Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells

We studied in vitro effects of glycogen synthase kinase 3β (GSK3β)-inhibitor lithium on the growth of hepatocellular carcinoma (HCC) cells. Lithium induced strong growth inhibition (>70%) in 75% (n = 9 of 12) of cell lines, apparently independent from the status of major genes that are mutated in HCC including p53, p16INK4a, β-catenin and Axin1. Comparative studies with a growth-sensitive Huh7 and growth-resistant Hep40 cell lines showed that lithium induces growth arrest in Huh7 cells but not in Hep40 cells. Lithium induced the accumulation of N-terminally phosphorylated inactive form of GSK3β with concomitant increase in β-catenin and β-catenin/TCF transcriptional activity in both cell lines. This suggests that lithium-mediated HCC growth inhibition is independent of its well-known stimulatory effect on Wnt-β-catenin signaling. The main differences between Huh7 and Hep40 responses to lithium treatment were observed at the levels PKB/Akt and cyclin E proteins. Lithium induced depletion of both proteins in growth-sensitive Huh7, but not in growth-resistant Hep40 cells. PKB/Akt and Cyclin E are 2 major proteins that are known to be constitutively active in HCC. The targeting of both proteins with lithium may be the main reason why most HCC cells are responsive to lithium-mediated growth inhibition, independent of their p53, retinoblastoma and Wnt-β-catenin pathways. The exploration of molecular mechanisms involved in lithium-mediated growth inhibition in relation with PKB/Akt and cyclin E downregulation may provide new insights for therapy of liver tumors. © 2005 Wiley-Liss, Inc

Cracking the code of oscillatory activity

Neural oscillations are ubiquitous measurements of cognitive processes and dynamic routing and gating of information. The fundamental and so far unresolved problem for neuroscience remains to understand how oscillatory activity in the brain codes information for human cognition. In a biologically relevant cognitive task, we instructed six human observers to categorize facial expressions of emotion while we measured the observers' EEG. We combined state-of-the-art stimulus control with statistical information theory analysis to quantify how the three parameters of oscillations (i.e., power, phase, and frequency) code the visual information relevant for behavior in a cognitive task. We make three points: First, we demonstrate that phase codes considerably more information (2.4 times) relating to the cognitive task than power. Second, we show that the conjunction of power and phase coding reflects detailed visual features relevant for behavioral response-that is, features of facial expressions predicted by behavior. Third, we demonstrate, in analogy to communication technology, that oscillatory frequencies in the brain multiplex the coding of visual features, increasing coding capacity. Together, our findings about the fundamental coding properties of neural oscillations will redirect the research agenda in neuroscience by establishing the differential role of frequency, phase, and amplitude in coding behaviorally relevant information in the brai

Stochastic Resonance of Ensemble Neurons for Transient Spike Trains: A Wavelet Analysis

By using the wavelet transformation (WT), we have analyzed the response of an ensemble of $N$ (=1, 10, 100 and 500) Hodgkin-Huxley (HH) neurons to {\it transient} $M$-pulse spike trains ($M=1-3$) with independent Gaussian noises. The cross-correlation between the input and output signals is expressed in terms of the WT expansion coefficients. The signal-to-noise ratio (SNR) is evaluated by using the {\it denoising} method within the WT, by which the noise contribution is extracted from output signals. Although the response of a single (N=1) neuron to sub-threshold transient signals with noises is quite unreliable, the transmission fidelity assessed by the cross-correlation and SNR is shown to be much improved by increasing the value of $N$: a population of neurons play an indispensable role in the stochastic resonance (SR) for transient spike inputs. It is also shown that in a large-scale ensemble, the transmission fidelity for supra-threshold transient spikes is not significantly degraded by a weak noise which is responsible to SR for sub-threshold inputs.Comment: 20 pages, 4 figure

Symmetrized mean-field description of magnetic instabilities in k-(BEDT-TTF)_2Cu[N(CN)]_2 Y salts

