Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells

BACKGROUND: Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines. METHODS: Growth inhibition was assessed by MTS assay. EGFR, Src and downstream proteins FAK, Akt, MAPK42/44, Stat3 expressions were measured by western blot. Cell adhesion, migration and invasion were performed with and without dasatinib treatment. RESULTS: The IC(50) of 9 cell lines ranged from 0.7 μM ~ 14.2 μM. In general the growth inhibition by dasatinib was related to total Src (t-Src) and the ratio of activated Src (p-Src) to t-Src. There was good correlation of the sensitivity to dasatinib and the inhibition level of p-Src, p-FAK576/577 and p-Akt. No inhibition was found on Stat3 and MAPK42/44 in all cell lines. The inhibition of cell adhesion, migration and invasion were correlated with p-FAK inhibition. CONCLUSION: Dasatinib inhibits the proliferation, adhesion, migration and invasion of HCC cells in vitro via inhibiting of Src tyrosine kinase and affecting SFK/FAK and PI3K/PTEN/Akt, but not Ras/Raf/MEK/ERK and JAK/Stat pathways. T-Src and p-Src/t-Src may be useful biomarkers to select HCC patients for dasatinib treatment

Towards Real-Time Detection and Tracking of Spatio-Temporal Features: Blob-Filaments in Fusion Plasma

A novel algorithm and implementation of real-time identification and tracking of blob-filaments in fusion reactor data is presented. Similar spatio-temporal features are important in many other applications, for example, ignition kernels in combustion and tumor cells in a medical image. This work presents an approach for extracting these features by dividing the overall task into three steps: local identification of feature cells, grouping feature cells into extended feature, and tracking movement of feature through overlapping in space. Through our extensive work in parallelization, we demonstrate that this approach can effectively make use of a large number of compute nodes to detect and track blob-filaments in real time in fusion plasma. On a set of 30GB fusion simulation data, we observed linear speedup on 1024 processes and completed blob detection in less than three milliseconds using Edison, a Cray XC30 system at NERSC.Comment: 14 pages, 40 figure

Two Pfam protein families characterized by a crystal structure of protein lpg2210 from Legionella pneumophila.

BackgroundEvery genome contains a large number of uncharacterized proteins that may encode entirely novel biological systems. Many of these uncharacterized proteins fall into related sequence families. By applying sequence and structural analysis we hope to provide insight into novel biology.ResultsWe analyze a previously uncharacterized Pfam protein family called DUF4424 [Pfam:PF14415]. The recently solved three-dimensional structure of the protein lpg2210 from Legionella pneumophila provides the first structural information pertaining to this family. This protein additionally includes the first representative structure of another Pfam family called the YARHG domain [Pfam:PF13308]. The Pfam family DUF4424 adopts a 19-stranded beta-sandwich fold that shows similarity to the N-terminal domain of leukotriene A-4 hydrolase. The YARHG domain forms an all-helical domain at the C-terminus. Structure analysis allows us to recognize distant similarities between the DUF4424 domain and individual domains of M1 aminopeptidases and tricorn proteases, which form massive proteasome-like capsids in both archaea and bacteria.ConclusionsBased on our analyses we hypothesize that the DUF4424 domain may have a role in forming large, multi-component enzyme complexes. We suggest that the YARGH domain may play a role in binding a moiety in proximity with peptidoglycan, such as a hydrophobic outer membrane lipid or lipopolysaccharide

Performance assessment of radio occultation data from GeoOptics by comparing with COSMIC data

Responding to the ever-growing demand for environmental information, the National Oceanic and Atmospheric Administration (NOAA) seeks to enter into contracts to purchase Global Navigation Satellite System (GNSS) radio occultation (RO) observations produced by commercial vendors at a low-cost. GeoOptics is one commercial vendor awarded a contract with NOAA. GeoOptics operates the Community Initiative for Cellular Earth Remote Observation (CICERO) constellation of low-earth-orbiting (LEO) 6U CubeSats. The 6U-sized CICERO will enable the deployment of GNSS array consisting of RO satellites in the Earth&rsquo;s atmosphere to obtain many atmospheric observations which can improve weather forecasting. Applying GeoOptics RO data to reliable weather forecasting requires an assessment of its performance. This study analyzes the performance of GeoOptics CubeSats measurements by comparing it with the Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) missions (COSMIC-1 and COSMIC-2). The performance analysis was carried on data coverage capabilities and measurement quality. The analysis of data coverage confirmed that GeoOptics can acquire global observational coverage with adequate low-altitude penetration capability, while there should be updated in local time coverage. The analysis of RO measurement quality showed that GeoOptics RO measurements are comparable to those of COSMIC-2, even though GeoOptics exhibited a lower signal-to-noise ratio (SNR). The potential of GeoOptics allows for the development of a GNSS array in the Earth&rsquo;s atmosphere and a large amount of effective RO measurements to be obtained for reliable weather forecasting. &nbsp;</p

The role of spin in the kinetic control of recombination in organic photovoltaics.

