Diversity of Fe2+ entry and oxidation in ferritins

The essential metal iron presents two major problems for life: it is potentially highly toxic due to its redox activity, and its extremely low solubility in aqueous solution in the presence of O2 can make it hard to acquire and store safely. Ferritins are part of nature’s answer to these problems, as they store iron in a safe but accessible form in all types of cells. How they achieve this has been the subject of intense research for several decades. Here, we highlight recent progress in elucidating the routes by which Fe2+ ions access the catalytic ferroxidase centers, and the mechanisms by which Fe2+ is oxidized. Emerging from this is a picture of diversity, both in terms of Fe2+ entry pathways and the roles played by the structurally distinct diiron ferroxidase centers

Tripartism in comparative and historical perspective

This special issue explores changes in the nature of tripartite arrangements between firms, governments and organized labour across the last century, focusing on their post-1945 heyday. Although tripartism has its origins at the turn of the Twentieth Century, the post-1945 long boom represented an historical high-water mark that may now be seen as quite distinct from our own long period of volatility and crisis. Historical concerns are frequently stimulated by those of the present and this is especially the case in contemporary history. Anglo-Saxon historians may feel that the age of tripartism is at an end, but the contributions within this issue show that although this may accurately reflect current perceptions, tripartism continues , albeit often in weak forms, in other national and transnational contexts; its history therefore retains contemporary resonance. In our present age, it is commonly assumed that the relative power of employers has increased at the expense of government – the central co-ordinating actor in tripartism – and organized labour. Within the firm, not only workers, but also traditional managers have been displaced by assertive investors and allied to them, a new managerial class that has little emotional capital sunk in the firm other than as a vehicle for shareholder value maximization or release, and personal enrichment. From the business historian’s viewpoint, these assumptions raise a number of issues surrounding long term trends and diversity in the nature of the capitalist ecosystem within which tripartism is located. In this connection, there are four alternative points of view on broad approaches to labour management. The first, rooted in the then apparent solidity of the British postwar tripartite settlement, was that the incorporation of labour’s institutions was structurally essential to the state’s role in avoiding or genuinely resolving crises. The second sees tripartism as very much an historical exception, representing to a large extent a product of a very specific set of historic circumstances around the Great Depression and the post-World War Two long boom. The third, a variant of the second, would see historic compromises between state, the firm, and workers as a reflection of the thirty year period of relative global prosperity and growth which had deeper historic roots stretching back at least into the Nineteenth Century. The fourth highlights national diversity in global capitalism and views the labour management options adopted according not only to temporal trends but also to such dimensions as space, scale, and global centre-periphery relations. The latter view implies that elements of post-war compromises may persist, even if, within many of the advanced societies, they do so in dilute form

Protein encapsulation within the internal cavity of a bacterioferritin

The thermal and chemical stability of 24mer ferritins has led to attempts to exploit their naturally occurring nanoscale (8 nm) internal cavities for biotechnological applications. An area of increasing interest is the encapsulation of molecules either for medical or biocatalysis applications. Encapsulation requires ferritin dissociation, typically induced using high temperature or acidic conditions (pH ≥ 2), which generally precludes the inclusion of fragile cargo such as proteins or peptide fragments. Here we demonstrate that minimizing salt concentration combined with adjusting the pH to ≤8.5 (i.e. low proton/metal ion concentration) reversibly shifts the naturally occurring equilibrium between dimeric and 24meric assemblies of Escherichia coli bacterioferritin (Bfr) in favour of the disassembled form. Interconversion between the different oligomeric forms of Bfr is sufficiently slow under these conditions to allow the use of size exclusion chromatography to obtain wild type protein in the purely dimeric and 24meric forms. This control over association state was exploited to bind heme at natural sites that are not accessible in the assembled protein. The potential for biotechnological applications was demonstrated by the encapsulation of a small, acidic [3Fe-4S] cluster-containing ferredoxin within the Bfr internal cavity. The capture of ∼4–6 negatively charged ferredoxin molecules per cage indicates that charge complementarity with the inner protein surface is not an essential determinant of successful encapsulation

