A Drug-Sensitive Genetic Network Masks Fungi from the Immune System

Fungal pathogens can be recognized by the immune system via their β-glucan, a potent proinflammatory molecule that is present at high levels but is predominantly buried beneath a mannoprotein coat and invisible to the host. To investigate the nature and significance of “masking” this molecule, we characterized the mechanism of masking and consequences of unmasking for immune recognition. We found that the underlying β-glucan in the cell wall of Candida albicans is unmasked by subinhibitory doses of the antifungal drug caspofungin, causing the exposed fungi to elicit a stronger immune response. Using a library of bakers' yeast (Saccharomyces cerevisiae) mutants, we uncovered a conserved genetic network that is required for concealing β-glucan from the immune system and limiting the host response. Perturbation of parts of this network in the pathogen C. albicans caused unmasking of its β-glucan, leading to increased β-glucan receptor-dependent elicitation of key proinflammatory cytokines from primary mouse macrophages. By creating an anti-inflammatory barrier to mask β-glucan, opportunistic fungi may promote commensal colonization and have an increased propensity for causing disease. Targeting the widely conserved gene network required for creating and maintaining this barrier may lead to novel broad-spectrum antimycotics

Corticosterone Regulates Both Naturally Occurring and Cocaine‐Induced Dopamine Signaling by Selectively Decreasing Dopamine Uptake

Stressful and aversive events promote maladaptive reward‐seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine\u27s effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast‐scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine

The Exceptionally Luminous Type Ia Supernova 2007If

SN 2007if was the third over-luminous Type Ia supernova (SN Ia) detected after 2003fg and 2006gz. We present the photometric and spectroscopic observations of the SN and its host by ROTSE-III, HET, and Keck. From the H a line identified in the host spectra, we determine a redshift of 0.0736. At this distance, the SN reached an absolute magnitude of -20.4, brighter than any other SNe Ia ever observed. If the source of luminosity is radioactive decay, a large amount of radioactive nickel (similar to 1.5 M(circle dot)) is required to power the peak luminosity, more than can be produced realistically in a Chandrasekhar mass progenitor. Low expansion velocity, similar to that of 2003fg, is also measured around the maximum light. The observations may suggest that SN 2007if was from a massive white dwarf progenitor, plausibly exploding with mass well beyond 1.4 M(circle dot). Alternatively, we investigate circumstellar interaction that may contribute to the excess luminosity.NASA NNX-08AN25G, NNX-08AV63GNSF AST-0707769, PHY-0801007Australian Research CouncilUniversity of New South WalesUniversity of TexasUniversity of MichiganAstronom

Particle Size Specific Magnetic Properties Across the Norwegian‐Greenland Seas: Insights Into the Influence of Sediment Source and Texture on Bulk Magnetic Records

We make fundamental observations of the particle size variability of magnetic properties from 71 core tops that span the southern Greenland and Norwegian Seas. These data provide the first detailed regional characterization of how bulk magnetic properties vary with sediment texture, sediment source, and sediment transport. Magnetic susceptibility (MS) and hysteresis parameters were measured on the bulk sediment and the five constituent sediment particle size fractions (clay, fine silt, medium silt, coarse silt, and sand). The median MS value of the medium silt size fraction is ~3–5 times higher than that of the sand and clay size fractions and results in a strong sensitivity of bulk MS to sediment texture. Hysteresis properties of the clay size fraction are relatively homogeneous and contrast that silt and sand size fractions which show regional differences across the study area. These coarser fractions are more transport limited and using medium silt hysteresis measurements and low temperature MS behavior we establish three endmembers that effectively explain the variability observed across the region. We model the response of bulk magnetic properties to changes in sediment texture and suggest that variations in sediment source are required to explain the bulk magnetic property variability observed in cores across the southern Greenland and Norwegian Seas. These findings imply that sediment source has a greater influence on driving bulk magnetic property variability across this region than has previously been assumed