In biological complexes, cascade structures promote the spatial separation of photogenerated electrons and holes, preventing their recombination. In contrast, the photogenerated excitons in organic photovoltaic cells are dissociated at a single donor-acceptor heterojunction formed within a de-mixed blend of the donor and acceptor semiconductors. The nanoscale morphology and high charge densities give a high rate of electron-hole encounters, which should in principle result in the formation of spin-triplet excitons, as in organic light-emitting diodes. Although organic photovoltaic cells would have poor quantum efficiencies if every encounter led to recombination, state-of-the-art examples nevertheless demonstrate near-unity quantum efficiency. Here we show that this suppression of recombination arises through the interplay between spin, energetics and delocalization of electronic excitations in organic semiconductors. We use time-resolved spectroscopy to study a series of model high-efficiency polymer-fullerene systems in which the lowest-energy molecular triplet exciton (T1) for the polymer is lower in energy than the intermolecular charge transfer state. We observe the formation of T1 states following bimolecular recombination, indicating that encounters of spin-uncorrelated electrons and holes generate charge transfer states with both spin-singlet ((1)CT) and spin-triplet ((3)CT) characters. We show that the formation of triplet excitons can be the main loss mechanism in organic photovoltaic cells. But we also find that, even when energetically favoured, the relaxation of (3)CT states to T1 states can be strongly suppressed by wavefunction delocalization, allowing for the dissociation of (3)CT states back to free charges, thereby reducing recombination and enhancing device performance. Our results point towards new design rules both for photoconversion systems, enabling the suppression of electron-hole recombination, and for organic light-emitting diodes, avoiding the formation of triplet excitons and enhancing fluorescence efficiency.This work was supported by the Engineering and Physical Sciences Research Council (EPSRC)This is the accepted version of the original publication available at: http://www.nature.com/nature/journal/v500/n7463/full/nature12339.html

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

Quantum Phase Transition in a Resonant Level Coupled to Interacting Leads

An interacting one-dimensional electron system, the Luttinger liquid, is distinct from the "conventional" Fermi liquids formed by interacting electrons in two and three dimensions. Some of its most spectacular properties are revealed in the process of electron tunneling: as a function of the applied bias or temperature the tunneling current demonstrates a non-trivial power-law suppression. Here, we create a system which emulates tunneling in a Luttinger liquid, by controlling the interaction of the tunneling electron with its environment. We further replace a single tunneling barrier with a double-barrier resonant level structure and investigate resonant tunneling between Luttinger liquids. For the first time, we observe perfect transparency of the resonant level embedded in the interacting environment, while the width of the resonance tends to zero. We argue that this unique behavior results from many-body physics of interacting electrons and signals the presence of a quantum phase transition (QPT). In our samples many parameters, including the interaction strength, can be precisely controlled; thus, we have created an attractive model system for studying quantum critical phenomena in general. Our work therefore has broadly reaching implications for understanding QPTs in more complex systems, such as cold atoms and strongly correlated bulk materials.Comment: 11 pages total (main text + supplementary

The Look-back Time Evolution of Far-Ultraviolet Flux from the Brightest Cluster Elliptical Galaxies at z < 0.2

We present the GALEX UV photometry of the elliptical galaxies in Abell clusters at moderate redshifts (z < 0.2) for the study of the look-back time evolution of the UV upturn phenomenon. The brightest elliptical galaxies (M_r < -22) in 12 remote clusters are compared with the nearby giant elliptical galaxies of comparable optical luminosity in the Fornax and Virgo clusters. The sample galaxies presented here appear to be quiescent without signs of massive star formation or strong nuclear activity, and show smooth, extended profiles in their UV images indicating that the far-UV (FUV) light is mostly produced by hot stars in the underlying old stellar population. Compared to their counterparts in nearby clusters, the FUV flux of cluster giant elliptical galaxies at moderate redshifts fades rapidly with ~ 2 Gyrs of look-back time, and the observed pace in FUV - V color evolution agrees reasonably well with the prediction from the population synthesis models where the dominant FUV source is hot horizontal-branch stars and their progeny. A similar amount of color spread (~ 1 mag) in FUV - V exists among the brightest cluster elliptical galaxies at z ~ 0.1, as observed among the nearby giant elliptical galaxies of comparable optical luminosity.Comment: Accepted for publication in the Special GALEX ApJ Supplement, December 200

GALEX Ultraviolet Photometry of Globular Clusters in M31

We present ultraviolet photometry for globular clusters (GCs) in M31 from 15 square deg of imaging using the Galaxy Evolution Explorer (GALEX). We detect 200 and 94 GCs with certainty in the near-ultraviolet (NUV; 1750 - 2750 Angstroms) and far-ultraviolet (FUV; 1350 - 1750 Angstroms) bandpasses, respectively. Our rate of detection is about 50% in the NUV and 23% in the FUV, to an approximate limiting V magnitude of 19. Out of six clusters with [Fe/H]>-1 seen in the NUV, none is detected in the FUV bandpass. Furthermore, we find no candidate metal-rich clusters with significant FUV flux, because of the contribution of blue horizontal-branch (HB) stars, such as NGC 6388 and NGC 6441, which are metal-rich Galactic GCs with hot HB stars. We show that our GALEX photometry follows the general color trends established in previous UV studies of GCs in M31 and the Galaxy. Comparing our data with Galactic GCs in the UV and with population synthesis models, we suggest that the age range of M31 and Galactic halo GCs are similar.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http://www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200