Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia.

An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications

Resveratrol given intraperitoneally does not inhibit the growth of high-risk t(4;11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model.

The efficacy of resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL SEM cell line. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with resveratrol (10 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). Comparisons of the percent of human leukemia cells in blood and survival curves showed resveratrol did not inhibit progression of the disease. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed resveratrol was rapidly metabolized to glucuronidated and sulfated forms 1 h post-injection, with low to no resveratrol or metabolites observed in sera by 24-48 h. These data indicate that in contrast to findings in in vitro models, parenterally administered resveratrol does not have potential as a preventive agent against high risk t(4;11) ALL

Registration of N614, A3N615, N616, and N617 Shattercane Genetic Stocks with Cytoplasmic or Nuclear Male Sterility and Juicy or Dry Midribs

Four shattercane [Sorghum bicolor subsp. drummondii (Nees ex Steud.) de Wet ex Davidse] genetic stocks—N614 (Reg. No. GS-652, PI 665684), A3N615 (Reg. No. GS-651, PI 665683), N616 (Reg. No. GS-653, PI 665685), and N617 (Reg. No. GS-654, PI 665686)—with A3 cytoplasmic male sterility or the nuclear male sterility gene ms3 containing either juicy (dd) or dry (DD) culms were developed jointly by the USDA-ARS; the Iowa Agricultural and Home Economics Experiment Station, College of Agriculture and Life Sciences, Iowa State University; and the Agricultural Research Division, Institute of Agriculture and Natural Resources, University of Nebraska. The stocks were released in July 2011. The source material for these genetic stocks was isolated from an archetypical shattercane population found near Lincoln, NE. Release of these genetic stocks makes available shattercane lines with both A3 cytoplasmic male sterility, and ms3 genetic (nuclear) male sterility to facilitate crossing. These genetic stocks also contain juicy (dd) or dry (DD) culms, a visible genetic marker to facilitate screening progeny resulting from crosses. The genetic stocks have immediate application for basic research involving gene flow from cultivated sorghum [Sorghum bicolor (L.) Moench] to shattercane and on the fitness of offspring resulting from such crosses

Plasma and serum oxylipin, endocannabinoid, bile acid, steroid, fatty acid and nonsteroidal anti-inflammatory drug quantification in a 96-well plate format

The goal of this research was to develop a high-throughput, cost-effective method for metabolic profiling of lipid mediators and hormones involved in the regulation of inflammation and energy metabolism, along with polyunsaturated fatty acids and common over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs). We describe a 96-well plate protein precipitation and filtration procedure for 50 μL of plasma or serum in the presence of 37 deuterated analogs and 2 instrument internal standards. Data is acquired in two back-to-back UPLC-MS/MS analyses using electrospray ionization with positive/negative switching and scheduled multiple reaction monitoring for the determination of 145 compounds, including oxylipins, endocannabinoids and like compounds, bile acids, glucocorticoids, sex steroids, polyunsaturated fatty acids, and 3 NSAIDs. Intra- and inter-batch variability was <25% for >70% of metabolites above the LOQ in both matrices, but higher inter-batch variability was observed for serum oxylipins and some bile acids. Results for NIST Standard Reference Material 1950, compared favorably with the 20 certified metabolite values covered by this assay, and we provide new data for oxylipins, N-acylethanolamides, glucocorticoids, and 17-hydroxy-progesterone in this material. Application to two independent cohorts of elderly men and women showed the routine detection of 86 metabolites, identified fasting state influences on essential fatty acid-derived oxylipins, N-acylethanolamides and conjugated bile acids, identified rare presence of high and low testosterone levels and the presence of NSAIDs in ∼10% of these populations. The described method appears valuable for investigations in large cohort studies to provide insight into metabolic cross-talk between the array of mediators assessed here

Widespread erosion on high plateaus during recent glaciations in Scandinavia

Glaciers create some of Earth’s steepest topography; yet, many areas that were repeatedly overridden by ice sheets in the last few million years include extensive plateaus. The distinct geomorphic contrast between plateaus and the glacial troughs that dissect them has sustained two long-held hypotheses: first, that ice sheets perform insignificant erosion beyond glacial troughs, and, second, that the plateaus represent ancient pre-glacial landforms bearing information of tectonic and geomorphic history prior to Pliocene–Pleistocene global cooling (~3.5 Myr ago). Here we show that the Fennoscandian ice sheets drove widespread erosion across plateaus far beyond glacial troughs. We apply inverse modelling to 118 new cosmogenic 10Be and 26Al measurements to quantify ice sheet erosion on the plateaus fringing the Sognefjorden glacial trough in western Norway. Our findings demonstrate substantial modification of the pre-glacial landscape during the Quaternary, and that glacial erosion of plateaus is important when estimating the global sediment flux to the oceans

Denmark and the United States

Despite high taxes, a large state budget and welfare state, much economic regulation, and a very open economy, Denmark continues to compete successfully against the other advanced capitalist economies. Hence, Denmark presents a paradox for neoliberalism, which predicts that these policies will hurt national competitiveness under conditions of economic globalization. Following the varieties of capitalism literature, this paper argues that Denmark’s success has been based in large part on its institutional competitiveness–its capacity to achieve socioeconomic success as a result of the competitive advantages that firms derive from operating within a particular set of political and economic institutions. The institutional basis for successfully coordinating labor markets, vocational training and skill formation programs, and industrial policy are examined for Denmark and the United States—two countries that are very different institutionally. The analysis shows that there is no one best way to achieve success in today’s global economy, except perhaps for reducing socioeconomic inequality; that the type of capitalism known as coordinated market economies are oversimplified in the literature; and that high taxes, state spending, and economic regulation can actually enhance socioeconomic performance

Knowledge Regimes and Comparative Political Economy

Comparative political economy has been dominated since the 1970s by two waves of research. The first one examined how different types of policy-making regimes affect policy making and, in turn, national economic competitiveness (e.g., Katzenstein 1978). The second one studied how different types of production regimes affect national competitiveness (e.g., Hall and Soskice 2001). Absent from all of this is much discussion about knowledge regimes. Knowledge regimes are sets of actors, organizations, and institutions that produce and disseminate policy ideas that affect how policy-making and production regimes are organized and operate in the first place. Knowledge regimes are important because they contribute data, research, theories, policy recommendations, and other ideas that influence public policy and, thus, national economic competitiveness (Baab 2001; Campbell 1998; Pedersen 2006)