Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma

<p>Abstract</p> <p>Background</p> <p>Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR^-/-) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat.</p> <p>Methods</p> <p>The wild type (WT) and AR^-/-mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4⁺CD25⁺T cells population.</p> <p>Results</p> <p>Deficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR^-/-mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4⁺CD25⁺FoxP3⁺) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat.</p> <p>Conclusion</p> <p>Our results using AR^-/-mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.</p

SIDEBAR. The Mid-Pleistocene Enigma

Variations in Earth’s orbit affect incoming solar radiation and have guided past glacial-​interglacial oscillations. These rhythmic changes in insolation are known as Milankovitch cycles. Approximately 900,000 years ago, Earth’s climate pacemaker skipped a beat and switched from the 41,000-year obliquity (Earth’s axial tilt) pacing of the Early Pleistocene to ~100,000-year eccentricity (circularity of Earth’s orbit around the sun) pacing of the Late Pleistocene. This glacial-to-interglacial shift, called the Mid-Pleistocene Transition (MPT), remains one of the most enduring mysteries of the Quaternary and in the field of paleoceanography. Recent reconstructions of atmospheric and oceanic processes and studies of the dynamic linkages between them have paved the way for a more detailed mechanistic understanding of this climatic transition and of Earth’s climate system at large

Dipl\uea. Sotto il segno del 'dilemma' nella poetica greca

The seven chapters of the book are devoted to illustrate and analyse, in the light of platonic and aristotelian aesthetical theories, the various problems of greek poetry in the view of seven couples of antithetical ideas, concepts and/or poetic formalities (for example: History vs. Poetry. Tragedy vs. Comedy. Narration vs. Representation. Reality vs. Fiction. etc.) with philological attention to the theoretic learnings of Antiquity and to their evolution in the following tradition

Proxy evidence for state-dependence of climate sensitivity in the Eocene greenhouse.

Despite recent advances, the link between the evolution of atmospheric CO2 and climate during the Eocene greenhouse remains uncertain. In particular, modelling studies suggest that in order to achieve the global warmth that characterised the early Eocene, warmer climates must be more sensitive to CO2 forcing than colder climates. Here, we test this assertion in the geological record by combining a new high-resolution boron isotope-based CO2 record with novel estimates of Global&nbsp;Mean&nbsp;Temperature. We find that Equilibrium&nbsp;Climate&nbsp;Sensitivity (ECS) was indeed higher during the warmest intervals of the Eocene, agreeing well with recent model simulations, and declined through the Eocene as global climate cooled. These observations indicate that the canonical IPCC range of ECS (1.5 to 4.5 °C per doubling) is unlikely to be appropriate for high-CO2 warm climates of the past, and the state dependency of ECS may play an increasingly important role in determining the state of future climate as the Earth continues to warm

NIST RM 8301 boron isotopes in marine carbonate (simulated coral and foraminifera solutions): inter‐laboratory δ 11 B and trace element ratio value assignment

The boron isotopic (δ11BSRM951) and trace element composition of marine carbonates are key proxies for understanding carbon cycling (pH) and palaeoceanographic change. However, comparability of results between laboratories requires carbonate reference materials. Here we report results of an inter‐laboratory comparison study to both assign δ11BSRM951 and trace element compositions to new marine carbonate reference materials (RM), NIST RM 8301 (Coral) and NIST RM 8301 (Foram) and to assess analytical variability among laboratories. Non‐certified reference values and expanded 95% uncertainties for δ11BSRM951 in NIST RM 8301 (Coral) (+24.17‰ ± 0.18‰) and NIST RM 8301 (Foram) (+14.51‰ ± 0.17‰) solutions were assigned by consensus approach using inter‐laboratory data. Differences reported among laboratories were considerably smaller than some previous inter‐laboratory comparisons, yet discrepancies could still lead to large differences in calculated seawater pH. Similarly, variability in reported trace element information values among laboratories (e.g., Mg/Ca ± 5%) was often greater than analytical precision (% RSD) within a single laboratory (e.g., Mg/Ca < 2%). Such differences potentially alter proxy‐reconstructed seawater temperature by more than 2 °C. These now well‐characterised solutions are useful reference materials to help the palaeoceanographic community build a comprehensive view of past ocean changes

Two-million-year-old snapshots of atmospheric gases from Antarctic ice

Over the past eight hundred thousand years, glacial-interglacial cycles oscillated with a period of one hundred thousand years ('100k world'1). Ice core and ocean sediment data have shown that atmospheric carbon dioxide, Antarctic temperature, deep ocean temperature, and global ice volume correlated strongly with each other in the 100k world2-6. Between about 2.8 and 1.2 million years ago, glacial cycles were smaller in magnitude and shorter in duration ('40k world'7). Proxy data from deep-sea sediments suggest that the variability of atmospheric carbon dioxide in the 40k world was also lower than in the 100k world8-10, but we do not have direct observations of atmospheric greenhouse gases from this period. Here we report the recovery of stratigraphically discontinuous ice more than two million years old from the Allan Hills Blue Ice Area, East Antarctica. Concentrations of carbon dioxide and methane in ice&nbsp;core samples older than two million years have been altered by respiration, but some younger samples are pristine. The recovered ice cores extend direct observations of atmospheric carbon dioxide, methane, and Antarctic temperature (based on the deuterium/hydrogen isotope ratio δDice, a proxy for regional temperature) into the 40k world. All climate properties before eight hundred thousand years ago fall within the envelope of observations from continuous deep Antarctic ice cores that characterize the 100k world. However, the lowest measured carbon dioxide and methane concentrations and Antarctic temperature in the 40k world are well above glacial values from the past eight hundred thousand years. Our results confirm that the amplitudes of glacial-interglacial variations in atmospheric greenhouse gases and Antarctic climate were reduced in the 40k world, and that the transition from the 40k to the 100k world was accompanied by a decline in minimum carbon dioxide concentrations during glacial maxima