RelA/NF-kappaB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

The balance between antiapoptotic and proapoptotic proteins of the Bcl-2 family is critical in determining the fate of T cells in response to death stimuli. Proapoptotic genes, such as bax, are generally regulated by the p53 family of transcription factors, whereas NF-kappaB subunits can activate the transcription of antiapoptotic Bcl-2 members. Here, we show that CD28 activation protects memory T cells from irradiation-induced apoptosis by both upregulating bcl-xL and inhibiting bax gene expression. We found that p73, but not p53, binds to and trans-activates the bax gene promoter in irradiated T cells. The activation of RelA/NF-kappaB subunit in CD28 costimulated T cells and its binding onto the bax gene promoter results in suppression of bax transcription and decrease in both p73 and RNA polymerase II recruitment in vivo. RelA recruitment on the bax gene promoter is also accompanied by the lost of p300 binding and the parallel appearance of histone deacetylase-1-containing complexes. These findings identify RelA/NF-kappaB as a critical regulator of T-cell survival by affecting the balance of Bcl-2 family members

Electrostatic interactions between viologens and a sulfated β-cyclodextrin; formation of insoluble aggregates with benzyl viologens

Viologens are important compounds and are used in several applications. The interactions between viologens and a negatively charged cyclodextrin, sulfated β-cyclodextrin (sβ-CD), were studied using electrochemistry, 1H NMR and UV–Vis spectroscopy. Weak electrostatic interactions were found between the dicationic viologens (V2+) and the anionic cyclodextrin. The diffusion coefficient of ethyl viologen (EV2+) was reduced from 5.33 × 10−6 to 1.98 × 10−6 cm2 s−1 with an excess of sβ-CD. More significant electrostatic interactions were found between benzyl viologen (BV2+) and sβ-CD. The H atoms in the benzyl substituent, which appear as a singlet in the NMR experiment, were split into a multiplet in the presence of the sβ-CD, while the chemical shift of the H in the β position to the quaternary nitrogen, was shifted by 0.17 ppm in the presence of sβ-CD. Greater electrostatic interactions were evident between the benzyl radical cation (BV·+) and sβ-CD. Using cyclic voltammetry, reduction of the radical cation to the neutral benzyl viologen (BV0) was shifted by 230 mV to a lower potential, indicating that the reduction of the radical cation becomes considerably more difficult in the presence of sβ-CD. This was attributed to the formation of an insoluble BV·+:sβ-CD aggregate, which was also evident in rotating disc voltammetry, where the typical diffusion-limited currents were not observed and in spectroelectrochemistry experiments, where the deposition of the aggregate at the ITO electrode increased the absorbance of the radical species

2D continuous spectrum of shear Alfven waves in the presence of a magnetic island

The radial structure of the continuous spectrum of shear Alfven modes is calculated in the presence of a magnetic island in tokamak plasmas. Modes with the same helicity of the magnetic island are considered in a slab model approximation. In this framework, with an appropriate rotation of the coordinates the problem reduces to 2 dimensions. Geometrical effects due to the shape of the flux surface's cross section are retained to all orders. On the other hand, we keep only curvature effects responsible of the beta induced gap in the low-frequency part of the continuous spectrum. New continuum accumulation points are found at the O-point of the magnetic island. The beta-induced Alfven Eigenmodes (BAE) continuum accumulation point is found to be positioned at the separatrix flux surface. The most remarkable result is the nonlinear modification of the BAE continuum accumulation point frequency

Dynamical correlations and collective excitations of Yukawa liquids

In dusty (complex) plasmas, containing mesoscopic charged grains, the grain-grain interaction in many cases can be well described through a Yukawa potential. In this Review we summarize the basics of the computational and theoretical approaches capable of describing many-particle Yukawa systems in the liquid and solid phases and discuss the properties of the dynamical density and current correlation spectra of three- and two-dimensional strongly coupled Yukawa systems, generated by molecular dynamics simulations. We show details of the $\omega(k)$ dispersion relations for the collective excitations in these systems, as obtained theoretically following the quasilocalized charge approximation, as well as from the fluctuation spectra created by simulations. The theoretical and simulation results are also compared with those obtained in complex plasma experiments.Comment: 54 pages, 31 figure

Jets, Stickiness and Anomalous Transport

Dynamical and statistical properties of the vortex and passive particle advection in chaotic flows generated by four and sixteen point vortices are investigated. General transport properties of these flows are found anomalous and exhibit a superdiffusive behavior with typical second moment exponent (\mu \sim 1.75). The origin of this anomaly is traced back to the presence of coherent structures within the flow, the vortex cores and the region far from where vortices are located. In the vicinity of these regions stickiness is observed and the motion of tracers is quasi-ballistic. The chaotic nature of the underlying flow dictates the choice for thorough analysis of transport properties. Passive tracer motion is analyzed by measuring the mutual relative evolution of two nearby tracers. Some tracers travel in each other vicinity for relatively large times. This is related to an hidden order for the tracers which we call jets. Jets are localized and found in sticky regions. Their structure is analyzed and found to be formed of a nested sets of jets within jets. The analysis of the jet trapping time statistics shows a quantitative agreement with the observed transport exponent.Comment: 17 pages, 17 figure

Novel Prognostic and Therapeutic Targets for Oral Squamous Cell Carcinoma

In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥ 30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials

Cancer stem cell metabolism: A potential target for cancer therapy

© 2016 The Author(s). Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells. This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy

Electrochemistry of viologens at polypyrrole doped with sulfonated β–cyclodextrin

The electrochemistry of methyl, ethyl and benzyl viologens was studied at polypyrrole doped with sulfonated cyclodextrin, PPysβ–CD, a cation exchange polymer. Three reduction waves were observed corresponding to the reduction of the viologen (V2+) to the radical cation (V•+) followed by the neutral compound (V0) and a third intense peak. This third reduction peak was associated with the ingress of V2+ as the PPysβ–CD film is reduced. As the incorporated V2+ is reduced to the neutral viologen, the influx of more V2+ occurs to achieve charge balance and this repeated influx and reduction of V2+ gives an intense reduction wave. These processes were only observed with sβ–CD as a dopant and this was attributed to the formation of an ion pair between the anionic cyclodextrin and the viologen. Lower diffusion coefficients and rate constants were observed for the reduction of V2+ and V•+ on adding an excess of sβ–CD to the viologen solution. Linear calibration curves were obtained extending from 1.0 μM to 80 μM when the PPysβ–CD was employed as a sensor for methyl viologen. While the PPysβ–CD is not suitable for the detection of low nM concentrations, the uptake and extraction of MV2+ was observed on polarising the PPysβ–CD in a solution of the viologen, highlighting the dual action of the polymer