The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma

The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel–/– mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel–/– Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel–/– Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel–/– TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel–/– mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-κB signalling in cancer

Density functional study of Aun_n (n=2-20) clusters: lowest-energy structures and electronic properties

We have investigated the lowest-energy structures and electronic properties of the Au$_n$(n=2-20) clusters based on density functional theory (DFT) with local density approximation. The small Au$_n$ clusters adopt planar structures up to n=6. Tabular cage structures are preferred in the range of n=10-14 and a structural transition from tabular cage-like structure to compact near-spherical structure is found around n=15. The most stable configurations obtained for Au$_{13}$ and Au$_{19}$ clusters are amorphous instead of icosahedral or fcc-like, while the electronic density of states sensitively depend on the cluster geometry. Dramatic odd-even alternative behaviors are obtained in the relative stability, HOMO-LUMO gaps and ionization potentials of gold clusters. The size evolution of electronic properties is discussed and the theoretical ionization potentials of Au$_n$ clusters compare well with experiments.Comment: 6 pages, 7 figure

Factor Varieties

The universal algebraic literature is rife with generalisations of discriminator varieties, whereby several investigators have tried to preserve in more general settings as much as possible of their structure theory. Here, we modify the definition of discriminator algebra by having the switching function project onto its third coordinate in case the ordered pair of its first two coordinates belongs to a designated relation (not necessarily the diagonal relation). We call these algebras factor algebras and the varieties they generate factor varieties. Among other things, we provide an equational description of these varieties and match equational conditions involving the factor term with properties of the associated factor relation. Factor varieties include, apart from discriminator varieties, several varieties of algebras from quantum and fuzzy logics

Molecular Mechanisms of Membrane Deformation by I-BAR Domain Proteins

SummaryBackgroundGeneration of membrane curvature is critical for the formation of plasma membrane protrusions and invaginations and for shaping intracellular organelles. Among the central regulators of membrane dynamics are the BAR superfamily domains, which deform membranes into tubular structures. In contrast to the relatively well characterized BAR and F-BAR domains that promote the formation of plasma membrane invaginations, I-BAR domains induce plasma membrane protrusions through a poorly understood mechanism.ResultsWe show that I-BAR domains induce strong PI(4,5)P2 clustering upon membrane binding, bend the membrane through electrostatic interactions, and remain dynamically associated with the inner leaflet of membrane tubules. Thus, I-BAR domains induce the formation of dynamic membrane protrusions to the opposite direction than do BAR and F-BAR domains. Strikingly, comparison of different I-BAR domains revealed that they deform PI(4,5)P2-rich membranes through distinct mechanisms. IRSp53 and IRTKS I-BARs bind membranes mainly through electrostatic interactions, whereas MIM and ABBA I-BARs additionally insert an amphipathic helix into the membrane bilayer, resulting in larger tubule diameter in vitro and more efficient filopodia formation in vivo. Furthermore, FRAP analysis revealed that whereas the mammalian I-BAR domains display dynamic association with filopodia, the C. elegans I-BAR domain forms relatively stable structures inside the plasma membrane protrusions.ConclusionsThese data define I-BAR domain as a functional member of the BAR domain superfamily and unravel the mechanisms by which I-BAR domains deform membranes to induce filopodia in cells. Furthermore, our work reveals unexpected divergence in the mechanisms by which evolutionarily distinct groups of I-BAR domains interact with PI(4,5)P2-rich membranes

Isotope effect in impure high T_c superconductors

The influence of various kinds of impurities on the isotope shift exponent \alpha of high temperature superconductors has been studied. In these materials the dopant impurities, like Sr in La_{2-x}Sr_xCuO_4, play different role and usually occupy different sites than impurities like Zn, Fe, Ni {\it etc} intentionally introduced into the system to study its superconducting properties. In the paper the in-plane and out-of-plane impurities present in layered superconductors have been considered. They differently affect the superconducting transition temperature T_c. The relative change of isotope shift coefficient, however, is an universal function of T_c/T_{c0} (T_{c0} reffers to impurity free system) {\it i.e.} for angle independent scattering rate and density of states function it does not depend whether the change of T_c is due to in- or out-of-plane impurities. The role of the anisotropic impurity scattering in changing oxygen isotope coefficient of superconductors with various symmetries of the order parameter is elucidated. The comparison of the calculated and experimental dependence of \alpha/\alpha_0, where \alpha_0 is the clean system isotope shift coefficient, on T_c/T_{c0} is presented for a number of cases studied. The changes of \alpha calculated within stripe model of superconductivity in copper oxides resonably well describe the data on La_{1.8}Sr_{0.2}Cu_{1-x}(Fe,Ni)_xO_4, without any fitting parameters.Comment: 8 pages, 6 figures, Phys. Rev. B67 (2003) accepte

Variational approach to a class of nonlinear oscillators with several limit cycles

We study limit cycles of nonlinear oscillators described by the equation $\ddot x + \nu F(\dot x) + x =0$. Depending on the nonlinearity this equation may exhibit different number of limit cycles. We show that limit cycles correspond to relative extrema of a certain functional. Analytical results in the limits $\nu ->0$ and $\nu -> \infty$ are in agreement with previously known criteria. For intermediate $\nu$ numerical determination of the limit cycles can be obtained.Comment: 12 pages, 3 figure