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.

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.

Feature Extraction for Classification in the Data Mining Process

Dimensionality reduction is a very important step in the data mining process. In this paper, we consider feature extraction for classification tasks as a technique to overcome problems occurring because of “the curse of dimensionality”. Three different eigenvector-based feature extraction approaches are discussed and three different kinds of applications with respect to classification tasks are considered. The summary of obtained results concerning the accuracy of classification schemes is presented with the conclusion about the search for the most appropriate feature extraction method. The problem how to discover knowledge needed to integrate the feature extraction and classification processes is stated. A decision support system to aid in the integration of the feature extraction and classification processes is proposed. The goals and requirements set for the decision support system and its basic structure are defined. The means of knowledge acquisition needed to build up the proposed system are considered.

COACHES, CLIMATES, “FIELD” GOALS, AND EFFICACY: A “DE-CONSTRUCTION” OF THE MASTERY-APPROACH TO COACHING AND EXAMINATION OF RELATIONSHIPS TO PSYCHOSOCIAL OUTCOMES IN A YOUTH FOOTBALL PLAYER DEVELOPMENT PROGRAM.

In support of the achievement goal theory (AGT), empirical research has demonstrated psychosocial benefits of the mastery-oriented learning climate. In this study, we examined the effects of perceived coaching behaviors on various indicators of psychosocial well-being (competitive anxiety, self-esteem, perceived competence, enjoyment, and future intentions for participation), as mediated by perceptions of the coach-initiated motivational climate, achievement goal orientations and perceptions of sport-specific skills efficacy. Using a pre-post test design, 1,464 boys, ages 10-15 (M = 12.84 years, SD = 1.44), who participated in a series of 12 football skills clinics were surveyed from various locations across the United States. Using structural equation modeling (SEM) path analysis and hierarchical regression analysis, the cumulative direct and indirect effects of the perceived coaching behaviors on the psychosocial variables at post-test were parsed out to determine what types of coaching behaviors are more conducive to the positive psychosocial development of youth athletes. The study demonstrated that how coaching behaviors are perceived impacts the athletes’ perceptions of the motivational climate and achievement goal orientations, as well as self-efficacy beliefs. These effects in turn affect the athletes’ self-esteem, general competence, sport-specific competence, competitive anxiety, enjoyment, and intentions to remain involved in the sport. The findings also clarify how young boys internalize and interpret coaches’ messages through modification of achievement goal orientations and sport-specific efficacy beliefs.

Työriitalain mukaisen ennakkoilmoitusvelvollisuuden laiminlyönti ja oikeus vahingonkorvaukseen

Tutkielman tarkoituksena on selvittää työriitalaissa säänneltävään ennakkoilmoitusvelvollisuuteen liittyviä ongelmakohtia. Aluksi selvennetään, mistä ennakkoilmoitus on ylipäänsä tehtävä, sillä velvollisuus ei liity kaikkiin työtaistelutoimenpiteisiin tai niiden laajentamiseen. Tämän lisäksi tarkastellaan, kenelle ennakkoilmoitus on osoitettava ja kenen on kyseinen velvollisuus täytettävä. Käsittelen ennakkoilmoitusvelvollisuutta niin työntekijä- kuin työnantajapuolen näkökulmasta. Ennakkoilmoitusvelvollisuus koskee molempia työmarkkinaosapuolia, vaikka työtaisteluoikeus yhdistetäänkin helpommin palkansaajapuolen oikeudeksi. Tutkimuksessa kuitenkin tarkastellaan työriitalakiin liittyviä ongelmakohtia enenevissä määrin työntekijäpuolen näkökulmasta. Käsittelen ennakkoilmoitusvelvollisuutta ensisijaisesti yksityisen sektorin näkökulmasta. Keskeisimpinä tutkimuskysymyksinäni on selvittää, mitä oikeusvaikutuksia ennakkoilmoituksen tekemisellä on ja mitä ennakkoilmoitusvelvollisuuden laiminlyönnistä voi ilmoitusvelvolliselle työmarkkinaosapuolelle seurata. Samalla arvioin nykysääntelylle asetettujen tavoitteiden legimiteettiä. Laiminlyönnin seuraamusten osalta keskityn erityisesti arvioimaan vahingonkorvausvelvollisuuden mahdollisuutta. Merkittävänä lähdeaineistona tutkielmassa on käytetty erityisesti kotimaista oikeuskirjallisuutta ja jossain määrin myös ulkomaalaista oikeuskirjallisuutta on hyödynnetty tarkasteltaessa vahingonkorvausvastuun mahdollisuutta muualla Euroopassa. Käytetystä oikeuskirjallisuudesta mainittakoon erityisesti Kari-Pekka Tiitisen ja Ilkka Ruposen teos Työriitojen sovittelu, joka on ainut laajempi kirjoitus työriitalaista sekä Seppo Koskisen artikkelit Työriitalain rikkominen ja vahingonkorvaus ja Työriitalain 7 §:n rikkomisesta: kuka rikkoo ja mitä? Vahingonkorvausvastuu soveltumisen osalta tarkastellaan tuoretta käräjäoikeuden ratkaisua, joka on tähän asti ainoa aihetta käsittelevä tuomioistuinratkaisu. Vahingonkorvausvastuun poissulkemiselle ei ole löydettävissä hyväksyttäviä perusteita. Rikkomalla työriitalain ennakkoilmoitusvelvollisuutta laiminlyödään työnseisaukselle asetettu ennakkoedellytys, minkä johdosta laiminlyöjä syyllistyy kriminalisoituun tekoon. Korvausvastuu tulee tällöin arvioitavaksi vahingonkorvauslain nojalla, koska sen soveltumista ei ole työriitalaissa suljettu pois. Korvausvastuun soveltuminen on omiaan vahventamaan työriitalain mukaista sovittelua ja antaa laittoman työnseisauksen kohteeksi joutuneelle tehokkaan oikeussuojakeinon.