Protein kinase C inhibitor and irradiation-induced apoptosis: Relevance of the cytochrome c-mediated caspase-9 death pathway

Caspases are a family of cysteine proteases that constitute the apoptotic cell death machinery, We report the importance of the cytochrome c-mediated caspase-9 death pathway for radiosensitization by the protein kinase C (PKC) inhibitors staurosporine (STP) and PKC-412. In our genetically defined tumor cells, treatment with low doses of STP or the conventional PKC-specific inhibitor PKC-412 in combination with irradiation (5 Gy) potently reduced viability, enhanced mitochondrial cytochrome c release into the cytosol, and specifically stimulated the initiator caspase-9. Whereas treatment with each agent alone had a minimal effect, combined treatment resulted in enhanced caspase-3 activation. This was prevented by broad-range and specific caspase-9 inhibitors and absent in caspase-9-deficient cells. The tumor suppressor p53 was required for apoptosis induction by combined treatment but was dispensable for dose-dependent STP-induced caspase activation. These results demonstrate the requirement for an intact caspase-9 pathway for apoptosis-based radiosensitization by PKC inhibitors and show that STP induces apoptosis independent of p53

Charge-Fluctuation-Induced Non-analytic Bending Rigidity

In this Letter, we consider a neutral system of mobile positive and negative charges confined on the surface of curved films. This may be an appropriate model for: i) a highly charged membrane whose counterions are confined to a sheath near its surface; ii) a membrane composed of an equimolar mixture of anionic and cationic surfactants in aqueous solution. We find that the charge fluctuations contribute a non-analytic term to the bending rigidity that varies logarithmically with the radius of curvature. This may lead to spontaneous vesicle formation, which is indeed observed in similar systems.Comment: Revtex, 9 pages, no figures, submitted to PR

A lattice model for the kinetics of rupture of fluid bilayer membranes

We have constructed a model for the kinetics of rupture of membranes under tension, applying physical principles relevant to lipid bilayers held together by hydrophobic interactions. The membrane is characterized by the bulk compressibility (for expansion), the thickness of the hydrophobic part of the bilayer, the hydrophobicity and a parameter characterizing the tail rigidity of the lipids. The model is a lattice model which incorporates strain relaxation, and considers the nucleation of pores at constant area, constant temperature, and constant particle number. The particle number is conserved by allowing multiple occupancy of the sites. An equilibrium ``phase diagram'' is constructed as a function of temperature and strain with the total pore surface and distribution as the order parameters. A first order rupture line is found with increasing tension, and a continuous increase in proto-pore concentration with rising temperature till instability. The model explains current results on saturated and unsaturated PC lipid bilayers and thicker artificial bilayers made of diblock copolymers. Pore size distributions are presented for various values of area expansion and temperature, and the fractal dimension of the pore edge is evaluated.Comment: 15 pages, 8 figure

HLA-J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer

The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA-G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA-J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a pseudogene by in silico sequence interpretation. HLA-J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA-J and frequently increased HLA-J mRNA levels after NACT. HLA-J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA-J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA-J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.Humane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA-G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA-J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA-J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA-J, und der HLA-J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt

Magnetospheric Emission from Extrasolar Planets

The magnetospheric emissions from extrasolar planets represent a science frontier for the next decade. All of the solar system giant planets and the Earth produce radio emissions as a result of interactions between their magnetic fields and the solar wind. In the case of the Earth, its magnetic field may contribute to its habitability by protecting its atmosphere from solar wind erosion and by preventing energetic particles from reaching its surface. Indirect evidence for at least some extrasolar giant planets also having magnetic fields includes the modulation of emission lines of their host stars phased with the planetary orbits, likely due to interactions between the stellar and planetary magnetic fields. If magnetic fields are a generic property of giant planets, then extrasolar giant planets should emit at radio wavelengths allowing for their direct detection. Existing observations place limits comparable to the flux densities expected from the strongest emissions. Additional sensitivity at low radio frequencies coupled with algorithmic improvements likely will enable a new means of detection and characterization of extrasolar planets within the next decade.Comment: Science white paper for Astro2010; submitted to PSF pane

