Inherited Disorders of Iron Overload

Dietary iron absorption and systemic iron traffic are tightly controlled by hepcidin, a liver-derived peptide hormone. Hepcidin inhibits iron entry into plasma by binding to and inactivating the iron exporter ferroportin in target cells, such as duodenal enterocytes and tissue macrophages. Hepcidin is induced in response to increased body iron stores to inhibit further iron absorption and prevent iron overload. The mechanism involves the BMP/SMAD signaling pathway, which triggers transcriptional hepcidin induction. Inactivating mutations in components of this pathway cause hepcidin deficiency, which allows inappropriately increased iron absorption and efflux into the bloodstream. This leads to hereditary hemochromatosis (HH), a genetically heterogenous autosomal recessive disorder of iron metabolism characterized by gradual buildup of unshielded non-transferrin bound iron (NTBI) in plasma and excessive iron deposition in tissue parenchymal cells. The predominant HH form is linked to mutations in the HFE gene and constitutes the most frequent genetic disorder in Caucasians. Other, more severe and rare variants are caused by inactivating mutations in HJV (hemojuvelin), HAMP (hepcidin) or TFR2 (transferrin receptor 2). Mutations in SLC40A1 (ferroportin) that cause hepcidin resistance recapitulate the biochemical phenotype of HH. However, ferroportin-related hemochromatosis is transmitted in an autosomal dominant manner. Loss-of-function ferroportin mutations lead to ferroportin disease, characterized by iron overload in macrophages and low transferrin saturation. Aceruloplasminemia and atransferrinemia are further inherited disorders of iron overload caused by deficiency in ceruloplasmin or transferrin, the plasma ferroxidase and iron carrier, respectively

Iron induces insulin resistance in cardiomyocytes via regulation of oxidative stress

York University Librarie

APPLICATION OF BED THICKNESS DISTRIBUTIONS IN LATE EOCENE-OLIGOCENE TURBIDITE DEPOSITS OF GREECE: SOME PRELIMINARY RESULTS

Μια απλή εφαρμογή των κατανομών πάχους στρωμάτων επιχειρήθηκε σε φυσικές τομές τουρβιδιτών Άνω Ηωκαινικής - Ολιγοκαινικής ηλικίας σε τρεις διαφορετικές περιοχές της Ελλάδας. Οι τρεις τομές που με^ήθηκαν βρίσκονται στο Ευηνοχώρι Αιτ/νίας (Δυτική Ελλάδα), το νησί της Καρπάθου (ΝΑ Ελλάδα) και το νησί της Λήμνου (ΒΑ Ελλάδα). Όλες οι τομές παρουσιάζουν παρόμοια ιζηματολογικά χαρακτηριστικά. Τρία είδη διαγραμμάτων χρησιμοποιήθηκαν: διάγραμμα λογαρίθμου- λογαρίθμου, λογαρίθμου-κλίμακας πιθανότητας και καμπύλης συχνότητας. Οι κατανομές του πάχους των στρωμάτων και στα τρία είδη διαγραμμάτων δείχνουν ομοιότητα ανάμεσα στους τουρβιδίτες Δυτικής και ΝΑ Ελλάδας και διαφορά τους από αυτούς της ΒΑ Ελλάδας. Το γεγονός αυτό πιθανά οφείλεται σε διαφορετική μορφολογία των λεκανών ιζηματογένεσης των τουρβιδιτών, λόγω διαφορετικών τεκτονικών διεργασιών.A simple application of bed thickness distributions was attempted in outcrops of Late Eocene-Oligocene turbidites in three dispersed localities of Greece. The three studied sections are located at Evinohori area (West Greece), Karpathos Island (SE Greece) and Limnos Island (NE Greece). All outcrops show similar sedimentological characteristics. Three types of plots were used: log-log, log-probability and frequency curves. Bed thickness data indicate similarity between West-SE Greece turbidites and discrimination from NE Greece turbidites which is attributed to different basin morphology due to different tectonic processes

The stylistic identity of the metapoet: a corpus-based comparative analysis using translations of modern Greek poetry

