The biologically active iron chelators 2-pyridylcarboxaldehyde isonicotinoylhydrazone, 2-pyridylcarboxaldehyde benzoylhydrazone monohydrate and 2-furaldehyde isonicotinoylhydrazone

In the crystal structures of the respective title compounds, C12H10N4O, C13H11N3O . H2O and C11K9N3O2, variations in the torsion angles of the aromatic pyridyl and benzoyl groups are observed, and the disposition of the heterocyclic aldehyde is shown to be influenced by the ring size of this group.

Synthesis and complexes of the sexidentate macrocycle 15-methyl-1,4,7,10,13-pentaazacyclohexadecan-15-amine

The potentially sexidentate polyamine macrocycle 15-methyl-1,4,7,10,13-pentaazacyclohexadecan-15-amine (1) was prepared via a copper(II)-templated route from 3,6,9-triazaundecan-1,ll-diamine, formaldehyde and nitroethane which first formed the copper(II) complex of the macrocycle 15-methyl-15-nitro-1,4,7,10,13-pentaazacyclohexadecane (2), reduced subsequently with zinc and aqueous acid to yield 1. The hexaamine 1, with five secondary amine groups in the macrocyclic ring and one pendant primary amine group, forms inert sexidentate octahedral complexes with cobalt(III), chromium(III) and iron(III). An X-ray structure of [Co(1)](ClO4)(3) defines the distorted octahedron of the complex cation and shows it is a symmetrical isomer with all nitrogens bound and the central aza group trans to the pendant primary amine group. The [M(1)](3+) ions are all stable indefinitely in aqueous solution and exhibit spectra consistent with MN6 d(3) (Cr), low-spin d(5) (Fe) and low-spin d(6) (Co) electronic ground states. For each complex, a reversible M(III/II) redox couple is observed. (C) 2000 Elsevier Science S.A. All rights reserved.

Iron deficiency, general health and fatigue: Results from the Australian Longitudinal Study on Women's Health

Associations between self-reported 'low iron', general health and well-being, vitality and tiredness in women, were examined using physical (PCS) and mental (MCS) component summary and vitality (VT) scores from the MOS short-form survey (SF-36). 14,762 young (18-23 years) and 14,072 mid-age (45-50 years) women, randomly selected from the national health insurance commission (Medicare) database, completed a baseline mailed self-report questionnaire and 12,328 mid-age women completed a follow-up questionnaire 2 years later. Young and mid-age women who reported (ever) having had 'low iron' reported significantly lower mean PCS, MCS and VT scores, and greater prevalence of 'constant tiredness' at baseline than women with no history of iron deficiency [Differences: young PCS = -2.2, MCS = -4.8, VT = -8.7; constant tiredness: 67% vs. 45%; mid-age PCS = -1.4, MCS = -3.1, VT = -5.9; constant tiredness: 63% vs. 48%]. After adjusting for number of children, chronic conditions, symptoms and socio-demographic variables, mean PCS, MCS and VT scores for mid-age women at follow-up were significantly lower for women who reported recent iron deficiency (in the last 2 years) than for women who reported past iron deficiency or no history of iron deficiency [Means: PCS - recent = 46.6, past = 47.8, never = 47.7; MCS - recent = 45.4, past = 46.9, never = 47.4; VT - recent = 54.8, past = 57.6, never = 58.6]. The adjusted mean change in PCS, MCS and VT scores between baseline and follow-up were also significantly lower among mid-age women who reported iron deficiency only in the last 2 years (i.e. recent iron deficiency) [Mean change: PCS = -3.2; MCS = -2.1; VT = -4.2]. The results suggest that iron deficiency is associated with decreased general health and well-being and increased fatigue.

Experimental study of phase equilibria in the systems Fe-Zn-O and Fe-Zn-Si-O at metallic iron saturation

The reported experimental work on the systems Fe-Zn-O and Fe-Zn-Si-O in equilibrium with metallic iron is part of a wider research program that combines experimental and thermodynamic computer modeling techniques to characterize zinc/lead industrial slags and sinters in the system PbO-ZnO-SiO2-CaO-FeO-Fe2O3. Extensive experimental,investigations using high-temperature equilibration and quenching techniques followed by electron probe X-ray microanalysis (EPMA) were carried out. Special experimental; procedures were developed to enable accurate measurements in these ZnO-containing systems to be performed in equilibrium with metallic iron; The systems Fe-Zn-O and FeZn-Si-O were experimentally investigated in equilibrium with metallic iron in the temperature ranges 900 degreesC to 1200 degreesC (1173 to 1473 K) and from 1000 degreesC to 1350 degreesC (1273 to 1623 K), respectively. The liquidus surface in the system Fe-Zn-Si-O in equilibrium with metallic iron was characterized in the composition ranges 0 to 33 wt pet ZnO and 0 to 40 wt pet SiO2. The wustite (Fe,Zn)O, zincite (Zn,Fe)O, willemite (Zn,Fe)(2)SiO4, arid fayalite: (Fe,Zn)(2)SiO4 solid solutions in equilibrium with metallic iron were measured.