Long-term outcome after early infrainguinal graft failure

AbstractPurpose: To determine the long-term outcome and prognostic factors after early infrainguinal graft failure (<30 days).Methods: Retrospective analysis of limb salvage data, patency data, and prognostic risk factors in 112 new infrainguinal bypass grafts from 1985 to 1995 that occluded within 30 days of operation.Result: Thirty-six femoropopliteal and 76 femorotibial/femoropedal arterial bypass (“index”) procedures were performed for rest pain (50%), tissue loss (31%), or disabling claudication (19%). In 103 patients, an immediate additional revascularization (“takeback”) procedure was performed at the time of early graft failure. Life table analysis of the takeback procedures for threatened limbs (n = 84) revealed limb salvage rates of 74%, 54%, 40%, and 31% at 1 month, 1 year, 3 years, and 5 years, respectively. The 1-month limb salvage rate (threatened limbs) was 12% (1 of 8) in patients who were not taken back for revascularization and 33% (4 of 12) in patients who had undergone more than one takeback procedure within 30 days. The secondary graft patency rates for the takeback procedures (n = 103) were 70%, 37%, 27%, and 23% at 1 month, 1 year, 3 years, and 5 years, respectively. Univariate and life table analysis revealed that patients who were given anticoagulation medication after the index procedure (before graft thrombosis) or patients who had undergone previous ipsilateral leg revascularization had significantly lower rates of limb salvage and graft patency (p < 0.05). The limb salvage rate was also significantly worse in patients who had single-vessel runoff compared with those who had multiple-vessel runoff (p < 0.01). Thrombectomy and revision or complete graft replacement had a better secondary patency rate than thrombectomy alone (p < 0.05). Autogenous vein grafts had better outcome than polytetrafluoroethylene-containing grafts, but statistical significance was not achieved. No significant differences in limb salvage or graft patency rates were found between femoropopliteal versus femorotibial/femoropedal bypass grafting, age, gender, previous inflow surgery, diabetes, hypertension, smoking, or cardiac, renal, or pulmonary disease.Conclusion: The long-term limb salvage and graft patency rates after takeback revascularization procedures for early graft failure are poor. Despite poor outcome, a single takeback procedure appears warranted in all patients. Multiple takeback procedures, however, do not appear to be justified, especially in patients who are given anticoagulation medication after the index bypass procedure, repeat leg bypass procedures, or if there is no potential for graft revision

Feasibility of Ultraviolet Light Emitting Diodes as an Alternative Light Source for Photocatalysis

The objective of this study was to determine whether ultraviolet light emitting diodes (UV-LEDs) could serve as an alternative photon source efficiently for heterogeneous photocatalytic oxidation (PCO). An LED module consisting of 12 high-power UV-A LEDs was designed to be interchangeable with a UV-A fluorescent black light blue (BLB) lamp in a Silica-Titania Composite (STC) packed bed annular reactor. Lighting and thermal properties were characterized to assess the uniformity and total irradiant output. A forward current of (I(sub F)) 100 mA delivered an average irradiance of 4.0 m W cm(exp -2), which is equivalent to the maximum output of the BLB, but the irradiance of the LED module was less uniform than that of the BLB. The LED- and BLB-reactors were tested for the oxidization of 50 ppmv ethanol in a continuous flow-through mode with 0.94 sec space time. At the same irradiance, the UV-A LED reactor resulted in a lower PCO rate constant than the UV-A BLB reactor (19.8 vs. 28.6 nM CO2 sec-I), and consequently lower ethanol removal (80% vs. 91%) and mineralization efficiency (28% vs. 44%). Ethanol mineralization increased in direct proportion to the irradiance at the catalyst surface. This result suggests that reduced ethanol mineralization in the LED- reactor could be traced to uneven irradiance over the photocatalyst, leaving a portion of the catalyst was under-irradiated. The potential of UV-A LEDs may be fully realized by optimizing the light distribution over the catalyst and utilizing their instantaneous "on" and "off' feature for periodic irradiation. Nevertheless, the current UV-A LED module had the same wall plug efficiency (WPE) of 13% as that of the UV-A BLB. These results demonstrated that UV-A LEDs are a viable photon source both in terms of WPE and PCO efficiency

Mucosal candidiasis elicits NF- B activation, proinflammatory gene expression and localized neutrophilia in zebrafish