Plasma Depletion and Mirror Waves Ahead of Interplanetary Coronal Mass Ejections

We find that the sheath regions between fast interplanetary coronal mass ejections (ICMEs) and their preceding shocks are often characterized by plasma depletion and mirror wave structures, analogous to planetary magnetosheaths. A case study of these signatures in the sheath of a magnetic cloud (MC) shows that a plasma depletion layer (PDL) coincides with magnetic field draping around the MC. In the same event, we observe an enhanced thermal anisotropy and plasma beta as well as anti-correlated density and magnetic fluctuations which are signatures of mirror mode waves. We perform a superposed epoch analysis of ACE and Wind plasma and magnetic field data from different classes of ICMEs to illuminate the general properties of these regions. For MCs preceded by shocks, the sheaths have a PDL with an average duration of 6 hours (corresponding to a spatial span of about 0.07 AU) and a proton temperature anisotropy ${T_{\perp p}\over T_{\parallel p}}\simeq 1.2$ -1.3, and are marginally unstable to the mirror instability. For ICMEs with preceding shocks which are not MCs, plasma depletion and mirror waves are also present but at a reduced level. ICMEs without shocks are not associated with these features. The differences between the three ICME categories imply that these features depend on the ICME geometry and the extent of upstream solar wind compression by the ICMEs. We discuss the implications of these features for a variety of crucial physical processes including magnetic reconnection, formation of magnetic holes and energetic particle modulation in the solar wind.Comment: fully refereed, accepted for publication in J. Geophys. Re

Negative electrostatic contribution to the bending rigidity of charged membranes and polyelectrolytes screened by multivalent counterions

Bending rigidity of a charged membrane or a charged polyelectrolyte screened by monovalent counterions is known to be enhanced by electrostatic effects. We show that in the case of screening by multivalent counterions the electrostatic effects reduce the bending rigidity. This inversion of the sign of the electrostatic contribution is related to the formation of two-dimensional strongly correlated liquids (SCL) of counterions at the charged surface due to strong lateral repulsion between them. When a membrane or a polyelectrolyte is bent, SCL is compressed on one side and stretched on the other so that thermodynamic properties of SCL contribute to the bending rigidity. Thermodynamic properties of SCL are similar to those of Wigner crystal and are anomalous in the sense that the pressure, compressibility and screening radius of SCL are negative. This brings about substantial negative correction to the bending rigidity. For the case of DNA this effect qualitatively agrees with experiment.Comment: 8 pages, 2 figure

A Statistical Study on the Morphology of Rays and Dynamics of Blobs in the Wake of Coronal Mass Ejections

In this paper, with a survey through the Large Angle and Spectrometric Coronagraph (LASCO) data from 1996 to 2009, we present 11 events with plasma blobs flowing outwards sequentially along a bright coronal ray in the wake of a coronal mass ejection. The ray is believed to be associated with the current sheet structure that formed as a result of solar eruption, and the blobs are products of magnetic reconnection occurring along the current sheet. The ray morphology and blob dynamics are investigated statistically. It is found that the apparent angular widths of the rays at a fixed time vary in a range of 2.1-6.6 (2.0-4.4) degrees with an average of 3.5 (2.9) degrees at 3 (4) Rs, respectively, and the observed durations of the events vary from 12 h to a few days with an average of 27 h. It is also found, based on the analysis of blob motions, that 58% (26) of the blobs were accelerated, 20% (9) were decelerated, and 22% (10) moved with a nearly-constant speed. Comparing the dynamics of our blobs and those that are observed above the tip of a helmet streamer, we find that the speeds and accelerations of the blobs in these two cases differ significantly. It is suggested that these differences of the blob dynamics stem from the associated magnetic reconnection involving different magnetic field configurations and triggering processes.Comment: 12 pages, 6 figures, accepted by Solar Physic