713 research outputs found
Global modeling of internal tides within an eddying ocean general circulation model
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91777/1/25-2_arbic_hi.pd
The Impact of an Intense Cyclone on Short-Term Sea Ice Loss in a Fully Coupled Atmosphere-Ocean-Ice Model
AbstractArctic cyclones may be associated with periods of locally enhanced sea ice loss during the summer, and some studies have found that an intense cyclone in August 2012 resulted in a rapid sea ice retreat. This study uses a coupled atmosphereâoceanâice model (NavyâESPC) to explore the relationship between the 2012 cyclone and shortâterm sea ice melting. There are two mechanisms of cycloneâinduced melting in NavyâESPC: turbulent mixing of a warm layer located at 15â to 35âm depth increases bottom melting and warm air advection by the strong surface winds increases surface melting. Although the rate of sea ice melt is substantially increased in association with the cyclone, this effect is confined to a relatively small region and only lasts for a few days. There is no clear signature of the cyclone on the overall Arctic sea ice extent in NavyâESPC
Skill tests of three-dimensional tidal currents in a global ocean model: A look at the North Atlantic
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92458/1/jgr_timkoetal_northatlatnictidalcurrentskilltest_2012.pd
The Effect of Single Versus Group ÎŒCT on the Detection of Trabecular and Cortical Disease Phenotypes in Mouse Bones
Microâcomputed tomography is a critical assessment tool for boneârelated preclinical research, especially in murine models. To expedite the scanning process, researchers often image multiple bones simultaneously; however, it is unknown if this impacts scan quality and alters the ability to detect differences between experimental groups. The purpose of this study was to assess the effect of multibone scanning on detecting diseaseâinduced changes in bone microarchitecture and mineral density by group scanning two murine models with known skeletal defects: the Col1a2 G610C/+ model of osteogenesis imperfecta and an adenineâinduced model of chronic kidney disease. Adult male femurs were scanned individually and in random groups of three and eight in a Bruker Skyscan 1172 and 1176, respectively, then assessed for standard trabecular and cortical bone measures. Although scanning methodology altered raw values, with trabecular microarchitecture values more affected than cortical properties, a disease phenotype was still detectable in both group and solo scans. However, tissue mineral density in both trabecular and cortical bone was significantly impacted by group versus solo scanning. Researchers may be able to use small groupings in a single ÎŒCT scan to expedite preclinical analyses when the overall bone phenotype is large to decrease costs and increase speed of discoveries; however the details of scanning (single or group) should always be reported
VAST: An ASKAP Survey for Variables and Slow Transients
The Australian Square Kilometre Array Pathfinder (ASKAP) will give us an
unprecedented opportunity to investigate the transient sky at radio
wavelengths. In this paper we present VAST, an ASKAP survey for Variables and
Slow Transients. VAST will exploit the wide-field survey capabilities of ASKAP
to enable the discovery and investigation of variable and transient phenomena
from the local to the cosmological, including flare stars, intermittent
pulsars, X-ray binaries, magnetars, extreme scattering events, interstellar
scintillation, radio supernovae and orphan afterglows of gamma ray bursts. In
addition, it will allow us to probe unexplored regions of parameter space where
new classes of transient sources may be detected. In this paper we review the
known radio transient and variable populations and the current results from
blind radio surveys. We outline a comprehensive program based on a multi-tiered
survey strategy to characterise the radio transient sky through detection and
monitoring of transient and variable sources on the ASKAP imaging timescales of
five seconds and greater. We also present an analysis of the expected source
populations that we will be able to detect with VAST.Comment: 29 pages, 8 figures. Submitted for publication in Pub. Astron. Soc.
