The Expression and Function of Wilms\u27 Tumor 1 in Malignant Glioma

The Wilms\u27 tumor 1 gene is overexpressed in many types of cancer and is associated with poor prognosis and resistance to anti-cancer therapies. In vitro studies in non-glioma cells types have demonstrated that WTl plays a role in increased proliferation, resistance to apoptosis, and increased cellular invasion. We aimed to thoroughly characterize the expression pattern of Wilms\u27 tumor 1 in human malignant glioma and discern its function in this complex disease process. We screened a large sample of established human malignant glioma cell lines and glioma tissue specimens of all grades for WT1 expression. The majority of cell lines and 80% of all glioma tissue expressed WTI mRNA, all of which expressed WTl(+KTS) isoforms. Further screening of the glioblastoma specimens for p53 mutation followed by logistic regression analysis demonstrated a positive correlation between WTl expression and wild-type p53 (p = 0.04). To determine if WTl and p53 functionally interacted, we generated LN-229 glioblastoma cells that stably expressed WTl. As LN-229 cells harbor a p53 mutation, transient transfection with wild-type p53 induced apoptosis. However, stable WTI expression did not protect cells from p53-mediated cell death. We then generated U87MG cells (p53 wild-type) that stably expressed WT1 to model an endogenous p53 response. It is well known that after treatment with ionizing radiation, U87MG cells readily undergo p53-mediated apoptosis. Again, WTI expression did not protect against ionizing radiation induced p53-mediated cell death. We next examined the effect of transient WTI silencing on ionizing radiation induced cell death in T98G and LN-18 cells which express endogenous WTl. Combination treatment with ionizing radiation and silencing of WTI using short interfering RNA caused a decrease in viability and clonogenic survival relative to radiation alone in both cell lines. Lastly, we studied the effect of stable WTl silencing using short hairpin RNA on glioblastoma cell tumorigenicity. Stable transduction of U25 1MG and LN-18 cells with WTI short hairpin RNA resulted in a marked decrease in proliferation. WTI silencing in U251MG cells also caused a decrease in in vitro invasion. WTl silencing in U251MG cells caused an increase in tumor latency and a decrease in tumor growth rate when cells were used to subcutaneously inoculate nude mice. Not only do these studies support an oncogenic role for WTI in glioma biology, they provide encouraging evidence that WTl may be a therapeutic target for molecular treatment of glioblastoma

Integrated tools for control-system analysis

The basic functions embedded within a user friendly software package (MATRIXx) are used to provide a high level systems approach to the analysis of linear control systems. Various control system analysis configurations are assembled automatically to minimize the amount of work by the user. Interactive decision making is incorporated via menu options and at selected points, such as in the plotting section, by inputting data. There are five evaluations such as the singular value robustness test, singular value loop transfer frequency response, Bode frequency response, steady-state covariance analysis, and closed-loop eigenvalues. Another section describes time response simulations. A time response for random white noise disturbance is available. The configurations and key equations used for each type of analysis, the restrictions that apply, the type of data required, and an example problem are described. One approach for integrating the design and analysis tools is also presented

Classical turning surfaces in solids: When do they occur, and what do they mean?

Classical turning surfaces of Kohn-Sham potentials, separating classically-allowed regions (CARs) from classically-forbidden regions (CFRs), provide a useful and rigorous approach to understanding many chemical properties of molecules. Here we calculate such surfaces for several paradigmatic solids. Our study of perfect crystals at equilibrium geometries suggests that CFRs are absent in metals, rare in covalent semiconductors, but common in ionic and molecular crystals. A CFR can appear at a monovacancy in a metal. In all materials, CFRs appear or grow as the internuclear distances are uniformly expanded. Calculations with several approximate density functionals and codes confirm these behaviors. A classical picture of conduction suggests that CARs should be connected in metals, and disconnected in wide-gap insulators. This classical picture is confirmed in the limits of extreme uniform compression of the internuclear distances, where all materials become metals without CFRs, and extreme expansion, where all materials become insulators with disconnected and widely-separated CARs around the atoms.Comment: Added supplemental information (63 pages), was missing in original submission. Minor typo corrections in Tables I and III for Eps_HO - vs(r) column (and CFR % volume for Pt monovacancy) for PBE data onl

Immunocompetent murine models for the study of glioblastoma immunotherapy.

Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches

The Degradation of Acetaldehyde in Estuary Waters in Southern California, USA

Acetaldehyde plays an important role in oxidative cycles in the troposphere. Estimates of its air-water flux are important in global models. Biological degradation is believed to be the dominant loss process in water, but there have been few measurements, none in estuaries. Acetaldehyde degradation rates were measured in surface waters at the inflow to the Upper Newport Back Bay estuary in Orange County, Southern California, USA, over a 6-month period including the rainy winter season. Deuterated acetaldehyde was added to filtered and unfiltered water samples incubated in glass syringes, and its loss analyzed by purge and trap gas chromatography mass spectrometry. Filtered samples showed no significant degradation, suggesting that particle-mediated degradation is the dominant removal process. Correlation between measured degradation rate constants in unfiltered incubations and bacteria counts suggests the loss is due to microorganisms. Degradation in unfiltered samples followed first-order kinetics, with rate constants ranging from 0.0006 to 0.025 min-1 (k; average 0.0043 ± 0.006 min-1). Turnover (1/k) ranged from 40 to 1667 min, consistent with prior studies in coastal waters. Acetaldehyde concentrations in the estuary are estimated to range from 30 to ~500 nM (average ~250 nM). Results suggest the estuary is a source of acetaldehyde to the atmosphere

In situ evaluation of an automated aerial bait delivery system for landscape-scale control of invasive brown treesnakes on Guam

After decades of biodiversity loss and economic burden caused by the brown treesnake invasion on the Pacific island of Guam, relief hovers on the horizon. Previous work by USDA Wildlife Services (WS) and its National Wildlife Research Center (NWRC) demonstrated that brown treesnake numbers in forested habitats can be dramatically suppressed by aerial delivery of dead newborn mouse (DNM) baits treated with 80 mg of acetaminophen. However, manual bait preparation and application is impractical for landscape-scale treatment. WS, NWRC, and the US Department of the Interior have collaborated with Applied Design Corporation to engineer an automated bait manufacturing and delivery system. The core technology is an aerially delivered biodegradable “bait cartridge” designed to tangle in the tree canopy, making the acetaminophen bait available to treesnakes and out of reach of terrestrial non-target organisms. When mounted on a rotary- or fixed-wing airframe, the automated dispensing module (ADM) unit can broadcast 3,600 bait cartridges at a rate of four per second and can treat 30 hectares of forest at a density of 120 acetaminophen baits per hectare within 15 minutes of firing time. We conducted the first in situ evaluation of the ADM in July 2016. Initial acetaminophen bait deployment rates (proper opening of the bait cartridge for canopy entanglement) were low, and mechanism jams were frequent due to internal friction and wind forces; on-site remedial engineering improved these performance measures. Bait cartridge placement and spacing were accurate (average 8.9 m along 9 m swaths) under various flight heights and speeds. Canopy entanglement of properly-deployed acetaminophen baits was high (66.6%). Although only a small proportion (5.9%) of radio transmitter-equipped acetaminophen baits were confirmed to have been taken by brown treesnakes, the baiting density was high enough to make it likely that a significant proportion of brown treesnakes in the area had taken acetaminophen baits. With subsequent improvements in system reliability, the automated bait cartridge manufacturing and delivery system is poised to transition from research and development to operational field implementation. Applications include reduction of brown treesnake numbers around transportation infrastructure and within core habitats for the reintroduction of native birds extirpated by this troublesome invasive predator

In situ evaluation of an automated aerial bait delivery system for landscape-scale control of invasive brown treesnakes on Guam

After decades of biodiversity loss and economic burden caused by the brown treesnake invasion on the Pacific island of Guam, relief hovers on the horizon. Previous work by USDA Wildlife Services (WS) and its National Wildlife Research Center (NWRC) demonstrated that brown treesnake numbers in forested habitats can be dramatically suppressed by aerial delivery of dead newborn mouse (DNM) baits treated with 80 mg of acetaminophen. However, manual bait preparation and application is impractical for landscape-scale treatment. WS, NWRC, and the US Department of the Interior have collaborated with Applied Design Corporation to engineer an automated bait manufacturing and delivery system. The core technology is an aerially delivered biodegradable “bait cartridge” designed to tangle in the tree canopy, making the acetaminophen bait available to treesnakes and out of reach of terrestrial non-target organisms. When mounted on a rotary- or fixed-wing airframe, the automated dispensing module (ADM) unit can broadcast 3,600 bait cartridges at a rate of four per second and can treat 30 hectares of forest at a density of 120 acetaminophen baits per hectare within 15 minutes of firing time. We conducted the first in situ evaluation of the ADM in July 2016. Initial acetaminophen bait deployment rates (proper opening of the bait cartridge for canopy entanglement) were low, and mechanism jams were frequent due to internal friction and wind forces; on-site remedial engineering improved these performance measures. Bait cartridge placement and spacing were accurate (average 8.9 m along 9 m swaths) under various flight heights and speeds. Canopy entanglement of properly-deployed acetaminophen baits was high (66.6%). Although only a small proportion (5.9%) of radio transmitter-equipped acetaminophen baits were confirmed to have been taken by brown treesnakes, the baiting density was high enough to make it likely that a significant proportion of brown treesnakes in the area had taken acetaminophen baits. With subsequent improvements in system reliability, the automated bait cartridge manufacturing and delivery system is poised to transition from research and development to operational field implementation. Applications include reduction of brown treesnake numbers around transportation infrastructure and within core habitats for the reintroduction of native birds extirpated by this troublesome invasive predator

Chromophoric Dissolved Organic Matter and Dissolved Organic Carbon in Lakes Across an Elevational Gradient From the Mountains to the Sea

Dissolved organic matter (DOM) in lakes across elevation gradients is a complex function of topography, climate, vegetation coverage, land use, and lake properties. To examine sources and processing of DOM from sea level to mountain lakes (3–1,574 m), we measured dissolved organic carbon (DOC) concentrations and chromophoric dissolved organic matter (CDOM) optical properties, lake characteristics, and water quality parameters in 62 freshwater lakes in the Pacific Northwest, USA. Higher elevation lakes had lower DOC concentrations and absorbance. These lakes had higher forest cover and minimal wetlands in their watershed, in addition to low nutrients, water temperatures, and chlorophyll a in the lake itself. Two humic-like and one protein-like fluorescent component were identified from excitation-emission matrix spectroscopy. The index of recent autochthonous contribution (BIX), fluorescence index (FIX), and SR optical indices showed that most lakes were dominated by terrestrially derived material. The humification index (HIX) and specific ultra-violet absorbance (SUVA254) were consistent with more aromatic humic CDOM at lower elevations. The lower fluorescence of humic-like components at higher elevation was attributed to lower inputs from vegetation. The relative contribution of the protein-like component increased at higher elevation. This may be due to reduced allochthonous terrestrial inputs relative to in situ production of autochthonous material or increased photochemical/biological degradation of allochthonous material. Differences in optical characteristics associated with the amount and source of CDOM were observed across the elevational gradient. These differences were driven by characteristics at both within-lake and watershed scales

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