history, significance and meaning vis-à-vis slavery, art and heritage. Examining the monuments at scale, we identify the monuments' patterns of production and provide data-led answers to specific questions such as what Britain's most significant monumental legacies of slavery are; how enslaved people appear in British public monuments; and how this data might support rethinking these monuments. [ABSTRACT FROM AUTHOR]

A study of the free surface flow on an ogee-crested fish bypass is presented. The commercial computational fluid dynamics (CFD) code Fluent 6.1 was used to perform the simulations. Structured/unstructured hybrid grids were used to accommodate the complex geometry that included gate slots, flow control gates, and an aeration slot. The volume of fluid (VOF) approach was used to model the water/air interface. The fish bypass exhibits complex free surface features including free nappes and air entrainment from the air slots. Free surface elevations on both sides of the nappe, pressure along the ogee surface, and discharge rating curves were compared against 1:24 experimental data from the laboratory model for different headwater elevations and gate settings. Limited comparison against measured velocities was also performed. Once deemed reliable through validation against experimental data, the computational model was used to analyze the flow field, supplementing the areas of limited experimental data. Though the paper presents the final fish bypass design, CFD was used to guide the design process and provide insight for several variations in the geometry. DOI: 10.1061/(ASCE)0733-9429(2008)134:8(1172) CE Database subject headings: Free surface; Fluid dynamics; Hydraulics; Spillways; Fish management.

This paper presents research on creating interactive prototypes for visualizing temporal spatial relationships in fictional literary texts. Developed within the context of the Chronotopic Cartographies project, a practice-led inquiry yielded dynamic visualizations from literary texts, the research explores the development and application of interactive three-dimensional environments illustrating the 'chronotopic', time-space relationships across a series of fictional literary texts. Expert feedback highlights the potential of the interaction model as a useful visual paradigm for supporting methods of reflective inquiry hypothesis making. The work also represents a potential model for creating interactive temporal visualizations which support hypothesis making across a broader sphere of the humanities. [ABSTRACT FROM AUTHOR]

This short methods paper emerges out of the AHRC-funded 'Chronotopic Cartographies' project for the digital mapping of place and space as represented in works of literature. The primary aim of that project was to find a way of mapping and visualizing represented literary worlds for which there is no corresponding real 'ground'. A solution was found in the form of topological graphs which allow for relative rather than absolute mapping (but also permit a relative imaginary map to be lain on top of a pre-existing cartesian form). Using a spatial schema to chunk out the text in terms of chronotopic (time-space) zones enables the generation of a series of visualizations that show different kinds of spatio-temporal constructions in texts. The visualizations are centred upon nodes that consist of chronotopes (e.g. 'the road') as well as locations (e.g. 'road to Geneva'); connections between them of different kinds and toporefs within them (references to other places from this one). The paper will articulate core methods from the project, outlining the stages involved in the process, from marking up the text, using a custom-made schema, through graph generation and into the implications for analysis. This will be illustrated in relation to two Victorian texts: the realist space of Dickens's Oliver Twist ; and the abstract poetic space of Browning's 'Childe Roland to the Dark Tower Came'. [ABSTRACT FROM AUTHOR]

Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(l)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(l) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(l). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets. [ABSTRACT FROM AUTHOR]

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells. [ABSTRACT FROM AUTHOR]

Zircon textures, chemistry and microstructures have been characterized in situ within Carboniferous sandstones from the Midland Valley of Scotland using back-scattered electron and cathodoluminescence images, electron backscatter diffraction techniques and chemical analyses. The study of polished thin sections reveals a variety of zircon types including unmodified detrital zircon, zircon outgrowths and different forms of modified zircon that formed in low-temperature conditions within the sedimentary rocks. These rocks have only experienced temperatures of <100 °C during burial; however, altered zircon is abundant and characterized by a low mean atomic number, with relatively high contents of non-formula elements and a nano-crystalline or microcrystalline structure. It forms by replacement of detrital zircon that subsequently became metamict. Two types of replacement mechanisms are effective in sedimentary environments and involve either dissolution–reprecipitation or solid-state reaction, but both require fluid access to the radiation-damaged areas. The former process appears to become the dominant replacement mechanism as temperature increases and produces highly porous, inclusion-rich zircon. Metamict zircon is extremely reactive in near-surface conditions and the production of low-temperature zircon is sensitive to both parent zircon characteristics and environmental conditions. As such, the alteration of zircon has the potential to yield unique information on the diagenetic history of sedimentary rocks. Low-temperature zircon would be unlikely to survive sedimentary transport or the rock crushing procedures that characterize many investigations of detrital zircon populations and consequently may generate severe biases in studies of this type. [ABSTRACT FROM AUTHOR]

Silicone wristbands present a noninvasive exposure assessment tool and an alternative to traditional biomonitoring; however, questions about their utility remain as validation studies are limited. We sought to determine if wristbands provide quantitative estimates of internal organophosphate ester (OPE) exposure. We evaluated internal dose by measuring metabolite masses excreted in 24-hour urine samples collected over five days among ten adults. We compared internal dose to OPE concentrations in paired wristbands worn during collection and, as a comparison, evaluated metabolite levels in spot urine samples. Three of six OPE metabolites evaluated were detected in >98% of urine samples, and 24 of 34 assessed OPEs were detected in at least one wristband. OPE uptake in wristbands was linear over time (range=0.54-61.8 ng/g/day). OPE concentrations in spot urine and wristbands were not correlated with total diphenyl phosphate (DPHP) excreted in urine, which may be due to the range of possible DPHP parent compounds or dietary exposure. However, for tris-(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris-(2-chloroisopropyl)phosphate (TCIPP), wristbands and spot urine samples were both moderately to strongly correlated with internal dose (all r s >0.56 and p<0.1), suggesting both perform well as integrated exposure estimates. Given the potential advantages of silicone wristbands, further studies investigating additional compounds are warranted.

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers., (©2015 American Association for Cancer Research.)

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) "reader" domains are part of the write-read-erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein-protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized.

Comparing the reactivity of the related lithium zincates [(THF)LiZn(TMP)(t)Bu(2)] (1) and [(PMDETA)LiZn(t)Bu(3)] (2) towards pyrazine discloses two new bimetallic approaches for the selective 2,5-dideprotonation and room temperature C-H alkylation of this sensitive heterocycle., (This journal is © The Royal Society of Chemistry 2012)