T lymphocytes encounter hypoxia when they migrate to pathological sites such as tumours and wounds. The inability of T cells to provide an efficient defence at these sites can in part be explained by the hypoxic environment. Kv1.3 channels, important components of the T cell activation process are inhibited by hypoxia and their inhibition accounts for a hypoxia-induced decrease in T cell proliferation. Although Kv1.3 channels play a key role in T cell O 2 sensing, the signalling mechanisms mediating their response to hypoxia are still not understood. In this study, we show that the src-protein tyrosine kinase p56Lck (Lck) is required for Kv1.3 channel response to hypoxia. Pre-exposure to the src inhibitor PP2 abolished the hypoxia-induced inhibition of Kv1.3 channels in primary human T lymphocytes. Moreover, Kv1.3 channel sensitivity to hypoxia was lost in Lck-deficient Jurkat T cells. Further studies with recombinant Kv1.3 channels showed that Kv1.3 channels lack intrinsic O 2 sensitivity, but delivery of Lck into the cells and transfection of a constitutively active Lck (Y505FLck) restored their sensitivity to hypoxia. Although Lck is necessary for the Kv1.3 channel response to hypoxia, it does not directly inhibit Kv1.3 channels. Indeed, under normal oxygen tension, delivery of active Lck into L929 cells and overexpression of Y505FLck did not decrease recombinant Kv1.3 currents. On the contrary, activation of endogenous src kinases increased wild-type Kv1.3 currents in T lymphocytes. Our findings indicate that Lck is required for the acute response to hypoxia of human T lymphocytes as it is necessary to confer O 2 sensitivity on Kv1.3 channels.

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Trim defines conditions for both design and analysis based on aircraft models. In fact, we often define these analysis points more broadly than the conditions normally associated with trim conditions to facilitate that analysis or design. In simulations, these analysis points establish initial conditions comparable to flight conditions. Based on aerodynamic and propulsion systems models of an aircraft, trim analysis can be used to provide the data needed to define the operating envelope or the performance characteristics. Linear models are typically derived at trim points. Control systems are designed and evaluated at points defined by trim conditions. And these trim conditions provide us a starting point for comparing one model against another, one implementation of a model against another implementation of the same model, and the model to flight-derived data. In this paper we define what we mean by trim, examine a variety of trim conditions that have proved useful and derive the equations defining those trim conditions. Finally we present a general approach to trim through constrained minimization of a cost function based on the nonlinear, six-degree-of freedom state equations coupled with the aerodynamic and propulsion system models. We provide an example of how a trim algorithm is used with a simulation by showing an example from JSBSim.

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