Effect of dietary arachidonic acid and n-3 polyunsaturated fatty acids on the production of eicosanoids

The major polyunsaturated fatty acid (PUFA) in the western diet is linoleic acid (LA), which is considered to be the major source of tissue arachidonic acid (AA), the principal precursor for the vaso-active eicosanoids via the cyclooxygenase enzymatic pathway. However, dietary AA may contribute significantly to tissue levels of AA in humans, leading to an increase in the production of eicosanoids, particularly the platelet aggregating, vasoconstricting, thromboxane (TXA2), hence increasing thrombosis risk. The aims of this study were to determine the extent to which dietary AA contributed to prostacyclin (PGI2) and TXA2 production in vivo and whether dietary long chain (LC) n-3 PUFA have a modulating influence on the metabolism of AA to these vaso-active eicosanoids. A gas chromatography -mass spectrometry (GCMS) method for urinary PGI2-M determination and a tandem GCMS/MS method for urinary TXA2-M determination were perfected for use within our laboratory (with the assistance of Dr Howard Knapp, University of Iowa and Professor Reinhard Lorenz, Ludwig Maximilian\u27s University, Munich, respectively). An initial animal study compared the in vitro production of PGI2 by aorta segments with the whole body in vivo production of PGI2 in rats fed ethyl arachidonate or the ethyl ester of eicosapentaenoic acid (EPA), at levels many times higher than encountered in human diets. During AA feeding both measures of PGI2 increased, although in vitro TXA2 production was not affected. EPA feeding lowered in vitro TXA2 and in vivo PGI2. Prior to determining the effects of AA and LC n-3 PUFA in humans, a study was carried out to determine the AA and LC n-3 PUFA content of foods and from these, an estimate of the mean daily intake of AA and other LC PUFA. Eggs, organ meats and paté were found to be the richest sources of AA. Of the meat and fish analysed, white meat was found to be relatively rich in AA but poor in LC n-3 PUFA. Lean red meat, particularly kangaroo had similar LC n-3 PUFA and AA content. Fish, although rich in AA, had extremely high levels of LC n-3 PUFA. The calculated mean daily intakes of AA in Australian adults was 130mg (males) and 96mg (females). For total LC n-3 PUFA intake, the mean daily values were 247mg (males) and 197mg (females). Two human pilot studies involving dietary intervention trials examined the effects of dietary AA and AA plus long chain n-3 PUFA on thrombosis risk, gauged by the change in the ratio of PGI2 / TXA2 as well as alterations to other recognised risk factors, such as lipoprotein lipids and platelet aggregation. The desired dietary amounts of AA and LC n-3 PUFA were achieved in the first study by combining food items with known levels of each fatty acid. In the second study, where a diet with approximately equal quantities of AA and LC n-3 PUFA was being examined, kangaroo meat was consumed, following a low-fat vegetarian diet used as a baseline. Diets rich in AA alone (~500mg/day) increased plasma phospholipid (PL) AA levels, PGIi and TXA2 production. When foods containing equal quantities of AA and EPA (∼500mg/day of each) were fed to subjects PGI2 increased, with no change in TXAs production. Low fat vegetarian diets lowered PGI2 production, the level of which was reestablished by an AA rich diet (∼300mg AA/day + ∼260mg/day LC n-3 PUFA) of kangaroo meat. However, TXA2 production was not altered. A final, larger human dietary intervention trial then examined the effects of diets relatively rich in AA alone, AA plus LC n-3 PUFA and LC n-3 PUFA, on the ratio of PGI2/TXA2- The dietary sources of these fatty acids were white meat, red meat and fish, respectively. Each contained a mean level of AA of ∼140mg/day, with varying LC n-3 PUFA levels (59, 161 and 3380mg/day, respectively). Neither meat diet altered PGI2 or TXA2 production significantly, despite increasing serum PL AA levels. The fish diet resulted in a decrease in the serum and platelet PL AA/EPA ratio and TXA2 production, thus increasing the PGI2 / TXA2 ratio. These results would indicate that stores of AA in the body are sufficiently high to have effectively saturated the cyclooxygenase pathway for production of both PGI2 and TXA2, thus making any small change in the plasma level of AA due to \u27normal\u27 dietary levels, inconsequential. However, as seen in the rat study and the two pilot studies higher dietary levels of AA can increase both PGI2 and TXA2 production. Increases in platelet levels of EPA and DHA were associated with a decrease in TXA2 production, or the maintenance of a constant TXA2 level, while AA tissue levels and PGI2 production increased. This suggests a possible inhibitory effect of LC n-3 PUFA on the metabolism of AA to TXA2, particularly in platelets. From these short term studies, conducted over 2-3 week periods, it can be concluded that diets rich in lean meats can raise plasma AA levels but do not affect TXA2 or PGI2 production, hence are not pro-thrombotic. Diets rich in long chain n-3 PUFA from fish, raise plasma EPA and DHA levels, lower TXA2 production and are anti-thrombotic. Diets which combine equal quantities of AA and LC n-3 PUFA appear to increase PGI2 production while keeping TXA2 production constant. In order for these LC PUFA to have a significant effect on eicosanoid production the dietary intake of these fatty acids through foods such as red meat or white meat would have to be higher than average current Australian consumption levels

Geographic contrasts between pre- and postzygotic barriers are consistent with reinforcement in Heliconius butterflies.

Identifying the traits causing reproductive isolation and the order in which they evolve isfundamental to understanding speciation. Here, we quantify prezygotic and intrinsicpostzygotic isolation between allopatric, parapatric and sympatric populations of thebutterflies Heliconius elevatus and Heliconius pardalinus. Sympatric populations from theAmazon (H. elevatus and H. p. butleri) exhibit strong prezygotic isolation and rarely mate incaptivity; however, hybrids are fertile. Allopatric populations from the Amazon(H. p. butleri) and Andes (H. p. sergestus) mate freely when brought together in captivity, butthe female F1 hybrids are sterile. Parapatric populations (H. elevatus and H. p. sergestus)exhibit both assortative mating and sterility of female F1s. Assortative mating in sympatricpopulations is consistent with reinforcement in the face of gene flow, where the driving force,selection against hybrids, is due to disruption of mimicry and other ecological traits ratherthan hybrid sterility. In contrast, the lack of assortative mating and hybrid sterility observedin allopatric populations suggests that geographic isolation enables the evolution of intrinsicpostzygotic reproductive isolation. Our results show how the types of reproductive barriersthat evolve between species may depend on geography

Polymer-based paclitaxel-eluting stents reduce in-stent neointimal tissue proliferation A serial volumetric intravascular ultrasound analysis from the TAXUS-IV trial

ObjectivesThe aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effects of polymer-based, paclitaxel-eluting stents on in-stent neointima formation and late incomplete stent apposition.BackgroundThe TAXUS-IV trial demonstrated that the slow-release, polymer-based, paclitaxel-eluting stent reduces angiographic restenosis and the need for repeat revascularization procedures. Serial IVUS studies reveal details of the pattern of vascular responses provoked by stent implantation that provide insight into device safety and efficacy.MethodsIn the TAXUS-IV trial, patients were randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). As part of a formal substudy, complete volumetric IVUS data were available in 170 patients, including 88 TAXUS patients and 82 controls, at implantation and at nine-month follow-up.ResultsNo baseline differences were present in the clinical characteristics or IVUS parameters between the control and TAXUS groups. At nine-month follow-up, IVUS lumen volumes were larger in the TAXUS group (123 ± 43 mm3vs. 104 ± 44 mm3, p = 0.005), due to a reduction in neointimal volume (18 ± 18 mm3vs. 41 ± 23 mm3, p < 0.001). Millimeter-by-millimeter analysis within the stent demonstrated uniform suppression of neointimal growth along the entire stent length. Late lumen loss was similar at the proximal edge of the stent between the two groups, and reduced with the TAXUS stent at the distal edge (p = 0.004). Incomplete stent apposition at nine months was observed in only 3.0% of control and 4.0% of TAXUS stents (p = 0.12).ConclusionsPolymer-based, paclitaxel-eluting TAXUS stents are effective in inhibiting neointimal tissue proliferation, and do not result in late incomplete stent apposition

Early changes in visuospatial episodic memory can help distinguish primary age‐related tauopathy from Alzheimer’s disease

From Wiley via Jisc Publications RouterHistory: received 2021-02-08, rev-recd 2021-03-19, accepted 2021-05-01, pub-electronic 2021-05-29Article version: VoRPublication status: PublishedFunder: Alzheimer's Research Trust; Id: http://dx.doi.org/10.13039/501100000319Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265Funder: Unilever; Id: http://dx.doi.org/10.13039/100007190Funder: Economic and Social Research Council; Id: http://dx.doi.org/10.13039/501100000269Funder: Alzheimer's Society; Id: http://dx.doi.org/10.13039/501100000320Funder: Wellcome Trust; Grant(s): 00388

Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans

Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. Conclusion: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis. (HEPATOLOGY 2012;56:1108–1116

Integrated miRNA/cytokine/chemokine profiling reveals severity-associated step changes and principal correlates of fatality in COVID-19

Inflammatory cytokines and chemokines (CC) drive COVID-19 pathology. Yet, patients with similar circulating CC levels present with different disease severity. Here, we determined 171 microRNAomes from 58 hospitalized COVID-19 patients (Cohort 1) and levels of 25 cytokines and chemokines (CC) in the same samples. Combining microRNA (miRNA) and CC measurements allowed for discrimination of severe cases with greater accuracy than using miRNA or CC levels alone. Severity group-specific associations between miRNAs and COVID-19-associated CC (e.g., IL6, CCL20) or clinical hallmarks of COVID-19 (e.g., neutrophilia, hypoalbuminemia) separated patients with similar CC levels but different disease severity. Analysis of an independent cohort of 108 patients from a different center (Cohort 2) demonstrated feasibility of CC/miRNA profiling in leftover hospital blood samples with similar severe disease CC and miRNA profiles, and revealed CCL20, IL6, IL10, and miR-451a as key correlates of fatal COVID-19. These findings highlight that systemic miRNA/CC networks underpin severe COVID-19

Genome-wide occupancy links Hoxa2 to Wnt–β-catenin signaling in mouse embryonic development

The regulation of gene expression is central to developmental programs and largely depends on the binding of sequence-specific transcription factors with cis-regulatory elements in the genome. Hox transcription factors specify the spatial coordinates of the body axis in all animals with bilateral symmetry, but a detailed knowledge of their molecular function in instructing cell fates is lacking. Here, we used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) to identify Hoxa2 genomic locations in a time and space when it is actively instructing embryonic development in mouse. Our data reveals that Hoxa2 has large genome coverage and potentially regulates thousands of genes. Sequence analysis of Hoxa2-bound regions identifies high occurrence of two main classes of motifs, corresponding to Hox and Pbx–Hox recognition sequences. Examination of the binding targets of Hoxa2 faithfully captures the processes regulated by Hoxa2 during embryonic development; in addition, it uncovers a large cluster of potential targets involved in the Wnt-signaling pathway. In vivo examination of canonical Wnt–β-catenin signaling reveals activity specifically in Hoxa2 domain of expression, and this is undetectable in Hoxa2 mutant embryos. The comprehensive mapping of Hoxa2-binding sites provides a framework to study Hox regulatory networks in vertebrate developmental processes

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure