Two to Tango: Regulation of Mammalian Iron Metabolism

Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. Iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the iron exporter ferroportin, and another that predominantly controls cellular iron metabolism through iron-regulatory proteins that bind iron-responsive elements in regulated messenger RNAs. We describe how the two distinct systems function and how they “tango” together in a coordinated manner. We also highlight some of the current questions in mammalian iron metabolism and discuss therapeutic opportunities arising from a better understanding of the underlying biological principles

Loading and fate of particulate organic carbon from the Himalaya to the Ganga–Brahmaputra delta

Author Posting. © Elsevier B.V., 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 72 (2008): 1767-1787, doi:10.1016/j.gca.2008.01.027.We use the evolution of river sediment characteristics and sedimentary Corg from the Himalayan range to the delta to study the transport of Corg in the Ganga-Brahmaputra system and especially its fate during floodplain transit. A detailed characterisation of both mineral and organic particles for a sampling set of river sediments allows taking into account the sediment heterogeneity characteristic of such large rivers. We study the relationships between sediment characteristics (mineralogy, grain size, specific area) and Corg content in order to evaluate the controls on Corg loading. Contributions of C3 and C4 plants are estimated from Corg stable isotopic composition (δ13Corg). We use the evolution of δ13Corg values from the Himalayan range to the delta in order to study the fate of Corg during floodplain transit. Ganga and Brahmaputra sediments define two distinct linear relations with specific area. In spite of 4 to 5 times higher specific area, Ganga sediments have similar Corg content, grain size and mineralogy as Brahmaputra sediments, indicating that specific area does not exert a primary control on Corg loading. The general correlation between the total Corg content and Al/Si ratio indicates that Corg loading is mainly related to: (1) segregation of organic particles under hydrodynamic forces in the river and, (2) the ability of mineral particles to form organo-mineral aggregates. Bed and suspended sediments have distinct δ13Corg values. In bed sediments, δ13Corg values are compatible with a dominant proportion of fossil Corg derived from Himalayan rocks erosion. Suspended sediments from Himalayan tributaries at the outflow of the range have low δ13Corg values (-24.8 ‰ average) indicating a dominant proportion of C3 plant inputs. In the Brahmaputra basin, δ13Corg values of suspended sediments are constant along the river course in the plain. On the contrary, suspended sediments of the Ganga in Bangladesh have higher δ13Corg values (-22.4 to -20.0‰), consistent with a significant contribution of C4 plant derived from the floodplain. Our data indicate that, during the plain transit, more than 50% of the recent biogenic Corg coming from the Himalaya is oxidised and replaced by floodplain Corg. This renewal process likely occurs 40 during successive deposition-erosion cycles and river course avulsions in the plain.This study was funded by CNRS-INSU programs "Eclipse" and "Relief de la Terre"

A Rouse-based method to integrate the chemical composition of river sediments : application to the Ganga basin

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): F04012, doi:10.1029/2010JF001947.The Ganga River is one of the main conveyors of sediments produced by Himalayan erosion. Determining the flux of elements transported through the system is essential to understand the dynamics of the basin. This is hampered by the chemical heterogeneity of sediments observed both in the water column and under variable hydrodynamic conditions. Using Acoustic Doppler Current Profiler (ADCP) acquisitions with sediment depth profile sampling of the Ganga in Bangladesh we build a simple model to derive the annual flux and grain size distributions of the sediments. The model shows that ca. 390 (±30) Mt of sediments are transported on average each year through the Ganga at Haring Bridge (Bangladesh). Modeled average sediment grain size parameters D50 and D84 are 27 (±4) and 123 (±9) μm, respectively. Grain size parameters are used to infer average chemical compositions of the sediments owing to a strong grain size chemical composition relation. The integrated sediment flux is characterized by low Al/Si and Fe/Si ratios that are close to those inferred for the Himalayan crust. This implies that only limited sequestration occurs in the Gangetic floodplain. The stored sediment flux is estimated to c.a. 10% of the initial Himalayan sediment flux by geochemical mass balance. The associated, globally averaged sedimentation rates in the floodplain are found to be ca. 0.08 mm/yr and yield average Himalayan erosion rate of ca. 0.9 mm/yr. This study stresses the need to carefully address the average composition of river sediments before solving large-scale geochemical budgets.This work was supported by INSU program “Relief de la Terre” and ANR Calimero. Valier Galy was supported by the U.S. National Science Foundation (grant OCE‐0851015)

Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen

SummaryBoth hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron)

The HOXB4 Homeoprotein Promotes the Ex Vivo Enrichment of Functional Human Embryonic Stem Cell-Derived NK Cells

Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34+CD45RA+ precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells

Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection

Background: How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear. Methods: We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells in vitro and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant TMPRSS6. We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency. Findings: We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity. Conclusions: Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field