A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse

The areca alkaloids comprise arecoline, arecaidine, guvacoline, and guvacine. Approximately 600 million users of areca nut products, for example, betel quid chewers, are exposed to these alkaloids, principally arecoline and arecaidine. Metabolism of arecoline (20 mg/kg p.o. and i.p.) and arecaidine (20 mg/kg p.o. and i.p.) was investigated in the mouse using a metabolomic approach employing ultra-performance liquid chromatography-time-of-flight mass spectrometric analysis of urines. Eleven metabolites of arecoline were identified, including arecaidine, arecoline N-oxide, arecaidine N-oxide, N-methylnipecotic acid, N-methylnipecotylglycine, arecaidinylglycine, arecaidinylglycerol, arecaidine mercapturic acid, arecoline mercapturic acid, and arecoline N-oxide mercapturic acid, together with nine unidentified metabolites. Arecaidine shared six of these metabolites with arecoline. Unchanged arecoline comprised 0.3-0.4%, arecaidine 7.1-13.1%, arecoline N-oxide 7.4-19.0%, and N-methylnipecotic acid 13.5-30.3% of the dose excreted in 0-12 h urine after arecoline administration. Unchanged arecaidine comprised 15.1-23.0%, and N-methylnipecotic acid 14.8%-37.7% of the dose excreted in 0-12 h urine after arecaidine administration. The major metabolite of both arecoline and arecaidine, N-methylnipecotic acid, is a novel metabolite arising from carbon-carbon double-bond reduction. Another unusual metabolite found was the monoacylglyceride of arecaidine. What role, if any, that is played by these uncommon metabolites in the toxicology of arecoline and arecaidine is not known. However, the enhanced understanding of the metabolic transformation of arecoline and arecaidine should contribute to further research into the clinical toxicology of the areca alkaloids.

Polymorphism and chromosomal location of the MC4R (melanocortin-4 receptor) gene in the dog and red fox

The melanocortin-4 receptor (MC4R) is expressed in the hypothalamus and regulates energy intake and body weight. In silico screening of the canine chromosome 1 sequence and a comparison with the porcine MC4R sequence by BLAST were performed. The nucleotide sequence of the whole coding region and 3'- and 5'-flanking regions of the dog (1214 bp) and red fox (1177 bp) MC4R gene was established and high conservation of the nucleotide sequences was revealed (99%). Five sets of PCR primers were designed and a search for polymorphism was performed by the SSCP technique in a group of 31 dogs representing nineteen breeds and 35 farm red foxes. Sequencing of DNA fragments, representing the identified SSCP patterns, revealed three single nucleotide polymorphisms (including a missense one) in dogs and four silent SNPs in red foxes. An average SNP frequency was approx. 1/400 bp in the dog and 1/300 bp in the red fox. We mapped the MC4R gene by FISH to the canine chromosome 1 (CFA1q1.1) and to the red fox chromosome 5 (VVU5p1.2).

La Yeguada volcanic complex, western Panama : an assessment of the geologic hazards using new 40AR/39Ar Ages

La Yeguada volcanic complex is one of three Quaternary volcanic centers in Panama, and is located on the southern slope of the Cordillera Central mountain range in western Panama, province of Veraguas. To assess potential geologic hazards, this study focused on the main dome complex near the village of La Laguna and also examined a cinder cone 10 km to the northwest next to the village of Media Luna. Based on newly obtained 40Ar/39Ar ages, the most recent eruption occurred approximately 32 000 years ago at the Media Luna cinder cone, while the youngest dated eruption at the main dome complex occurred 0.357 ± 0.019 Ma, producing the Castillo dome unit. Cerro Picacho is a separate dome located 1.5 km east of the main complex with a date of 4.47 ± 0.23 Ma, and the El Satro Pyroclastic Flow unit surrounds the northern portion of the volcanic complex and has an age of 11.26 ± 0.17 Ma. No Holocene (10 000 years ago to present) activity is recorded at the La Yeguada volcanic complex and therefore, it is unlikely to produce another eruption. The emergence of a new cinder cone is a possibility, but the associated hazards tend to be low and localized, and this does not pose a significant threat to the small communities scattered throughout the area. The main geologic hazard at the La Yeguada volcanic complex is from landslides coming off the many steep slopes.

Reclaiming Indigenous Narratives through Critical Discourses and the Autonomy of the Trickster

How do prevailing narratives about Native Americans, particularly in the medium of film, conspire to promote the perspective of the dominant culture? What makes the appropriation of Indigenous images so metaphorically popular? In the past hundred years, little has changed in the forms of representation favored by Hollywood. The introductory chapter elucidates the problem and outlines the scope of this study. As each subsequent chapter makes clear, the problem is as relevant today as it has been throughout the entire course of filmic history. Chapter Two analyzes representational trends and defines each decade according to its favorite stereotype. The binary of the bloodthirsty savage is just as prevalent as it was during the 1920s and 30s. The same holds true for the drunken scapegoat and the exotic maiden, which made their cinematic debuts in the 1940s and 50s. But Hollywood has added new types as well. The visionary peacemaker and environmental activist have also made an appearance within the last forty years. What matters most is not the realism of these images, but rather the purposes to which they can be put toward validating whatever concerns the majority filmmakers wish to promote. Whether naïvely or not, such representations continue to evacuate Indigenous agency to the advantage of the majority. A brief historical overview confirms this legacy. Various disciplines have sought to interrogate this problem. Chapter three investigates the field of postcolonial studies, which makes inquiry into the various ways these narratives are produced, marketed, and consumed. It also raises the key questions of for whom, and by whom, these narratives are constructed. Additional consideration is given to their value as commodities in the mass marketplace. Typically the products of a boutique-multiculturalism, their storylines are apt to promote the prevailing point of view. Critical theory provides a foundational framework for chapter four. What is the blockbuster formula and how do the instruments of capital promote it? Concepts such as culture industry and repressive tolerance examine both the function and form of the master narrative, as well as its use to control the avenues of dissent. Moreover, the public sphere and its diminishment highlight the challenges inherent in the widespread promotion of an alternative set of narratives. Nonetheless, challenges to prevailing narratives do exist, particularly in the form of Trickster narratives. Often subject to persistent misrecognition, the Trickster demonstrates a potent form of agency that undeniably dismantles the hegemony of Western cinema. The final chapter examines some of the Trickster's more subtle and obscure productions. Usually subjugated to the realm of the mystical, rather than the mythical, these misinterpreted forms have the power to speak in circles around a majority audience. Intended for an Other audience, they are coded in a language that delivers a type of direction through indirection, promoting a poignant agency all their own.

THE FANNED FLAMES OF DISCONTENT: A SOLIDARITY-INSPIRED HISTORY OF THE IDENTITY/IDEOLOGY, CULTURAL HISTORY, AND RHETORICAL STRATEGIES OF THE WOBBLIES DURING THE 1916 MINNESOTA IRON ORE STRIKE

Rooted in critical scholarship this dissertation is an interdisciplinary study, which contends that having a history is a basic human right. Advocating a newly conceived and termed, Solidarity-inspired History framework/practice perspective, the dissertation argues for and then delivers a restorative voice to working-class historical actors during the 1916 Minnesota Iron Ore Strike. Utilizing an interdisciplinary methodological framework the dissertation combines research methods from the Humanities and the Social Sciences to form a working-class history that is a corrective to standardized studies of labor in the late 19th and early 20th centuries. Oftentimes class interests and power relationships determine the dominant perspectives or voices established in history and disregard people and organizations that run counter to, or in the face of, customary or traditional American themes of patriotism, the Protestant work ethic, adherence to capitalist dogma, or United States exceptionalism. This dissertation counteracts these traditional narratives with a unique, perhaps even revolutionary, examination of the 1916 Minnesota Iron Ore Strike. The intention of this dissertation's critical perspective is to poke, prod, and prompt academics, historians, and the general public to rethink, and then think again, about the place of those who have been dislocated from or altogether forgotten, misplaced, or underrepresented in the historical record. Thus, the purpose of the dissertation is to give voice to historical actors in the dismembered past. Historical actors who have run counter to traditional American narratives often have their body of "evidence" disjointed or completely dislocated from the story of our nation. This type of disremembering creates an artificial recollection of our collective past, which de-articulates past struggles from contemporary groups seeking solidarity and social justice in the present. Class-conscious actors, immigrants, women, the GLBTQ community, and people of color have the right to be remembered on their own terms using primary sources and resources they produced. Therefore, similar to the Wobblies industrial union and its rank-and-file, this dissertation seeks to fan the flames of discontented historical memory by offering a working-class perspective of the 1916 Strike that seeks to interpret the actions, events, people, and places of the strike anew, thus restoring the voices of these marginalized historical actors.

Diverse Readings of the Court of Justice Judgments on Copyright Work

EU law’s impact on the meaning of the copyright work for a long time seemed limited to software and databases. But recent judgments of the CJEU (Infopaq, BSA, FootballAssociation [Murphy], Painer) suggest we have entered an era of harmonization of copyright subject-matter, after decades of focus on the scope of exclusive rights and their duration. Unlike before however, it is the Court and not the legislator that takes centre stage in shaping pivotal concepts. This article reviews the different readings and criticisms the recent case law on copyright works evokes in legal doctrine across the EU. It puts them in the wider perspective of the on-goingdevelopment towards uniform law and the role of the preliminary reference procedure in that process.

THE DOMAINS OF THE CATALYTIC SUBUNIT OF THE EUKARYOTIC RNA DEGRADING EXOSOME, RRP44P, HAVE DISTINCT FUNCTIONS

The exosome is a 3’ to 5’ exoribonuclease complex that consists of ten essential subunits. In the cytoplasm, the exosome degrades mRNA in a general mRNA turnover pathway and in several mRNA surveillance pathways. In the nucleus, the exosome processes RNA precursors to form small, stable, mature RNA species, including rRNA, snRNA, and snoRNA. In addition to processing these RNAs, the nuclear exosome is also involved in degrading aberrantly processed forms of these RNAs, and others, including mRNA. The 3’ to 5’ exoribonuclease activity of the exosome is contributed by the RNB domain of the only catalytically active subunit, Rrp44p, a member of the RNase II family of enzymes. In addition to the RNB domain, Rrp44p consists of three putative RNA binding domains and has an uncharacterized N-terminus, which includes a CR3 region and PIN domain. In an effort to characterize the cellular functions of the domains of Rrp44p, this study identified a second nuclease active site in the PIN domain. Specifically, the PIN domain exhibits endoribonuclease activity in vitro and is essential for exosome function. Further analysis of the nuclease activities of Rrp44p indicate a role for the exoribonuclease activity of Rrp44p in the cytoplasmic and nuclear exosome. This work has also characterized the CR3 region of Rrp44p, a region that has not yet been characterized in any other protein. This region is needed for the majority, if not all, of the cytoplasmic exosome functions as well as for interaction with the exosome. The CR3 region, along with a histidine residue in the N-terminus of Rrp44p, may coordinate a zinc atom. Preliminary evidence supports a role for this coordination in exosome function. Further investigation, however, is needed to determine the molecular dependence of the exosome on the CR3 region of Rrp44p. Despite its initial discovery thirteen years ago, the essential function of Rrp44p, and the exosome, is not yet known. The studies presented here, however, indicate that the essential function of Rrp44p and the exosome is in the nucleus and depends on the nuclease activities of Rrp44p.

Transcriptional regulation of the mouse $\alpha$2(I) collagen gene

The mouse $\alpha$2(I) collagen gene is specifically expressed in a limited number of cell types in the body including fibroblasts and osteoblasts. We had previously shown that a promoter containing the sequences between $-$350 and +54 bp was expressed at low levels in a cell- and tissue-specific fashion in transgenic mice. Further studies suggested that the sequence between $-$315 and $-$284 bp could mediate cell- and tissue-specific expression of reporter genes in cell culture and in transgenic mice. We report here characterization of the proteins binding to this segment and propose a model for the cell-specific expression conferred by this sequence. In this study we also identified a strong enhancer for the mouse $\alpha$2(I) collagen gene located approximately 13.5 to 19.5 kb upstream of the transcriptional start site. This enhancer segment is characterized by the presence of three cell-specific hypersensitive sites and can drive high levels of cell-specific expression of a heterologous 220-bp mouse $\alpha$1(I) collagen promoter. In the course of this study, we identified a novel zinc finger transcription factor (designated murine epithelial zinc finger, mEZF) which was transiently expressed in the mesenchymal cells which give rise to the skeletal primordia and the metanephric kidney during the early stages of embryogenesis. In newborn mice, the mEZF gene is expressed at high levels in differentiated epithelial cells of the skin, oral mucosa, tongue, esophagus, stomach and colon. Chromosomal mapping suggested that the mEZF gene mapped to mouse Chromosome 4 and that the human homolog of mEZF would likely map to human Chromosome 9q31. This region of the human genome contains tumor suppressor genes for basal cell carcinomas of the skin as well as for squamous cell carcinomas of various organs. We cloned and characterized the human homolog of mEZF and mapped its chromosomal position as a first step in determining whether or not this gene plays a role in the development of these tumors. ^

Separation of the Ribbon from globally distributed energetic neutral Atom Flux using the first five Years of Ibex Observations

The Interstellar Boundary Explorer (IBEX) observes the IBEX ribbon, which stretches across much of the sky observed in energetic neutral atoms (ENAs). The ribbon covers a narrow (~20°-50°) region that is believed to be roughly perpendicular to the interstellar magnetic field. Superimposed on the IBEX ribbon is the globally distributed flux that is controlled by the processes and properties of the heliosheath. This is a second study that utilizes a previously developed technique to separate ENA emissions in the ribbon from the globally distributed flux. A transparency mask is applied over the ribbon and regions of high emissions. We then solve for the globally distributed flux using an interpolation scheme. Previously, ribbon separation techniques were applied to the first year of IBEX-Hi data at and above 0.71 keV. Here we extend the separation analysis down to 0.2 keV and to five years of IBEX data enabling first maps of the ribbon and the globally distributed flux across the full sky of ENA emissions. Our analysis shows the broadening of the ribbon peak at energies below 0.71 keV and demonstrates the apparent deformation of the ribbon in the nose and heliotail. We show global asymmetries of the heliosheath, including both deflection of the heliotail and differing widths of the lobes, in context of the direction, draping, and compression of the heliospheric magnetic field. We discuss implications of the ribbon maps for the wide array of concepts that attempt to explain the ribbon's origin. Thus, we present the five-year separation of the IBEX ribbon from the globally distributed flux in preparation for a formal IBEX data release of ribbon and globally distributed flux maps to the heliophysics community.

Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage.

Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.

Validation of a Spatially Continuous EDEN Water-Surface Model for the Everglades, Florida

The Everglades Depth Estimation Network (EDEN) is an integrated network of realtime water-level monitoring, ground-elevation modeling, and water-surface modeling that provides scientists and managers with current (2000-present), online water-stage and water-depth information for the entire freshwater portion of the Greater Everglades. Continuous daily spatial interpolations of the EDEN network stage data are presented on grid with 400-square-meter spacing. EDEN offers a consistent and documented dataset that can be used by scientists and managers to: (1) guide large-scale field operations, (2) integrate hydrologic and ecological responses, and (3) support biological and ecological assessments that measure ecosystem responses to the implementation of the Comprehensive Everglades Restoration Plan (CERP) (U.S. Army Corps of Engineers, 1999). The target users are biologists and ecologists examining trophic level responses to hydrodynamic changes in the Everglades. The first objective of this report is to validate the spatially continuous EDEN water-surface model for the Everglades, Florida developed by Pearlstine et al. (2007) by using an independent field-measured data-set. The second objective is to demonstrate two applications of the EDEN water-surface model: to estimate site-specific ground elevation by using the validated EDEN water-surface model and observed water depth data; and to create water-depth hydrographs for tree islands. We found that there are no statistically significant differences between model-predicted and field-observed water-stage data in both southern Water Conservation Area (WCA) 3A and WCA 3B. Tree island elevations were derived by subtracting field water-depth measurements from the predicted EDEN water-surface. Water-depth hydrographs were then computed by subtracting tree island elevations from the EDEN water stage. Overall, the model is reliable by a root mean square error (RMSE) of 3.31 cm. By region, the RMSE is 2.49 cm and 7.77 cm in WCA 3A and 3B, respectively. This new landscape-scale hydrological model has wide applications for ongoing research and management efforts that are vital to restoration of the Florida Everglades. The accurate, high-resolution hydrological data, generated over broad spatial and temporal scales by the EDEN model, provides a previously missing key to understanding the habitat requirements and linkages among native and invasive populations, including fish, wildlife, wading birds, and plants. The EDEN model is a powerful tool that could be adapted for other ecosystem-scale restoration and management programs worldwide.

Achieving effective biosurveillance with the Nationwide Health Information Network

The federal government is currently developing the Nationwide Health Information Network (NHIN). Described as a “network of networks,” the NHIN seeks to provide a nationwide, interoperable health information infrastructure that will securely connect consumers with those involved in health care. As part of the national health information technology (HIT) agenda, the NHIN aims to improve individual and population health by enabling health information to follow the consumer, be available for clinical decision-making, and support important public health measures such as biosurveillance. While the NHIN promises to improve clinical care to individuals and to reduce U.S. health care system costs overall, this electronic environment presents novel challenges for protecting individually identifiable health information. A major barrier to achieving public trust in the NHIN is the development of, and adherence to, a consistent and coordinated approach to privacy and security of health information. This paper will analyze the policy framework for electronic health information exchange with the NHIN. This exercise will demonstrate that the current policy is an effective framework for achieving effective biosurveillance with the NHIN. ^

Molecular and evolutionary genetics of the X -linked visual pigment genes in humans and New World monkeys

Normal humans have one red and at least one green visual pigment genes. These genes are tightly linked as tandem repeats on the X chromosome and each of them has six exons. There is only one X-linked visual pigment gene in New World monkeys (NWMs) but the locus has three polymorphic alleles encoding red, yellow and green visual pigments, respectively. The spectral properties of the squirrel monkey and the marmoset (both NWMs) have been studied and partial sequences of the three alleles are available. To study the evolutionary history of these X-linked opsin genes in humans and NWMs, coding and intron sequences of the three squirrel monkey alleles and the three marmoset alleles were amplified by PCR followed by subcloning and sequencing. Introns 2 and 4 of the human red and green pigment genes were also sequenced. The results obtained are as follows: (1) The sequences of introns 2 and 4 of the human red and green opsin genes are significantly more similar between the two genes than are coding sequences, contrary to the usual situation where coding regions are better conserved in evolution than are introns. The high similarities in the two introns are probably due to recent gene conversion events during evolution of the human lineage. (2) Phylogenetic analysis of both intron and exon sequences indicates that the phylogenetic tree of the available primate opsin genes is the same as the species tree. The two human genes were derived from a gene duplication event after the divergence of the human and NWM lineages. The three alleles in each of the two NWM species diverged after the split of the two NWMs but have persisted in the population for at least 5 million years. (3) Allelic gene conversion might have occurred between the three squirrel monkey alleles. (4) A model of additive effect of hydroxyl-bearing amino acids on spectral tuning is proposed by treating some unknown variables as groups. Under the assumption that some residues have no effect, it is found that at least five amino acid residues, at positions 178 (3 nm), 180 (5 nm), 230 ($-$4 nm), 277 (9 nm) and 285 (13 nm), have linear spectral tuning effects. (5) Adaptive evolution of the opsin genes to different spectral peaks was observed at four residues that are important for spectral tuning. ^

The shift of paradigm in the organizations like foundation of the style of ethical leadership

La presente investigación tiene por objeto analizar el cambio de paradigma en las organizaciones como fundamento del liderazgo ético desde una realidad postmoderna a fin de detectar la necesidad de un liderazgo ético en las organizaciones donde los líderes sean formadores de valores a través del modelaje directivo; es un estilo de liderazgo en el que la visión ética, sistémica e integradora son unas de las principales aptitudes que el líder ético ha de poner en la práctica. Se han desarrollado teorías de liderazgo centradas no tanto en los rasgos o comportamientos de los líderes, sino en la relación entre líder y sus seguidores

Distribution of Cycladophora davisiana davisiana in upper Pliocene and Pleistocene sediments of the North Atlantic and Labrador Sea

Upper Pliocene and Pleistocene abundance fluctuations of the radiolarian Cycladophora davisiana (Ehrenberg) davisiana (Petrushevskaya) are documented from North Atlantic (Site 609) and Labrador Sea (Site 646B) to provide the first long-term correlation of its abundance fluctuations to oxygen isotope stages 1-114. Also examined are temporal and regional fluctuations in abundances C. d. davisiana and the global dispersal routes of the species. The first occurrence of C. d. davisiana in the eastern North Atlantic Ocean (Site 609) occurred between 2.586 and 2.435 Ma (oxygen isotope stages 109.66-102.19). During the early Matuyama Chron, prior to oxygen isotope stage 63, C. d. davisiana abundances were less than 1% and never greater than 12%, while abundances of greater than 5% are found in stages 65.71-73, 74, and 83-84. The initial major abundance peak (35.7%) of C. d. davisiana was noted near the stage 63/62 boundary. Abundance peaks of greater than 15%, between oxygen isotope stages 35 and 63, are limited to stages 63.02, 58.07, 55.07-54.26, and 50.76-50.22. These represent the only such abundance peaks detected during the first c. 1.5 million years of the species within the North Atlantic. The character of C. d. davisiana abundance fluctuations in Site 609 changes after oxygen isotope stage 35; average abundances are greater (7.7% vs. 4.3%) and abundance maxima of more than 15% are more frequent. Many, but not all, peak abundances of C. d. davisiana occur in glacial stages (e.g., 8, 14, 18, 20, 26, 30, 34, 50, 54, and 58). Increased abundances of the species are also noted in weak interglacial stages (e.g., stages 3, 23, 39, and 41), and significant cool periods of robust interglacial periods (e.g., late stage 11). Sample spacing is adequate in some stages to note some rapid changes in abundance near stage transitions (e.g., stages 4/5, 25/26, 62/63). The sample density in Holes 609 and 611 and the upper portion of 646B is sufficient to detect a synchroneity of many abundance maxima and minima among sites. Some abundance peaks are undetected in one or more of the two holes, warranting further sampling to obtain a more accurate record of regional abundance fluctuations. Prior to stage 36, few ages of Hole 611 peaks are the same as those in the more precisely dated Hole 609. The highest abundances of C. d. davisiana were noted in Labrador Sea Hole 646B where the earliest known occurrence of the species is documented (3.08-2.99 Ma). C. d. davisiana is inferred to have evolved in the Labrador Sea (or Arctic), and migrated next through the Arctic into the North Pacific (2.62-2.64 Ma, stage 114) before migrating into the Norwegian Sea (2.63-2.53 Ma) and North Atlantic (2.59-2.44 Ma, stages 109-102). Additional migration of C. d. dauisiana into the southern South Atlantic (Site 704) occurred much later (2.06 Ma, stage 83).