Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1402-1405 ◽  
Author(s):  
Jeanne-Claire Lesbordes-Brion ◽  
Lydie Viatte ◽  
Myriam Bennoun ◽  
Dan-Qing Lou ◽  
Guillemette Ramey ◽  
...  
Keyword(s):  
Iron Overload ◽  
Negative Regulator ◽  
Iron Release ◽  
Coding Region ◽  
Targeted Disruption ◽  
Excess Iron ◽  
Almost All ◽  
Parenchymal Cells ◽  
First Time

Abstract We previously reported that mice made deficient for the transcriptional factor USF2 fail to express hepcidin 1 and hepcidin 2 genes as a consequence of targeted disruption of the Usf2 gene lying just upstream in the locus. These mice developed an iron overload phenotype with excess iron deposition in parenchymal cells and decreased reticuloendothelial iron. At that time, although the role of USF2 was still confounding, we proposed for the first time the role of hepcidin as a negative regulator of iron absorption and iron release from macrophages. Accordingly, we subsequently demonstrated that hyperexpression of hepcidin 1, but not hepcidin 2, resulted in a profound hyposideremic anemia. To analyze the consequences of hepcidin 1 deletion on iron metabolism without any disturbance due to USF2 deficiency, we disrupted the hepcidin 1 gene by targeting almost all the coding region. Confirming our prior results, Hepc1–/– mice developed early and severe multivisceral iron overload, with sparing of the spleen macrophages, and demonstrated increased serum iron and ferritin levels as compared with their controls.

Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 783-788 ◽  
Author(s):  
Tomas Ganz
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Negative Regulator ◽  
Hfe Gene ◽  
Iron Release ◽  
Nonsense Mutations ◽  
Amino Acid Peptide ◽  
Juvenile Hemochromatosis ◽  
Anemia Of Inflammation

Abstract Human hepcidin, a 25–amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.

scholarly journals THE METHODOLOGY OF ANALYSIS OF J. JOYCE'S NOVEL "ULISSES" (EMPHASES OF DARIA VIKONSKA)

2021 ◽  
pp. 67-75
Author(s):  
M. Moklytsia
Keyword(s):  
Research Work ◽  
The Novel ◽  
Literary Forms ◽  
Literary Process ◽  
Self Knowledge ◽  
Ethical Norms ◽  
Almost All ◽  
First Time ◽  
School Curricula

The relevance of the study is due to the need to include the novel "Ulysses" by J. Joyce in university and, if possible, school curricula in foreign literature, as well as the need for its interpretation, despite the excessive complexity of the text and difficulty of perception. It is also important to return the legacy of D. Vikonska, a writer, critic, art critic and literary critic, to modern Ukrainian culture. Research methodology: a model of analysis of the modernist novel "Ulysses", created on the basis of the research work of D. Vikonska “James Joyce. The secret of his artistic face” (1934). Scientific novelty: for the first time the analysis of the novel "Ulysses" is carried out with the broad involvement of the half-forgotten studio of D. Vikonska, which has not lost its relevance, clearly articulates the modernist nature of the work, including surreal style. The purpose of the study: to draw attention to the outstanding figure of D. Vikonska as the founder of Ukrainian Joyce studies, to include her in the modern literary process, to show with her help the significant role of Joyce's novel "Ulysses". Conclusions. The answer to the question why Joyce's novel Ulysses is considered a landmark work of modernism should be concise but convincing, based on macro- and microanalysis of the text. First of all, it is a unique example of the author's self-expression, extreme subjectivism (the whimsy of Joyce's nature), transformed into universalism. No one is as subjective as Joyce is, no one is as universal as he is. Such can only be a conscious modernist who has passed the difficult path of search outside, in the world of culture, and inside, looking into the irrational depths of his own psyche. This is the most rational, intellectual and at the same time irrational, or visionary, according to K.G. Jung, type of creativity. Second: this is the boldest (revolutionary, in the words of Vikonska) challenge to tradition (or Cultural Canon, according to K.G. Jung), which manifested itself in the ironic parody of almost all known literary forms and narrative means, many moral and ethical norms. Third: it is a brilliant example of the author's style, a variant of surrealism, which grows out of naturalism and turns into neomythologism. Joyce's style is characterized by the following features: associative metaphorical writing, author's dictionary, which includes numerous innovations, narrative reception of the flow of consciousness; use of dreams, delusions, other boundary conditions; a bizarre intertwining of past and present, when dead and living characters are equal in meaning; consistent reflection of the external in the internal and vice versa; a labyrinth of human wanderings in search of pleasures, meaning, cognition and self-knowledge. Joyce modeled the next stage in the development of culture – the transition from modernism to postmodernism, from an ironic re-reading of tradition to playing with it.

scholarly journals The essence оf the Christian dogma by Erich Fromm

2015 ◽  
pp. 116-126
Author(s):  
N. B. Buriak
Keyword(s):  
Comparative Analysis ◽  
Old Testament ◽  
Historical Evolution ◽  
Erich Fromm ◽  
Complex Issue ◽  
Man And Nature ◽  
Evolution Of Ideas ◽  
Almost All ◽  
First Time

The essence оf the Christian dogma by Erich Fromm. In the article is widely considered the dynamics of religious beliefs Erich Fromm. For the first time a comparative analysis of all Fromm’s work relating to the theme of religion. Fromm devoted to the search itself and society in faith quite a lot of time because such research is very important and requires a recess in the nature of some of the world’s religions, including Christianity. Questions and countermeasures manifestations of humanism and authoritarian Christianity, its historical evolution and ideals throw a kind of challenge to the outstanding philosopher, and forced him to work on this complex issue almost all his life. Dogma Erich Fromm developed so that initially there was an idea of the man who became God, and turned on the idea of God became man. The concept of the Old Testament prophets world extend beyond relationships between people, harmony should prevail between man and nature. Peace between man and nature is harmony between them. Erich Fromm permanently broke with Judaism in ‘26 and has since considered himself a Christian. But Christianity Fromm, his understanding of God, the role of Christ in history, the interpretation of the evolution of ideas and Savior is surprising for its boldness.

Vessel Traffic Services (VTS): Are We Ready For The New Millenium?

1998 ◽  
Vol 51 (3) ◽  
pp. 404-420 ◽  
Author(s):  
Terry Hughes
Keyword(s):  
Information Exchange ◽  
Weather Conditions ◽  
Long Beach ◽  
Traffic Surveillance ◽  
Traffic Efficiency ◽  
Set Up ◽  
Almost All ◽  
Real Time Information ◽  
First Time

In 1948, the port of Liverpool was probably the pioneer of European VTS, when they set up a radar station, in order to facilitate the boarding of pilots from the cutter. In 1951, Long Beach in California established a radar and VHF to facilitate port operations. Le Havre established another system and so, gradually, other ports followed. At this time commercial radar was comparatively new, and made it possible for the first time, under almost all weather conditions, to observe vessel traffic from the shore. In combination with VHF radio, a traffic surveillance system was achieved and real- time information exchange between the shore and ships became possible. Nevertheless, it was not until 1985 that the role of VTS in connection with navigation safety, traffic efficiency and environmental protection gained international recognition. This recognition is contained in an IMO resolution, which constitutes the VTS guidelines.

scholarly journals Effects of Therapeutic Probiotics on Modulation of microRNAs

2020 ◽  
Author(s):  
Amirhossein Davoodvandi ◽  
Havva Marzban ◽  
Pouya Goleij ◽  
Amirhossein Sahebkar ◽  
Korosh Morshedi ◽  
...  
Keyword(s):  
Current Evidence ◽  
Therapeutic Effects ◽  
Disease States ◽  
Urogenital Infections ◽  
Adhesion Sites ◽  
Beneficial Impact ◽  
Inflammatory Bowel ◽  
Almost All ◽  
First Time

Abstract Probiotics are beneficial bacteria that exist within the human gut, and which are also present in different food products and supplements. They have been investigated for some decades, due to their potential beneficial impact on human health. Probiotics compete with pathogenic microorganisms for adhesion sites within the gut, to antagonize them or to regulate the host immune response resulting in preventive and therapeutic effects. Therefore, dysbiosis, defined as an impairment in the gut microbiota, could play a role in various pathological conditions, such as lactose intolerance, gastrointestinal and urogenital infections, various cancers, cystic fibrosis, allergies, inflammatory bowel disease, and can also be caused by antibiotic side effects. MicroRNAs (miRNAs) are short non-coding RNAs that can regulate gene expression in a post-transcriptional manner. miRNAs are biochemical biomarkers that play an important role in almost all cellular signaling pathways in many healthy and disease states. For the first time, the present review summarizes current evidence suggesting that the beneficial properties of probiotics could be explained based on the pivotal role of miRNAs.