Experimental study of phase equilibria in the "FeO"-ZnO-(CaO+SiO2) system with CaO/SiO2 weight ratios of 0.33, 0.93, and 1.2 in equilibrium with metallic iron

The pseudoternary sections FeO-ZnO-(CaO + SiO2) with CaO/SiO2 weight ratios of 0.33, 0.93, and 1.2 in equilibrium with metallic iron have been experimentally investigated in the temperature range from 1000 degreesC to 1300 degreesC (1273 to 1573 K). The liquidus surfaces in these pseudoternary sections have been experimentally determined in the composition range from 0 to 33 wt pct ZnO and 30 to 70 wt pct (CaO + SiO2). The sections contain primary-phase fields of wustite (FexZn1-xO1+y), zincite (ZnzFe1-zO), fayalite (Fu(w)Zn(2-w)SiO(4)), melilite (Ca2ZnuFe1-uSi2O7), willemite (ZnvFe2-vSiO4), dicalcium silicate (Ca2SiO4), pseudowollastonite and wollastonite (CaSiO3), and tridymite (SiO2). The phase equilibria involving the liquid phase and the solid solutions-have also been measured.

Expression of the iron regulatory peptide hepcidin is reduced in patients with chronic liver disease

Disturbances in iron metabolism often accompany liver disease in humans and hepatic iron deposition is a frequent finding. Since the peptide hepcidin, a major regulator of body iron homeostasis, is synthesised in the liver, alterations in hepcidin expression could be responsible for these effects. To investigate this possibility, we studied hepcidin expression in liver biopsies from patients with hepatitis C virus (HCV) infection, non-alcoholic fatty liver disease (NAFLD) and hemochromatosis (HC). Total RNA was extracted from the liver tissue of 24 HCV, 17 NASH and 5 HC patients, and 17 liver transplant donors (controls). The levels of mRNA for hepcidin and several other molecules involved in iron metabolism (DMT1, Dcytb, hephaestin, ferroportin, TfR1, TfR2, HFE and HJV) were examined by ribonuclease protection assay and expressed relative to the housekeeping gene GAPDH. The expression of hepcidin was significantly decreased in HCV and NASH patients relative to control liver (109±16 and 200±44 versus 325±26 respectively; P=0.008 and 0.02). We have previously reported similar findings in patients with HC, and this was confirmed in the current analysis (176±21; P=0.003). In both HCV and NAFLD patients the expression of the iron reductase Dcytb and the transferrin binding regulatory molecule TfR2 was also decreased, while the cellular iron exporter ferroportin showed a significant increase. Levels of the mRNA for the iron oxidase hephaestin were lower in HCV patients alone, while expression of the major transferrin binding molecule TfR1 was decreased only in NAFLD patients. Of particular interest was the finding that the expression of HJV (which is mutated in patients with juvenile HC) was significantly increased in NAFLD patients. No changes were seen in the expression of the iron importer DMT1 or the regulatory molecule HFE. Decreased expression of hepcidin in patients with HCV and NAFLD provides an explanation why iron homeostasis could be perturbed in these disorders. Reduced hepcidin levels would increase intestinal iron absorption and iron release from macrophages, which could contribute to hepatic iron accumulation. This in turn could lead to alterations in the expression of various proteins involved in iron transport and its regulation. Indeed most of the changes in the expression of such molecules observed in this study are consistent with this. However, the mechanisms leading to changes in the expression of hepcidin in these diseases remain to be elucidated.

