Inhibition of the Redox Function of APE1/Ref-1 in Myeloid Leukemia Cell Lines Results in a Hypersensitive Response to Retinoic Acid-induced Differentiation and Apoptosis

Objective The standard of care for promyelocytic leukemia includes use of the differentiating agent all-trans retinoic acid (RA) and chemotherapy. RA induces cell differentiation through retinoic acid receptor (RAR) transcription factors. Because redox mechanisms influence how readily transcription factors bind to DNA response elements (RARE), the impact of small molecule (E3330) inhibition of the redox regulatory protein, apurinic-apyrimidinic endonuclease/redox effector factor (APE1/Ref-1) on RAR DNA binding and function in RA-induced myeloid leukemia cell differentiation and apoptosis was investigated. Materials and Methods The redox function of APE1 was studied using the small molecule inhibitor E3330 in HL-60 and PLB acute myeloid leukemia cells. Electrophoretic mobility shift assays were employed to determine effect of inhibitor on APE1/Ref-1 redox signaling function. Trypan blue assays, Annexin-V/propidium iodide and CD11b staining, and real-time polymerase chain reaction analyses were employed to determine survival, apoptosis, and differentiation status of cells in culture. Results RARα binds to its RARE in a redox-dependent manner mediated by APE1/Ref-1 redox regulation. Redox-dependent RAR-RARE binding is blocked by E3330, a small molecule redox inhibitor of APE1/Ref-1. Combination treatment of RA + E3330 results in a profound hypersensitivity of myeloid leukemia cells to RA-induced differentiation and apoptosis. Additionally, redox inhibition by E3330 results in enhanced RAR target gene, BLR-1, expression in myeloid leukemia cells. Conclusions The redox function of APE1/Ref-1 regulates RAR binding to its DNA RAREs influencing the response of myeloid leukemia cells to RA-induced differentiation. Targeting of APE1/Ref-1 redox function may allow manipulation of the retinoid response with therapeutic implications

Image and information management system

A system and methods through which pictorial views of an object's configuration, arranged in a hierarchical fashion, are navigated by a person to establish a visual context within the configuration. The visual context is automatically translated by the system into a set of search parameters driving retrieval of structured data and content (images, documents, multimedia, etc.) associated with the specific context. The system places hot spots, or actionable regions, on various portions of the pictorials representing the object. When a user interacts with an actionable region, a more detailed pictorial from the hierarchy is presented representing that portion of the object, along with real-time feedback in the form of a popup pane containing information about that region, and counts-by-type reflecting the number of items that are available within the system associated with the specific context and search filters established at that point in time

Image and information management system

A system and methods through which pictorial views of an object's configuration, arranged in a hierarchical fashion, are navigated by a person to establish a visual context within the configuration. The visual context is automatically translated by the system into a set of search parameters driving retrieval of structured data and content (images, documents, multimedia, etc.) associated with the specific context. The system places ''hot spots'', or actionable regions, on various portions of the pictorials representing the object. When a user interacts with an actionable region, a more detailed pictorial from the hierarchy is presented representing that portion of the object, along with real-time feedback in the form of a popup pane containing information about that region, and counts-by-type reflecting the number of items that are available within the system associated with the specific context and search filters established at that point in time

Patterns of Extinction Risk and Threat for Marine Vertebrates and Habitat-Forming Species in the Tropical Eastern Pacific

Marine conservation activities around the globe are largely undertaken in the absence of comprehensive species-specific information. To address this gap, complete regional species assemblages of major marine taxa are being progressively assessed against the Categories and Criteria of the International Union for the Conservation of Nature (IUCN) Red List of Threatened Species. The present study is the first analysis of entire major components of the biota of a large marine biogeographic region conducted in the Tropical Eastern Pacific (TEP). It is based on recently completed IUCN Red List assessments for all known species of bony and cartilaginous shorefishes, corals, mangroves, and seagrasses in the TEP. Twelve percent of the \u3e1600 species assessed are in threatened categories, indicative of elevated extinction risk. Spatial analysis of all assessed taxonomic groups, including previous IUCN Red List assessments for seabirds, marine mammals, and marine turtles, highlights specific geographical areas of elevated threatenedspecies richness. The distribution of threatened species in the TEP is primarily linked to areas with high rates of overfishing, habitat loss, and increasing El Niño-Southern Oscillation (ENSO) event impacts, as well as oceanic islands with high stochastic risk factors for endemic species. Species assigned to the highest threat categories have life history traits that likely decrease their resilience to various regional and site-specific threats. Comprehensive information in the form of IUCN Red List assessments combined with spatial analysis will greatly help to refine both site- and species-specific marine conservation priorities in the TEP

