Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells. Ten distinct metalloinsertors with varying lipophilicities have been synthesized and their mismatch binding affinities and biological activities determined. Although DNA photocleavage experiments demonstrate that their binding affinities are quite similar, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments have uncovered a relationship between the subcellular distribution of these metalloinsertors and their biological activities. Specifically, we find that all of our metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. However, the metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells, whereas metalloinsertors with less mitochondrial rhodium show activity that is highly selective for MMR-deficient versus proficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cell-selective cytotoxic and antiproliferative activities. The selectivity in cellular targeting depends upon binding to mismatches in genomic DNA

Mechanistic Analysis of Nucleophilic Substrates Oxidation by Functional Models of Vanadium-Dependent Haloperoxidases: A Density Functional Theory Study

Density functional theory has been used to investigate the structural, electronic, and reactivity properties of an established functional model for vanadium-dependent haloperoxidases, K[VO(O 2 )Hheida] (Hheida 2– = 2,2′-[(2-hydroxyethyl)imino]diacetate). Possible solution species were determined on the basis of potential exogenous donors present under the conditions necessary for reactivity. The energetically favored solution-state species is a 1:1 complex of Hheida and vanadium with a coordinated hydroxyethyl donor trans to the vanadium–oxido bond which is in agreement with the reported solid-state structure for K[VO(O 2 )Hheida]. Transition states of the oxidation reaction were located for four substrates: chloride, bromide, iodide, and dimethyl sulfide. The role of protonation and its effects on reactivity were examined for each substrate. Protonation of the peroxido moiety leads to a significant drop in the activation barrier for oxidation. In contrast no transition states could be located for an oxido-transfer process involving the oxido ligand. Barriers of activation calculated for halide oxidation were similar, providing support to the hypothesis that the p K a of the halide in acetonitrile is responsible for the decrease in reactivity between I – , Br – , and Cl – . The results presented herein provide a mechanistic correlation between a functional model and the enzyme, making K[VO(O 2 )Hheida] a “complete” functional model for vanadium-dependent haloperoxidase.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55972/1/515_ftp.pd

Effects of increasing soybean hulls in finishing diets with wet or modified distillers grains plus solubles on performance and carcass characteristics of beef steers

Two experiments evaluated feeding soybean hulls (SBH) in finishing diets that contain distillers grains plus solubles on performance and carcass characteristics. Dietary concentrations of SBH were 0, 12.5, 25, and 37.5% of diet DM. In Exp. 1, 167 crossbred yearling steers (395 ± 22 kg of BW) were fed for 117 d in a randomized block design in which pelleted SBH replaced dry-rolled corn. All diets contained 25% modified distillers grains plus solubles, 15% corn silage, and 5% liquid supplement. As SBH concentration increased, DMI decreased linearly (P = 0.04). Gain and G:F decreased linearly (P \u3c 0.01) in response to increasing concentrations of SBH, which decreased relative energy value from 91 to 79% of corn. Hot carcass weight linearly decreased (P \u3c 0.01) by 24 kg as SBH increased. In Exp. 2, a randomized block design used 160 backgrounded steer calves (363 ± 16 kg of BW) in a 138-d finishing study with 0, 12.5, 25, or 37.5% SBH in the meal form. Basal ingredients consisted of a 1:1 ratio of high-moisture corn and dry-rolled corn, 40% wet distillers grains plus solubles, 8% sorghum silage, and 4% dry meal supplement. There was a tendency (P = 0.12) for a quadratic increase in ADG and G:F as dietary SBH increased, with numerically greatest ADG and G:F with 12.5% SBH. Feeding 12.5 to 25% SBH with 40% wet distillers grains plus solubles (Exp. 2) had little effect on performance but decreased ADG and G:F in diets with 25% modified distillers grains plus solubles (Exp. 1)

New Constraints on Cosmic Reionization from the 2012 Hubble Ultra Deep Field Campaign

Understanding cosmic reionization requires the identification and characterization of early sources of hydrogen-ionizing photons. The 2012 Hubble Ultra Deep Field (UDF12) campaign has acquired the deepest infrared images with the Wide Field Camera 3 aboard Hubble Space Telescope and, for the first time, systematically explored the galaxy population deep into the era when cosmic microwave background (CMB) data indicates reionization was underway. The UDF12 campaign thus provides the best constraints to date on the abundance, luminosity distribution, and spectral properties of early star-forming galaxies. We synthesize the new UDF12 results with the most recent constraints from CMB observations to infer redshift-dependent ultraviolet (UV) luminosity densities, reionization histories, and electron scattering optical depth evolution consistent with the available data. Under reasonable assumptions about the escape fraction of hydrogen ionizing photons and the intergalactic medium clumping factor, we find that to fully reionize the universe by redshift z~6 the population of star-forming galaxies at redshifts z~7-9 likely must extend in luminosity below the UDF12 limits to absolute UV magnitudes of M_UV\sim -13 or fainter. Moreover, low levels of star formation extending to redshifts z~15-25, as suggested by the normal UV colors of z\simeq7-8 galaxies and the smooth decline in abundance with redshift observed by UDF12 to z\simeq10, are additionally likely required to reproduce the optical depth to electron scattering inferred from CMB observations.Comment: Version accepted by ApJ (originally submitted Jan 5, 2013). The UDF12 website can be found at http://udf12.arizona.ed

On the non-abelian Brumer-Stark conjecture and the equivariant Iwasawa main conjecture

