Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis

Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption. Most cases arise from a founder mutation in HFE (845G-->A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with beta2-microglobulin. Mice homozygous with respect to a null allele of Hfe (Hfe-/-) or homozygous with respect to the orthologous 882G-->A mutation (Hfe(845A/845A)) develop iron overload that recapitulates hereditary hemochromatosis in humans, confirming that hereditary hemochromatosis arises from loss of HFE function. Much work has focused on an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells is thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (also called DMT1, DCT1 and NRAMP2) and SLC11A3 (also called IREG1, ferroportin and MTP1; ref. 3). Published data on the expression of these transporters in the duodenum of HFE-deficient mice and humans are contradictory. In this report, we used a custom microarray to assay changes in duodenal and hepatic gene expression in Hfe-deficient mice. We found unexpected alterations in the expression of Slc39a1 (mouse ortholog of SLC11A3) and Cybrd1, which encode key iron transport proteins, and Hamp (hepcidin antimicrobial peptide), a hepatic regulator of iron transport. We propose that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.     

Attractor dynamics of network UP states in the neocortex

The cerebral cortex receives input from lower brain regions, and its function is traditionally considered to be processing that input through successive stages to reach an appropriate output. However, the cortical circuit contains many interconnections, including those feeding back from higher centres, and is continuously active even in the absence of sensory inputs. Such spontaneous firing has a structure that reflects the coordinated activity of specific groups of neurons. Moreover, the membrane potential of cortical neurons fluctuates spontaneously between a resting (DOWN) and a depolarized (UP) state, which may also be coordinated. The elevated firing rate in the UP state follows sensory stimulation and provides a substrate for persistent activity, a network state that might mediate working memory. Using two-photon calcium imaging, we reconstructed the dynamics of spontaneous activity of up to 1,400 neurons in slices of mouse visual cortex. Here we report the occurrence of synchronized UP state transitions ('cortical flashes') that occur in spatially organized ensembles involving small numbers of neurons. Because of their stereotyped spatiotemporal dynamics, we conclude that network UP states are circuit attractors--emergent features of feedback neural networks that could implement memory states or solutions to computational problems.     

Uptake of dissolved organic carbon and trace elements by zebra mussels

Zebra mussels (Dreissena polymorpha) are widespread and abundant in major freshwater ecosystems in North America, even though the phytoplankton food resources in some of these systems seem to be too low to sustain them. Because phytoplankton biomass is greatly depleted in ecosystems with large D. polymorpha populations and bacteria do not seem to be an important food source for this species, exploitation of alternative carbon sources may explain the unexpected success of D. polymorpha in such environments. Here we examine the possibility that absorption of dissolved organic carbon (DOC) from water could provide a nutritional supplement to zebra mussels. We find that mussels absorb 14C-labelled DOC produced by cultured diatoms with an efficiency of 0.23%; this indicates that DOC in natural waters could contribute up to 50% of the carbon demand of zebra mussels. We also find that zebra mussels absorb some dissolved metals that have been complexed by the DOM; although absorption of dissolved selenium was unaffected by DOC, absorption of dissolved cadmium, silver and mercury by the mussels increased 32-, 8.7- and 3.6-fold, respectively, in the presence of high-molecular-weight DOC.     

Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28

Linkage disequilibrium (LD), or the non-random association of alleles, is poorly understood in the human genome. Population genetic theory suggests that LD is determined by the age of the markers, population history, recombination rate, selection and genetic drift. Despite the uncertainties in determining the relative contributions of these factors, some groups have argued that LD is a simple function of distance between markers. Disease-gene mapping studies and a simulation study gave differing predictions on the degree of LD in isolated and general populations. In view of the discrepancies between theory and experimental observations, we constructed a high-density SNP map of the Xq25-Xq28 region and analysed the male genotypes and haplotypes across this region for LD in three populations. The populations included an outbred European sample (CEPH males) and isolated population samples from Finland and Sardinia. We found two extended regions of strong LD bracketed by regions with no evidence for LD in all three samples. Haplotype analysis showed a paucity of haplotypes in regions of strong LD. Our results suggest that, in this region of the X chromosome, LD is not a monotonic function of the distance between markers, but is more a property of the particular location in the human genome.     

Observations on the toxicity and metabolic relationships of polygodial,the chemical defense of the nudibranchDendrodoris limbata

Summary Polygodial (1), the defense metabolite stored in the skin of the nudibranchDendrodoris limbata, is toxic for the mollusc itself when injected into the hepatopancreas. Biosynthetic experiments using labeled mevalonic acid were devised to investigate a possible metabolic relationship between1 and the mixture of sesquiterpenoidic esters2, stored in the hepatopancreas. The results suggest that1 and2 are biosynthesized by independent pathways.Thanks are due to G. Villani for supplyingDendrodoris limbata and to A. Trabucco for technical assistance.     

以龙舌兰蔗渣作为还原剂使磁铁矿精矿有效地金属化

The reduction behavior and metallization degree of magnetite concentrate with agave bagasse were investigated in an inert atmosphere. The effects of temperature, biomass content, and residence time on reduction experiments and metallization degree were investigated by X-ray diffraction and scanning electron microscopy. Compared with other types of biomass, agave bagasse had lower contents of nitrogen, sulfur, and ash. X-ray diffraction analysis showed that the metallization degree improved with increasing temperature and biomass content. Complete metallization was achieved at 1100°C for 30 min with 65:35 and 50:50 ratios of the magnetite concentrate to the agave bagasse. These results demonstrate that agave bagasse promotes the efficient metallization of magnetite concentrate without the external addition of a reducing agent. Therefore, this biomass is a technical suitable alternative to replace fossil fuels in steelmaking.     

Effect of glucose administration on bilirubin excretion in the rabbit

Summary The effect of i.v. infusion of glucose on the hepatic handling of bilirubin was examined in rabbits. A significant increase in the excretion of conjugated bilirubin into the bile was observed, accompanied by a decrease in bilirubinemia. Hepatic bilirubin concentrations were lowered and the UDP-glucose concentrations and liver UDP-glucuronosyl and UDP-glucosyl transferase activities increased.     

Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids

Anti-inflammatory glucocorticoids inhibit prostaglandin (PG) biosynthesis by preventing arachidonic acid release from phospholipids rather than inhibiting the cyclooxygenase. As in other cells, this steroid action depends on receptor occupation and de novo protein/RNA biosynthesis. We have previously shown in guinea pig perfused lungs and rat peritoneal leukocytes that the effect of steroids in PG generation is mediated by an uncharacterized 'second messenger'. Now, we report that this factor (which we have named 'macrocortin') is an intracellular polypeptide whose release and synthesis are stimulated by steroids. Macrocortin derived from rat peritoneal leukocytes is very similar to that released from guinea pig lungs.