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Search Results: 1 - 10 of 300013 matches for " J. Craig Forrest "
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Unbiased Mutagenesis of MHV68 LANA Reveals a DNA-Binding Domain Required for LANA Function In Vitro and In Vivo
Clinton R. Paden,J. Craig Forrest,Scott A. Tibbetts,Samuel H. Speck
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002906
Abstract: The Latency-Associated Nuclear Antigen (LANA), encoded by ORF73, is a conserved gene among the γ2-herpesviruses (rhadinoviruses). The Kaposi's Sarcoma-Associated Herpesvirus (KSHV) LANA is consistently expressed in KSHV-associated malignancies. In the case of the rodent γ2-herpesvirus, murine gammaherpesvirus 68 (MHV68), the LANA homolog (mLANA) is required for efficient virus replication, reactivation from latency and immortalization of murine fetal liver-derived B cells. To gain insights into mLANA function(s), knowing that KSHV LANA binds DNA and can modulate transcription of a variety of promoters, we sought out and identified a mLANA-responsive promoter which maps to the terminal repeat (TR) of MHV68. Notably, mLANA strongly repressed activity from this promoter. We extended these analyses to demonstrate direct, sequence-specific binding of recombinant mLANA to TR DNA by DNase I footprinting. To assess whether the DNA-binding and/or transcription modulating function is important in the known mLANA phenotypes, we generated an unbiased library of mLANA point mutants using error-prone PCR, and screened a large panel of mutants for repression of the mLANA-responsive promoter to identify loss of function mutants. Notably, among the mutant mLANA proteins recovered, many of the mutations are in a predicted EBNA-1-like DNA-binding domain. Consistent with this prediction, those tested displayed loss of DNA binding activity. We engineered six of these mLANA mutants into the MHV68 genome and tested the resulting mutant viruses for: (i) replication fitness; (ii) efficiency of latency establishment; and (iii) reactivation from latency. Interestingly, each of these mLANA-mutant viruses exhibited phenotypes similar to the mLANA-null mutant virus, indicating that DNA-binding is critical for mLANA function.
Phosphoproteomic Analyses Reveal Signaling Pathways That Facilitate Lytic Gammaherpesvirus Replication
James A. Stahl,Shweta S. Chavan,Jeffrey M. Sifford,Veronica MacLeod,Daniel E. Voth,Ricky D. Edmondson,J. Craig Forrest
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003583
Abstract: Lytic gammaherpesvirus (GHV) replication facilitates the establishment of lifelong latent infection, which places the infected host at risk for numerous cancers. As obligate intracellular parasites, GHVs must control and usurp cellular signaling pathways in order to successfully replicate, disseminate to stable latency reservoirs in the host, and prevent immune-mediated clearance. To facilitate a systems-level understanding of phosphorylation-dependent signaling events directed by GHVs during lytic replication, we utilized label-free quantitative mass spectrometry to interrogate the lytic replication cycle of murine gammaherpesvirus-68 (MHV68). Compared to controls, MHV68 infection regulated by 2-fold or greater ca. 86% of identified phosphopeptides – a regulatory scale not previously observed in phosphoproteomic evaluations of discrete signal-inducing stimuli. Network analyses demonstrated that the infection-associated induction or repression of specific cellular proteins globally altered the flow of information through the host phosphoprotein network, yielding major changes to functional protein clusters and ontologically associated proteins. A series of orthogonal bioinformatics analyses revealed that MAPK and CDK-related signaling events were overrepresented in the infection-associated phosphoproteome and identified 155 host proteins, such as the transcription factor c-Jun, as putative downstream targets. Importantly, functional tests of bioinformatics-based predictions confirmed ERK1/2 and CDK1/2 as kinases that facilitate MHV68 replication and also demonstrated the importance of c-Jun. Finally, a transposon-mutant virus screen identified the MHV68 cyclin D ortholog as a viral protein that contributes to the prominent MAPK/CDK signature of the infection-associated phosphoproteome. Together, these analyses enhance an understanding of how GHVs reorganize and usurp intracellular signaling networks to facilitate infection and replication.
Clouds in the Coldest Brown Dwarfs: FIRE Spectroscopy of Ross 458C
Adam J. Burgasser,Robert A. Simcoe,John J. Bochanski,Didier Saumon,Eric E. Mamajek,Michael C. Cushing,Mark S. Marley,Craig McMurtry,Judith L. Pipher,William J. Forrest
Physics , 2010, DOI: 10.1088/0004-637X/725/2/1405
Abstract: Condensate clouds are a salient feature of L dwarf atmospheres, but have been assumed to play little role in shaping the spectra of the coldest T-type brown dwarfs. Here we report evidence of condensate opacity in the near-infrared spectrum of the brown dwarf candidate Ross 458C, obtained with the Folded-Port Infrared Echellette (FIRE) spectrograph at the Magellan Telescopes. These data verify the low-temperature nature of this source, indicating a T8 spectral classification, log Lbol/Lsun = -5.62+/-0.03, Teff = 650+/-25 K, and a mass at or below the deuterium burning limit. The data also reveal enhanced emission at K-band associated with youth (low surface gravity) and supersolar metallicity, reflecting the properties of the Ross 458 system (age = 150-800 Myr, [Fe/H] = +0.2 to +0.3). We present fits of FIRE data for Ross 458C, the T9 dwarf ULAS J133553.45+113005.2, and the blue T7.5 dwarf SDSS J141624.08+134826.7B, to cloudless and cloudy spectral models from Saumon & Marley. For Ross 458C we confirm a low surface gravity and supersolar metallicity, while the temperature differs depending on the presence (635 [+25,-35] K) or absence (760 [+70,-45] K) of cloud extinction. ULAS J1335+1130 and SDSS J1416+1348B have similar temperatures (595 [+25,-45] K), but distinct surface gravities (log g = 4.0-4.5 cgs versus 5.0-5.5 cgs) and metallicities ([M/H] ~ +0.2 versus -0.2). In all three cases, cloudy models provide better fits to the spectral data, significantly so for Ross 458C. These results indicate that clouds are an important opacity source in the spectra of young cold T dwarfs, and should be considered when characterizing the spectra of planetary-mass objects in young clusters and directly-imaged exoplanets. The characteristics of Ross 458C suggest it could itself be regarded as a planet, albeit one whose cosmogony does not conform with current planet formation theories.
Cool Star Science with the FIRE Spectrograph
Adam J. Burgasser,Robert A. Simcoe,John J. Bochanski,Carl Melis,Craig McMurtry,Judy Pipher,William Forrest,Michael C. Cushing,Dagny L. Looper,Subhanjoy Mohanty
Physics , 2010,
Abstract: The Folded-port InfraRed Echellette (FIRE) has recently been commissioned on the Magellan 6.5m Baade Telescope. This single object, near-infrared spectrometer simultaneously covers the 0.85-2.45 micron window in both cross-dispersed (R ~ 6000) or prism-dispersed (R ~ 250-350) modes. FIRE's compact configuration, high transmission optics and high quantum efficiency detector provides considerable sensitivity in the near-infrared, making it an ideal instrument for studies of cool stars and brown dwarfs. Here we present some of the first cool star science results with FIRE based on commissioning and science verification observations, including evidence of clouds in a planetary-mass brown dwarf, accretion and jet emission in the low-mass T Tauri star TWA 30B, radial velocities of T-type brown dwarfs, and near-infrared detection of a debris disk associated with the DAZ white dwarf GALEX 1931+01.
A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo
Carrie B. Coleman,Jennifer E. McGraw,Emily R. Feldman,Alexa N. Roth,Lisa R. Keyes,Katrina R. Grau,Stephanie L. Cochran,Thomas J. Waldschmidt,Chengyu Liang,J. Craig Forrest,Scott A. Tibbetts
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003916
Abstract: Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells.
Constraints on the Universal CIV Mass Density at z~6 from Early IR Spectra Obtained with the Magellan FIRE Spectrograph
Robert A. Simcoe,Kathy L. Cooksey,Michael E. Matejek,Adam J. Burgasser,John Bochanski,Elizabeth Lovegrove,Rebecca A. Bernstein,Judith L. Pipher,William J. Forrest,Craig McMurtry,Xiaohui Fan,John O'Meara
Physics , 2011, DOI: 10.1088/0004-637X/743/1/21
Abstract: We present a new determination of the intergalactic CIV mass density at 4.3 < z < 6.3. Our constraints are derived from high signal-to-noise spectra of seven quasars at z > 5.8 obtained with the newly commissioned FIRE spectrograph on the Magellan Baade telescope, coupled with six observations of northern objects taken from the literature. We confirm the presence of a downturn in the CIV abundance at =5.66 by a factor of 4.1 relative to its value at =4.96, as measured in the same sightlines. In the FIRE sample, a strong system previously reported in the literature as CIV at z=5.82 is re-identified as MgII at z=2.78, leading to a substantial downward revision in $\Omega_{CIV}$ for these prior studies. Additionally we confirm the presence of at least two systems with low-ionization CII, SiII, and OI absorption but relatively weak signal from CIV. The latter systems systems may be of interest if the downward trend in $\Omega_{CIV}$ at high redshift is driven in part by ionization effects.
