Previous work has shown that aspects of the evolution of large-scale structures, particularly in forced and transitional mixing layers and jets, can be described by linear and nonlinear stability theories. However, questions persist as to the choice of the basic (steady) flow field to perturb, and the extent to which disturbances in natural (unforced), initially turbulent jets may be modelled with the theory. For unforced jets, identification is made difficult by the lack of a phase reference that would permit a portion of the signal associated with the instability wave to be isolated from other, uncorrelated fluctuations. In this paper, we investigate the extent to which pressure and velocity fluctuations in subsonic, turbulent round jets can be described as linear perturbations to the mean flow field. The disturbances are expanded about the experimentally measured jet mean flow field, and evolved using linear parabolized stability equations (PSE) that account, in an approximate way, for the weakly nonparallel jet mean flow field. We utilize data from an extensive microphone array that measures pressure fluctuations just outside the jet shear layer to show that, up to an unknown initial disturbance spectrum, the phase, wavelength, and amplitude envelope of convecting wavepackets agree well with PSE solutions at frequencies and azimuthal wavenumbers that can be accurately measured with the array. We next apply the proper orthogonal decomposition to near-field velocity fluctuations measured with particle image velocimetry, and show that the structure of the most energetic modes is also similar to eigenfunctions from the linear theory. Importantly, the amplitudes of the modes inferred from the velocity fluctuations are in reasonable agreement with those identified from the microphone array. The results therefore suggest that, to predict, with reasonable accuracy, the evolution of the largest-scale structures that comprise the most energetic portion of the turbulent spectrum of natural jets, nonlinear effects need only be indirectly accounted for by considering perturbations to the mean turbulent flow field, while neglecting any non-zero frequency disturbance interactions.

T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110δ, and class IB, p110γ catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110δ, but not p110γ. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G protein–coupled receptor signaling in β-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of β-selection and demonstrated a requirement for CXCR4 during thymic development in CXCR4-deficient embryos. Finally, we demonstrate that CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 thymocytes in the absence of supporting stromal cells. These findings establish a role for CXCR4-mediated PI3K signaling that, together with signals from Notch and the preTCR, contributes to continued T cell development beyond β-selection.

We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.