scholarly journals GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Lingjuan Wang ◽  
Sijin Ouyang ◽  
Bin Li ◽  
Hao Wu ◽  
Fengli Wang
Keyword(s):  
Iron Homeostasis ◽  
Lipid Peroxides ◽  
Iron Level ◽  
The Past ◽  
Cellular Iron ◽  
Regulatory Circuits ◽  
Positive Modulator ◽  
Gsk 3Β ◽  
Insight Into

AbstractFerroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.

scholarly journals An improved structural model of the human iron exporter ferroportin. Insight into the role of pathogenic mutations in hereditary hemochromatosis type 4

2017 ◽  
Vol 13 (4) ◽  
Author(s):  
Valentina Tortosa ◽  
Maria Carmela Bonaccorsi di Patti ◽  
Valentina Brandi ◽  
Giovanni Musci ◽  
Fabio Polticelli
Keyword(s):  
Membrane Protein ◽  
Crystal Structures ◽  
Iron Homeostasis ◽  
Structural Model ◽  
Hereditary Hemochromatosis ◽  
Structural Models ◽  
Pivotal Role ◽  
Cellular Iron ◽  
Insight Into

AbstractFerroportin (Fpn) is a membrane protein representing the major cellular iron exporter, essential for metal translocation from cells into plasma. Despite its pivotal role in human iron homeostasis, many questions on Fpn structure and biology remain unanswered. In this work, we present two novel and more reliable structural models of human Fpn (hFpn; inward-facing and outward-facing conformations) obtained using as templates the recently solved crystal structures of a bacterial homologue of hFpn,

National Museums, National Narratives, and Identity Politics

2017 ◽  
Author(s):  
Cristina Lleras
Keyword(s):  
Identity Politics ◽  
Resistance To Change ◽  
National Museum ◽  
Traditional Role ◽  
National Narratives ◽  
The Past ◽  
National Museums ◽  
Insight Into

The purpose of this chapter is to examine the surge of identity politics and the diversification of heritage and the tensions that arise with the traditional role of national museums that are expected to support the model of a unitary national identity through their narratives and collections. Engaging with distinct patrimonies and transformations in museums checkmates stagnant notions of heritage, but in turn, these actions might also instigate resistance to change. A case study at the National Museum of Colombia will provide an insight into competing notions of heritage, which can be understood as the relics of a material past, but may also be seen as the meanings created about the past. This analysis instigates thoughts about the role that history and historians might play in the elaboration of narratives of identity.

University Startup Accelerators: Startup Launchpads or Vehicles for Entrepreneurial Learning?

2020 ◽  
pp. 251512742093175
Author(s):  
Lynn E. Metcalf ◽  
Thomas M. Katona ◽  
Jonathan L. York
Keyword(s):  
Return On Investment ◽  
Future Research ◽  
Uniform Structure ◽  
Primary Role ◽  
Entrepreneurial Ecosystem ◽  
The Past ◽  
Mode Of Operation ◽  
The University ◽  
Insight Into

Over the past decade, universities have invested heavily in startup accelerator programs; however, their role in the university entrepreneurial ecosystem is ambiguous. Are university startup accelerators intended to educate or are they created to facilitate business starts and to contribute to regional economic development? In contrast, most private-sector startup accelerators serve a consistent and differentiated role in the entrepreneurial ecosystem—they provide programming and resources to startups to increase the probability of a return on investment. Understanding the role of university startup accelerators is an important precursor to evaluating their impact and whether or not the return is worth the considerable investment. In this study, we poll university accelerator directors to gain their perspective on the role(s) that university startup accelerators play and to identify how they are structured and operated. Our research reveals a fairly uniform structure and mode of operation. While facilitating business starts is a key role for some, it confirms education as the primary role for university startup accelerators. We outline appropriate means of assessing the learning that takes place in accelerator programs, offer insight into how these findings can help accelerator directors deliver on outcomes and demonstrate impact, and propose avenues for future research.

The Zebrafish Hypochromic Mutant [iItalic]Shiraz[/iItalic] Encodes a Novel Mitochondrial Glutaredoxin That Establishes a Link between Heme and Fe/S Production.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 51-51
Author(s):  
Rebecca A. Wingert ◽  
Bruce Barut ◽  
Helen Foott ◽  
Paula Fraenkel ◽  
Kimberly Dooley ◽  
...  
Keyword(s):  
Positional Cloning ◽  
Iron Homeostasis ◽  
Rna Binding ◽  
Fetal Liver ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Hemoglobin Synthesis ◽  
Cellular Iron ◽  
Hemoglobin Production

Abstract Iron is required in the mitochondria both to produce heme, which is used for hemoglobin synthesis, and to make iron-sulfur (Fe/S) clusters, which confer electron transfer or catalytic functions to proteins. Cellular iron utilization and Fe/S cluster production are thought to occur independently, yet the processes are coordinated through currently uncharacterized pathways. The shiraz (sir) zebrafish mutant manifests a hypochromic, microcytic anemia. Positional cloning of sir discovered a deletion at the locus that included the zebrafish orthologue to glutaredoxin 5 (grx5), a gene required in yeast for Fe/S cluster assembly. We found that grx5 is highly expressed in the developing blood and fetal liver of both zebrafish and mouse embryos. Antisense-mediated morpholino knockdown of grx5 prevented hemoglobin production, and overexpression of zebrafish, yeast, mouse, or human grx5 RNA in sir embryos completely rescued hemoglobin production, indicating that grx5 is the gene responsible for the sir phenotype. Expression of zebrafish grx5 was found to rescue Fe/S protein production in the yeast Δgrx5 strain, demonstrating that the role of grx5 in Fe/S cluster assembly is conserved among eukaryotes. The surprising finding that mutating a gene necessary for Fe/S cluster assembly caused a lack of hemoglobin synthesis suggested that we had discovered a connection between these pathways. In vertebrates, iron regulatory protein 1 (IRP1) acts as a sensor of intracellular iron levels and controls cellular iron homeostasis via posttranscriptional regulation of iron uptake, storage, and utilization genes. For instance, IRP1 binds to the 5′ iron response element (IRE) in the aminolevulinate synthase 2 (ALAS2) mRNA, blocking translation when cellular iron is low. However, when cellular iron is replete, IRP1 binds a Fe/S cluster and its RNA-binding activity is abolished. We hypothesized that the loss of Fe/S cluster assembly in sir would activate IRP1 and block ALAS2 synthesis, resulting in hypochromia. In support of this model, overexpression of ALAS2 RNA without the 5′ IRE rescued sir hypochromia, while overexpression of ALAS2 including the IRE did not facilitate rescue. Furthermore, antisense morpholino knockdowns of IRP1 caused rescue of hemoglobin synthesis in sir embryos. The combination of these data indicate that hemoglobin production in the differentiating red cell is monitored through Fe-S cluster assembly as a mechanism to gauge iron levels and accordingly direct heme synthesis. This finding illustrates a crucial role for the mitochondrial Fe/S cluster assembly machinery during hemoglobin production, and has broad implications for the role of such genes in human hypochromic anemias.

A “Radical” Problem: The Poor and the English Reformers in the Mid-Seventeenth Century

1990 ◽  
Vol 29 (2) ◽  
pp. 118-146 ◽  
Author(s):  
Lotte Mulligan ◽  
Judith Richards
Keyword(s):  
Seventeenth Century ◽  
Social Reform ◽  
Economic Organization ◽  
Social Differentiation ◽  
Left Wing ◽  
The Past ◽  
The Poor ◽  
Problems And Solutions ◽  
Insight Into

Debates about poverty in mid-seventeenth-century England have, for some years, been a staple of historical studies. In our own time, where the numbers of the dispossessed continue to challenge the success of current modes of social and economic organization, such an interest is understandable and to be welcomed. But the relevance of studies of past problems and solutions and their applicability to present purposes is more complex than is usually recognized.The immediate benefit of studying discussions for change in mid-seventeenth-century England is that they provide an unusual insight into how members of that society conceived of it. In particular, their observations about the problems of poverty and the role of the poor offer us an understanding of the perceived social structure, the ethical bases for social differentiation, and the degree to which the future could be envisioned as differing from the past or present. Such understandings of proposed social change are invaluable for historians wishing to grasp the underlying assumptions on which past thought and action was predicated.Past proposals for social reform, however, have also been the focus of a significantly different enquiry by historians. In order to render those past programs more comprehensible (and more directly “relevant”) to modern readers, they are often placed on a “conservative” versus “radical” continuum, one end of which has sometimes been marked “extreme left wing.” This article argues that any such classification inevitably leads to misunderstandings of the authors and of their programs and, consequently, misrepresents both to the present.

scholarly journals What is the role of depression in the discrepancy between estimated and actual iPhone use? An exploratory analysis using cubic response surface analysis