We show that for an odd prime p, the p-primary parts of refinements of the (imprimitive) non-abelian Brumer and Brumer-Stark conjectures are implied by the equivariant Iwasawa main conjecture (EIMC) for totally real fields. Crucially, this result does not depend on the vanishing of the relevant Iwasawa mu-invariant. In combination with the authors' previous work on the EIMC, this leads to unconditional proofs of the non-abelian Brumer and Brumer-Stark conjectures in many new cases.Comment: 33 pages; to appear in Mathematische Zeitschrift; v3 many minor updates including new title; v2 some cohomological arguments simplified; v1 is a revised version of the second half of arXiv:1408.4934v

Evaluation of the Value of Fiber in Distillers Grains Plus Solubles on Performance of Finishing Cattle

A finishing study was conducted to determine the value of the fiber in distillers grains plus solubles on cattle performance. Five treatments were evaluated: a corn control diet, 20 or 40% modified distillers grains plus solubles, plus two diets containing corn germ meal and corn bran balanced to equal the fiber content of the two modified distillers grains plus solubles diets. Th ere was a significant improvement in ADG and F:G for cattle fed modified distillers grains plus solubles compared to control. Cattle fed the corn germ meal and bran diets had increased DMI, slightly lower ADG, and poorer F:G compared to the control. Th e isolated fiber component had 83– 90% the feeding value of corn, while modified distillers grains plus solubles had 107– 108%. Other components in distillers besides fiber must improve the value of distillers compared to corn

Hubble Space Telescope and Ground-Based Observations of the Type Iax Supernovae SN 2005hk and SN 2008A

We present Hubble Space Telescope (HST) and ground-based optical and near-infrared observations of SN 2005hk and SN 2008A, typical members of the Type Iax class of supernovae (SNe). Here we focus on late-time observations, where these objects deviate most dramatically from all other SN types. Instead of the dominant nebular emission lines that are observed in other SNe at late phases, spectra of SNe 2005hk and 2008A show lines of Fe II, Ca II, and Fe I more than a year past maximum light, along with narrow [Fe II] and [Ca II] emission. We use spectral features to constrain the temperature and density of the ejecta, and find high densities at late times, with n_e >~ 10^9 cm^-3. Such high densities should yield enhanced cooling of the ejecta, making these objects good candidates to observe the expected "infrared catastrophe," a generic feature of SN Ia models. However, our HST photometry of SN 2008A does not match the predictions of an infrared catastrophe. Moreover, our HST observations rule out a "complete deflagration" that fully disrupts the white dwarf for these peculiar SNe, showing no evidence for unburned material at late times. Deflagration explosion models that leave behind a bound remnant can match some of the observed properties of SNe Iax, but no published model is consistent with all of our observations of SNe 2005hk and 2008A.Comment: 20 pages, 15 figure

The First Extrasolar Planet Discovered with a New Generation High Throughput Doppler Instrument

We report the detection of the first extrasolar planet, ET-1 (HD 102195b), using the Exoplanet Tracker (ET), a new generation Doppler instrument. The planet orbits HD 102195, a young star with solar metallicity that may be part of the local association. The planet imparts radial velocity variability to the star with a semiamplitude of $63.4\pm2.0$ m s$^{-1}$ and a period of 4.11 days. The planetary minimum mass ($m \sin i$) is $0.488\pm0.015$ $M_J$.Comment: 42 pages, 11 figures and 5 tables, Accepted for publication in Ap

The Version-2 Global Precipitation Climatology Project (GPCP) Monthly Precipitation Analysis (1979–Present)

The Global Precipitation Climatology Project (GPCP) Version-2 Monthly Precipitation Analysis is described. This globally complete, monthly analysis of surface precipitation at 2.58 latitude 3 2.58 longitude resolution is available from January 1979 to the present. It is a merged analysis that incorporates precipitation estimates from low-orbit satellite microwave data, geosynchronous-orbit satellite infrared data, and surface rain gauge obser-vations. The merging approach utilizes the higher accuracy of the low-orbit microwave observations to calibrate, or adjust, the more frequent geosynchronous infrared observations. The dataset is extended back into the prem-icrowave era (before mid-1987) by using infrared-only observations calibrated to the microwave-based analysis of the later years. The combined satellite-based product is adjusted by the rain gauge analysis. The dataset archive also contains the individual input fields, a combined satellite estimate, and error estimates for each field. This monthly analysis is the foundation for the GPCP suite of products, including those at finer temporal resolution. The 23-yr GPCP climatology is characterized, along with time and space variations of precipitation. 1

Herschel Observations of a Potential Core Forming Clump: Perseus B1-E

We present continuum observations of the Perseus B1-E region from the Herschel Gould Belt Survey. These Herschel data reveal a loose grouping of substructures at 160 - 500 micron not seen in previous submillimetre observations. We measure temperature and column density from these data and select the nine densest and coolest substructures for follow-up spectral line observations with the Green Bank Telescope. We find that the B1-E clump has a mass of ~ 100 solar masses and appears to be gravitationally bound. Furthermore, of the nine substructures examined here, one substructure (B1-E2) appears to be itself bound. The substructures are typically less than a Jeans length from their nearest neighbour and thus, may interact on a timescale of ~ 1 Myr. We propose that B1-E may be forming a first generation of dense cores, which could provide important constraints on the initial conditions of prestellar core formation. Our results suggest that B1-E may be influenced by a strong, localized magnetic field, but further observations are still required.Comment: 14 pages, 8 figures, published in A&A: Minor calibration correctio