scholarly journals CHOOSE YOUR PARADISE. THE LIFE AND DEATH OF MONK GENSHIN IN SETSUWA TALES

2021 ◽  
pp. 64-81
Author(s):  
NADEZHDA N. TRUBNIKOVA ◽  
◽  
IGOR V. GORENKO ◽  
Keyword(s):  
Main Character ◽  
Pure Land ◽  
Life And Death ◽  
Japanese Buddhism ◽  
Lay People ◽  
12Th Century ◽  
History Of ◽  
Almost All ◽  
First Time

Monk Genshin (942-1017) went down in the history of Japanese Buddhism not only as a teacher of the Tendai school, who for the first time substantiated the teaching of Buddha Amida and the Pure Land, as a compiler of interpretations of sutras, treatises, sermons and many other works, but also as a hero of setsuwa didactic tales. Stories about him appear in the collection of legends about the miracles of the Lotus Sutra in the middle of the 11th century, then in the book of stories about the rebirth in the Pure Land and in the Konjaku monogatari shū of the early 12th century. Then, in almost all major collections of setsuwa, tales about Genshin are found, with the early detailed narratives being replaced by brief descriptions of individual episodes from his life. The stories talk about how Genshin from a temple monk became a hermit, about his relationship with his mother, about the works of the Buddhist scribe and his meetings with other monks and lay people, about miracles at the hour of his death. The peculiarity of these tales is that Genshin does not always appear in them as the main character: he often plays the more modest role of waki wanderer, a guest of other monks, priests and laity: in response to his questions, they reveal their understanding of the Buddhist path.

scholarly journals Silencing of the Baculovirus Op-iap3 Gene by RNA Interference Reveals that It Is Required for Prevention of Apoptosis during Orgyia pseudotsugata M Nucleopolyhedrovirus Infection of Ld652Y Cells

2003 ◽  
Vol 77 (8) ◽  
pp. 4481-4488 ◽  
Author(s):  
John C. Means ◽  
Israel Muro ◽  
Rollie J. Clem
Keyword(s):  
Rna Interference ◽  
Double Stranded Rna ◽  
Orgyia Pseudotsugata ◽  
Baculovirus Gene ◽  
Wide Range ◽  
Infected Cells ◽  
Rnai Technique ◽  
Almost All ◽  
First Time

ABSTRACT The Op-iap3 gene from the baculovirus Orgyia pseudotsugata M nucleopolyhedrovirus (OpMNPV) inhibits apoptosis induced by a mutant of Autographa californica MNPV (AcMNPV) that lacks the antiapoptotic gene p35, as well as apoptosis induced by a wide range of other stimuli in both mammalian and insect cells. However, the role of Op-iap3 during OpMNPV infection has not been previously examined. To determine the function of the Op-IAP3 protein during OpMNPV infection, we used RNA interference (RNAi) to silence Op-iap3 expression during OpMNPV infection of Ld652Y cells. Infected cells treated with Op-iap3 double-stranded RNA (dsRNA) did not accumulate detectable Op-iap3 mRNA, confirming that the Op-iap3 gene was effectively silenced. Op-IAP3 protein was found to be a component of the budded virion; however, in OpMNPV-infected cells treated with Op-iap3 dsRNA, the Op-IAP3 protein that was introduced by the inoculum virus decreased to almost undetectable levels by 12 h after dsRNA addition. Apoptosis was observed in infected cells treated with Op-iap3 dsRNA beginning at 12 h, and by 48 h, almost all of the cells had undergone apoptosis. These results show for the first time that Op-IAP3 is necessary to prevent apoptosis during OpMNPV infection. In addition, our results demonstrate that the RNAi technique can be an effective tool for studying baculovirus gene function.

scholarly journals Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

1996 ◽  
Vol 7 (12) ◽  
pp. 2029-2044 ◽  
Author(s):  
R Y Hampton ◽  
R G Gardner ◽  
J Rine
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
Mevalonate Pathway ◽  
26S Proteasome ◽  
Negative Regulator ◽  
Sterol Synthesis ◽  
Endoplasmic Reticulum Membrane ◽  
Coding Region ◽  
Coa Reductase