2021 ◽  
Author(s):  
Craig Sewall ◽  
Douglas Parry
Keyword(s):  
Response Surface ◽  
Digital Media ◽  
Surface Analysis ◽  
Media Use ◽  
Response Surface Analysis ◽  
Self Report ◽  
The Past ◽  
Almost All ◽  
Insight Into

The association between depression and digital media use has received substantial research and popular attention in recent years. While meta-analytic evidence indicates that there is a small, positive relationship between digital media use and depression, almost all studies rely on self-report measures of digital media use. Evidence suggests these measures are poor reflections of usage measures derived from digital trace data. Additionally, a recent study showed that the error in self-reported digital media use is likely biased systematically by factors that are fundamental to the effect being investigated: respondents’ volume of use and level of depression. The current exploratory study harnesses cubic response surface analysis—a novel analytical approach in this domain—to advance our understanding of how inaccuracies in self-report measures of digital media use can be explained by respondent attributes, in this case their level of depression and actual iPhone usage. A sample of 325 iPhone users provided estimates of their total iPhone use over the past week, their actual iPhone use as recorded by the Apple Screen Time application, and a measure of their depression (CESD-R-10). The results of the analysis indicate that depression is i.) more strongly associated with estimated than device-logged DMU; ii.) more associated with over-estimating than under-estimating of DMU; and iii.) more associated with inaccuracy at lower versus higher levels of DMU. The findings raise important questions concerning the validity of conclusions in this area and provide insight into the structure of measurement error in self-report estimates of digital media use.

scholarly journals The Role of Public-Private Partnerships in Higher Education How Tertiary Institutions in emerging Economies benefit from Public-Private Partnerships

2017 ◽  
Vol 2 (1) ◽  
pp. 1-7
Author(s):  
Ronak Warasthe
Keyword(s):  
Higher Education ◽  
Emerging Economies ◽  
Tertiary Education ◽  
Added Value ◽  
Public Private Partnerships ◽  
Tertiary Institutions ◽  
The Past ◽  
Different Types ◽  
Insight Into

Abstract The number of Public-Private Partnerships in the education sector is growing in developing and emerging economies. Traditionally governments are the main financial contributor to education however, the involvement of the private sector is an increasing one. While more established in primary and secondary education, PPPs in tertiary education are a phenomenon rather slowly growing in the past decades (Patrinos, Barrera-Osorio, & Guaqueta, 2009). There are various concepts of PPPs in higher education each targeting different goals. In order to give an insight into different types of PPPs, the typology according to Mabizela has been briefly displayed and the case of a PPP in Namibia is given. The framework of the partnership was compiled to give an outlook on the practicability of partnerships. The paper exemplifies that both partners within a PPP can benefit from the added value they may generate for their target group. Thus, the benefit depends on quality, relevance and execution of the partnership.

Tricetin Suppresses Migration and Presenilin-1 Expression of Nasopharyngeal Carcinoma through Akt/GSK-3β Pathway

2020 ◽  
Vol 48 (05) ◽  
pp. 1203-1220 ◽  
Author(s):  
Hsin-Yu Ho ◽  
Frank Cheau-Feng Lin ◽  
Pei-Ni Chen ◽  
Mu-Kuan Chen ◽  
Chung-Han Hsin ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Molecular Regulation ◽  
Presenilin 1 ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Mitogen Activated Protein ◽  
Gsk 3Β ◽  
Insight Into

Lymph node migration results in poor prognoses for nasopharyngeal carcinoma (NPC) patients. Tricetin, a flavonoid derivative, regulates tumorigenesis activity through its antiproliferative and antimetastatic properties. However, the molecular mechanism of tricetin affecting the migration and invasion of NPC cells remains poorly understood. In this paper, we examined the antimetastatic properties of tricetin in human NPC cells. Our results demonstrated that tricetin at noncytotoxic concentrations (0–80 3M) noticeably reduced the migration and invasion of NPC cells (HONE-1, NPC-39, and NPC-BM). Moreover, tricetin suppressed the indicative protease, presenilin-1 (PS-1), as indicated by protease array. PS-1 was transcriptionally inhibited via the Akt signaling pathway but not mitogen-activated protein kinase pathways, such as the JNK, p38, and ERK1/2 pathways. In addition to upregulating GSK-3[Formula: see text] phosphorylation through Akt suppression, tricetin may downregulate the activity of PS-1. Overall, our study provides new insight into the role of tricetin-induced molecular regulation in the suppression of NPC metastasis and suggests that tricetin has prospective therapeutic applications for patients with NPC.

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

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