Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis

Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of regulation of dietary iron absorption and excessive iron deposition in major organs of the body. Recently, a candidate gene for HH (also called HFE) was identified that encodes a novel MHC class I-like protein. Most patients with HH are homozygous for the same mutation in the HFE gene, resulting in a C282Y change in the HFE protein. Studies in cultured cells show that the C282Y mutation abrogates the binding of the recombinant HFE protein to β2-microglobulin (β2M) and disrupts its transport to the cell surface. The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body. In the studies presented here, we demonstrate by immunohistochemistry that the HFE protein is expressed in human placenta in the apical plasma membrane of the syncytiotrophoblasts, where the transferrin-bound iron is normally transported to the fetus via receptor-mediated endocytosis. Western blot analyses show that the HFE protein is associated with β2M in placental membranes. Unexpectedly, the transferrin receptor was also found to be associated with the HFE protein/β2M complex. These studies place the normal HFE protein at the site of contact with the maternal circulation where its association with transferrin receptor raises the possibility that the HFE protein plays some role in determining maternal/fetal iron homeostasis. These findings also raise the question of whether mutations in the HFE gene can disrupt this association and thereby contribute to some forms of neonatal iron overload.

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder known in humans. A candidate gene for HH called HFE has recently been cloned that encodes a novel member of the major histocompatibility complex class I family. Most HH patients are homozygous for a Cys-282→Tyr (C282Y) mutation in HFE gene, which has been shown to disrupt interaction with β2-microglobulin; a second mutation, His-63→Asp (H63D), is enriched in HH patients who are heterozygous for C282Y mutation. The aims of this study were to determine the effects of the C282Y and H63D mutations on the cellular trafficking and degradation of the HFE protein in transfected COS-7 cells. The results indicate that, while the wild-type and H63D HFE proteins associate with β2-microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. We present biochemical and immunofluorescence data that indicate that the C282Y mutant protein: (i) is retained in the endoplasmic reticulum and middle Golgi compartment, (ii) fails to undergo late Golgi processing, and (iii) is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provide a possible basis for impaired function of this mutant protein in HH.

Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study

Objectives: To investigate whether baseline serum cholestanol:cholesterol ratio, which is negatively related to cholesterol synthesis, could predict reduction of coronary events in the Scandinavian simvastatin survival study.

Expression of membrane-associated carbonic anhydrase XIV on neurons and axons in mouse and human brain

Although long suspected from histochemical evidence for carbonic anhydrase (CA) activity on neurons and observations that CA inhibitors enhance the extracellular alkaline shifts associated with synaptic transmission, an extracellular CA in brain had not been identified. A candidate for this CA was suggested by the recent discovery of membrane CA (CA XIV) whose mRNA is expressed in mouse and human brain and in several other tissues. For immunolocalization of CA XIV in mouse and human brain, we developed two antibodies, one against a secretory form of enzymatically active recombinant mouse CA XIV, and one against a synthetic peptide corresponding to the 24 C-terminal amino acids in the human enzyme. Immunostaining for CA XIV was found on neuronal membranes and axons in both mouse and human brain. The highest expression was seen on large neuronal bodies and axons in the anterolateral part of pons and medulla oblongata. Other CA XIV-positive sites included the hippocampus, corpus callosum, cerebellar white matter and peduncles, pyramidal tract, and choroid plexus. Mouse brain also showed a positive reaction in the molecular layer of the cerebral cortex and granular cellular layer of the cerebellum. These observations make CA XIV a likely candidate for the extracellular CA postulated to have an important role in modulating excitatory synaptic transmission in brain.

Two Consistent Many-Valued Logics for Paraconsistent Phenomena

In this reviewing paper, we recall the main results of our papers [24, 31] where we introduced two paraconsistent semantics for Pavelka style fuzzy logic. Each logic formula a is associated with a 2 x 2 matrix called evidence matrix. The two semantics are consistent if they are seen from 'outside'; the structure of the set of the evidence matrices M is an MV-algebra and there is nothing paraconsistent there. However, seen from "inside,' that is, in the construction of a single evidence matrix paraconsistency comes in, truth and falsehood are not each others complements and there is also contradiction and lack of information (unknown) involved. Moreover, we discuss the possible applications of the two logics in real-world phenomena.

Advances in Research on Semantic Roles

Especially in functional-typological linguistics, semantic roles have been studied thoroughly, because they constitute a good starting point for any study on argument marking due to their semantically defined nature. However, the very concept of semantic roles is far from being without problems, and there is still no consensus on how the roles are best defined. In this volume, the notion will be discussed from novel perspectives with the aim of providing new insights into our understanding of semantic roles. Two of the papers deal with semantic role clusters, one with semantic roles in verbless constructions, one with diachrony of semantic roles and two with individual semantic roles that have not been studied in too much detail in previous studies. The book may not offer answers to all questions the readers may have, but at least it raises interesting further questions relevant to arriving at a better understanding of semantic roles.

Estimating evapotranspiration in a humid region

Prepared in cooperation with Ohio Agricultural Research and Development Center.

Recent advances in alcohol-induced adduct formation

This article presents the proceedings of a symposium presented at the ISBRA 12th World Congress on Biomedical Alcohol Research, held in Heidelberg/Mannheim, Germany, September 29 through October 2, 2004. The organizers of the symposium were Simon Worrall and Victor Preedy, and the symposium was chaired by Onni Niemelä and Geoffrey Thiele. The presentations scheduled for this symposium were (1) Adduct chemistry and mechanisms of adduct formation, by Thomas L. Freeman; (2) Malondialdehyde- acetaldehyde adducts: the 2004 update, by Geoffrey Thiele; (3) Adduct formation in the liver, by Simon Worrall; (4) Protein adducts in alcoholic cardiomyopathy, by Onni Niemelä; and (5) Alcoholic skeletal muscle myopathy: a role for protein adducts, by Victor R. Preedy.

Cognitive Bias in Knowledge Engineering Course

The paper presents experience in teaching of knowledge and ontological engineering. The teaching framework is targeted on the development of cognitive skills that will allow facilitating the process of knowledge elicitation, structuring and ontology development for scaffolding students’ research. The structuring procedure is the kernel of ontological engineering. The 5-steps ontology designing process is described. Special stress is put on “beautification” principles of ontology creating. The academic curriculum includes interactive game-format training of lateral thinking, interpersonal cognitive intellect and visual mind mapping techniques.