Suppression of steady-state, but not stimulus-induced NF-kappaB activity inhibits alphavirus-induced apoptosis.

Recent studies have established cell type- specific, proapoptotic, or antiapoptotic functions for the transcription factor NF-kappaB. In each of these studies, inhibitors of NF-kappaB activity have been present before the apoptotic stimulus, and so the role of stimulus- induced NF-kappaB activation in enhancing or inhibiting survival could not be directly assessed. Sindbis virus, an alphavirus, induces NF-kappaB activation and apoptosis in cultured cell lines. To address whether Sindbis virus- induced NF-kappaB activation is required for apoptosis, we used a chimeric Sindbis virus that expresses a superrepressor of NF-kappaB activity. Complete suppression of virus-induced NF-kappaB activity neither prevents nor potentiates Sindbis virus-induced apoptosis. In contrast, inhibition of NF-kappaB activity before infection inhibits Sindbis virus-induced apoptosis. Our results demonstrate that suppression of steady-state, but not stimulus-induced NF-kappaB activity, regulates expression of gene products required for Sindbis virus-induced death. Furthermore, we show that in the same cell line, NF-kappaB can be proapoptotic or antiapoptotic depending on the death stimulus. We propose that the role of NF-kappaB in regulating apoptosis is determined by the death stimulus and by the timing of modulating NF-kappaB activity relative to the death stimulus

Chiral phase transition at finite temperature and conformal dynamics in large Nf QCD

We investigate the chiral phase transition at finite temperature (T) in colour SU(Nc=3) Quantum Chromodynamics (QCD) with six species of fermions (Nf=6) in the fundamental representation by using lattice QCD with improved staggered fermions. By considering lattices with several temporal extensions Nt, we observe asymptotic scaling for Nt > 4. We then extract the dimensionless ratio Tc/Lambda_L (Lambda_L = Lattice Lambda-parameter) for Nf = 6 and Nf = 8, the latter relying on our earlier results. Further, we collect the critical couplings beta^c for the chiral phase transition at Nf = 0 (quenched), and Nf = 4 at a fixed Nt = 6. The results are consistent with enhanced fermionic screening at larger Nf. The Tc/Lambda_L depends very mildly on Nf in the Nf = 0 - 4 region, starts increasing at Nf = 6, and becomes significantly larger at Nf = 8, close to the edge of the conformal window. We discuss interpretations of these results as well as their possible interrelation with preconformal dynamics in the light of a functional renormalization group analysis.Comment: 8 pages, 9 figure

Regulation of NF-κB by PML and PML-RARα

Promyelocytic Leukemia (PML) is a nuclear protein that forms sub-nuclear structures termed nuclear bodies associated with transcriptionally active genomic regions. PML is a tumour suppressor and regulator of cell differentiation. We demonstrate that PML promotes TNFα-induced transcriptional responses by promoting NF-κB activity. TNFα-treated PML−/− cells show normal IκBα degradation and NF-κB nuclear translocation but significantly reduced NF-κB DNA binding and phosphorylation of NF-κB p65. We also demonstrate that the PML retinoic acid receptor-α (PML-RARα) oncofusion protein, which causes acute promyelocytic leukemia, inhibits TNFα induced gene expression and phosphorylation of NF-κB. This study establishes PML as an important regulator of NF-κB and demonstrates that PML-RARα dysregulates NF-κB

The Computer Misuse Act 1990: lessons from its past and predictions for its future

The age of the internet has thrown down some real challenges to the Computer Misuse Act 1990. Recently, the Government made changes to this piece of legislation, in an attempt to meet two of those challenges--the proliferation of “ Denial of Service” (DoS) attacks, and the creation and dissemination of “ Hackers' tools” --and to fulfil international commitments on cybercrime. Yet some of these new measures invite criticisms of policy, form and content, and bring doubts about how easy to interpret, and how enforceable, they will be

How the projection domains of NF-L and alpha-internexin determine the conformations of NF-M and NF-H in neurofilaments

Making use of a numerical self-consistent field method and polymer brush concepts, we model the solvated corona of neurofilaments (NF) composed of projection domains (unstructured tails) of constituent proteins. Projections are modeled with amino acid resolution. We focus on the importance of the two shortest ones (alpha-internexin and NF-L) in regulating the conformations of the two longer ones (NF-M and NF-H) in an isolated NF. We take the wild-type NF with no alpha-internexin as the reference, for which the phosphorylation-induced translocation of M- and H-tails has been examined previously. We demonstrate that a subbrush of L-tails creates an electrostatic potential profile with an approximately parabolic shape. An experimentally relevant (2:1) ratio of L- to alpha-projections reduces the charge density of the L subbrush and shifts the translocation transition of the H-tails to slightly higher degrees of phosphorylation. Replacing all L-tails by alpha-projections destroys the substructure of the NF corona and this alters the NF response to the phosphorylation of long tail

Oscillation dynamics underlie functional switching of NF-κB for B-cell activation.

