Structural and Functional Analysis of Human SIRT1

SIRT1 is a NAD^+-dependent deacetylase that plays important roles in many cellular processes. SIRT1 activity is uniquely controlled by a C-terminal regulatory segment (CTR). Here we present crystal structures of the catalytic domain of human SIRT1 in complex with the CTR in an open apo form and a closed conformation in complex with a cofactor and a pseudo-substrate peptide. The catalytic domain adopts the canonical sirtuin fold. The CTR forms a β hairpin structure that complements the β sheet of the NAD^+-binding domain, covering an essentially invariant hydrophobic surface. The apo form adopts a distinct open conformation, in which the smaller subdomain of SIRT1 undergoes a rotation with respect to the larger NAD^+-binding subdomain. A biochemical analysis identifies key residues in the active site, an inhibitory role for the CTR, and distinct structural features of the CTR that mediate binding and inhibition of the SIRT1 catalytic domain

SDSSJ14584479+3720215: A Benchmark JHK Blazar Light Curve from the 2MASS Calibration Scans

Active galactic nuclei (AGNs) are well-known to exhibit flux variability across a wide range of wavelength regimes, but the precise origin of the variability at different wavelengths remains unclear. To investigate the relatively unexplored near-IR variability of the most luminous AGNs, we conduct a search for variability using well sampled JHKs-band light curves from the 2MASS survey calibration fields. Our sample includes 27 known quasars with an average of 924 epochs of observation over three years, as well as one spectroscopically confirmed blazar (SDSSJ14584479+3720215) with 1972 epochs of data. This is the best-sampled NIR photometric blazar light curve to date, and it exhibits correlated, stochastic variability that we characterize with continuous auto-regressive moving average (CARMA) models. None of the other 26 known quasars had detectable variability in the 2MASS bands above the photometric uncertainty. A blind search of the 2MASS calibration field light curves for AGN candidates based on fitting CARMA(1,0) models (damped-random walk) uncovered only 7 candidates. All 7 were young stellar objects within the {\rho} Ophiuchus star forming region, five with previous X-ray detections. A significant {\gamma}-ray detection (5{\sigma}) for the known blazar using 4.5 years of Fermi photon data is also found. We suggest that strong NIR variability of blazars, such as seen for SDSSJ14584479+3720215, can be used as an efficient method of identifying previously-unidentified {\gamma}-ray blazars, with low contamination from other AGN.Comment: 6 pages, 3 figures, ApJ Accepte

Molecular Basis for the Anchoring of Proto-Oncoprotein Nup98 to the Cytoplasmic Face of the Nuclear Pore Complex

The cytoplasmic filament nucleoporins of the nuclear pore complex (NPC) are critically involved in nuclear export and remodeling of mRNA ribonucleoprotein particles and are associated with various human malignancies. Here, we report the crystal structure of the Nup98 C-terminal autoproteolytic domain, frequently missing from leukemogenic forms of the protein, in complex with the N-terminal domain of Nup82 and the C-terminal tail fragment of Nup159. The Nup82 β propeller serves as a noncooperative binding platform for both binding partners. Interaction of Nup98 with Nup82 occurs through a reciprocal exchange of loop structures. Strikingly, the same Nup98 groove promiscuously interacts with Nup82 and Nup96 in a mutually excusive fashion. Simultaneous disruption of both Nup82 interactions in yeast causes severe defects in mRNA export, while the severing of a single interaction is tolerated. Thus, the cytoplasmic filament network of the NPC is robust, consistent with its essential function in nucleocytoplasmic transport

Transfusion Rates in Emergency General Surgery: High but Modifiable

Background: Transfusion of red blood cells (RBC) increases morbidity and mortality, and emergency general surgery (EGS) cases have increased risk for transfusion and complication given case complexity and patient acuity. Transfusion reduction strategies and blood-conservation technology have been developed to decrease transfusions. This study explores whether transfusion rates in EGS have decreased as these new strategies have been implemented. Methods: This is a retrospective review of the American College of Surgeons\u27 National Surgical Quality Improvement Program (ACS NSQIP) data from three academic medical centers. Operations performed by general surgeons on adults (aged ≥18 years) were selected. Data were analyzed from two periods: 2011-2013 and 2014-2016. Cases were grouped by the first four digits of the primary procedure Current Procedural Terminology code. Transfusion was defined as any RBC transfusion during or within 72 hours following the operation. Composite morbidity was defined as any NSQIP complication within 30 days following the operation. Results: Overall general surgery transfusion rates decreased from 6.4% to 4.8% from period 1 to period 2 (emergent: 16.6%–11.5%; non-emergent 4.9%–3.7%; Fisher’s exact p values \u3c 0.001). Among patients transfused, the number of units received decreased slightly (median 2 U (IQR 2–3) to median 2 U (IQR 1–3), Mann-Whitney U test p = 0.005). Morbidity decreased (overall: 13.8%–12.3%, p = 0.001; emergent: 26.3%–20.6%, p \u3c 0.001) while mortality did not change. Discussion: Rates of RBC transfusion decreased in both emergent and non-emergent cases. Efforts to reduce transfusion may have been successful in the EGS population. Morbidity improved over the time periods while mortality was unchanged. Level of Evidence: Level III

