The major fungal pathogen of humans, Aspergillus fumigatus, lacks a defined sexual cycle, although the presence of genes encoding putative mating type idiomorphs and regulators of Aspergillus sexual development heightens the potential for cryptic sexuality in this deuteromycete. To test the functionality of these genetic determinants, we transferred the alpha box-encoding mat1-1 idiomorph from an A. fumigatus isolate to the homothallic fertile species Aspergillus nidulans. Abundant formation of fruiting bodies (cleistothecia) containing viable ascospores establishes functionality of this mating type gene product in the transgenic strain. Using a similar approach, we also established that the conserved transcriptional regulator from A. fumigatus, the nsdD gene product, can act as a functional, positively acting factor for A. nidulans cleistothecium development; moreover, high-level expression of NsdD in the endogenous host A. fumigatus profoundly alters hyphal development by triggering the formation of coiled hyphae. Our findings demonstrate that the presumably asexual pathogen A. fumigatus encodes functional regulators of mating and sexual development, thereby potentiating the case for cryptic sexuality in this fungal pathogen.
1. Previous studies have shown that an arterial-to-portal glucose concentration gradient may be an important signal for insulin-dependent net hepatic glucose uptake. It is not known whether intestinal factors also contribute to the regulation of hepatic glucose utilization. This problem was studied in a newly developed model which allows luminal perfusion of the small intestine via the pyloric sphincter and a combined vascular perfusion of the small intestine via the gastroduodenal artery and superior mesenteric artery, and of the liver via the hepatic artery and portal vein. 2. In both the presence and the absence of 1 mM-glutamine in the vascular perfusate, only about 7% of a luminal bolus of 5500 mumol (1 g) of glucose was absorbed by the small intestine, and nothing was taken up by the liver. 3. With small doses of 75-380 mumol (11-55 mg) of luminal glutamine, but not with 300 mumol of alanine, the intestinal absorption of the luminal glucose bolus was increased almost linearly from 7% to a maximum of 40% and the hepatic uptake from 0% to a maximum of 22%. 4. The increase of hepatic glucose uptake caused by luminal glutamine was only observed when the glucose load was applied into the intestinal lumen, rather than into the superior mesenteric artery. 5. The relative hepatic glucose uptake (uptake/portal supply) was enhanced from 0% to 55% with an increase in portal supply by luminal glutamine, whereas with a similar range of portal glucose supply the relative hepatic uptake by the isolated liver, perfused simultaneously via the hepatic artery and portal vein, was slightly decreased, from 20% to 15%. 6. Addition of various amounts of portal glutamine and/or alterations in the Na+ content of the portal perfusate failed to mimic the luminal glutamine-dependent activation of hepatic glucose uptake. Therefore the luminal-glutamine-elicited activation of hepatic glucose uptake was apparently not caused by a simple increase in the portal-arterial glucose gradient, by glutamine itself or by Na(+)-dependent alterations in hepatic cell volume. The results suggest that luminal glutamine caused not only an increase in intestinal glucose absorption by unknown mechanisms but also the generation of one or more humoral or nervous 'hepatotropic' signals in the small intestine which enhanced the hepatic uptake of absorbed glucose.
Two weeks after intraportal transplantation of 2,000 neonatal pancreatic islets, recipient rats completely recovered from streptozotocin-induced diabetes. The reversal of diabetes could be documented by the normalization of blood glucose levels, by a restored weight gain, by normal glucagon and insulin levels in blood, and by a disappearance of polyuria and polydipsia. The reversal remained stable for at least 9 months. This study determined whether intraportally transplanted pancreatic islets were reinnervated after transplantation and whether the secretion of insulin and glucagon from pancreatic islets might be modulated by the vegetative innervation of recipient livers. Predominantly catecholaminergic but also cholinergic nerve fibers were detected not only within the portal tracts around hepatic arteries, portal veins, and bile ducts, but also at the borderline of hepatocytes and beta-cells and in islet cell complexes between beta-cells. Corresponding electron micrographs showed beta-cells in close contact with axons of nonmyelinated nerve fibers. Isolated livers were single pass perfused via both the hepatic artery and the portal vein. An increase in glucose level from 5 to 14 mmol/l enhanced hepatic glucose uptake and increased insulin secretion from transplanted islets with a biphasic secretion profile but had no effect on glucagon output. Stimulation of the nerve plexus around the hepatic artery and the portal vein (7.5 Hz, 2 min), which activates primarily the sympathetic system, not only reduced glucose uptake and perfusion flow but also completely reversed the glucose-stimulated increase in insulin secretion. Nerve stimulation did not influence glucagon secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
The soil microbiome comprises numerous filamentous fungi and bacteria that mutually react and challenge each other by the production of bioactive secondary metabolites. Herein, we show in liquid co-cultures that the presence of filamentous Streptomycetes producing antifungal glycopeptide antibiotics induces the production of the antibacterial and iron-chelating tropolones anhydrosepedonin (1) and antibiotic C (2) in the mold Aspergillus nidulans. Additionally, the biosynthesis of the related polyketide tripyrnidone (5) was induced, whose novel tricyclic scaffold we elucidated by NMR and HRESIMS data. The corresponding biosynthetic polyketide synthase-encoding gene cluster responsible for the production of these compounds was identified. The tropolones as well as tripyrnidone (5) are produced by genes that belong to the broad reservoir of the fungal genome for the synthesis of different secondary metabolites, which are usually silenced under standard laboratory conditions. These molecules might be part of the bacterium-fungus competition in the complex soil environment, with the bacterial glycopeptide antibiotic as specific environmental trigger for fungal induction of this cluster.
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