Mechanism of ribonuclease inhibition by ribonuclease inhibitor protein based on the crystal structure of its complex with ribonuclease A

We describe the mechanism of ribonuclease inhibition by ribonuclease inhibitor, a protein built of leucine-rich repeats, based on the crystal structure of the complex between the inhibitor and ribonuclease A. The structure was determined by molecular replacement and refined to an R(cryst) of 19.4% at 2.5 Angstrom resolution. Ribonuclease A binds to the concave region of the inhibitor protein comprising its parallel beta-sheet and loops. The inhibitor covers the ribonuclease active site and directly contacts several active-site residues. The inhibitor only partially mimics the RNase-nucleotide interaction and does not utilize the pi phosphate-binding pocket of ribonuclease A, where a sulfate ion remains bound. The 2550 Angstrom(2) of accessible surface area buried upon complex formation may be one of the major contributors to the extremely tight association (K-i = 5.9 x 10(-14) M). The interaction is predominantly electrostatic; there is a high chemical complementarity with 18 putative hydrogen bonds and salt links, but the shape complementarity is lower than in most other protein-protein complexes. Ribonuclease inhibitor changes its conformation upon complex formation; the conformational change is unusual in that it is a plastic reorganization of the entire structure without any obvious hinge and reflects the conformational flexibility of the structure of the inhibitor. There is a good agreement between the crystal structure and other biochemical studies of the interaction. The structure suggests that the conformational flexibility of RI and an unusually large contact area that compensates for a lower degree of complementarity may be the principal reasons for the ability of RI to potently inhibit diverse ribonucleases. However, the inhibition is lost with amphibian ribonucleases that have substituted most residues corresponding to inhibitor-binding residues in RNase A, and with bovine seminal ribonuclease that prevents inhibitor binding by forming a dimer. (C) 1996 Academic Press Limited

A transformation toughening white cast iron

An experimental white cast iron with the unprecedented fracture tough ness of 40 MPa m(1/2) is currently being studied to determine the mechanisms of toughening. This paper reports the investigation of the role of strain-induced martensitic (SIM) transformation. The dendritic microconstituent in the toughened alloy consists primarily of retained austenite, with precipitated M(7)C(3) carbides and some martensite. Refrigeration experiments and differential scanning calorimetry (DSC) were used to demonstrate, firstly, that this retained austenite has an ''effective'' sub-ambient M(S) temperature and, secondly, that SIM transformation can occur at ambient temperatures. Comparison between room temperature and elevated temperature K-Ic tests showed that the observed SIM produces a transformation toughening response in the alloy, contributing to, but not fully accounting for, its high tough ness. SIM as a mechanism for transformation toughening has not previously been reported for white cast irons. Microhardness traverses on crack paths and X-ray diffraction (XRD) on fracture surfaces confirmed the interpretation of the K-Ic experiments. Further DSC and quantitative XRD showed that, as heat-treatment temperature is varied, there is a correlation between fracture toughness and the volume fraction of unstable retained austenite.

Transmission electron microscopy of a transformation toughened white cast iron

Transmission electron microscopy has been used to study the microstructure of an experimental white cast iran, in which a combination of modified alloy composition and unconventional heat treatment has resulted in a fracture toughness of 40 MPa m(-1/2). Microstructural features of the alloy that contribute to the toughness improvement and hence distinguish it from conventional white irons have been investigated. In the as-cast condition the dendrites are fully austenitic and the eutectic consists of M7C3 carbides and martensite. During heat treatment at 1130 degrees C the austenite is partially destabilized by precipitation of chromium-rich M7C3 carbides. This results in a dendritic microconstituent consisting of bulk retained austenite and secondary carbides which are sheathed with martensite. The martensite sheaths, which contain interlath films of retained austenite, are irregular in shape with some laths extending into the bulk retained austenite. Emphasis has been placed on the morphology, distribution, and stability of the retained austenite and its transformation products in the dendrites. The implications of these findings on the transformation toughening mechanism in this alloy are discussed.

Substrate-bound carbohydrates stimulate signal transduction and neurite outgrowth in an olfactory neuron cell line

SUBPOPULATIONS of olfactory receptor neurons, which are dispersed throughout the olfactory neuroepithelium, express specific cell surface carbohydrates and project to discrete regions of the olfactory bulb. Cell surface carbohydrates such as N-acetyl-lactosamine have been postulated to mediate sorting and selective fasciculation of discrete axon subpopulations during development of the olfactory pathway. Substrate-bound N-acetyl-lactosamine promotes neurite outgrowth by both clonal olfactory receptor neuron cell lines and olfactory receptor neurons in vitro, indicating that cell surface carbohydrates may be ligands for receptor-mediated stimulation of axon growth in vivo. In the present study, the role of transmembrane signaling in N-acetyl-lactosamine-stimulated neurite outgrowth was examined in the clonal olfactory neuron cell line 4.4.2. Substrate-bound N-acetyl-lactosamine stimulated neurite outgrowth which was specifically inhibited by antagonists to N- and L-type calcium channels and to tyrosine kinase phosphorylation. These results indicate that N-acetyl-lactosamine can evoke transmembrane receptor-mediated responses capable of influencing neurite outgrowth.