Activity-based scenarios for and approaches to ubiquitous e-Learning

This paper presents scenarios for ubiquitous e-Learning in heterogeneous networks. It concludes by arguing for the development of a learning-focused analogue, activity-based e-Learning extensions (ABLE), of activity-based computing (ABC). The goal would be to offer the learning-support/performance-support equivalent of ABC’s support for human activities in a ubiquitous computing environment, relevant to areas that are hard to model today: informal on-the-job learning; peer-to-peer support and informal sharing of content in ad hoc work groups; formal and informal ways to capture and share knowledge-focused insights and processes; content and systems to aid reflection. Just as ABC supplements traditional computing approaches (in ABC, data- and application-oriented) to suit ‘multiple, parallel and mobile work activities’ (Bardram et al. in Support for ABC in a personal computing operating system. CHI 2006 proceedings. Montréal, Québec, Canada, 22–27 April 2006, pp 211–220), so ABLE could supplement traditional e-learning approaches (often largely content-focused, sometimes little more than page-turning) to suit those same work activities, and make e-Learning potentially more resilient to interruptions, more fun and more memorable

Natural product-inspired pyranonaphthoquinone inhibitors of indoleamine 2,3-dioxygenase-1 (IDO-1)

A series of pyranonaphthoquinone derivatives possessing structural features present in both natural products annulin B and exiguamine A have been shown to exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. One particular analogue, triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. These results have extended the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature.10 page(s

Formation of an N-formylkynurenine-derived fluorophore and its use for measuring indoleamine 2,3-dioxygenase 1 activity

Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme whose expression by a broad range of clinical tumors is associated with immunosuppression and poor patient outcome. Here we describe a new fluorescence assay for measuring IDO1 activity suitable for high-throughput screening of compound libraries for novel IDO1 inhibitors. This assay is easy to perform, requiring the addition of only one reagent prior to readout. In place of measuring kynurenine, it uses the in situ formation of an N-formylkynurenine- derived fluorophore (NFKPIP) measured at an excitation wavelength of 400 nm and an emission wavelength of 500 nm. The fluorescence intensity of the NFKPIP formed is directly related to the amount of enzyme activity, and the signal is stable over 8 h. This assay has a lower limit of detection, equating to 153 nM N-formylkynurenine, which is over 30-fold lower than the limits of detection of existing assays for IDO1 activity. When we compared the performance of the new assay with that of the published colorimetric absorbance assay in screening the National Cancer Institute Diversity Set III of 1,597 compounds for IDO1 inhibitors, we obtained an identical list of the 25 most active compounds in the two assays. Although 93 compounds (aldehydes, ketones, and aromatic amines) in the library interfered with the absorbance readout, only 18 compounds (conjugated systems and fused cycles) interfered with the readout of the new fluorescence assay. IC50 values determined using the new assay for three known IDO1 inhibitors - 1,4-naphthoquinone, 4-amino-N-(3-chloro-4- fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide and 4-phenyl-1H-imidazole - were consistent with their literature values, further validating the new assay for measuring IDO1 activity.10 page(s

Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC₅₀ = 0.25 ± 0.07 μM) to be 32-fold more potent than 2-hydrazinobenzothiazole (IC₅₀ = 8.0 ± 2.3 μM) in inhibiting rhIDO1 and that it inhibited cellular IDO1 at concentrations that were noncytotoxic to cells. Here, phenylhydrazine is shown to inhibit IDO1 through binding to haem.9 page(s