Chromospheric Activity of HAT-P-11: an Unusually Active Planet-Hosting K Star

Kepler photometry of the hot Neptune host star HAT-P-11 suggests that its spot latitude distribution is comparable to the Sun's near solar maximum. We search for evidence of an activity cycle in the CaII H & K chromospheric emission $S$-index with archival Keck/HIRES spectra and observations from the echelle spectrograph on the ARC 3.5 m Telescope at APO. The chromospheric emission of HAT-P-11 is consistent with a $\gtrsim 10$ year activity cycle, which plateaued near maximum during the Kepler mission. In the cycle that we observed, the star seemed to spend more time near active maximum than minimum. We compare the $\log R^\prime_{HK}$ normalized chromospheric emission index of HAT-P-11 with other stars. HAT-P-11 has unusually strong chromospheric emission compared to planet-hosting stars of similar effective temperature and rotation period, perhaps due to tides raised by its planet.Comment: 16 pages, 8 figures; accepted to the Astrophysical Journa

The SDSS-2MASS-WISE Ten Dimensional Stellar Color Locus

We present the fiducial main sequence stellar locus traced by 10 photometric colors observed by SDSS, 2MASS, and WISE. Median colors are determined using 1,052,793 stars with r-band extinction less than 0.125. We use this locus to measure the dust extinction curve relative to the r-band, which is consistent with previous measurements in the SDSS and 2MASS bands. The WISE band extinction coefficients are larger than predicted by standard extinction models. Using 13 lines of sight, we find variations in the extinction curve in H, Ks, and WISE bandpasses. Relative extinction decreases towards Galactic anti-center, in agreement with prior studies. Relative extinction increases with Galactic latitude, in contrast to previous observations. This indicates a universal mid-IR extinction law does not exist due to variations in dust grain size and chemistry with Galactocentric position. A preliminary search for outliers due to warm circumstellar dust is also presented, using stars with high signal-to-noise in the W3-band. We find 199 such outliers, identified by excess emission in Ks-W3. Inspection of SDSS images for these outliers reveals a large number of contaminants due to nearby galaxies. Six sources appear to be genuine dust candidates, yielding a fraction of systems with infrared excess of 0.12$\pm$0.05%.Comment: 11 pages, 10 figures, MNRAS Accepted. Tables 1 and 2 available online: https://github.com/jradavenport/wise_locu

Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation

Double plant homeodomain finger 2 (DPF2) is a highly evolutionarily conserved member of the d4 protein family that is ubiquitously expressed in human tissues and was recently shown to inhibit the myeloid differentiation of hematopoietic stem/progenitor and acute myelogenous leukemia cells. Here, we present the crystal structure of the tandem plant homeodomain finger domain of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts with the acetylated tails of both histones 3 and 4 via bipartite binding pockets on the DPF2 surface. Blocking these interactions through targeted mutagenesis of DPF2 abolishes its recruitment to target chromatin regions as well as its ability to prevent myeloid differentiation in vivo. Our findings suggest that the histone binding of DPF2 plays an important regulatory role in the transcriptional program that drives myeloid differentiation

High-precision 2MASS JHK_s Light Curves and Other Data For RR Lyrae Star SDSS J015450 + 001501: Strong Constraints For Nonlinear Pulsation Models

We present and discuss an extensive data set for the non-Blazhko ab-type RR Lyrae star SDSS J015450+001501, including optical Sloan Digital Sky Survey ugriz light curves and spectroscopic data, LINEAR and Catalina Sky Survey unfiltered optical light curves, and infrared Two Micron All Sky Survey (2MASS) JHK_s and Wide-field Infrared Survey Explorer W1 and W2 light curves. Most notable is that light curves obtained by 2MASS include close to 9000 photometric measures collected over 3.3 yr and provide an exceedingly precise view of near-infrared variability. These data demonstrate that static atmosphere models are insufficient to explain multiband photometric light-curve behavior and present strong constraints for nonlinear pulsation models for RR Lyrae stars. It is a challenge to modelers to produce theoretical light curves that can explain data presented here, which we make publicly available