We present a novel and convenient mean-field method, and apply it to study the metallic/antiferromagnetic interface of k-(BEDT-TTF)_2Cu[N(CN)]_2 Y organic superconductors (BEDT_TTF is bis-ethylen-dithio-tetrathiafulvalene, Y=Cl, Br). The method, which fully exploits the crystal symmetry, allows one to obtain the mean-field solution of the 2D Hubbard model for very large lattices, up to 6x10^5 sites, yielding a reliable description of the phase boundary in a wide region of the parameter space. The metal/antiferromagnet transtion appears to be second order, except for a narrow region of the parameter space, where the transition is very sharp and possibly first order. The cohexistence of metallic and antiferromagnetic properties is only observed for the transient state in the case of smooth second order transitions. The relevance of the present resaults to the complex experimental behavior of centrosymmetric k-phase BEDT-TTF salts is discussed.Comment: 9 pages in PS format, 7 figures (included in PS), 1 tabl

Optimal Control of Molecular Motion Expressed Through Quantum Fluid Dynamics

A quantum fluid dynamic control formulation is presented for optimally manipulating atomic and molecular systems. In quantum fluid dynamic the control quantum system is expressed in terms of the probability density and the quantum current. This choice of variables is motivated by the generally expected slowly varying spatial-temporal dependence of the fluid dynamical variables. The quantum fluid dynamic approach is illustrated for manipulation of the ground electronic state dynamics of HCl induced by an external electric field.Comment: 18 pages, latex, 3 figure

Priorities for nucleotide trace, sequence and annotation data capture at the Ensembl Trace Archive and the EMBL Nucleotide Sequence Database

The Ensembl Trace Archive (http://trace.ensembl.org/) and the EMBL Nucleotide Sequence Database (http://www.ebi.ac.uk/embl/), known together as the European Nucleotide Archive, continue to see growth in data volume and diversity. Selected major developments of 2007 are presented briefly, along with data submission and retrieval information. In the face of increasing requirements for nucleotide trace, sequence and annotation data archiving, data capture priority decisions have been taken at the European Nucleotide Archive. Priorities are discussed in terms of how reliably information can be captured, the long-term benefits of its capture and the ease with which it can be captured

Gamma Power Is Phase-Locked to Posterior Alpha Activity

Neuronal oscillations in various frequency bands have been reported in numerous studies in both humans and animals. While it is obvious that these oscillations play an important role in cognitive processing, it remains unclear how oscillations in various frequency bands interact. In this study we have investigated phase to power locking in MEG activity of healthy human subjects at rest with their eyes closed. To examine cross-frequency coupling, we have computed coherence between the time course of the power in a given frequency band and the signal itself within every channel. The time-course of the power was calculated using a sliding tapered time window followed by a Fourier transform. Our findings show that high-frequency gamma power (30–70 Hz) is phase-locked to alpha oscillations (8–13 Hz) in the ongoing MEG signals. The topography of the coupling was similar to the topography of the alpha power and was strongest over occipital areas. Interestingly, gamma activity per se was not evident in the power spectra and only became detectable when studied in relation to the alpha phase. Intracranial data from an epileptic subject confirmed these findings albeit there was slowing in both the alpha and gamma band. A tentative explanation for this phenomenon is that the visual system is inhibited during most of the alpha cycle whereas a burst of gamma activity at a specific alpha phase (e.g. at troughs) reflects a window of excitability

Measures in Visualization Space

Postponed access: the file will be available after 2021-08-12Measurement is an integral part of modern science, providing the fundamental means for evaluation, comparison, and prediction. In the context of visualization, several different types of measures have been proposed, ranging from approaches that evaluate particular aspects of visualization techniques, their perceptual characteristics, and even economic factors. Furthermore, there are approaches that attempt to provide means for measuring general properties of the visualization process as a whole. Measures can be quantitative or qualitative, and one of the primary goals is to provide objective means for reasoning about visualizations and their effectiveness. As such, they play a central role in the development of scientific theories for visualization. In this chapter, we provide an overview of the current state of the art, survey and classify different types of visualization measures, characterize their strengths and drawbacks, and provide an outline of open challenges for future research.acceptedVersio

Transcriptional Regulation of BMP2 Expression by the PTH-CREB Signaling Pathway in Osteoblasts

Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts