Omeprazole Impairs Vascular Redox Biology And Causes Xanthine Oxidoreductase-mediated Endothelial Dysfunction

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Proton pump inhibitors (PPIs) are widely used drugs that may increase the cardiovascular risk by mechanisms not entirely known. While PPIs increase asymmetric dimethylarginine (ADMA) levels and inhibit nitric oxide production, it is unknown whether impaired vascular redox biology resulting of increased xanthine oxidoreductase (XOR) activity mediates PPIs-induced endothelial dysfunction (ED). We examined whether increased XOR activity impairs vascular redox biology and causes ED in rats treated with omeprazole. We also examined whether omeprazole aggravates the ED found in hypertension. Treatment with omeprazole reduced endothelium-dependent aortic responses to acetylcholine without causing hypertension. However, omeprazole did not aggravate two-kidney, one-clip (2KIC) hypertension, nor hypertension-induced ED. Omeprazole and 2K1C increased vascular oxidative stress as assessed with dihydroethidium (DHE), which reacts with superoxide, and by the lucigenin chemiluminescence assay. The selective XOR inhibitor febuxostat blunted both effects induced by omeprazole. Treatment with omeprazole increased plasma ADMA concentrations, XOR activity and systemic markers of oxidative stress. Incubation of aortic rings with ADMA increased XOR activity, DHE fluorescence and lucigenin chemiluminescence signals, and febuxostat blunted these effects. Providing functional evidence that omeprazole causes ED by XOR-mediated mechanisms, we found that febuxostat blunted the ED caused by omeprazole treatment. This study shows that treatment with omeprazole impairs the vascular redox biology by XOR-mediated mechanisms leading to ED. While omeprazole did not further impair hypertension-induced ED, further studies in less severe animal models are warranted. Our findings may have major relevance, particularly to patients with cardiovascular diseases taking PPIs. (C) 2016 The Authors. Published by Elsevier B.V.9134143Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2014-23946-0]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)CAPES (Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Madera enigmática y primera evidencia de tetrápodos en Formación Yaguarí (Pérmico medio-superior), Uruguay

This article describes an intriguing fossil material recently found in the fine-grained sandstone levels from the upper section of the Yaguarí Formation of Uruguay. The nature of this specimen and its relationships were, initially, not easy to determine with confidence although it was subjected to several analyses, such as morphological and comparative examination complemented with preparation of thin sections and microanatomical and chemical studies under SEM. However, the anatomical structure shown in the performed transversal thin sections allowed solving the issue on the different animal or plant interpretations of the fossil specimen, which was finally discerned in favor of the latter. Therefore, after a detailed comparative study of the thin sections, we concluded that the specimen is a wood fragment related to the Dadoxylon-Araucarioxylon complex. Moreover, in order to provide a better biostratigraphic calibration for these deposits until now devoid of fossils, we include a preliminary description of recently found fossil footprints, which represent the first evidence of the presence of tetrapods in levels of the Yaguarí Formation (sensu Elizalde et al., 1970), below the conglomerates that have yielded the Colonia Orozco Fauna. The footprints were preliminary assigned to the ichnotaxa cf. Karoopes isp, cf. Capitosauroides isp., and cf. Pachypes isp., suggesting the presence of gorgonopsids and therocephalian therapsids and pareiasauromorphs, respectively. The Middle-Late Permian age recently suggested for the Yaguarí Formation based on paleomagnetic and radioisotopic studies is here supported by the described fossils, which thus constitute preliminary but nonetheless relevant discoveries for deposits whose fossiliferous potential has yet to be explored.Este artículo describe un intrigante fósil recientemente descubierto en niveles de areniscas finas a medias de la sección superior de la Formación Yaguarí de Uruguay. La naturaleza y las afinidades de este espécimen no fueron inicialmente fáciles de determinar, a pesar de ser sometido a numerosos estudios, incluido un análisis anatómico-comparativo complementado con la preparación de secciones delgadas y análisis de su microestructura bajo Microscopio Electrónico de Barrido. La microestructura mostrada por las láminas delgadas en corte transversal permitió finalmente resolver el problema sobre discernir entre una naturaleza animal o vegetal del espécimen, siendo la última la aceptada. El detallado estudio comparativo de las secciones delgadas reveló que el espécimen es un fragmento de madera relacionado al complejo Dadoxylon-Araucarioxylon. Asimismo, para proveer una mejor calibración temporal de los depósitos de la sección superior de la Formación Yaguarí (Miembro Villa Viñoles), también se incluye en este trabajo una descripción preliminar de huellas de tetrápodos recientemente halladas en esta unidad, las cuales representan la primera evidencia de la presencia de tetrápodos en niveles de la Formación Yaguarí (sensu Elizalde et al., 1970) subyacentes a los conglomerados portadores de la Fauna de Colonia Orozco. Las huellas fueron asignadas a los icnotaxa cf. Karoopes isp., cf. Capitosauroides isp. y cf. Pachypes isp., sugiriendo la presencia de terápsidos gorgonópsidos y therocefalidos y de pareiasauromorfos, respectivamente. La edad Pérmico Medio a Tardío recientemente sugerida para la Formación Yaguarí, basado en estudios de paleomagnetismo sustentados por dataciones radioisotópicas, es congruente con la aportada por los fósiles aquí descriptos, que, aunque fragmentarios, constituyen descubrimientos preliminarmente relevantes para depósitos cuyo potencial fosilífero no ha sido aún explorado.CSIC: I+D 2016_24

Is The Amphibian Tree of Life really fatally flawed?

Wiens (2007, Q. Rev. Biol. 82, 55–56) recently published a severe critique of Frost et al.\u27s (2006, Bull. Am. Mus. Nat. Hist. 297, 1–370) monographic study of amphibian systematics, concluding that it is “a disaster” and recommending that readers “simply ignore this study”. Beyond the hyperbole, Wiens raised four general objections that he regarded as “fatal flaws”: (1) the sampling design was insufficient for the generic changes made and taxonomic changes were made without including all type species; (2) the nuclear gene most commonly used in amphibian phylogenetics, RAG-1, was not included, nor were the morphological characters that had justified the older taxonomy; (3) the analytical method employed is questionable because equally weighted parsimony “assumes that all characters are evolving at equal rates”; and (4) the results were at times “clearly erroneous”, as evidenced by the inferred non-monophyly of marsupial frogs. In this paper we respond to these criticisms. In brief: (1) the study of Frost et al. did not exist in a vacuum and we discussed our evidence and evidence previously obtained by others that documented the non-monophyletic taxa that we corrected. Beyond that, we agree that all type species should ideally be included, but inclusion of all potentially relevant type species is not feasible in a study of the magnitude of Frost et al. and we contend that this should not prevent progress in the formulation of phylogenetic hypotheses or their application outside of systematics. (2) Rhodopsin, a gene included by Frost et al. is the nuclear gene that is most commonly used in amphibian systematics, not RAG-1. Regardless, ignoring a study because of the absence of a single locus strikes us as unsound practice. With respect to previously hypothesized morphological synapomorphies, Frost et al. provided a lengthy review of the published evidence for all groups, and this was used to inform taxonomic decisions. We noted that confirming and reconciling all morphological transformation series published among previous studies needed to be done, and we included evidence from the only published data set at that time to explicitly code morphological characters (including a number of traditionally applied synapomorphies from adult morphology) across the bulk of the diversity of amphibians (Haas, 2003, Cladistics 19, 23–90). Moreover, the phylogenetic results of the Frost et al. study were largely consistent with previous morphological and molecular studies and where they differed, this was discussed with reference to the weight of evidence. (3) The claim that equally weighted parsimony assumes that all characters are evolving at equal rates has been shown to be false in both analytical and simulation studies. (4) The claimed “strong support” for marsupial frog monophyly is questionable. Several studies have also found marsupial frogs to be non-monophyletic. Wiens et al. (2005, Syst. Biol. 54, 719–748) recovered marsupial frogs as monophyletic, but that result was strongly supported only by Bayesian clade confidence values (which are known to overestimate support) and bootstrap support in his parsimony analysis was \u3c 50%. Further, in a more recent parsimony analysis of an expanded data set that included RAG-1 and the three traditional morphological synapomorphies of marsupial frogs, Wiens et al. (2006, Am. Nat. 168, 579–596) also found them to be non-monophyletic. Although we attempted to apply the rule of monophyly to the naming of taxonomic groups, our phylogenetic results are largely consistent with conventional views even if not with the taxonomy current at the time of our writing. Most of our taxonomic changes addressed examples of non-monophyly that had previously been known or suspected (e.g., the non-monophyly of traditional Hyperoliidae, Microhylidae, Hemiphractinae, Leptodactylidae, Phrynobatrachus, Ranidae, Rana, Bufo; and the placement of Brachycephalus within “Eleutherodactylus”, and Lineatriton within “Pseudoeurycea”), and it is troubling that Wiens and others, as evidenced by recent publications, continue to perpetuate recognition of non-monophyletic taxonomic groups that so profoundly misrepresent what is known about amphibian phylogeny

Quantum Computation with Quantum Dots

We propose a new implementation of a universal set of one- and two-qubit gates for quantum computation using the spin states of coupled single-electron quantum dots. Desired operations are effected by the gating of the tunneling barrier between neighboring dots. Several measures of the gate quality are computed within a newly derived spin master equation incorporating decoherence caused by a prototypical magnetic environment. Dot-array experiments which would provide an initial demonstration of the desired non-equilibrium spin dynamics are proposed.Comment: 12 pages, Latex, 2 ps figures. v2: 20 pages (very minor corrections, substantial expansion), submitted to Phys. Rev.

Cytotoxic T cells and mycobacteria

How the immune system kills Mycobacterium tuberculosis is still a puzzle. the classical picture of killing due to phagocytosis by activated macrophages may be only partly correct. Based on recent evidence, we express here the view that cytotoxic T lymphocytes also make an important contribution and suggest that DNA vaccines might be a good way to enhance this. (C) 2001 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.Univ São Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, BrazilUniv São Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Bromatol & Toxicol, BR-14049 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Microbiol & Immunol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol & Immunol, São Paulo, BrazilWeb of Scienc

Gamma ray flares from Mrk421 in 2008 observed with the ARGO-YBJ detector

In 2008 the blazar Markarian 421 entered a very active phase and was one of the brightest sources in the sky at TeV energies, showing frequent flaring episodes. Using the data of ARGO-YBJ, a full coverage air shower detector located at Yangbajing (4300 m a.s.l., Tibet, China), we monitored the source at gamma ray energies E > 0.3 TeV during the whole year. The observed flux was variable, with the strongest flares in March and June, in correlation with X-ray enhanced activity. While during specific episodes the TeV flux could be several times larger than the Crab Nebula one, the average emission from day 41 to 180 was almost twice the Crab level, with an integral flux of (3.6 +-0.6) 10^-11 photons cm^-2 s^-1 for energies E > 1 TeV, and decreased afterwards. This paper concentrates on the flares occurred in the first half of June. This period has been deeply studied from optical to 100 MeV gamma rays, and partially up to TeV energies, since the moonlight hampered the Cherenkov telescope observations during the most intense part of the emission. Our data complete these observations, with the detection of a signal with a statistical significance of 3.8 standard deviations on June 11-13, corresponding to a gamma ray flux about 6 times larger than the Crab one above 1 TeV. The reconstructed differential spectrum, corrected for the intergalactic absorption, can be represented by a power law with an index alpha = -2.1 extending up to several TeV. The spectrum slope is fully consistent with previous observations reporting a correlation between the flux and the spectral index, suggesting that this property is maintained in different epochs and characterizes the source emission processes.Comment: Accepted for publication on ApJ