SUMMARYThe epithelium performs a balancing act at the interface between an animal and its environment to enable both pathogen killing and tolerance of commensal microorganisms. Candida albicans is a clinically important human commensal that colonizes all human mucosal surfaces, yet is largely prevented from causing mucosal infections in immunocompetent individuals. Despite the importance of understanding host-pathogen interactions at the epithelium, no immunocompetent vertebrate model has been used to visualize these dynamics non-invasively. Here we demonstrate important similarities between swimbladder candidiasis in the transparent zebrafish and mucosal infection at the mammalian epithelium. Specifically, in the zebrafish swimmbladder infection model, we show dimorphic fungal growth, both localized and tissue-wide epithelial NF-κB activation, induction of NF-κB -dependent proinflammatory genes, and strong neutrophilia. Consistent with density-dependence models of host response based primarily on tissue culture experiments, we show that only high-level infection provokes widespread activation of NF-κB in epithelial cells and induction of proinflammatory genes. Similar to what has been found using in vitro mammalian models, we find that epithelial NF-κB activation can occur at a distance from the immediate site of contact with epithelial cells. Taking advantage of the ability to non-invasively image infection and host signaling at high resolution, we also report that epithelial NF-κB activation is diminished when phagocytes control the infection. This is the first system to model host response to mucosal infection in the juvenile zebrafish, and offers unique opportunities to investigate the tripartite interactions of C. albicans, epithelium and immune cells in an intact host

Star formation histories of dwarf galaxies in the FIRE simulations: dependence on mass and Local Group environment

We study star formation histories (SFHs) of $\simeq500$ dwarf galaxies (stellar mass $M_\ast = 10^5 - 10^9\,M_\odot$) from FIRE-2 cosmological zoom-in simulations. We compare dwarfs around individual Milky Way (MW)-mass galaxies, dwarfs in Local Group (LG)-like environments, and true field (i.e. isolated) dwarf galaxies. We reproduce observed trends wherein higher-mass dwarfs quench later (if at all), regardless of environment. We also identify differences between the environments, both in terms of "satellite vs. central" and "LG vs. individual MWvs. isolated dwarf central." Around the individual MW-mass hosts, we recover the result expected from environmental quenching: central galaxies in the "near field" have more extended SFHs than their satellite counterparts, with the former more closely resemble isolated ("true field") dwarfs (though near-field centrals are still somewhat earlier forming). However, this difference is muted in the LG-like environments, where both near-field centrals and satellites have similar SFHs, which resemble satellites of single MW-mass hosts. This distinction is strongest for $M_\ast = 10^6 - 10^7\,M_\odot$ but exists at other masses. Our results suggest that the paired halo nature of the LG may regulate star formation in dwarf galaxies even beyond the virial radii of the MW and Andromeda. Caution is needed when comparing zoom-in simulations targeting isolated dwarf galaxies against observed dwarf galaxies in the LG.Comment: Main text: 11 pages, 8 figures; appendices: 4 pages, 4 figures. Submitted to MNRAS; comments welcom

High-Velocity Line Forming Regions in the Type Ia Supernova 2009ig

We report measurements and analysis of high-velocity (> 20,000 km/s) and photospheric absorption features in a series of spectra of the Type Ia supernova (SN) 2009ig obtained between -14d and +13d with respect to the time of maximum B-band luminosity. We identify lines of Si II, Si III, S II, Ca II and Fe II that produce both high-velocity (HVF) and photospheric-velocity (PVF) absorption features. SN 2009ig is unusual for the large number of lines with detectable HVF in the spectra, but the light-curve parameters correspond to a slightly overluminous but unexceptional SN Ia (M_B = -19.46 mag and Delta_m15 (B) = 0.90 mag). Similarly, the Si II lambda_6355 velocity at the time of B-max is greater than "normal" for a SN Ia, but it is not extreme (v_Si = 13,400 km/s). The -14d and -13d spectra clearly resolve HVF from Si II lambda_6355 as separate absorptions from a detached line forming region. At these very early phases, detached HVF are prevalent in all lines. From -12d to -6d, HVF and PVF are detected simultaneously, and the two line forming regions maintain a constant separation of about 8,000 km/s. After -6d all absorption features are PVF. The observations of SN 2009ig provide a complete picture of the transition from HVF to PVF. Most SN Ia show evidence for HVF from multiple lines in spectra obtained before -10d, and we compare the spectra of SN 2009ig to observations of other SN. We show that each of the unusual line profiles for Si II lambda_6355 found in early-time spectra of SN Ia correlate to a specific phase in a common development sequence from HVF to PVF.Comment: 19 pages, 11figures, 4 tables, submitted to Ap