Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Bound-to-bound and bound-to-continuum optical transitions in combined quantum dot - superlattice systems

By combining band gap engineering with the self-organized growth of quantum dots, we present a scheme of adjusting the mid-infrared absorption properties to desired energy transitions in quantum dot based photodetectors. Embedding the self organized InAs quantum dots into an AlAs/GaAs superlattice enables us to tune the optical transition energy by changing the superlattice period as well as by changing the growth conditions of the dots. Using a one band envelope function framework we are able, in a fully three dimensional calculation, to predict the photocurrent spectra of these devices as well as their polarization properties. The calculations further predict a strong impact of the dots on the superlattices minibands. The impact of vertical dot alignment or misalignment on the absorption properties of this dot/superlattice structure is investigated. The observed photocurrent spectra of vertically coupled quantum dot stacks show very good agreement with the calculations.In these experiments, vertically coupled quantum dot stacks show the best performance in the desired photodetector application.Comment: 8 pages, 10 figures, submitted to PR

Phosphorylation/dephosphorylation of the beta-adrenergic receptor regulates its functional coupling to adenylate cyclase and subcellular distribution.

Prolonged exposure of cells or tissues to drugs or hormones such as catecholamines leads to a state of refractoriness to further stimulation by that agent, known as homologous desensitization. In the case of the beta-adrenergic receptor coupled to adenylate cyclase, this process has been shown to be intimately associated with the sequestration of the receptors from the cell surface through a cAMP-independent process. Recently, we have shown that homologous desensitization in the frog erythrocyte model system is also associated with increased phosphorylation of the beta-adrenergic receptor. We now provide evidence that the phosphorylation state of the beta-adrenergic receptor regulates its functional coupling to adenylate cyclase, subcellular translocation, and recycling to the cell surface during the process of agonist-induced homologous desensitization. Moreover, we show that the receptor phosphorylation is reversed by a phosphatase specifically associated with the sequestered subcellular compartment. At 23 degrees C, the time courses of beta-adrenergic receptor phosphorylation, sequestration, and adenylate cyclase desensitization are identical, occurring without a lag, exhibiting a t1/2 of 30 min, and reaching a maximum at approximately 3 hr. Upon cell lysis, the sequestered beta-adrenergic receptors can be partially recovered in a light membrane vesicle fraction that is separable from the plasma membranes by differential centrifugation. The increased beta-adrenergic receptor phosphorylation is apparently reversed in the sequestered vesicle fraction as the sequestered receptors exhibit a phosphate/receptor stoichiometry that is similar to that observed under basal conditions. High levels of a beta-adrenergic receptor phosphatase activity appear to be associated with the sequestered vesicle membranes. The functional activity of the phosphorylated beta-adrenergic receptor was examined by reconstituting purified receptor with its biochemical effector the guanine nucleotide regulatory protein (Ns) in phospholipid vesicles and assessing the receptor-stimulated GTPase activity of Ns. Compared to controls, phosphorylated beta-adrenergic receptors, purified from desensitized cells, were less efficacious in activating the Ns GTPase activity. These results suggest that phosphorylation of the beta-adrenergic receptor leads to its functional uncoupling and physical translocation away from the cell surface into a sequestered membrane domain. In the sequestered compartment, the phosphorylation is reversed thus enabling the receptor to recycle back to the cell surface and recouple with adenylate cyclase

Historical-institutionalist perspectives on the development of the EU budget system

The EU budget has only recently started to feature in theories of European integration. Studies typically adopt a historical-institutionalist framework, exploring notions such as path dependency. They have, however, generally been rather aggregated, or coarse-grained, in their approach. The EU budget has thus been treated as a single entity rather than a series of inter-linked institutions. This paper seeks to address these lacunae by adopting a fine-grained approach. This enables us to emphasize the connections that exist between EU budgetary institutions, in both time and space. We show that the initial set of budgetary institutions was unable, over time, to achieve consistently their treaty-based objectives. In response, rather than reform these institutions at potentially high political cost, additional institutions were layered on top of the extant structures. We thus demonstrate how some EU budgetary institutions have remained unchanged, whilst others have been added or changed over time

Valence band photoemission from the GaN(0001) surface

A detailed investigation by one-step photoemission calculations of the GaN(0001)-(1x1) surface in comparison with recent experiments is presented in order to clarify its structural properties and electronic structure. The discussion of normal and off-normal spectra reveals through the identified surface states clear fingerprints for the applicability of a surface model proposed by Smith et al. Especially the predicted metallic bonds are confirmed. In the context of direct transitions the calculated spectra allow to determine the valence band width and to argue in favor of one of two theoretical bulk band structures. Furthermore a commonly used experimental method to fix the valence band maximum is critically tested.Comment: 8 pages, 11 eps files, submitted to PR

A search for deeply bound kaonic nuclear states

We have measured proton and neutron energy spectra by stopping negative kaons on liquid helium4. Two distinct peak structures were found on both spectra, which were assigned to the formation of new kinds of strange stribaryons. In this paper, we summarize both results.Comment: 7 pages, 3 figures, HYP2003 conference proceeding

New Algorithm for Mixmaster Dynamics

We present a new numerical algorithm for evolving the Mixmaster spacetimes. By using symplectic integration techniques to take advantage of the exact Taub solution for the scattering between asymptotic Kasner regimes, we evolve these spacetimes with higher accuracy using much larger time steps than previously possible. The longer Mixmaster evolution thus allowed enables detailed comparison with the Belinskii, Khalatnikov, Lifshitz (BKL) approximate Mixmaster dynamics. In particular, we show that errors between the BKL prediction and the measured parameters early in the simulation can be eliminated by relaxing the BKL assumptions to yield an improved map. The improved map has different predictions for vacuum Bianchi Type IX and magnetic Bianchi Type VI$_0$ Mixmaster models which are clearly matched in the simulation.Comment: 12 pages, Revtex, 4 eps figure