Reaction of O2 with a di-iron protein generates a mixed valent Fe2+/Fe3+ center and peroxide

The gene encoding the cyanobacterial ferritin SynFtn is up-regulated in response to copper stress. Here, we show that, while SynFtn does not interact directly with copper, it is highly unusual in several ways. First, its catalytic diiron ferroxidase center is unlike those of all other characterized prokaryotic ferritins and instead resembles an animal H-chain ferritin center. Second, as demonstrated by kinetic, spectroscopic, and high-resolution X-ray crystallographic data, reaction of O2 with the di-Fe2+ center results in a direct, one-electron oxidation to a mixed-valent Fe2+/Fe3+ form. Iron–O2 chemistry of this type is currently unknown among the growing family of proteins that bind a diiron site within a four α-helical bundle in general and ferritins in particular. The mixed-valent form, which slowly oxidized to the more usual di-Fe3+ form, is an intermediate that is continually generated during mineralization. Peroxide, rather than superoxide, is shown to be the product of O2 reduction, implying that ferroxidase centers function in pairs via long-range electron transfer through the protein resulting in reduction of O2 bound at only one of the centers. We show that electron transfer is mediated by the transient formation of a radical on Tyr40, which lies ∼4 Å from the diiron center. As well as demonstrating an expansion of the iron–O2 chemistry known to occur in nature, these data are also highly relevant to the question of whether all ferritins mineralize iron via a common mechanism, providing unequivocal proof that they do not

Interactions between the Physical and Social Environments with Adverse Pregnancy Events Related to Placental Disorders—A Scoping Review

Background: Due to different social and physical environments across Africa, understanding how these environments differ in interacting with placental disorders will play an important role in developing effective interventions. Methods: A scoping review was conducted, to identify current knowledge on interactions between the physical and social environment and the incidence of placental disease in Africa. Results: Heavy metals were said to be harmful when environmental concentrations are beyond critical limits. Education level, maternal age, attendance of antenatal care and parity were the most investigated social determinants. Conclusions: More evidence is needed to determine the relationships between the environment and placental function in Africa. The results show that understanding the nature of the relationship between social determinants of health (SDH) and placental health outcomes plays a pivotal role in understanding the risk in the heterogenous communities in Africa

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study

INTRODUCTION: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR. METHODS: NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80 years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52 weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study. RESULTS: Tezepelumab reduced the AAER over 52 weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline. CONCLUSION: These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers\u27 treatment decisions

Bacterial iron detoxification at the molecular level.

Iron is an essential micronutrient, and, in the case of bacteria, its availability is commonly a growth-limiting factor. However, correct functioning of cells requires that the labile pool of chelatable "free" iron be tightly regulated. Correct metalation of proteins requiring iron as a cofactor demands that such a readily accessible source of iron exist, but overaccumulation results in an oxidative burden that, if unchecked, would lead to cell death. The toxicity of iron stems from its potential to catalyze formation of reactive oxygen species that, in addition to causing damage to biological molecules, can also lead to the formation of reactive nitrogen species. To avoid iron-mediated oxidative stress, bacteria utilize iron-dependent global regulators to sense the iron status of the cell and regulate the expression of proteins involved in the acquisition, storage, and efflux of iron accordingly. Here, we survey the current understanding of the structure and mechanism of the important members of each of these classes of protein. Diversity in the details of iron homeostasis mechanisms reflect the differing nutritional stresses resulting from the wide variety of ecological niches that bacteria inhabit. However, in this review, we seek to highlight the similarities of iron homeostasis between different bacteria, while acknowledging important variations. In this way, we hope to illustrate how bacteria have evolved common approaches to overcome the dual problems of the insolubility and potential toxicity of iron

Population Pharmacokinetics of Lamivudine in Adult Human Immunodeficiency Virus-Infected Patients Enrolled in Two Phase III Clinical Trials

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4+ cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4+ cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis