Comparison of the Interactions of Transferrin Receptor and Transferrin Receptor 2 with Transferrin and the Hereditary Hemochromatosis Protein HFE

The transferrin receptor (TfR) interacts with two proteins important for iron metabolism, transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625). TfR2 has a pattern of expression and regulation that is distinct from TfR, and mutations in TfR2 have been recognized as the cause of a non-HFE linked form of hemochromatosis (Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P. (2000) Nat. Genet. 25, 14-15). To investigate the relationship between TfR, TfR2, Tf, and HFE, we performed a series of binding experiments using soluble forms of these proteins. We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay. The affinity of TfR2 for iron-loaded Tf was determined to be 27 nM, 25-fold lower than the affinity of TfR for Tf. These results imply that HFE regulates Tf-mediated iron uptake only from the classical TfR and that TfR2 does not compete for HFE binding in cells expressing both forms of TfR

Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors.

IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1α and IL-1β are translated as proforms that require cleavage for full cytokine activity and release, while IL-1α is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1α (csIL-1α) is contested, how IL-1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1α after ligation of TLRs. Pro-IL-1α tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-γ, independent of expression level. We also reveal how prior csIL-1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1α, but rather via soluble IL-1α. We believe these data are important for determining the local or systemic context in which IL-1α can contribute to disease and/or physiological processes.Work was funded by British Heart Foundation Grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 to MCHC, the BHF Cambridge CRE RE/13/6/30180, and the Cambridge NIHR Biomedical Research Centr

Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor

AbstractHFE is an MHC-related protein that is mutated in the iron-overload disease hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 Å crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex

The terrestrial landscapes of tetrapod evolution in earliest Carboniferous seasonal wetlands of SE Scotland

The Lower Mississippian (Tournaisian) Ballagan Formation in SE Scotland yields tetrapod fossils that provide fresh insights into the critical period when these animals first moved onto land. The key to understanding the palaeoenvironments where they lived is a detailed analysis of the sedimentary architecture of this formation, one of the thickest and most completely documented examples of a coastal floodplain and marginal marine succession from this important transitional time anywhere in the world. Palaeosols are abundant, providing a unique insight into the early Carboniferous habitats and climate. More than 200 separate palaeosols are described from three sections through the formation. The palaeosols range in thickness from 0.02 to 1.85 m and are diverse: most are Entisols and Inceptisols (63%), indicating relatively brief periods of soil development. Gleyed Inseptisols and Vertisols are less common (37%). Vertisols are the thickest palaeosols (up to 185 cm) in the Ballagan Formation and have common vertic cracks. Roots are abundant through all the palaeosols, from shallow mats and thin hair-like traces to sporadic thicker root traces typical of arborescent lycopods. Geochemical, isotope and clay mineralogical analyses of the palaeosols indicate a range in soil alkalinity and amount of water logging. Estimates of mean annual rainfall from palaeosol compositions are 1000 –1500 mm per year. The high mean annual rainfall and variable soil alkalinities contrast markedly with dry periods that developed deep penetrating cracks and evaporite deposits. It is concluded that during the early Carboniferous, this region experienced a sharply contrasting seasonal climate and that the floodplain hosted a mosaic of closely juxtaposed but distinct habitats in which the tetrapods lived. The diversification of coastal floodplain environments identified here may link to the evolution and movement of tetrapods into the terrestrial realm

Barriers and facilitators to delivery of group audiological rehabilitation programs : a survey based on the COM-B model

OBJECTIVE : To canvas the views of Australia-based hearing healthcare clinicians regarding group audiological rehabilitation practices. DESIGN : A national cross-sectional self-report survey. Data were analysed using descriptive statistics and content analysis. STUDY SAMPLE : Sixty-two Australia-based hearing healthcare clinicians, with experience working in an adult rehabilitation setting. RESULTS : Clinicians appeared to positively view the provision of group audiological rehabilitation services, yet were limited in their ability to deliver these services due to organisational barriers. Although some organisational barriers were non-modifiable by the clinician (such as group AR services not prioritised within their workplace, a lack of support from colleagues/managers, lack of resources, and a lack of funding for the delivery of group AR services), others were within the clinicians’ ability to change (such as habit formation for recommending these services during clinical appointments). Participants expressed a desire for resources to assist them in delivering group AR, including downloadable lesson plans and information sheets for clients, clinician training videos and client educational videos. Clinicians called for increased diversity in program offerings, specifically relating to the emotional, relational and social impacts of hearing loss. CONCLUSIONS : These results provide a framework for the development of interventional studies to increase the utilisation of group audiological rehabilitation services.https://www.tandfonline.com/loi/iija202022-06-13hj2022Speech-Language Pathology and Audiolog

GPS-Prot: A web-based visualization platform for integrating host-pathogen interaction data

<p>Abstract</p> <p>Background</p> <p>The increasing availability of HIV-host interaction datasets, including both physical and genetic interactions, has created a need for software tools to integrate and visualize the data. Because these host-pathogen interactions are extensive and interactions between human proteins are found within many different databases, it is difficult to generate integrated HIV-human interaction networks.</p> <p>Results</p> <p>We have developed a web-based platform, termed GPS-Prot <url>http://www.gpsprot.org</url>, that allows for facile integration of different HIV interaction data types as well as inclusion of interactions between human proteins derived from publicly-available databases, including MINT, BioGRID and HPRD. The software has the ability to group proteins into functional modules or protein complexes, generating more intuitive network representations and also allows for the uploading of user-generated data.</p> <p>Conclusions</p> <p>GPS-Prot is a software tool that allows users to easily create comprehensive and integrated HIV-host networks. A major advantage of this platform compared to other visualization tools is its web-based format, which requires no software installation or data downloads. GPS-Prot allows novice users to quickly generate networks that combine both genetic and protein-protein interactions between HIV and its human host into a single representation. Ultimately, the platform is extendable to other host-pathogen systems.</p

Quantum-Dense Metrology

Quantum metrology utilizes entanglement for improving the sensitivity of measurements. Up to now the focus has been on the measurement of just one out of two non-commuting observables. Here we demonstrate a laser interferometer that provides information about two non-commuting observables, with uncertainties below that of the meter's quantum ground state. Our experiment is a proof-of-principle of quantum dense metrology, and uses the additional information to distinguish between the actual phase signal and a parasitic signal due to scattered and frequency shifted photons. Our approach can be readily applied to improve squeezed-light enhanced gravitational-wave detectors at non-quantum noise limited detection frequencies in terms of a sub shot-noise veto-channel.Comment: 5 pages, 3 figures; includes supplementary material

Sea ice extent and seasonality for the Early Pliocene northern Weddell Sea

Growth increment analysis coupled with stable isotopic data (δ18O/δ13C) from Early Pliocene (ca 4.7 Ma) Austrochlamys anderssoni from shallow marine sediments of the Cockburn Island Formation, northern Antarctic Peninsula, suggest these bivalves grew through much of the year, even during the coldest parts of winter recorded in the shells. The high frequency fluctuation in growth increment width of A. anderssoni appears to reflect periodic, but year-round, agitation of the water column enhancing benthic food supply from organic detritus. This suggests that Austrochlamys favoured waters that were largely sea ice free. Our data support interpretation of the Cockburn Island Formation as an interglacial marine deposit and the previous hypothesis that Austrochlamys retreated from the Antarctic as sea ice extent expanded, this transition occurring during climate cooling in the Late Pliocene