[Show abstract][Hide abstract] ABSTRACT: IDO is the rate-limiting enzyme in the kynurenine pathway, catabolizing tryptophan to kynurenine. Tryptophan depletion by IDO-expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells. Because mammalian cells cannot synthesize tryptophan, it remains unclear how IDO(+) tumor cells overcome the detrimental effects of local tryptophan depletion. We demonstrate that IDO(+) tumor cells express a novel amino acid transporter, which accounts for ∼50% of the tryptophan uptake. The induced transporter is biochemically distinguished from the constitutively expressed tryptophan transporter System L by increased resistance to inhibitors of System L, resistance to inhibition by high concentrations of most amino acids tested, and high substrate specificity for tryptophan. Under conditions of low extracellular tryptophan, expression of this novel transporter significantly increases tryptophan entry into IDO(+) tumors relative to tryptophan uptake through the low-affinity System L alone, and further decreases tryptophan levels in the microenvironment. Targeting this additional tryptophan transporter could be a way of pharmacological inhibition of IDO-mediated tumor escape. These findings highlight the ability of IDO-expressing tumor cells to thrive in a tryptophan-depleted microenvironment by expressing a novel, highly tryptophan-specific transporter, which is resistant to inhibition by most other amino acids. The additional transporter allows tumor cells to strike the ideal balance between supply of tryptophan essential for their own proliferation and survival, and depleting the extracellular milieu of tryptophan to inhibit T cell proliferation.
The Journal of Immunology 08/2011; 187(4):1617-25. · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aspergillus fumigatus is the causative agent of aspergillosis, a frequently invasive colonization of the lungs of immunocompromised patients. GNA1 (D-glucosamine-6-phosphate N-acetyltransferase) catalyses the acetylation of GlcN-6P (glucosamine-6-phosphate) to GlcNAc-6P (N-acetylglucosamine-6-phosphate), a key intermediate in the UDP-GlcNAc biosynthetic pathway. Gene disruption of gna1 in yeast and Candida albicans has provided genetic validation of the enzyme as a potential target. An understanding of potential active site differences between the human and A. fumigatus enzymes is required to enable further work aimed at identifying selective inhibitors for the fungal enzyme. In the present study, we describe crystal structures of both human and A. fumigatus GNA1, as well as their kinetic characterization. The structures show significant differences in the sugar-binding site with, in particular, several non-conservative substitutions near the phosphate-binding pocket. Mutagenesis targeting these differences revealed drastic effects on steady-state kinetics, suggesting that the differences could be exploitable with small-molecule inhibitors.
[Show abstract][Hide abstract] ABSTRACT: How does one's game character gain value in online multiplayer game? What are the elements that contribute to the overall virtual identity of a player? Throughout the history of Massively Multiplayer Online Games (MMOGs) game characters have remained central figures for all types of in-game interaction and value perception. Recently, MMOGs have evolved to a stage where at least parts of one's identity are for sale. In this paper, we apply a motivational framework to analyse the specific value structures of one's virtual identity. As a result, we indicate how achievement, social and immersive aspects of one's game character form the personal value that player bestows on the game character. Furthermore, we conclude how these aspects offer possibilities for new business implications on the future MMOGs.
[Show abstract][Hide abstract] ABSTRACT: A study on how role-play through narrative elements of social communication can be implemented in a computer-based environment.
Contemporary computer role-playing games do not support playing roles in a social aspect. Play is conducted in a functional
and task-oriented way due to the design of the gameplay. An experimental role-playing game, Castle of Oulu, 1651 was constructed to test aspects of social play and elements borrowed from more traditional forms of role-play. The aim is
to determine some essential elements the players need to assume a role and play towards socially structured goals.
Keywordsrole-play-narrative elements-computer game
[Show abstract][Hide abstract] ABSTRACT: This paper proposes and outlines a novel method for designing multiplayer computer role-playing games that revolve around
procedural interactive narratives, which are further developed by the participating players. The proposed Plot Cluster system
is evaluated practically during the design and construction of the experimental game Castle of Oulu 1651. The functionality and applicability of the approach is further validated with the empirical field experiment with 260 test
subjects. Plot clusters enable the game designers to create controlled but re-playable emergent storylines that intertwine
the participating players using multi-tier network structures.
Technologies for Interactive Digital Storytelling and Entertainment, Third International Conference, TIDSE 2006, Darmstadt, Germany, December 4-6, 2006.; 01/2006
[Show abstract][Hide abstract] ABSTRACT: Today's computer games offer players stunning audiovisual environments, intense action, adventures, puzzles and crowded worlds with vast amounts of other players to play with. Consequently, play experience is a combination of numerable variables. This study focuses on understanding how interaction manifestations of games participate in the process of experiencing multiplayer game environments. Rich Interaction Model  is used as a theoretical framework for analysing experiencing of interaction. Two experimental games are used in the analysis as examples. The results of this study are preliminary guidelines of how interaction manifestations affect experiencing games.