Reactive Oxygen Species via Redox Signaling to PI3K/AKT Pathway Contribute to the Malignant Growth of 4-Hydroxy Estradiol-Transformed Mammary Epithelial Cells

The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes – nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor – NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen-induced malignant breast lesions.

On the microstructure, growth pattern and original porosity of belemnite rostra: insights from calcitic Jurassic belemnites

Calcitic belemnite rostra are usually employed to perform paleoenvironmental studies based on geochemical data. However, several questions, such as their original porosity and microstructure, remain open, despite they are essential to make accurate interpretations based on geochemical analyses.This paper revisits and enlightens some of these questions. Petrographic data demonstrate that calcite crystals of the rostrum solidum of belemnites grow from spherulites that successively develop along the apical line, resulting in a “regular spherulithic prismatic” microstructure. Radially arranged calcite crystals emerge and diverge from the spherulites: towards the apex, crystals grow until a new spherulite is formed; towards the external walls of the rostrum, the crystals become progressively bigger and prismatic. Adjacent crystals slightly vary in their c-axis orientation, resulting in undulose extinction. Concentric growth layering develops at different scales and is superimposed and traversed by a radial pattern, which results in the micro-fibrous texture that is observed in the calcite crystals in the rostra.Petrographic data demonstrate that single calcite crystals in the rostra have a composite nature, which strongly suggests that the belemnite rostra were originally porous. Single crystals consistently comprise two distinct zones or sectors in optical continuity: 1) the inner zone is fluorescent, has relatively low optical relief under transmitted light (TL) microscopy, a dark-grey color under backscatter electron microscopy (BSEM), a commonly triangular shape, a “patchy” appearance and relatively high Mg and Na contents; 2) the outer sector is non-fluorescent, has relatively high optical relief under TL, a light-grey color under BSEM and low Mg and Na contents. The inner and fluorescent sectors are interpreted to have formed first as a product of biologically controlled mineralization during belemnite skeletal growth and the non-fluorescent outer sectors as overgrowths of the former, filling the intra- and inter-crystalline porosity. This question has important implications for making paleoenvironmental and/or paleoclimatic interpretations based on geochemical analyses of belemnite rostra.Finally, the petrographic features of composite calcite crystals in the rostra also suggest the non-classical crystallization of belemnite rostra, as previously suggested by other authors.

The Good Liberal and the Scoundrel Author: Fantasy, Dissent, and neoliberal subjectivity in Philip Pullman’s His Dark Materials

Philip Pullman, author of the His Dark Materials trilogy, has acquired an impressive critical reputation and acquired a favored role in British culture as a social commentator. This essay attempts to link the pleasures associated with the trilogy with the politics inscribed in them, and consider both in the context of Pullman’s role in the civil society. The essay suggests that The Northern Lights offers pleasures in fantastical and metaphysical possibilities, and social confederacies that potentially offset the affective privations of neoliberalism. These possibilities are set in the context of recent theories of the “enterprise society.” The essay draws attention to a number of discontinuities that unfold as the trilogy progresses, and suggests that these undermine the possibilities inherent in the first novel. These disconti - nuities throw the role of fantasy and alternative universes into question, and reveal the limitations of Pullman’s fiction. The essay considers the limit and scope of Pullman’s political vision, both as a function of his fiction and his public engagement with social issues, and suggests that he exemplifies Raymond Williams’s concept of “bourgeois dissent” in which political critique and a continuing investment in traditional institutions and class hierarchy can be mutually reinforcing.

Keep up the good work Lexington County! : RECYCLE USED MOTOR OIL, FILTERS, BOTTLES & TIRES!

This document describes the kinds of items accepted for recycling at Lexington County recycling centers.

Organic acids in Kakadu plum (Terminalia ferdinandiana): The good (ellagic), the bad (oxalic) and the uncertain (ascorbic)

The phenolic ellagic acid (EA) is receiving increasing attention for its nutritional and pharmacological potential as an antioxidant and antimicrobial agent. The Australian native Kakadu plum (Terminalia ferdinandiana) fruit is an abundant source of this phytochemical. The fruit also contains large amounts of vitamin C (mainly as ascorbic acid, AA) and possibly the undesirable oxalic acid (OA). Regular consumption of high oxalate foods poses a variety of health risks in humans including interference with calcium absorption and kidney stone formation. Oxalate is also the end-product of AA metabolism so that consumption of fruit with heightened AA content has the potential to elevate urinary oxalate levels. The aims of this study were to investigate the distribution of EA and the presence of other bioactives in other Kakadu plum tissues. Chemical analysis of Kakadu plum fruit and leaves for EA (free and total), OA (water-soluble and total), calcium (Ca) and AA indicated that EA and AA concentrations were high in the fruit while the leaves had significantly higher EA levels but little or no detectable AA. OA content in fruit and leaves was substantial with the fruit being placed in the high-Oxalate category. These findings suggest that there is potential to elevate oxalate levels in the urine of susceptible people and intake of fruit-derived products should be closely monitored. By measuring tissues collected from specific trees, high EA-producing or low OA-containing individuals were identified.

HIST 429F: History of the University of Maryland The Good, the Bad, and the Ugly

Presentation from the MARAC conference in Boston, MA on March 18-21, 2015. S12 - History in Action: Collaboration in Academia

Ontogeny and nutritional programming of the hepatic growth hormone-insulin-like growth factor-prolactin axis in the sheep

The liver is an important metabolic and endocrine organ in the fetus but the extent to which its hormone receptor (R) sensitivity is developmentally regulated in early life is not fully established. We, therefore, examined developmental changes in mRNA abundance for the growth hormone (GH) and prolactin (PRL) receptors (R) plus insulin-like growth factor (IGF)-I and –II and their receptors. Fetal and postnatal sheep were sampled at either 80, or 140 days gestation, 1, 30 days or six months of age. The effect of maternal nutrient restriction between early to mid (i.e. 28 to 80 days gestation, the time of early liver growth) gestation on gene expression was also examined in the fetus and juvenile offspring. Gene expression for the GHR, PRLR and IGF-IR increased through gestation peaking at birth, whereas IGF-I was maximal near to term. In contrast, IGF-II mRNA decreased between mid and late gestation to increase after birth whereas IGF-IIR remained unchanged. A substantial decline in mRNA abundance for GHR, PRLR and IGF-IR then occurred up to six months. Maternal nutrient restriction reduced GHR and IGF-IIR mRNA abundance in the fetus, but caused a precocious increase in the PRLR. Gene expression for IGF-I and –II were increased in juvenile offspring born to nutrient restricted mothers. In conclusion, there are marked differences in the developmental ontogeny and nutritional programming of specific hormones and their receptors involved in hepatic growth and development in the fetus. These could contribute to changes in liver function during adult life.

“In The Good Old Days of Long Ago": Echoes of Vaudeville and Minstrelsy in the Music of Uncle Dave Macon

Uncle Dave Macon provided an essential link between nineteenth-century, urban popular stage music (especially the minstrel show and vaudeville) and commercialized country music of the 1920s. He preserved through his recordings a large body of songs and banjo techniques that had their origins in urban-based, nineteenth-century vaudeville and minstrelsy. Like the minstrel and vaudeville performers of the nineteenth century, Macon told jokes and stories, employed attention-grabbing stage gimmicks, marketed himself with boastful or outrageous slogans, and dressed with individual flair. At the same time, Macon incorporated many features from the rural-based folk music of Middle Tennessee. Overall, Macon’s repertoire, musical style, and stage persona (which included elements of the rube, country gentleman, and old man) demonstrated his deep absorption, and subsequent reinterpretation, of nineteenth-century musical traditions. Macon’s career offers a case study in how nineteenth-century performance styles, repertoire, and stage practices became a part of country music in the 1920s. As an artist steeped in two separate, but overlapping, types of nineteenth-century music—stage and folk—Macon was well-positioned to influence the development of the new commercial genre. He brought together several strains of nineteenth-century music to form a modern, twentieth-century musical product ideally suited to the new mass media of records, radio, and film. By tracing Macon’s career and studying his music, we can observe how the cross-currents of rural and popular entertainment during the nineteenth and early twentieth centuries interacted to form the commercial genre we now know as country music.

Usefulness of the Hepatocyte Growth Factor as a Predictor of Mortality in Patients Hospitalized With Acute Heart Failure Regardless of Ejection Fraction

Hepatocyte growth factor (HGF) plays a role in the improvement of cardiac function and remodeling. Their serum levels are strongly related with mortality in chronic systolic heart failure (HF). The aim of this study was to study prognostic value of HGF in acute HF, interaction with ejection fraction, renal function, and natriuretic peptides. We included 373 patients (age 76 ± 10 years, left ventricular ejection fraction [LVEF] 46 ± 14%, 48% men) consecutively admitted for acute HF. Blood samples were obtained at admission. All patients were followed up until death or close of study (>1 year, median 371 days). HGF concentrations were determined using a commercial enzyme-linked immunosorbent assay (human HGF immunoassay). The predictive power of HGF was estimated by Cox regression with calculation of Harrell C-statistic. HGF had a median of 1,942 pg/ml (interquartile rank 1,354). According to HGF quartiles, mortality rates (per 1,000 patients/year) were 98, 183, 375, and 393, respectively (p <0.001). In Cox regression analysis, HGF (hazard ratio1SD = 1.5, 95% confidence interval 1.1 to 2.1, p = 0.002) and N-terminal pro b-type natriuretic peptide (NT-proBNP; hazard ratio1SD = 1.8, 95% confidence interval 1.2 to 2.6, p = 0.002) were independent predictors of mortality. Interaction between HGF and LVEF, origin, and renal function was nonsignificant. The addition of HGF improved the predictive ability of the models (C-statistic 0.768 vs 0.741, p = 0.016). HGF showed a complementary value over NT-proBNP (p = 0.001): mortality rate was 490 with both above the median versus 72 with both below. In conclusion, in patients with acute HF, serum HGF concentrations are elevated and identify patients at higher risk of mortality, regardless of LVEF, ischemic origin, or renal function. HGF had independent and additive information over NT-proBNP.

Is the meander growth in the Brazil Current system off Southeast Brazil due to baroclinic instability?

Temporally-growing frontal meandering and occasional eddy-shedding is observed in the Brazil Current (BC) as it flows adjacent to the Brazilian Coast. No study of the dynamics of this phenomenon has been conducted to date in the region between 22 degrees S and 25 degrees S. Within this latitude range, the flow over the intermediate continental slope is marked by a current inversion at a depth that is associated with the Intermediate Western Boundary Current (IWBC). A time series analysis of 10-current-meter mooring data was used to describe a mean vertical profile for the BC-IWBC jet and a typical meander vertical structure. The latter was obtained by an empirical orthogonal function (EOF) analysis that showed a single mode explaining 82% of the total variance. This mode structure decayed sharply with depth, revealing that the meandering is much more vigorous within the BC domain than it is in the IWBC region. As the spectral analysis of the mode amplitude time series revealed no significant periods, we searched for dominant wavelengths. This search was done via a spatial EOF analysis on 51 thermal front patterns derived from digitized AVHRR images. Four modes were statistically significant at the 95% confidence level. Modes 3 and 4, which together explained 18% of the total variance, are associated with 266 and 338-km vorticity waves, respectively. With this new information derived from the data, the [Johns, W.E., 1988. One-dimensional baroclinically unstable waves on the Gulf Stream potential vorticity gradient near Cape Hatteras. Dyn. Atmos. Oceans 11, 323-350] one-dimensional quasi-geostrophic model was applied to the interpolated mean BC-IWBC jet. The results indicated that the BC system is indeed baroclinically unstable and that the wavelengths depicted in the thermal front analysis are associated with the most unstable waves produced by the model. Growth rates were about 0.06 (0.05) days(-1) for the 266-km (338-km) wave. Moreover, phase speeds for these waves were low compared to the surface BC velocity and may account for remarks in the literature about growing standing or stationary meanders off southeast Brazil. The theoretical vertical structure modes associated with these waves resembled very closely to the one obtained for the current-meter mooring EOF analysis. We interpret this agreement as a confirmation that baroclinic instability is an important mechanism in meander growth in the BC system. (C) 2008 Elsevier B.V. All rights reserved.

Nutrients limiting the Algal Growth Potential (AGP) in the Gulf of Riga, eastern Baltic Sea, in spring and early summer 1996

In May, June and July 1996, samples wcre collected along one transect greatly influenced by river discharge (eastern side of the gulf), along one transect slightly influence by river discharge (western side), at one station Iocated in the mouth of the main river (River Daugava), at one station located in the center of the Gulf and at several nearshore locations of the western side. Ratios of rnolecular concentrations of in situ dissolved ioorganic nitrogen, phosphorus and silicon, as weIl as enrichment bioassays were llsed to dctcrrnine which nutrient (s) lirnited the potential biomass of phytoplankton. Both comparison of (NO.d-N02+NJ.L): P04 (DIN: DIP) values with Redfic1d's ratio and bioassay inspection led to the sarne conclusions. Phosphorus was clearly the nutrient most limiting for the potcntial biornass of test species in nitrogen- rich waters, which occurred in mid spring, in the upper layer of the southern-eastern part of the Gulf which is greatly influenced by river discharge. In late spring, with the decrease of the total DIN reserve, nitrogen and phosphorus showed an equallimiting role. In deeper layers of this area and out of the river plume (western side and central part of the gulf), nitrogen was the limiting nutrient. In summer, whcn river discharge was the lowest, a11 DIN concentrations but one ranged between 1.6 and 2.6 µM, and the whole area was nitrogen-limited for both the cyanobacterial and the algal test strains. In 74% of the samples for which nitrogen was the limiting nutrient, phosphorus was recorded to be the second potentially limiting nutrient. In contrast, silicon never appeared as limiting the growth potential of either Microcystis aeruginosa or Phaeodactylum tricornutum; phosphorus was the limiting nutrient when DIN: Si03 values were >1 (in May), but DIN: Si03 was <1 when nitrogen was limiting (June and July). The authors conclude that the recently reported decrease of silicon loading in coastal waters and its subsequent enhanced importance in pushing the outcome of species competition towards harmful species may not yet be the most important factor for the Gulf of Riga. Iron appeared for 12% of the tests in the list of nutrients limiting the potential biomass. Tentative results also indicated that a significant fraction of the nitrogen (~,4 µg-atom N 1(-1) taken up by Microcystis aeruginosa may have been in the form of dissolved organic nitrogen (DON). It is thus also suggested tentatively that more attention be paid to these nitrients during further research in the Gulf of Riga.

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome

Introduction: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Methods: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Results: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.