Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.

[1] Solar wind protons detected within Magnetic Holes (MHs) and Magnetic Decreases (MDs) are found to be preferentially heated perpendicular toB 0 . The MHs/MDs are associated with the phase-steepened edges of nonlinear Alfvén waves. The proton anisotropies can lead to the proton cyclotron and mirror mode plasma instabilities. We examine the Ponderomotive Force (PF), a phenomenon due to wave pressure gradients, and show that for this plasma regime and for phase-steepened Alfvén waves, the PF proton acceleration/energization will primarily be orthogonal to B 0 . It is suggested that accelerated ions create the MHs/MDs by a diamagnetic effect.

[1] Ulysses magnetic field data are used to study magnetic field microstructure over the solar poles. Magnetic holes (MHs) and magnetic decreases (MDs) are found to be located at the phasesteepened edges of nonlinear Alfvén waves. The phase-steepened edges (directional discontinuities) occur in time-coincidence with MHs, one edge of an MD, or throughout the whole MD. These MH-and MD-related discontinuities have both rotational and compressive properties, perhaps explaining why many directional discontinuities detected in interplanetary space have non-MHD properties. The dispersive, dissipative and compressive features of nonlinear Alfvén waves may be important for the heating of the solar corona.

Background: Age-related macular degeneration (ARMD) is a leading cause of blindness in the United States, but the mechanisms that initiate and promote the disease remain ill defined. There are several risk factors that ARMD shares with atherosclerosis, and these diseases may have similar pathogenic mechanisms that involve inflammation. Chlamydia pneumoniae, a prokaryotic pathogen that causes chronic inflammation is now emerging as a risk factor in the development of cardiovascular diseases. It is therefore plausible that this microorganism also contributes to the pathogenesis of ARMD. Methods: To examine if C pneumoniae infection is associated with ARMD, serum samples from 25 consecutive patients with ARMD and from 18 without the disease were collected and assayed for the presence of the antibodies to C pneumoniae elementary bodies, Chla-mydia trachomatis heat shock protein 60 (cHsp60), C trachomatis heat shock protein 10 (cHsp10), Escherichia coli GroEL, and E coli GroES. Results: A serological association was found between ARMD and anti-C pneumoniae antibodies (P =.047) but not between ARMD and the anti-C trachomatis or anti-E coli heat shock protein antibodies. The association remained statistically significant after adjusting for age and smoking, both established risk factors for ARMD. Conclusions: These data indicate that C pneumoniae infection may be associated with ARMD. Further studies on larger cohorts of individuals are necessary to determine if this pathogen plays a role in the pathogenesis of ARMD.