The aim of this study is to explore the stylistic identity of four translators of modern Greek poetry into English and to outline each translator’s distinct stylistic profile. In line with views on the subject expressed by Malmkjær (1996) and Baker (2000) a translator’s profile is seen as being composed by consistent patterns that can be identified throughout their work and which leave their personal mark on the text. A corpus-based methodology is used for the identification and exploration of these patterns, through a Specialized Corpus of English Translations of Modern Greek Poetry (SCETOMGP). This corpus contains translations by Rae Dalven, Kimon Friar, Edmund Keeley & Phillip Sherrard (working in collaboration) and David Connolly. The source-texts are taken from C.P. Cavafy, George Seferis, Yiannis Ritsos and Odysseus Elytis, who were extensively translated during the second half of the 20th century. The main purpose of the corpus is to facilitate direct comparison between the retranslations of the same poem. Such direct comparisons form the core of this study and have the advantage of making the issue of source-text influence on each translator directly observable, alongside their other stylistic traits. A detailed account of the theoretical views or reflections each translator has put forth is also presented. Following Holmes (1994) the translator of poetry is seen here as a meta-poet who requires skills similar to those of a critic and an original poet, and certain skills that are specific only to the translator. Consequently, the translators’ views on issues of language, literature, style and translation not only provide the backdrop for exploring any stylistic patterns found in the texts, but are seen as part of their stylistic profile. The distinguishing stylistic features for each translator are explored in both quantitative and qualitative terms. Overall word frequencies for each translator are examined, the stylistic features that are prominent in each case are identified, and their impact is considered. Special attention is also paid to the way those stylistic features that Boase-Beier (2005) calls ‘universal aspects of literature’ are treated by each translator. The next stage of the study involves the identification and sorting out of the patterns of stylistic features that consistently manifest in a translator’s work and examining how these patterns relate to their theoretical views and reflections. In the final stage, the stylistic profile of each translator is compiled by complementing the textual and contextual data together with each translator’s use of paratexts and extra-textual material

Oral iron supplementation: new formulations, old questions

Iron deficiency anemia and pre-anemic iron deficiency are the most frequent pathologies. The first line of treatment involves oral iron supplementation. The simplest, least expensive, and most frequently prescribed drug is ferrous sulfate, while other ferrous salts and ferric complexes with polysaccharides or succinylated milk proteins are also widely used. In recent years, novel iron formulations have been developed, such as the lipophilic iron donor ferric maltol, or nanoparticle encapsulated sucrosomial® iron. Oral iron supplementation is usually efficacious in correcting iron deficiency anemia and replenishing iron stores but causes gastrointestinal side effects that reduce compliance. When oral iron supplementation is contraindicated, intravenous iron therapy can rapidly achieve therapeutic targets without gastrointestinal complications. Herein, we critically review literature on relative efficacy and tolerability of currently available oral iron supplements, and summarize recent data on optimal dosage and frequency

THE USE OF STATISTICAL ANALYSIS IN THE LITHOSTRATIGRAPHY OF SUBMARINE FAN DEPOSITS. AN EXAMPLE FROM SOUTHEAST GREECE (KARPATHOS ISLAND)

Τα τελευταία χρόνια γίνεται προσπάθεια από πολλούς γεωλόγους στην κατεύθυνση της ποσοτικοποίησης και στατιστικής ανάλυσης των γεωλογικών δεδομένων. Ένα από τα πεδία αυτής της έρευνας είναι οι αποθέσεις υποθαλάσσιων ριπιδίων («φλύσχης»). Η στατιστική ανάλυση σε τέτοιου είδους αποθέσεις εστιάζεται κυρίως στο πάχος των στρωμάτων και έχει σαν στόχο τον προσδιορισμό παραμέτρων όπως το περιβάλλον απόθεσης, η πηγή τροφοδοσίας ιζήματος, οι υδροδυναμικές συνθήκες απόθεσης κτλ. Κύρια εργαλεία ανάλυσης είναι οι λογαριθμικές κατανομές του πάχους των στρωμάτων. Στην παρουσίαση δίνονται παραδείγματα διαφόρων ειδών λογαριθμικών κατανομών που έχουν προταθεί τα τελευταία χρόνια, καθώς και ένα παράδειγμα εφαρμογής τους σε αποθέσεις υποθαλάσσιων ριπιδίων στη ΝΑ Ελλάδα (Κάρπαθος).Examples of various types of statistical analysis of submarine fan bed thickness distributions that have been proposed in the past are reported, as well as an example of their application in Late Eocene-Oligocene submarine fan deposits of SE Greece (Karpathos Island). Generally, the sandstone bed thickness data measured in two outcrops of Karpathos submarine fans seems to follow power law (fractal) cumulative distributions. A deviation from the power law was observed as amalgamationprocedures become more frequent. These observations gave important information about Tertiary turbidite sedimentation in the area which probably was punctuated and had a single main sediment source. Information taken from statistical analysis of submarine fans bed thickness data has immediate applicability in hydrocarbon exploration because sandstones constitute ideal reservoirs

Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity

<p>Abstract</p> <p>Background</p> <p>Iron regulatory protein 2 (IRP2), a post-transcriptional regulator of cellular iron metabolism, undergoes iron-dependent degradation via the ubiquitin-proteasome pathway. A stretch of 73 amino acids within the N-terminal domain 1 of the protein was reported to function as an iron sensor. However, mutants lacking this fragment remain sensitive to degradation in iron-replete cells.</p> <p>Results</p> <p>To identify elements within IRP2 involved in the control of its stability, we undertook a systematic mutagenesis approach. Truncated versions of IRP2 were expressed in H1299 cells and analyzed for their response to iron. Deletion mutants lacking the entire C-terminal domain 4 (amino acids 719–963) of IRP2 remained stable following iron treatments. Moreover, the replacement of domain 4 of IRP1 with the corresponding region of IRP2 sensitized the chimerical IRP1_1–3/IRP2₄protein to iron-dependent degradation, while the reverse manipulation gave rise to a stable chimerical IRP2_1–3/IRP1₄protein. The deletion of just 26 or 34 C-terminal amino acids stabilized IRP2 against iron. However, the fusion of C-terminal IRP2 fragments to luciferase failed to sensitize the indicator protein for degradation in iron-loaded cells.</p> <p>Conclusion</p> <p>Our data suggest that the C-terminus of IRP2 contains elements that are necessary but not sufficient for iron-dependent degradation. The functionality of these elements depends upon the overall IRP structure.</p

Accelerated CCl4-Induced Liver Fibrosis in Hjv-/- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression

Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/-) mice and wild type (wt) controls were intoxicated with CCl4. Hjv-/- mice developed earlier (by 2-4 weeks) and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv−/− animals. Even though livers of naïve Hjv−/− mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2–3 fold vs. wt, p<0.05) levels of α1-(I)-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis

Tumorigenic Properties of Iron Regulatory Protein 2 (IRP2) Mediated by Its Specific 73-Amino Acids Insert

Iron regulatory proteins, IRP1 and IRP2, bind to mRNAs harboring iron responsive elements and control their expression. IRPs may also perform additional functions. Thus, IRP1 exhibited apparent tumor suppressor properties in a tumor xenograft model. Here we examined the effects of IRP2 in a similar setting. Human H1299 lung cancer cells or clones engineered for tetracycline-inducible expression of wild type IRP2, or the deletion mutant IRP2Δ73 (lacking a specific insert of 73 amino acids), were injected subcutaneously into nude mice. The induction of IRP2 profoundly stimulated the growth of tumor xenografts, and this response was blunted by addition of tetracycline in the drinking water of the animals, to turnoff the IRP2 transgene. Interestingly, IRP2Δ73 failed to promote tumor growth above control levels. As expected, xenografts expressing the IRP2 transgene exhibited high levels of transferrin receptor 1 (TfR1); however, the expression of other known IRP targets was not affected. Moreover, these xenografts manifested increased c-MYC levels and ERK1/2 phosphorylation. A microarray analysis identified distinct gene expression patterns between control and tumors containing IRP2 or IRP1 transgenes. By contrast, gene expression profiles of control and IRP2Δ73-related tumors were more similar, consistently with their growth phenotype. Collectively, these data demonstrate an apparent pro-oncogenic activity of IRP2 that depends on its specific 73 amino acids insert, and provide further evidence for a link between IRPs and cancer biology