The essential micronutrient copper is tightly regulated in organisms, as environmental exposure or homeostasis defects can cause toxicity and neurodegenerative disease. The principal target(s) of ...copper toxicity have not been pinpointed, but one key effect is impaired supply of iron-sulfur (FeS) clusters to the essential protein Rli1 (ABCE1). Here, to find upstream FeS biosynthesis/delivery protein(s) responsible for this, we compared copper sensitivity of yeast-overexpressing candidate targets. Overexpression of the mitochondrial ferredoxin Yah1 produced copper hyper-resistance. 55Fe turnover assays revealed that FeS integrity of Yah1 was particularly vulnerable to copper among the test proteins. Furthermore, destabilization of the FeS domain of Yah1 produced copper hypersensitivity, and YAH1 overexpression rescued Rli1 dysfunction. This copper-resistance function was conserved in the human ferredoxin, Fdx2. The data indicate that the essential mitochondrial ferredoxin is an important copper target, determining a tipping point where plentiful copper supply becomes excessive. This knowledge could help in tackling copper-related diseases.
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•Expression level of the essential mitochondrial ferredoxin determines Cu resistance•Copper targets the FeS domain of yeast Yah1•Copper action at Yah1 affects downstream, essential FeS-protein function•The function in copper resistance is conserved in the human ferredoxin, Fdx2
Vallières et al. identify the conserved ferredoxin Yah1 (Fdx2 in humans) as an important target of copper excess in cells. Copper targets the FeS domain of the ferredoxin, needed for the essential process of FeS-cluster biogenesis. This knowledge could help in tackling copper-related diseases.
In 2005, U.S. employers spent more than $500 billion on health insurance. I argue that firms invest in worker health to mitigate the depreciation in human capital that occurs when workers get sick, ...which increases the productivity of human and physical capital. Using firm-level health insurance data, I find firms that have higher labor productivity, spend more on research and development, and are larger invest more in health capital. Further, health capital investment positively affects firm value and overall productivity. To identify these effects, I instrument for insurance with state mandates and the number of persons covered by insurance contracts.
Populations of genetically uniform microorganisms exhibit phenotypic heterogeneity, where individual cells have varying phenotypes. Such phenotypes include fitness‐determining traits. Phenotypic ...heterogeneity has been linked to increased population‐level fitness in laboratory studies, but its adaptive significance for wild microorganisms in the natural environment is unknown. Here, we addressed this by testing heterogeneity in yeast isolates from diverse environmental sites, each polluted with a different principal contaminant, as well as from corresponding control locations. We found that cell‐to‐cell heterogeneity (in resistance to the appropriate principal pollutant) was prevalent in the wild yeast isolates. Moreover, isolates with the highest heterogeneity were consistently observed in the polluted environments, indicating that heterogeneity is positively related to survival in adverse conditions in the wild. This relationship with survival was stronger than for the property of mean resistance (IC₅₀) of an isolate. Therefore, heterogeneity could be the major determinant of microbial survival in adverse conditions. Indeed, growth assays indicated that isolates with high heterogeneities had a significant competitive advantage during stress. Analysis of yeasts after cultivation for ≥ 500 generations additionally showed that high heterogeneity evolved as a heritable trait during stress. The results showed that environmental stress selects for wild microorganisms with high levels of phenotypic heterogeneity.
Oxidative stress mediated by reactive oxygen species (ROS) is linked to degenerative conditions in humans and damage to an array of cellular components. However, it is unclear which molecular ...target(s) may be the primary "Achilles' heel" of organisms, accounting for the inhibitory action of ROS. Rli1p (ABCE1) is an essential and highly conserved protein of eukaryotes and archaea that requires notoriously ROS-labile cofactors (Fe-S clusters) for its functions in protein synthesis. In this study, we tested the hypothesis that ROS toxicity is caused by Rli1p dysfunction. In addition to being essential, Rli1p activity (in nuclear ribosomal-subunit export) was shown to be impaired by mild oxidative stress in yeast. Furthermore, prooxidant resistance was decreased by RLI1 repression and increased by RLI1 overexpression. This Rlip1 dependency was abolished during anaerobicity and accentuated in cells expressing a FeS cluster-defective Rli1p construct. The protein's FeS clusters appeared ROS labile during in vitro incubations, but less so in vivo. Instead, it was primarily (55)FeS-cluster supply to Rli1p that was defective in prooxidant-exposed cells. The data indicate that, owing to its essential nature but dependency on ROS-labile FeS clusters, Rli1p function is a primary target of ROS action. Such insight could help inform new approaches for combating oxidative stress-related disease.
There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective ...target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone.
U.S. International Equity Investment AMMER, JOHN; HOLLAND, SARA B.; SMITH, DAVID C. ...
Journal of accounting research,
December 2012, Letnik:
50, Številka:
5
Journal Article
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Using a comprehensive data set of all U.S. investment in foreign equities, we find that the single most important determinant of the amount of U.S. investment a foreign firm receives is whether the ...firm cross-lists on a U.S. exchange. Correcting for selection biases, cross-listing leads to a doubling (or more) in U.S. investment, an impact greater than all other factors combined. Much of this increased U.S. investment is purchased in the foreign market, implying that the cross-listing effect reflects something more fundamental about a firm than easier acquisition of its securities. We also demonstrate that cross-listing is an important determinant of U.S. international investment at the country level and describe easy-to-implement methods for including a cross-listing variable as an endogenous control.
When a firm offers health benefits to workers, it exposes the firm to the risk of making payments when workers get sick. A firm can either pay health expenses out of its general assets, keeping the ...risk inside the firm, or it can purchase insurance, shifting the risk outside the firm. Using data on insurance decisions, we find that smaller firms, firms with more investment opportunities, and firms that face a convex tax schedule are more likely to hedge the risk of health benefit payments. We show how firms trade off the benefits that come from financing and investment characteristics with the costs of regulation when choosing insurance. We provide understanding of how firms' policy and financial characteristics affect firm outcomes as the Affordable Care Act provisions impacting plan funding continue to evolve.
The molecular mode(s)-of-action of the toxic metal chromium has yet to be fully resolved. This Mini review focuses on interactions between chromate and sulfur in biological systems. Cr binds sulfur ...ligands, with cysteine and glutathione having the capacity to aggravate or ameliorate Cr toxicity. Competition between chromate and sulfate for uptake and in metabolism provokes sulfur starvation, which can be growth limiting. Recent data indicate that sulfur deficiency determines protein damage-related Cr toxicity, due to mRNA mistranslation caused by Cr-induced S limitation. Sulfur deprivation could contribute to additional aspects of Cr toxicity, including oxidative DNA damage and Cr related disease.
We investigated the relevance of gene expression heterogeneity to virulence properties of a major fungal pathogen, Candida glabrata. The organism's key virulence-associated factors include ...glycosylphosphatidylinositol-anchored adhesins, encoded subtelomerically by the EPA gene family. Individual-cell analyses of expression revealed very striking heterogeneity for Epa1, an adhesin that mediates ∼95% of adherence to epithelial cells in vitro. The heterogeneity in Epa1 was markedly greater than that known for other yeast genes. Sorted cells expressing high or low levels of Epa1 exhibited high and low adherence to epithelial cells, indicating a link between gene expression noise and potential virulence. The phenotypes of sorted subpopulations reverted to mixed phenotypes within a few generations. Variation in single-cell Epa1 protein and mRNA levels was correlated, consistent with transcriptional regulation of heterogeneity. Sir-dependent transcriptional silencing was the primary mechanism driving heterogeneous Epa1 expression in C. glabrata BG2, but not in CBS138 (ATCC 2001). Inefficient silencing in the latter strain was not due to a difference in EPA1 sequence or (sub)telomere length and was overcome by ectopic SIR3 expression. Moreover, differences between strains in the silencing dependence of EPA1 expression were evident across a range of clinical isolates, with heterogeneity being the greatest in strains where EPA1 was subject to silencing. The study shows how heterogeneity can impact the virulence-related properties of C. glabrata cell populations, with potential implications for microbial pathogenesis more broadly.
Chromate toxicity is well documented, but the underlying toxic mechanism(s) has yet to be fully elucidated. Following a Cr toxicity screen against > 6000 heterozygous yeast mutants, here we show that ...Cr resistance requires normal function of the cortical actin cytoskeleton. Furthermore, Cr-stressed yeast cells exhibited an increased number of actin patches, the sites of endocytosis. This was coincident with a marked stimulation of endocytosis following Cr exposure. Genetic dissection of actin nucleation from endocytosis revealed that endocytosis, specifically, was required for Cr resistance. A series of further endocytosis mutants (sac6Δ, chc1Δ, end3Δ) exhibited elevated Cr sensitivity. These mutants also showed markedly elevated cellular Cr accumulation, explaining their sensitivities. In wild-type cells, an initial endocytosis-independent phase of Cr uptake was followed by an endocytosis-dependent decline in Cr accumulation. The results indicate that actin-mediated endocytosis is required to limit Cr accumulation and toxicity. It is proposed that this involves ubiquitin-dependent endocytic inactivation of a plasma membrane Cr transporter(s). We showed that such an action was not dependent on the transporters that have been characterized to date, the sulfate (and chromate) permeases Sul1p and Sul2p.
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