Transcription factor nuclear factor kappa B (NF-κB) shows cooperative switch-like activation followed by prolonged oscillatory nuclear translocation in response to extracellular stimuli. These dynamics are important for activation of the NF-κB transcriptional machinery, however, NF-κB activity regulated by coordinated actions of these dynamics has not been elucidated at the system level. Using a variety of B cells with artificially rewired NF-κB signaling networks, we show that oscillations and switch-like activation of NF-κB can be dissected and that, under some conditions, these two behaviors are separated upon antigen receptor activation. Comprehensive quantitative experiments and mathematical analysis showed that the functional role of switch activation in the NF-κB system is to overcome transient IKK (IκB kinase) activity to amplify nuclear translocation of NF-κB, thereby inducing the prolonged NF-κB oscillatory behavior necessary for target gene expression and B-cell activation

Correlation between amygdala BOLD activity and frontal EEG asymmetry during real-time fMRI neurofeedback training in patients with depression

Real-time fMRI neurofeedback (rtfMRI-nf) is an emerging approach for studies and novel treatments of major depressive disorder (MDD). EEG performed simultaneously with an rtfMRI-nf procedure allows an independent evaluation of rtfMRI-nf brain modulation effects. Frontal EEG asymmetry in the alpha band is a widely used measure of emotion and motivation that shows profound changes in depression. However, it has never been directly related to simultaneously acquired fMRI data. We report the first study investigating electrophysiological correlates of the rtfMRI-nf procedure, by combining rtfMRI-nf with simultaneous and passive EEG recordings. In this pilot study, MDD patients in the experimental group (n=13) learned to upregulate BOLD activity of the left amygdala using an rtfMRI-nf during a happy emotion induction task. MDD patients in the control group (n=11) were provided with a sham rtfMRI-nf. Correlations between frontal EEG asymmetry in the upper alpha band and BOLD activity across the brain were examined. Average individual changes in frontal EEG asymmetry during the rtfMRI-nf task for the experimental group showed a significant positive correlation with the MDD patients' depression severity ratings, consistent with an inverse correlation between the depression severity and frontal EEG asymmetry at rest. Temporal correlations between frontal EEG asymmetry and BOLD activity were significantly enhanced, during the rtfMRI-nf task, for the amygdala and many regions associated with emotion regulation. Our findings demonstrate an important link between amygdala BOLD activity and frontal EEG asymmetry. Our EEG asymmetry results suggest that the rtfMRI-nf training targeting the amygdala is beneficial to MDD patients, and that alpha-asymmetry EEG-nf would be compatible with the amygdala rtfMRI-nf. Combination of the two could enhance emotion regulation training and benefit MDD patients.Comment: 28 pages, 16 figures, to appear in NeuroImage: Clinica

The laminA/NF-Y protein complex reveals an unknown transcriptional mechanism on cell proliferation

Lamin A is a component of the nuclear matrix that also controls proliferation by largely unknown mechanisms. NF-Y is a ubiquitous protein involved in cell proliferation composed of three subunits (-YA -YB -YC) all required for the DNA binding and transactivation activity. To get clues on new NF-Y partner(s) we performed a mass spectrometry screening of proteins that co-precipitate with the regulatory subunit of the complex, NF-YA. By this screening we identified lamin A as a novel putative NF-Y interactor. Co-immunoprecipitation experiments and confocal analysis confirmed the interaction between the two endogenous proteins. Interestingly, this association occurs on euchromatin regions, too. ChIP experiments demonstrate lamin A enrichment in several promoter regions of cell cycle related genes in a NF-Y dependent manner. Gain and loss of function experiments reveal that lamin A counteracts NF-Y transcriptional activity. Taking advantage of a recently generated transgenic reporter mouse, called MITO-Luc, in which an NF-Y–dependent promoter controls luciferase expression, we demonstrate that lamin A counteracts NF-Y transcriptional activity not only in culture cells but also in living animals. Altogether, our data demonstrate the occurrence of lamin A/NF-Y interaction and suggest a possible role of this protein complex in regulation of NF-Y function in cell proliferatio