Mechanism for Multiple Ligand Recognition by the Human Transferrin Receptor

Transferrin receptor 1 (TfR) plays a critical role in cellular iron import for most higher organisms. Cell surface TfR binds to circulating iron-loaded transferrin (Fe-Tf) and transports it to acidic endosomes, where low pH promotes iron to dissociate from transferrin (Tf) in a TfR-assisted process. The iron-free form of Tf (apo-Tf) remains bound to TfR and is recycled to the cell surface, where the complex dissociates upon exposure to the slightly basic pH of the blood. Fe-Tf competes for binding to TfR with HFE, the protein mutated in the iron-overload disease hereditary hemochromatosis. We used a quantitative surface plasmon resonance assay to determine the binding affinities of an extensive set of site-directed TfR mutants to HFE and Fe-Tf at pH 7.4 and to apo-Tf at pH 6.3. These results confirm the previous finding that Fe-Tf and HFE compete for the receptor by binding to an overlapping site on the TfR helical domain. Spatially distant mutations in the TfR protease-like domain affect binding of Fe-Tf, but not iron-loaded Tf C-lobe, apo-Tf, or HFE, and mutations at the edge of the TfR helical domain affect binding of apo-Tf, but not Fe-Tf or HFE. The binding data presented here reveal the binding footprints on TfR for Fe-Tf and apo-Tf. These data support a model in which the Tf C-lobe contacts the TfR helical domain and the Tf N-lobe contacts the base of the TfR protease-like domain. The differential effects of some TfR mutations on binding to Fe-Tf and apo-Tf suggest differences in the contact points between TfR and the two forms of Tf that could be caused by pH-dependent conformational changes in Tf, TfR, or both. From these data, we propose a structure-based model for the mechanism of TfR-assisted iron release from Fe-Tf

Additional special purpose stocks

Additional special purpose stock

Both the environment and genes are important for concentrations of cadmium and lead in blood.

Concentrations of cadmium and lead in blood (BCd and BPb, respectively) are traditionally used as biomarkers of environmental exposure. We estimated the influence of genetic factors on these markers in a cohort of 61 monozygotic and 103 dizygotic twin pairs (mean age = 68 years, range = 49-86). BCd and BPb were determined by graphite furnace atomic absorption spectrophotometry. Variations in both BCd and BPb were influenced by not only environmental but also genetic factors. Interestingly, the genetic influence was considerably greater for nonsmoking women (h(2) = 65% for BCd and 58% for BPb) than for nonsmoking men (13 and 0%, respectively). The shared familial environmental (c(2)) influence for BPb was 37% for men but only 3% for women. The association between BCd and BPb could be attributed entirely to environmental factors of mutual importance for levels of the two metals. Thus, blood metal concentrations in women reflect not only exposure, as previously believed, but to a considerable extent hereditary factors possibly related to uptake and storage. Further steps should focus on identification of these genetic factors and evaluation of whether women are more susceptible to exposure to toxic metals than men

First-principles study of Co- and Cu-doped Ni2MnGa along the tetragonal deformation path

The influence of Co and Cu doping on Ni-Mn-Ga Heusler alloy is investigated using the first-principles exact muffin-tin orbital method in combination with the coherent-potential approximation. Single-element doping and simultaneous doping by both elements are investigated in Ni50−xCoxMn25−yGa25−zCuy+z alloys, with dopant concentrations x,y, and z up to 7.5 at. %. Doping with Co in the Ni sublattice decreases the (c/a)NM ratio of the nonmodulated (NM) martensite, but it simultaneously increases the cubic phase stability with respect to the NM phase. Doping with Cu in the Mn or in Ga sublattices does not change the (c/a)NM ratio significantly and it decreases the cubic phase stability. For simultaneous doping by Co in the Ni sublattice and Cu in the Mn or Ga sublattices, the effects of the individual dopants are independent and about the same as for the single-element doping. Thus, the (c/a)NM ratio can be adjusted by Co doping while the phase stability can be balanced by Cu doping, resulting in stable martensite with a reduced (c/a)NM. The local stability of the cubic phase with respect to the tetragonal deformation can be understood on the basis of a density-of-states analysis.Peer reviewe

First ice core records of NO3− stable isotopes from Lomonosovfonna, Svalbard

Samples from two ice cores drilled at Lomonosovfonna, Svalbard, covering the period 1957–2009, and 1650–1995, respectively, were analyzed for NO3− concentrations, and NO3− stable isotopes (δ15N and δ18O). Post-1950 δ15N has an average of (−6.9 ± 1.9) ‰, which is lower than the isotopic signal known for Summit, Greenland, but agrees with values observed in recent Svalbard snow and aerosol. Pre-1900 δ15N has an average of (4.2 ± 1.6) ‰ suggesting that natural sources, enriched in the 15 N-isotope, dominated before industrialization. The post-1950 δ18O average of (75.1 ± 4.1) ‰ agrees with data from low and polar latitudes, suggesting similar atmospheric NOy (NOy = NO + NO2 + HNO3) processing pathways. The combination of anthropogenic source δ15N and transport isotope effect was estimated as −29.1 ‰ for the last 60 years. This value is below the usual range of NOx (NOx = NO + NO2) anthropogenic sources which is likely the result of a transport isotope effect of –32 ‰. We suggest that the δ15N recorded at Lomonosovfonna is influenced mainly by fossil fuel combustion, soil emissions and forest fires; the first and second being responsible for the marked decrease in δ15N observed in the post-1950s record with soil emissions being associated to the decreasing trend in δ15N observed up to present time, and the third being responsible for the sharp increase of δ15N around 2000

Two-Dimensional Materials from Data Filtering and Ab Initio Calculations

Progress in materials science depends on the ability to discover new materials and to obtain and understand their properties. This has recently become particularly apparent for compounds with reduced dimensionality, which often display unexpected physical and chemical properties, making them very attractive for applications in electronics, graphene being so far the most noteworthy example. Here, we report some previously unknown two-dimensional materials and their electronic structure by data mining among crystal structures listed in the International Crystallographic Structural Database, combined with density-functional-theory calculations. As a result, we propose to explore the synthesis of a large group of two-dimensional materials, with properties suggestive of applications in nanoscale devices, and anticipate further studies of electronic and magnetic phenomena in low-dimensional systems.Peer reviewe

Phosphorus dynamics in biogeochemically distinct regions of the southeast subtropical Pacific Ocean

The southeast subtropical Pacific Ocean was sampled along a zonal transect between the coasts of Chile and Easter Island. This remote area of the world’s ocean presents strong gradients in physical (e.g., temperature, density and light), chemical (e.g., salinity and nutrient concentrations) and microbiological (e.g., cell abundances, biomass and specific growth rates) properties. The goal of this study was to describe the phosphorus (P) dynamics in three main ecosystems along this transect: the upwelling regime off the northern Chilean coast, the oligotrophic area associated with the southeast subtropical Pacific gyre and the transitional area in between these two biomes. We found that inorganic phosphate (Pi) concentrations were high and turnover times were long (>210 nmol l−1 and >31 d, respectively) in the upper water column, along the entire transect. Pi uptake rates in the gyre were low (euphotic layer integrated rates were 0.26 mmol m−2 d−1 in the gyre and 1.28 mmol m−2 d−1 in the upwelling region), yet not only driven by decreases in particle mass or cell abundance (particulate P- and cell- normalized Pi uptake rates in the euphotic layer were ∼1–4 times and ∼3–15 times lower in the gyre than in the upwelling, respectively). However these Pi uptake rates were at or near the maximum Pi uptake velocity (i.e., uptake rates in Pi amended samples were not significantly different from those at ambient concentration: 1.5 and 23.7 nmol l−1 d−1 at 50% PAR in the gyre and upwelling, respectively). Despite the apparent Pi replete conditions, selected dissolved organic P (DOP) compounds were readily hydrolyzed. Nucleotides were the most bioavailable of the DOP substrates tested. Microbes actively assimilated adenosine-5′-triphosphate (ATP) leading to Pi and adenosine incorporation as well as Pi release to the environment. The southeast subtropical Pacific Ocean is a Pi-sufficient environment, yet DOP hydrolytic processes are maintained and contribute to P-cycling across the wide range of environmental conditions present in this ecosystem

Spatial and Temporal Dynamics of Inorganic Phosphate and Adenosine-5’-Triphosphate in the North Pacific Ocean

Temporal variability in dissolved inorganic, organic phosphate (Pi, DOP) and particulate phosphorus (PPO4) concentrations, and microbial utilization of Pi and dissolved adenosine-5′-triphosphate (DATP) was studied at Station ALOHA (22.75◦N, 158◦W) in the North Pacific Subtropical Gyre (NPSG) over a multi-year period. Spatial variability of the same properties was investigated along two transects, to and from Hawaii, that traversed the NPSG boundaries to the east (2014) and north (2016). Radiotracer techniques were employed to measure the turnover time of Pi and DATP pools to calculate Pi uptake rates and the Pi hydrolysis rates of DATP. Pi concentrations were more variable, both in time and space, than DOP, ranging two orders of magnitude compared to a factor of two for DOP. The DATP pool, while constituting on average 0.2 μm size class dominating the DATP uptake. Our results indicate that during Pi limiting conditions, regenerated P is rapidly consumed, and that Pi limitation occurs locally and transiently but does not appear to be the predominant condition in the upper water column of the NPSG

van der Waals Bonding in Layered Compounds from Advanced Density-Functional First-Principles Calculations

Although the precise microscopic knowledge of van der Waals interactions is crucial for understanding bonding in weakly bonded layered compounds, very little quantitative information on the strength of interlayer interaction in these materials is available, either from experiments or simulations. Here, using many-body perturbation and advanced density-functional theory techniques, we calculate the interlayer binding and exfoliation energies for a large number of layered compounds and show that, independent of the electronic structure of the material, the energies for most systems are around 20  meV/Å2. This universality explains the successful exfoliation of a wide class of layered materials to produce two-dimensional systems, and furthers our understanding the properties of layered compounds in general.Peer reviewe