Background: Current phenotyping of chronic rhinosinusitis (CRS) into CRS with nasal polyps and without nasal polyps may not adequately reflect the pathophysiologic diversity within CRS.

T cytokine levels, eosinophilic/neutrophilic patterns, and SE-specific IgE expressions show extreme diversity among patients with CRS from Europe, Asia, and Oceania.

The end-Permian mass extinction was the most severe biodiversity crisis in Earth history. To better constrain the timing, and ultimately the causes of this event, we collected a suite of geochronologic, isotopic, and biostratigraphic data on several well-preserved sedimentary sections in South China. High-precision U-Pb dating reveals that the extinction peak occurred just before 252.28 ± 0.08 million years ago, after a decline of 2 per mil (‰) in δ(13)C over 90,000 years, and coincided with a δ(13)C excursion of -5‰ that is estimated to have lasted ≤20,000 years. The extinction interval was less than 200,000 years and synchronous in marine and terrestrial realms; associated charcoal-rich and soot-bearing layers indicate widespread wildfires on land. A massive release of thermogenic carbon dioxide and/or methane may have caused the catastrophic extinction.

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BACKGROUND & AIMS Capillarization, characterized by loss of differentiation of liver sinusoidal endothelial cell (LSEC), precedes the onset of hepatic fibrosis. We investigated whether restoring differentiation to LSEC in liver affects their interactions with hepatic stellate cells (HSCs) and thereby promotes quiescence of HSCs and regression of fibrosis. METHODS Rat LSECs were cultured with inhibitors and/or agonists and examined by scanning electron microscopy for fenestrae in sieve plates. Cirrhosis was induced in rats using thioacetamide, followed by administration of BAY 60-2770, an activator of soluble guanylate cyclase (sGC). Fibrosis was assessed by Sirius red staining; expression of α-smooth muscle actin was measured by immunoblot analysis. RESULTS Maintenance of LSEC differentiation requires vascular endothelial growth factor-A stimulation of nitric oxide (NO)-dependent signaling (via sGC and cGMP) and NO-independent signaling. In rats with thioacetamide-induced cirrhosis, BAY 60-2770 accelerated the complete reversal of capillarization (restored differentiation of LSEC) without directly affecting activation of HSC or fibrosis. Restoration of differentiation to LSEC led to quiescence of HSC and regression of fibrosis, in the absence of further exposure to BAY 60-2770. Activation of sGC with BAY 60-2770, prevented progression of cirrhosis, despite continued administration of thioacetamide. CONCLUSIONS Differentiation of LSEC has an important role in activation of HSC and the fibrotic process in rats.

Capillarization precedes hepatic fibrosis. We hypothesize that capillarization of sinusoidal endothelial cells (SEC) is permissive for hepatic stellate cell (HSC) activation and therefore permissive for fibrosis. We examined whether freshly isolated SECs prevent activation of HSCs and promote reversion to quiescence, and whether this effect was lost in capillarization. HSCs were cultured alone or co-cultured with differentiated or capillarized SECs. Results: Co-culture with freshly isolated SECs markedly decreased HSC activation after 3 days in culture, but co-culture with capillarized SEC had no effect.

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Previous studies have shown that ␤-carotene 15,15-monooxygenase catalyzes the cleavage of ␤-carotene at the central carbon 15,15-double bond but cleaves lycopene with much lower activity. However, expressing the mouse carotene 9,10-monooxygenase (CMO2) in ␤-carotene/lycopene-synthesizing and -accumulating Escherichia coli strains leads to both a color shift and formation of apo-10-carotenoids, suggesting the oxidative cleavage of both carotenoids at their 9,10-double bond. Here we provide information on the biochemical characterization of CMO2 of the ferret, a model for human carotenoid metabolism, in terms of the kinetic analysis of ␤-carotene/lycopene cleavage into ␤-apo-10-carotenal/apo-10-lycopenal in vitro and the formation of apo-10-lycopenoids in ferrets in vivo. We demonstrate that the recombinant ferret CMO2 catalyzes the excentric cleavage of both all-trans-␤-carotene and the 5-cis-and 13-cis-isomers of lycopene at the 9,10-double bond but not all-trans-lycopene. The cleavage activity of ferret CMO2 was higher toward lycopene cis-isomers as compared with ␤-carotene as substrate. Iron was an essential co-factor for the reaction. Furthermore, all-trans-lycopene supplementation in ferrets resulted in significant accumulation of cis-isomers of lycopene and the formation of apo-10-lycopenol, as well as upregulation of the CMO2 expression in lung tissues. In addition, in vitro incubation of apo-10-lycopenal with the post-nuclear fraction of hepatic homogenates of ferrets resulted in the production of both apo-10-lycopenoic acid and apo-10-lycopenol, respectively, depending upon the presence of NAD ؉ or NADH as cofactors. Our finding of bioconversion of cis-isomers of lycopene into apo-10-lycopenoids by CMO2 is significant because cis-isomers of lycopene are a predominant form of lycopene in mammalian tissues and apo-lycopenoids may have specific biological activities related to human health.Carotenoids are lipophilic plant pigments with polyisoprenoid structures, typically containing a series of conjugated double bonds in the central chain of the molecule, which makes them susceptible to oxidative cleavage, and isomerization from trans to cis forms, with the formation of potentially bioactive metabolites. Knowledge of the biological effects of carotenoids, particularly for the impact of oxidation on these carotenoids and the potential for beneficial effects of small quantities or harmful effects of large quantities of the resulting metabolic products, has been reviewed recently (1). For provitamin A carotenoids, such as ␤-carotene, ␣-carotene, and ␤-cryptoxanthin, central cleavage is a major pathway leading to vitamin A formation (2, 3). This pathway has been substantiated by the cloning of the central cleavage enzyme at their 15,15Ј-double bond, ␤-carotene 15,15Ј-monooxygenase (CMO1, 2 formerly called ␤-carotene 15,15Ј-dioxygenase) in different species (4, 5), further classification of this enzyme as a non-heme iron monooxygenase (6), and recent biochemical and structural characterizations (7-11). Very rece...