Development of sensitive long-wave infrared detector arrays for passively cooled space missions
Craig McMurtry,Donald Lee,James Beletic,Chi-Yi A. Chen,Richard T. Demers,Meghan Dorn,Dennis Edwall,Candice Bacon Fazar,William J. Forrest,Fengchuan Liu,Amanda K. Mainzer,Judith L. Pipher,Aristo Yulius
Physics , 2013, DOI: 10.1117/1.OE.52.9.091804
Abstract: The near-earth object camera (NEOCam) is a proposed infrared space mission designed to discover and characterize most of the potentially hazardous asteroids larger than 140 m in diameter that orbit near the Earth. NASA has funded technology development for NEOCam, including the development of long wavelength infrared detector arrays that will have excellent zodiacal background emission-limited performance at passively cooled focal plane temperatures. Teledyne Imaging Sensors has developed and delivered for test at the University of Rochester the first set of approximately 10 micron cutoff, 1024 x 1024 pixel HgCdTe detector arrays. Measurements of these arrays show the development to be extremely promising: noise, dark current, quantum efficiency, and well depth goals have been met by this technology at focal plane temperatures of 35 to 40 K, readily attainable with passive cooling. The next set of arrays to be developed will address changes suggested by the first set of deliverables.
Lack of an Effect of Protease Inhibitor Use on Glucose Tolerance During Pregnancy
Mara J. Dinsmoor,Scott T. Forrest
Infectious Diseases in Obstetrics and Gynecology , 2002, DOI: 10.1155/s1064744902000212
Abstract: Objective: We hypothesized that HIV-positivewomen on protease inhibitors (PIs) would be more likely to have an elevated glucola test result than those not on PIs.
Nothing a Hot Bath Won't Cure: Infection Rates of Amphibian Chytrid Fungus Correlate Negatively with Water Temperature under Natural Field Settings
Matthew J. Forrest, Martin A. Schlaepfer
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028444
Abstract: Dramatic declines and extinctions of amphibian populations throughout the world have been associated with chytridiomycosis, an infectious disease caused by the pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd). Previous studies indicated that Bd prevalence correlates with cooler temperatures in the field, and laboratory experiments have demonstrated that Bd ceases growth at temperatures above 28°C. Here we investigate how small-scale variations in water temperature correlate with Bd prevalence in the wild. We sampled 221 amphibians, including 201 lowland leopard frogs (Rana [Lithobates] yavapaiensis), from 12 sites in Arizona, USA, and tested them for Bd. Amphibians were encountered in microhabitats that exhibited a wide range of water temperatures (10–50°C), including several geothermal water sources. There was a strong inverse correlation between the water temperature in which lowland leopard frogs were captured and Bd prevalence, even after taking into account the influence of year, season, and host size. In locations where Bd was known to be present, the prevalence of Bd infections dropped from 75–100% in water <15°C, to less than 10% in water >30°C. A strong inverse correlation between Bd infection status and water temperature was also observed within sites. Our findings suggest that microhabitats where water temperatures exceed 30°C provide lowland leopard frogs with significant protection from Bd, which could have important implications for disease dynamics, as well as management applications. There must be quite a few things a hot bath won't cure, but I don't know many of them - Sylvia Plath, “The Bell Jar” (1963).
An intronic SNP in the thyroid hormone receptor β gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor β2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone
Anna Alberobello, Valentina Congedo, Hong Liu, Craig Cochran, Monica C Skarulis, Douglas Forrest, Francesco S Celi
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-144
Abstract: Screening and in vitro characterization of polymorphisms of the intron enhancer region of the THRB gene in the index case of pituitary-selective RTH.The index case of pituitary-selective resistance is characterized by the missense R338W exon 9 mutation in cis with two common SNPs, rs2596623T and rs2596622C, located in the intron enhancer region of the THRB gene. Reporter gene assay experiments in GH3 pituitary-derived cells indicate that rs2596623T generates an increased pituitary cell-specific activity of the TR β2 promoter suggesting that rs2596623T leads to pituitary over-expression of the mutant allele.The combined coding mutation and non-coding SNP therefore generate a tissue-specific dominant-negative condition recapitulating the patient's peculiar phenotype. This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases.Mutations in the THRB gene, encoding thyroid hormone receptor β (TRβ), result in the syndrome of resistance to thyroid hormone (RTH)[1,2]. RTH is a rare autosomal dominant disease with two main clinical presentations. The generalized RTH (GRTH) is characterized by elevated levels of TH, inappropriately normal or elevated levels of TSH [3], and a variable clinical presentation, ranging from asymptomatic to severe hypothyroidism [4,5]. A rarer form of RTH is characterized by selective resistance mostly limited to the pituitary (PRTH), with a prevalence of hyperthyroid symptoms since peripheral tissues are relatively less resistant to TH action but are exposed to elevated TH levels [6]. Most RTH mutations are localized in "hot spots" in the C-terminal coding exons of THRB, that generate dominant negative proteins with impaired ligand binding [7]. Despite striking differences among the clinical presentations, there is a lack of strict genotype-phenotype correlation and identical THRB gene mutations have been observed in PRTH or GRTH patients [8].The THRB gene expresses N-terminal variant TR β1 and T
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