Gravitational Chern-Simons Lagrangians and black hole entropy

We analyze the problem of defining the black hole entropy when Chern-Simons terms are present in the action. Extending previous works, we define a general procedure, valid in any odd dimensions both for purely gravitational CS terms and for mixed gauge-gravitational ones. The final formula is very similar to Wald's original formula valid for covariant actions, with a significant modification. Notwithstanding an apparent violation of covariance we argue that the entropy formula is indeed covariant.Comment: 39 page

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

A surprising consistency between the far-infrared galaxy luminosity functions of the field and Coma

We present new deep images of the Coma Cluster from the ESA Herschel Space Observatory at wavelengths of 70, 100 and 160 μm, covering an area of 1.75 × 1.0 square degrees encompassing the core and south-west infall region. Our data display an excess of sources at flux densities above 100 mJy compared to blank-field surveys, as expected. We use extensive optical spectroscopy of this region to identify cluster members and hence produce cluster luminosity functions in all three photometric bands. We compare our results to the local field galaxy luminosity function, and the luminosity functions from the Herschel Virgo Cluster Survey. We find consistency between the shapes of the Coma and field galaxy luminosity functions at all three wavelengths; however, we do not find the same level of agreement with that of the Virgo Cluster

Extracellular vesicles:Emerging modulators of cancer drug resistance

Extracellular vesicles (EVs) have recently emerged as crucial modulators of cancer drug resistance. Indeed, it has been shown that they can directly sequester anti-tumor drugs, decreasing their effective concentration at target sites. Moreover, they facilitate the horizontal transfer of specific bioactive cargoes able to regulate proliferative, apoptotic, and stemness programs in recipient cells, potentially conferring a resistant phenotype to drug-sensitive cancer cells. Finally, EVs can mediate the communication between the tumor and both stromal and immune cells within the microenvironment, promoting treatment escape. In this context, clarifying the EV-driven resistance mechanisms might improve not only tumor diagnosis and prognosis but also therapeutic outcomes. Detailed cellular and molecular events occurring during the development of EV-mediated cancer drug resistance are described in this review article

TRPC3 signalling contributes to the biogenesis of extracellular vesicles

Extracellular vesicles (EVs) contribute to a wide range of pathological processes including cancer progression, yet the molecular mechanisms underlying their biogenesis remain incompletely characterized. The development of tetraspanin-based pHluorin reporters has enabled the real-time analysis of EV release at the plasma membrane. Here, we employed CD81-pHluorin to investigate mechanisms of EV release in ovarian cancer (OC) cells and report a novel role for the Ca2+-permeable transient receptor potential (TRP) channel TRPC3 in EV-mediated communication. We found that specific activation of TRPC3 increased Ca2+ signalling in SKOV3 cells and stimulated an immediate increase in EV release. Ca2+-stimulants histamine and ionomycin likewise induced EV release, and imaging analysis revealed distinct stimulation-dependent temporal and spatial release dynamics. Interestingly, inhibition of TRPC3 attenuated histamine-stimulated Ca2+-entry and EV release, indicating that TRPC3 is likely to act downstream of histamine signalling in EV biogenesis. Furthermore, we found that direct activation of TRPC3 as well as the application of EVs derived from TRPC3-activated cells increased SKOV3 proliferation. Our data provides insights into the molecular mechanisms and dynamics underlying EV release in OC cells, proposing a key role for TRPC3 in EV biogenesis

The HST/ACS Coma Cluster Survey - X. Nuclear star clusters in low-mass early-type galaxies: scaling relations

We present scaling relations between structural properties of nuclear star clusters and their host galaxies for a sample of early-type dwarf galaxies observed as part of the Hubble Space Telescope (HST) Advanced Camera for Surveys (ACS) Coma Cluster Survey. We have analysed the light profiles of 200 early-type dwarf galaxies in the magnitude range 16.0 < mF814W < 22.6 mag, corresponding to -19.0 < MF814W < -12.4 mag. Nuclear star clusters are detected in 80 per cent of the galaxies, thus doubling the sample of HST-observed early-type dwarf galaxies with nuclear star clusters.We confirm that the nuclear star cluster detection fraction decreases strongly towards faint magnitudes. The luminosities of nuclear star clusters do not scale linearly with host galaxy luminosity. A linear fit yields Lnuc ~ L0.57±0.05 gal. The nuclear star cluster–host galaxy luminosity scaling relation for low-mass early-type dwarf galaxies is consistent with formation by globular cluster (GC) accretion. We find that at similar luminosities, galaxies with higher S´ersic indices have slightly more luminous nuclear star clusters. Rounder galaxies have on average more luminous clusters. Some of the nuclear star clusters are resolved, despite the distance of Coma. We argue that the relation between nuclear star cluster mass and size is consistent with both formation by GC accretion and in situ formation. Our data are consistent with GC inspiralling being the dominant mechanism at low masses, although the observed trend with S´ersic index suggests that in situ star formation is an important second-order effect