ProtoDESI: First On-Sky Technology Demonstration for the Dark Energy Spectroscopic Instrument

The Dark Energy Spectroscopic Instrument (DESI) is under construction to measure the expansion history of the universe using the baryon acoustic oscillations technique. The spectra of 35 million galaxies and quasars over 14,000 square degrees will be measured during a 5-year survey. A new prime focus corrector for the Mayall telescope at Kitt Peak National Observatory will deliver light to 5,000 individually targeted fiber-fed robotic positioners. The fibers in turn feed ten broadband multi-object spectrographs. We describe the ProtoDESI experiment, that was installed and commissioned on the 4-m Mayall telescope from August 14 to September 30, 2016. ProtoDESI was an on-sky technology demonstration with the goal to reduce technical risks associated with aligning optical fibers with targets using robotic fiber positioners and maintaining the stability required to operate DESI. The ProtoDESI prime focus instrument, consisting of three fiber positioners, illuminated fiducials, and a guide camera, was installed behind the existing Mosaic corrector on the Mayall telescope. A Fiber View Camera was mounted in the Cassegrain cage of the telescope and provided feedback metrology for positioning the fibers. ProtoDESI also provided a platform for early integration of hardware with the DESI Instrument Control System that controls the subsystems, provides communication with the Telescope Control System, and collects instrument telemetry data. Lacking a spectrograph, ProtoDESI monitored the output of the fibers using a Fiber Photometry Camera mounted on the prime focus instrument. ProtoDESI was successful in acquiring targets with the robotically positioned fibers and demonstrated that the DESI guiding requirements can be met.Comment: Accepted versio

Shape-based peak identification for ChIP-Seq

We present a new algorithm for the identification of bound regions from ChIP-seq experiments. Our method for identifying statistically significant peaks from read coverage is inspired by the notion of persistence in topological data analysis and provides a non-parametric approach that is robust to noise in experiments. Specifically, our method reduces the peak calling problem to the study of tree-based statistics derived from the data. We demonstrate the accuracy of our method on existing datasets, and we show that it can discover previously missed regions and can more clearly discriminate between multiple binding events. The software T-PIC (Tree shape Peak Identification for ChIP-Seq) is available at http://math.berkeley.edu/~vhower/tpic.htmlComment: 12 pages, 6 figure

Evidence for coeval Late Triassic terrestrial impacts from the Rochechouart (France) meteorite crater

High temperature impact melt breccias from the Rochechouart (France) meteorite crater record magnetization component with antipodal, normal and reverse polarities. The corresponding paleomagnetic pole for this component lies between the 220 Ma and 210 Ma reference poles on the Eurasian apparent polar wander path, consistent with the 214 $\pm$ 8 Ma 40Ar/39Ar age of the crater. Late Triassic tectonic reconstructions of the Eurasian and North American plates place this pole within 95% confidence limits of the paleomagnetic pole from the Manicouagan (Canada) meteorite impact crater, which is dated at 214 $\pm$ 1 Ma. Together, these observations reinforce the hypothesis of a Late Triassic, multiple meteorite impact event on Earth

MethCancerDB – aberrant DNA methylation in human cancer

Early detection, classification and prognosis of human cancers by analysis of CpG methylation carry huge diagnostic potential. MethCancerDB collects and annotates genes and sequences from the abundance of published methylation studies and interlinks them to all methylation-relevant bioinformatical resources. MethCancerDB starts with 4720 entries from 348 sources and is freely accessible at http://www.methcancerdb.net

Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation.

Reliable, non-invasive methods for diagnosing and prognosing sinusoidal obstruction syndrome (SOS) early after hematopoietic cell transplantation (HCT) are needed. We used a quantitative mass spectrometry-based proteomics approach to identify candidate biomarkers of SOS by comparing plasma pooled from 20 patients with and 20 patients without SOS. Of 494 proteins quantified, we selected six proteins [L-Ficolin, vascular-cell-adhesion-molecule-1 (VCAM1), tissue-inhibitor of metalloproteinase-1, von Willebrand factor, intercellular-adhesion-molecule-1, and CD97] based on a differential heavy/light isotope ratio of at least 2 fold, information from the literature, and immunoassay availability. Next, we evaluated the diagnostic potential of these six proteins and five selected from the literature [suppression of tumorigenicity-2 (ST2), angiopoietin-2 (ANG2), hyaluronic acid (HA), thrombomodulin, and plasminogen activator inhibitor-1] in samples from 80 patients. The results demonstrate that together ST2, ANG2