Hearing dysfunction in heterozygous M itf Mi‐wh /+ mice, a model for W aardenburg syndrome type 2 and T ietz syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95364/1/pcmr12030.pd

Quantum strategies

We consider game theory from the perspective of quantum algorithms. Strategies in classical game theory are either pure (deterministic) or mixed (probabilistic). We introduce these basic ideas in the context of a simple example, closely related to the traditional Matching Pennies game. While not every two-person zero-sum finite game has an equilibrium in the set of pure strategies, von Neumann showed that there is always an equilibrium at which each player follows a mixed strategy. A mixed strategy deviating from the equilibrium strategy cannot increase a player's expected payoff. We show, however, that in our example a player who implements a quantum strategy can increase his expected payoff, and explain the relation to efficient quantum algorithms. We prove that in general a quantum strategy is always at least as good as a classical one, and furthermore that when both players use quantum strategies there need not be any equilibrium, but if both are allowed mixed quantum strategies there must be.Comment: 8 pages, plain TeX, 1 figur

Reduced Coupling of Oxidative Phosphorylation In Vivo Precedes Electron Transport Chain Defects Due to Mild Oxidative Stress in Mice

Oxidative stress and mitochondrial function are at the core of many degenerative conditions. However, the interaction between oxidative stress and in vivo mitochondrial function is unclear. We used both pharmacological (2 week paraquat (PQ) treatment of wild type mice) and transgenic (mice lacking Cu, Zn-superoxide dismutase (SOD1−/−)) models to test the effect of oxidative stress on in vivo mitochondrial function in skeletal muscle. Magnetic resonance and optical spectroscopy were used to measure mitochondrial ATP and oxygen fluxes and cell energetic state. In both models of oxidative stress, coupling of oxidative phosphorylation was significantly lower (lower P/O) at rest in vivo in skeletal muscle and was dose-dependent in the PQ model. Despite this reduction in efficiency, in vivo mitochondrial phosphorylation capacity (ATPmax) was maintained in both models, and ex vivo mitochondrial respiration in permeabilized muscle fibers was unchanged following PQ treatment. In association with the reduced P/O, PQ treatment led to a dose-dependent reduction in PCr/ATP ratio and increased phosphorylation of AMPK. These results indicate that oxidative stress uncouples oxidative phosphorylation in vivo and results in energetic stress in the absence of defects in the mitochondrial electron transport chain

Toxic Exposure of Songbirds to Lead in the Southeast Missouri Lead Mining District

Mining and smelting in the Southeast Missouri Lead Mining District has caused widespread contamination of soils with lead (Pb) and other metals. Soils from three study sites sampled in the district contained from approximately 1,000–3,200 mg Pb/kg. Analyses of earthworms [33–4,600 mg Pb/kg dry weight (dw)] collected in the district showed likely high Pb exposure of songbirds preying on soil organisms. Mean tissue Pb concentrations in songbirds collected from the contaminated sites were greater (p \u3c 0.05) than those in songbirds from reference sites by factors of 8 in blood, 13 in liver, and 23 in kidney. Ranges of Pb concentrations in livers (mg Pb/kg dw) were as follows: northern cardinal (Cardinalis cardinalis) = 0.11–3.0 (reference) and 1.3–30 (contaminated) and American robin (Turdus migratorius) = 0.43–8.5 (reference) and 7.6–72 (contaminated). Of 34 adult and juvenile songbirds collected from contaminated sites, 11 (32 %) had hepatic Pb concentrations that were consistent with adverse physiological effects, 3 (9 %) with systemic toxic effects, and 4 (12 %) with life-threatening toxic effects. Acid-fast renal intranuclear inclusion bodies, which are indicative of Pb poisoning, were detected in kidneys of two robins that had the greatest renal Pb concentrations (952 and 1,030 mg/kg dw). Mean activity of the enzyme delta-aminolevulinic acid dehydratase (ALAD) in red blood cells, a well-established bioindicator of Pb poisoning in birds, was decreased by 58–82 % in songbirds from the mining sites. We conclude that habitats within the mining district with soil Pb concentrations of C1,000 mg Pb/kg are contaminated to the extent that they are exposing ground-feeding songbirds to toxic concentrations of Pb

Toxic Exposure of Songbirds to Lead in the Southeast Missouri Lead Mining District

Mining and smelting in the Southeast Missouri Lead Mining District has caused widespread contamination of soils with lead (Pb) and other metals. Soils from three study sites sampled in the district contained from approximately 1,000–3,200 mg Pb/kg. Analyses of earthworms [33–4,600 mg Pb/kg dry weight (dw)] collected in the district showed likely high Pb exposure of songbirds preying on soil organisms. Mean tissue Pb concentrations in songbirds collected from the contaminated sites were greater (p \u3c 0.05) than those in songbirds from reference sites by factors of 8 in blood, 13 in liver, and 23 in kidney. Ranges of Pb concentrations in livers (mg Pb/kg dw) were as follows: northern cardinal (Cardinalis cardinalis) = 0.11–3.0 (reference) and 1.3–30 (contaminated) and American robin (Turdus migratorius) = 0.43–8.5 (reference) and 7.6–72 (contaminated). Of 34 adult and juvenile songbirds collected from contaminated sites, 11 (32 %) had hepatic Pb concentrations that were consistent with adverse physiological effects, 3 (9 %) with systemic toxic effects, and 4 (12 %) with life-threatening toxic effects. Acid-fast renal intranuclear inclusion bodies, which are indicative of Pb poisoning, were detected in kidneys of two robins that had the greatest renal Pb concentrations (952 and 1,030 mg/kg dw). Mean activity of the enzyme delta-aminolevulinic acid dehydratase (ALAD) in red blood cells, a well-established bioindicator of Pb poisoning in birds, was decreased by 58–82 % in songbirds from the mining sites. We conclude that habitats within the mining district with soil Pb concentrations of C1,000 mg Pb/kg are contaminated to the extent that they are exposing ground-feeding songbirds to toxic concentrations of Pb

An analysis of appropriate delivery of postoperative radiation therapy for endometrial cancer using the RAND/UCLA Appropriateness Method: Executive summary

PurposeTo summarize the results of American Society for Radiation Oncology (ASTRO)'s analysis of appropriate delivery of postoperative radiation therapy (RT) for endometrial cancer using the RAND/University of California, Los Angeles (UCLA) Appropriateness Method, outline areas of convergence and divergence with the 2014 ASTRO endometrial Guideline, and highlight where this analysis provides new information or perspective.Methods and materialsThe RAND/UCLA Appropriateness Method was used to combine available evidence with expert opinion. A comprehensive literature review was conducted and a multidisciplinary panel rated the appropriateness of RT options for different clinical scenarios. Treatments were categorized by the median rating as Appropriate, Uncertain, or Inappropriate.ResultsThe ASTRO endometrial Guideline and this analysis using the RAND/UCLA Appropriateness Method did not recommend adjuvant RT for early-stage, low-risk endometrioid cancers and largely agree regarding use of vaginal brachytherapy for low-intermediate and high-intermediate risk patients. For more advanced endometrioid cancer, chemotherapy with RT is supported by both documents. The Guideline and the RAND/UCLA analysis diverged regarding use of pelvic radiation. For stages II and III, this analysis rated external beam RT plus vaginal brachytherapy Appropriate, whereas the Guideline preferred external beam alone. In addition, this analysis offers insight on the role of histology, extent of nodal dissection, and para-aortic nodal irradiation; the use of intensity modulated RT; and management of stage IVA.ConclusionsThis analysis based on the RAND/UCLA Method shows significant agreement with the 2014 endometrial Guideline. Areas of divergence, often in scenarios with low-level evidence, included use of external beam RT plus vaginal brachytherapy in stages II and III and external beam RT alone in early-stage patients. Furthermore, the analysis explores other important questions regarding management of this disease site

Cymantrene–Triazole "Click" Products: Structural Characterization and Electrochemical Properties

We report the first known examples of triazole-derivatized cymantrene complexes (η5-[4-substituted triazol-1-yl]cyclopentadienyl)tricarbonylmanganese(I), obtained via a “click” chemical synthesis, bearing a phenyl, 3-aminophenyl, or 4-aminophenyl moiety at the 4-position of the triazole ring. Structural characterization data using multinuclear NMR, UV–vis, ATR-IR, and mass spectrometric methods are provided, as well as crystallographic data for (η5-[4-phenyltriazol-1-yl]cyclopentadienyl)tricarbonylmanganese(I) and (η5-[4-(3-aminophenyl)triazol-1-yl]cyclopentadienyl)tricarbonylmanganese(I). Cyclic voltammetric characterization of the redox behavior of each of the three cymantrene–triazole complexes is presented together with digital simulations, in situ infrared spectroelectrochemistry, and DFT calculations to extract the associated kinetic and thermodynamic parameters. The trypanocidal activity of each cymantrene–triazole complex is also examined, and these complexes are found to be more active than cymantrene alone

A Novel Antibody-Based Biomarker for Chronic Algal Toxin Exposure and Sub-Acute Neurotoxicity

The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins

A comparative study of fragment screening methods on the p38α kinase: new methods, new insights

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(™) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(™)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-011-9454-9) contains supplementary material, which is available to authorized users