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R), a key enzyme of sterol synthesis, is an integral membrane protein of the endoplasmic reticulum (ER). In both humans and yeast, HMG-R is degraded at or in the ER. The degradation of HMG-R is regulated as part of feedback control of the mevalonate pathway. Neither the mechanism of degradation nor the nature of the signals that couple the degradation of HMG-R to the mevalonate pathway is known. We have launched a genetic analysis of the degradation of HMG-R in Saccharomyces cerevisiae using a selection for mutants that are deficient in the degradation of Hmg2p, an HMG-R isozyme. The underlying genes are called HRD (pronounced "herd"), for HMG-CoA reductase degradation. So far we have discovered mutants in three genes: HRD1, HRD2, and HRD3. The sequence of the HRD2 gene is homologous to the p97 activator of the 26S proteasome. This p97 protein, also called TRAP-2, has been proposed to be a component of the mature 26S proteasome. The hrd2-1 mutant had numerous pleiotropic phenotypes expected for cells with a compromised proteasome, and these phenotypes were complemented by the human TRAP-2/p97 coding region. In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound. The Hrd3p protein was homologous to the Caenorhabditis elegans sel-1 protein, a negative regulator of at least two different membrane proteins, and contained an HRD3 motif shared with several other proteins. Hrd1p had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrd1p and Hrd3p proteins conspire to deliver HMG-R to the 26S proteasome. Moreover, our results lend in vivo support to the proposed role of the p97/TRAP-2/Hrd2p protein as a functionally important component of the 26S proteasome. Because the HRD genes were required for the degradation of both regulated and unregulated substrates of ER degradation, the HRD genes are the agents of HMG-R degradation but not the regulators of that degradation.

global regulation of mycotoxin accumulation during pathogenicity of Penicillium expansum in postharvest fruits

2014 ◽  
Author(s):  
Dov Prusky ◽  
Nancy P. Keller ◽  
Amir Sherman
Keyword(s):  
Signaling Pathways ◽  
Gene Cluster ◽  
Secondary Metabolite ◽  
Gluconic Acid ◽  
Apple Fruit ◽  
Negative Regulator ◽  
Global Regulator ◽  
Exogenous Treatment ◽  
First Time

Background to the topic- Penicilliumas a postharvest pathogen and producer of the mycotoxin PAT. Penicilliumspp. are destructive phytopathogens, capable of causing decay in many deciduous fruits, during postharvest handling and storage; and the resulting losses can amount to 10% of the stored produce and the accumulation of large amounts of the mycotoxinpatulin. The overall goal of this proposal is to identify critical host and pathogen factors that modulate P. expansummycotoxin genes and pathways which are required for PAT production and virulence. Our preliminary results indicated that gluconic acid are strongly affecting patulin accumulation during colonization. P. expansumacidifies apple fruit tissue during colonization in part through secretion of gluconic acid (GLA). Several publications suggested that GLA accumulation is an essential factor in P. expansumpathogenicity. Furthermore, down regulation of GOX2 significantly reduced PAT accumulation and pathogenicity. PAT is a polyketide and its biosynthesis pathway includes a 15-gene cluster. LaeA is a global regulator of mycotoxin synthesis. It is now known that patulin synthesis might be subjected to LaeA and sometimes by environmental sensing global regulatory factors including the carbon catabolite repressor CreA as well as the pH regulator factor PacC and nitrogen regulator AreA. The mechanisms by which LaeA regulates patulin synthesis was not fully known and was part of our work. Furthermore, the regulatory system that controls gene expression in accordance with ambient pH was also included in our work. PacC protein is in an inactive conformation and is unable to bind to the promoter sites of the target genes; however, under alkaline growth conditions activated PacC acts as both an activator of alkaline-expressed genes and a repressor of acid-expressed genes. The aims of the project- This project aims to provide new insights on the roles of LaeA and PacC and their signaling pathways that lead to GLA and PAT biosynthesis and pathogenicity on the host. Specifically, our specific aims were: i) To elucidate the mechanism of pH-controlled regulation of GLA and PAT, and their contribution to pathogenesis of P. expansum. We are interested to understanding how pH and/or GLA impact/s under PacC regulation affect PAT production and pathogenesis. ii) To characterize the role of LaeA, the global regulator of mycotoxin production, and its effect on PAT and PacC activity. iii) To identify the signaling pathways leading to GLA and PAT synthesis. Using state- of-the-art RNAseq technologies, we will interrogate the transcriptomes of laeAand pacCmutants, to identify the common signaling pathways regulating synthesis of both GLA and PAT. Major conclusions, solutions, achievements- In our first Aim our results demonstrated that ammonia secreted at the leading edge of the fungal colony induced transcript activation of the global pH modulator PacC and PAT accumulation in the presence of GLA. We assessed these parameters by: (i) direct exogenous treatment of P. expansumgrowing on solid medium; (ii) direct exogenous treatment on colonized apple tissue; (iii) growth under self-ammonia production conditions with limited carbon; and (iv) analysis of the transcriptional response to ammonia of the PAT biosynthesis cluster. Ammonia induced PAT accumulation concurrently with the transcript activation of pacCand PAT biosynthesis cluster genes, indicating the regulatory effect of ammonia on pacCtranscript expression under acidic conditions. Transcriptomic analysis of pH regulated processes showed that important genes and BARD Report - Project 4773 Page 2 of 10 functionalities of P. expansumwere controlled by environmental pH. The differential expression patterns of genes belonging to the same gene family suggest that genes were selectively activated according to their optimal environmental conditions to enable the fungus to cope with varying conditions and to make optimal use of available enzymes. Concerning the second and third Aims, we demonstrated that LaeA regulates several secondary metabolite genes, including the PAT gene cluster and concomitant PAT synthesis invitro. Virulence studies of ΔlaeAmutants of two geographically distant P. expansumisolates (Pe-21 from Israel and Pe-T01 from China) showed differential reduction in disease severity in freshly harvested fruit ranging from no reduction for Ch-Pe-T01 strains in immature fruit to 15–25% reduction for both strains in mature fruit, with the ΔlaeAstrains of Is-Pe-21 always showing a greater loss in virulence. Results suggest the importance of LaeA regulation of PAT and other secondary metabolites on pathogenicity. Our work also characterized for the first time the role of sucrose, a key nutritional factor present in apple fruit, as a negative regulator of laeAexpression and consequent PAT production in vitro. This is the first report of sugar regulation of laeAexpression, suggesting that its expression may be subject to catabolite repression by CreA. Some, but not all of the 54 secondary metabolite backbone genes in the P. expansumgenome, including the PAT polyketide backbone gene, were found to be regulated by LaeA. Together, these findings enable for the first time a straight analysis of a host factor that potentially activates laeAand subsequent PAT synthesis. 

scholarly journals The First Trimester Gravid Serum Regulates Procalcitonin Expression in Human Macrophages Skewing Their PhenotypeIn Vitro

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Damiano Rami ◽  
Martina La Bianca ◽  
Chiara Agostinis ◽  
Giorgio Zauli ◽  
Oriano Radillo ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
First Trimester ◽  
M1 Macrophages ◽  
Peripheral Tissues ◽  
Inflammatory Stimuli ◽  
Almost All ◽  
Parenchymal Cells ◽  
Immunological Homeostasis ◽  
Pregnancy Hormones

Procalcitonin (PCT) is one of the best diagnostic and prognostic markers in clinical practice, widely used to evaluate the evolution of bacterial infections. Although it is mainly produced by thyroid, during sepsis almost all the peripheral tissues are involved in PCT production. Parenchymal cells have been suggested as the main source of PCT expression; however the contribution of macrophages is not clear yet. In response to environmental cues, tissue macrophages acquire distinct functional phenotypes, ranging from proinflammatory (M1) to anti-inflammatory (M2) phenotype. Macrophages at the fetal-maternal interface show immunosuppressive M2-like activities required for the maintenance of immunological homeostasis during pregnancy. This study aims to clarify the ability to synthesise PCT of fully differentiated (M0), polarized (M1/M2) macrophages and those cultured either in the presence of first trimester gravid serum (GS) or pregnancy hormones. We found out that M1 macrophages upregulate PCT expression following LPS stimulation compared to M0 and M2. The GS downregulates PCT expression in macrophages, skewing them towards an M2-like phenotype. This effect seems only partially mediated by the hormonalmilieu. Our findings strengthen the key role of macrophages in counteracting inflammatory stimuli during pregnancy, suggesting PCT as a possible new marker of M1-like macrophages.

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