Australi
Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells
Enediyne natural products are a class of compounds that were recognized for their potential as chemotherapeutic agents many years ago, but found to be highly cytotoxic due to their propensity for low thermal activation. Bergman cyclization of the enediyne moiety produces a diradical intermediate, and may subsequently induce DNA damage and account for the extreme cytotoxicity. While difficulties in controlling the thermal cyclization reaction have limited the clinical use of cyclic enediynes, we have previously shown that enediyne activity, and thus toxicity at physiological temperatures can be modulated by metallation of acyclic enediynes. Furthermore, the cytotoxicity of "metalloenediynes" can be potentiated by hyperthermia. In this study, we characterized a suite of novel metallated enediyne motifs that usually induced little or no cytotoxicity when two different human cancer cell lines were treated with the compounds at 37°C, but showed a significant enhancement of cytotoxicity after cells were exposed to moderate hyperthermia during drug treatment. Cultured U-1 melanoma or MDA-231 breast cancer cells were treated with various concentrations of Cu, Fe and Zn complexes of the enediyne (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) and clonogenic survival was assessed to determine the effects of the drugs at 37°C and 42.5°C. Toxicity at 37°C varied for each compound, but hyperthermia potentiated the cytotoxicity of each compound in both cell lines. Cytotoxicity was concentration-, time- and temperature-dependent. Heating cells during drug treatment resulted in enhanced apoptosis, but the role of cell cycle perturbation in the response of the cells to the drugs was less clear. Lastly, we showed that hyperthermia enhanced the number of DNA double-strand breaks (DSBs) induced by the compounds, and inhibited their repair after drug treatment. Thus, thermal enhancement of cytotoxicity may be due, at least in part, to the propensity of the enediyne moiety to induce DSBs, and/or a reduction in DSB repair efficiency. We propose that "tuning" of metalloenediyne toxicity through better-controlled reactivity could have potential clinical utility, since we envision that such compounds could be administered systemically as relatively non-toxic agents, but cytotoxicity could be enhanced in, and confined to a tumor volume when subjected to localized heating
Non-Additive Effects of Combined NOX1/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
Chronic kidney diseaseâmineral and bone disorder (CKDâMBD) increases cardiovascular calcification and skeletal fragility in part by increasing systemic oxidative stress and disrupting mineral homeostasis through secondary hyperparathyroidism. We hypothesized that treatments to reduce reactive oxygen species formation and reduce parathyroid hormone (PTH) levels would have additive beneficial effects to prevent cardiovascular calcification and deleterious bone architecture and mechanics before endâstage kidney disease. To test this hypothesis, we treated a naturally progressive model of CKDâMBD, the Cy/+ rat, beginning early in CKD with the NADPH oxidase (NOX1/4) inhibitor GKTâ137831 (GKT), the preclinical analogue of the calcimimetic etelcalcetide, KPâ2326 (KP), and their combination. The results demonstrated that CKD animals had elevated blood urea nitrogen, PTH, fibroblast growth factor 23 (FGF23), and phosphorus. Treatment with KP reduced PTH levels compared with CKD animals, whereas GKT treatment increased Câterminal FGF23 levels without altering intact FGF23. GKT treatment alone reduced aortic calcification and NOX4 expression but did not alter the oxidative stress marker 8âOHdG in the serum or aorta. KP treatment reduced aortic 8âOHdG and inhibited the ability for GKT to reduce aortic calcification. Treatments did not alter heart calcification or left ventricular mass. In the skeleton, CKD animals had reduced trabecular bone volume fraction and trabecular number with increased trabecular spacing that were not improved with either treatment. The cortical bone was not altered by CKD or by treatments at this early stage of CKD. These results suggest that GKT reduces aortic calcification while KP reduces aortic oxidative stress and reduces PTH, but the combination was not additive
Effect of Advanced Glycation EndâProducts (AGE) Lowering Drug ALTâ711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKDâMBD
Chronic kidney diseaseâmineral bone disorder (CKDâMBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation endâproducts (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKDâMBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALTâ711), or with calcium in the drinking water to mimic calcium phosphate binders for 10âweeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALTâ711 had no effect on kidney function or PTH, but 3âmg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALTâ711, with parallel decreases in left ventricular hypertrophy. ALTâ711 (3âmg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3âmg/kg ALTâ711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKDâMBD with an AGE breaker ALTâ711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALTâ711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKDâMBD. © 2019 American Society for Bone and Mineral Research
Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent
Background: Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use. We recently showed that enediyne toxicity at 37 °C can be mitigated by metallation, but cytotoxic effects of 'metalloenediynes' on cultured tumor cells are potentiated by hyperthermia. Reduction of cytotoxicity at normothermia suggests metalloenediynes will have a large therapeutic margin, with cell death occurring primarily in the heated tumor. Based on our previous in vitro findings, FeSO4-PyED, an Fe co-factor complex of (Z)-N,N'-bis[1-pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine, was prioritized for further in vitro and in vivo testing in normal human melanocytes and melanoma cells.
Methods: Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO4-PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO4-PyED at 37 or 42.5 °C.
Results: FeSO4-PyED is a DNA-binding compound. Enhancement of FeSO4-PyED cytotoxicity by hyperthermia in melanoma cells was due to Bergman cyclization, diradical formation, and increased apoptosis. Thermal enhancement, however, was not observed in melanocytes. FeSO4-PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage.
Conclusion: By leveraging the unique thermal activation properties of metalloenediynes, we propose that localized moderate hyperthermia can be used to confine the cytotoxicity of these compounds to tumors, while sparing normal tissue
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