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.     

An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice

Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. Hamp is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggest a previously unidentified role for Hfe in innate immunity and ACD.     

Ionic liquids and eutectic mixtures as solvent and template in synthesis of zeolite analogues

The challenges associated with synthesizing porous materials mean that new classes of zeolites (zeotypes)-such as aluminosilicate zeolites and zeolite analogues-together with new methods of preparing known zeotypes, continue to be of great importance. Normally these materials are prepared hydrothermally with water as the solvent in a sealed autoclave under autogenous pressure. The reaction mixture usually includes an organic template or 'structure-directing agent' that guides the synthesis pathway towards particular structures. Here we report the preparation of aluminophosphate zeolite analogues by using ionic liquids and eutectic mixtures. An imidazolium-based ionic liquid acts as both solvent and template, leading to four zeotype frameworks under different experimental conditions. The structural characteristics of the materials can be traced back to the solvent chemistry used. Because of the vanishingly low vapour pressure of ionic liquids, synthesis takes place at ambient pressure, eliminating safety concerns associated with high hydrothermal pressures. The ionic liquid can also be recycled for further use. A choline chloride/urea eutectic mixture is also used in the preparation of a new zeotype framework.     

A one-hit model of cell death in inherited neuronal degenerations

In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often assumed to reflect the occurrence of age-dependent cumulative damage. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules. A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration and Parkinson's and Huntington's diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies.     

Tripling the capacity of wireless communications using electromagnetic polarization

Wireless communications are a fundamental part of modern information infrastructure. But wireless bandwidth is costly, prompting a close examination of the data channels available using electromagnetic waves. Classically, radio communications have relied on one channel per frequency, although it is well understood that the two polarization states of planar waves allow two distinct information channels; techniques such as 'polarization diversity' already take advantage of this. Recent work has shown that environments with scattering, such as urban areas or indoors, also possess independent spatial channels that can be used to enhance capacity greatly. In either case, the relevant signal processing techniques come under the heading of 'multiple-input/multiple-output' communications, because multiple antennae are required to access the polarization or spatial channels. Here we show that, in a scattering environment, an extra factor of three in channel capacity can be obtained, relative to the conventional limit using dual-polarized radio signals. The extra capacity arises because there are six distinguishable electric and magnetic states of polarization at a given point, rather than two as is usually assumed.     

Transverse and longitudinal variation in woody riparian vegetation along a montane river

This study explores how the relationship between flow and riparian vegetation varies along a montane river. We mapped occurrence of woody riparian plant communities along 58 km of the San Miguel River in southwestern Colorado. We determined the recurrence interval of inundation for each plant community by combining step-backwater hydraulic modeling at 4 representative reaches with Log-Pearson analysis of 4 stream gaging stations. Finally, we mapped bottomland surficial geology and used a Geographic Information System to overlay the coverages of geology and vegetation. Plant communities were distinctly arrayed along the hydrologic gradient. The Salix exigua Nuttall (sandbar willow) community occurred mostly on surfaces with a recurrence interval of inundation shorter than 2.2 years; the Betula occidentalis Hooker (river birch) community peaked on sites with recurrence intervals of inundation between 2.2 and 4.6 years. The hydrologic position occupied by communities dominated by Populus angustifolia James (narrowleaf cottonwood) was strongly related to age of trees and species composition of understory shrubs. The fraction of riparian vegetation on surfaces historically inundated by the river decreased in the upstream direction from almost 100% near Uravan to <50% along the South Fork of the San Miguel River. In upstream reaches much of the physical disturbance necessary to maintain riparian vegetation is provided by valley-side processes including debris flows, floods from minor tributaries, landslides, and beaver activity. Where valley-side processes are important, prediction of riparian vegetation change based on alterations of river flow will be incomplete.