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Lessons learnt from assembling screening libraries for drug discovery for neglected diseases
No full textTo enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 252 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1697 compounds for a focused kinase set. Compiling these libraries required a robust strategy for compound selection. Rules for unwanted groups were defined and selection criteria to enrich for lead-like compounds which facilitate straightforward structure-activity relationship exploration were established. Further, a literature and patent review was undertaken to extract key recognition elements of kinase inhibitors ("core fragments") to assemble a focused library for hit discovery for kinases. Computational and experimental characterisation of the general screening library revealed that the selected compounds 1) span a broad range of lead-like space, 2) show a high degree of structural integrity and purity, and 3) demonstrate appropriate solubility for the purposes of biochemical screening. The implications of this study for compound selection, especially in an academic environment with limited resources, are considered.</p
Three-dimensional null point reconnection regimes
No full textRecent advances in theory and computational experiments have shown the need to refine the previous categorization of magnetic reconnection at three-dimensional null points-points at which the magnetic field vanishes. We propose here a division into three different types, depending on the nature of the flow near the spine and fan of the null. The spine is an isolated field line which approaches the null (or recedes from it), while the fan is a surface of field lines which recede from it (or approach it). So-called torsional spine reconnection occurs when field lines in the vicinity of the fan rotate, with current becoming concentrated along the spine so that nearby field lines undergo rotational slippage. In torsional fan reconnection field lines near the spine rotate and create a current that is concentrated in the fan with a rotational flux mismatch and rotational slippage. In both of these regimes, the spine and fan are perpendicular and there is no flux transfer across spine or fan. The third regime, called spine-fan reconnection, is the most common in practice and combines elements of the previous spine and fan models. In this case, in response to a generic shearing motion, the null point collapses to form a current sheet that is focused at the null itself, in a sheet that locally spans both the spine and fan. In this regime the spine and fan are no longer perpendicular and there is flux transfer across both of them.</p
'The aerodrome':art, heritage and landscape at former RAF Coltishall
No full textEnglish Heritage and others are often called upon to record historic aviation sites, along with a range of other comparable (in scale and complexity) former military and industrial places. Recording typically takes place once the site is abandoned and prior to its redevelopment. RAF Coltishall (Norfolk, UK) presented a rare opportunity to record the site while it remained in use, and to continue to record it during the period of drawdown and closure; to watch as things were packed away and as families left. This seemed too good an opportunity to miss, and to take full advantage English Heritage decided to share the task, gathering together a team of artists and archaeologists whose interests were focused on the types of material culture and methodological issues which Coltishall presented in abundance. In this article we describe the background to this project, the methodology we developed, and ultimately our various (and at times very different) responses to the site
An ultra-compact micro-valve for low pressure gas flow control
No full textWe describe the fabrication and performance characterisation of a ~0.1cm3 micro-valve, designed to regulate a compressed gas supply at pressures <1bar. The electro-active components were fabricated by ultra-precision grinding in combination with standard micro-fabrication techniques. The structural components were made from a photo-etchable glass-ceramic. Steady jets with velocities greater than 200m/s were measured using supply pressures = 60kPa and static actuation voltages = 40V. The gauge jet pressure ratio was linearly related to the static actuation voltage below 60kPa. The exceptional light weight of the valves and their simple construction could open up new possibilities for active aerodynamic flow-control systems, for medical diagnostics and for personalised healthcare systems, amongst other applications
Probing localized states distributions in semiconductors by Laplace transform transient photocurrent spectroscopy
No full textWe report on the effectiveness of two methods for recovering the density of electronic states from transient photocurrent data, one employing an exact solution of the Laplace transformed multiple-trapping rate equations and one a Tikhonov regularization technique. In order to evaluate these methods for recovery of energetically broad and narrower distributions of states we have applied each to data obtained from plasma-enhanced chemical vapor deposition (PECVD) a-Si:H films subjected to progressive light soaking and also to a single crystal sample of tin-doped crystalline CdTe. Both methods are found to perform equally well in terms of accuracy and resolution but the exact method is more sensitive to noise on the input data. A featureless increase in defect density in the PECVD a-Si:H film of a factor of 5–10 is observed on light soaking. Preliminary analysis of the CdTe:Sn data indicates the presence of two narrow bands of states, approximately 0.15 and 0.36 eV below the conduction band edge
Particle manipulation in a microfluidic channel with an electronically controlled linear piezoelectric array
Full text linkUltrasonic standing wave manipulation has been proved to be a simple, robust technology to be integrated in microfluidic systems for a range of applications such as particle filtration and concentration, particle trapping and washing, and sensor enhancement. Here we report recent progress in the design, fabrication and experimental demonstration of an electronically controlled ultrasonic array device used for 1-D manipulation of particles along a microfluidic channel. In a previous paper [1], the particle manipulation feasibility has been demonstrated by a 12 element, 500 µm pitch array device. In this paper, an improved 30-element, 200 µm pitch array device made from PZ26 piezoelectric composite has been fabricated and connected to control electronics. The control system comprises a Xilinx Spartan 3a FPGA development board and bespoke analogue driving circuitry, designed for signal multiplexing for array element excitation. A rectangular capillary forming a half wavelength resonance microfluidic chamber was coupled to the array to make a multilayer planar resonator. Manipulation under electronic control was demonstrated with 10 µm fluorescent microspheres suspended in water
Devising the Plot:communicating designers thinking through storytelling
No full textThe way practice-centred design researchers use language to communicate their creative practice in an academic context is a problem. In current design research writing, the voice of the practitioner is lost because the relation between thinking and making is not adequately discussed and argued. This paper shares the results of a small qualitative study aiming to develop an approach to critical writing about designing that draws upon individual thinking practices (i.e. tools, techniques and methods for nurturing individual creativity). Discussion attends to the challenges facing the design researcher when communicating the rhetorical relation between personal, subjective experiences and objective communication of concepts, strategies and operational decisions in design thinking. In the study, storytelling is used as the means of developing a style of writing that bridges academic writing and visual research; creative thinking and research language; individual creativity and collective communication. As such, the paper asks if the method of storytelling is an effective, efficient and valuable method for communicating practice-centred research to a diverse audience. Through analysis of stories and evaluation of workshop discourses, the paper closes by articulating a series of recommendations for developing a strategy for practice-centred design researchers to communicate their thinking through writing to diverse audiences. <br/
Contemplating Moments
No full textMoment, is an art installation that asks you to pause for a moment to contemplate This article reflects on the process of the collaboration as well as Lithium! the conceptual and practical issues of the project. The work was realized within the framework of the European Mobile Lab for Interactive Artists (e-MobiLArt) and funded through the CULTURE 2007 Programme of the European Union</p
Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases:characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases
No full textWe have isolated the human genes encoding the Pyst1 (MKP-3) and Pyst2 (MKP-X) MAP kinase phosphatases. Both genes consist of three exons interrupted by two introns and lack an intron which is conserved in all the other members of this gene family characterised to date. This reinforces the conclusion that Pyst1 and Pyst2 are members of a distinct and structurally homologous subfamily of dual-specificity (Thr/Tyr) MAP kinase phosphatases. We find that Pyst2 mRNA is constitutively expressed in a wide variety of human cell lines including those derived from ovarian, bladder and breast cancers. While there is no evidence for inducible expression of Pyst2 mRNA in human skin fibroblasts in response to cellular stress, Pyst2 mRNA levels are moderately increased in response to serum stimulation. Pyst2 protein is predominantly cytosolic when expressed in COS-1 cells. In common with Pyst1, Pyst2 shows substrate selectivity for the classical p42 (ERK2) isoform of MAP kinase both in vitro and in vivo, displaying much reduced activity towards stress activated MAP kinase isoforms such as JNK-1 and p38/RK. Pyst2 binds p42 MAP kinase in vivo and both MAP kinase binding and substrate selectivity correlate with the ability of different recombinant MAP and SAP kinases to cause catalytic activation of the Pyst2 phosphatase in vitro
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