Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin

Background: Insulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity of insulin by inhibiting its catabolism, which is mediated primarily by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite interest in pharmacological inhibition of IDE as an attractive anti-diabetic approach dating to the 1950s, potent and selective inhibitors of IDE have not yet emerged. Methodology/Principal Findings: We used a rational design approach based on analysis of combinatorial peptide mixtures and focused compound libraries to develop novel peptide hydroxamic acid inhibitors of IDE. The resulting compounds are ∼106 times more potent than existing inhibitors, non-toxic, and surprisingly selective for IDE vis-à-vis conventional zinc-metalloproteases. Crystallographic analysis of an IDE-inhibitor complex reveals a novel mode of inhibition based on stabilization of IDE's “closed,” inactive conformation. We show further that pharmacological inhibition of IDE potentiates insulin signaling by a mechanism involving reduced catabolism of internalized insulin. Conclusions/Significance: The inhibitors we describe are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily. The distinctive structure of IDE's active site, and the mode of action of our inhibitors, suggests that it may be possible to develop inhibitors that cross-react minimally with conventional zinc-metalloproteases. Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes

Risk factors for hepatitis C virus infection among blood donors in southern Brazil: a case-control study

BACKGROUND: In Brazil, it is estimated that between 2.5 and 4.9% of the general population present anti-hepatitis C virus (HCV) antibodies, which corresponds to as many as 3.9 to 7.6 million chronic carriers. Chronic liver disease is associated with HCV infection in 20% to 58% of the Brazilian patients. The objective of this case-control study was to investigate the risk factors for presence of anti-HCV antibody in blood donors in southern Brazil. METHODS: One hundred and seventy eight blood donors with two positive ELISA results for anti-HCV were cases, and 356 controls tested negative. A standardized questionnaire was used to collect data concerning demographic and socioeconomic aspects, history of previous hepatitis infection, social and sexual behaviors, and number of donations. Variables were grouped into sets of hierarchical categories. Cases and controls were compared using logistic regression, odds ratios, and 95% confidence intervals. The statistical significance of the associations was assessed through likelihood ratio tests based on a P value < 0.05. RESULTS: The prevalence of anti-HCV among blood donors was 1.1%. Most of the donors were white and males. In the multivariate analysis, independent predictors of anti-HCV positivity were: intravenous drug use, blood transfusion >10 years earlier, having had two to four sexually transmitted diseases, incarceration, tattooing, sex with a hepatitis B or C virus carrier or with intravenous drug users. CONCLUSION: Intravenous drug use, blood transfusion, and tattooing were the main risk factors for anti-HCV positivity among blood donors from southern Brazil, but sexual HCV transmission should also be considered

Spt6 is a maintenance factor for centromeric CENP-A

Replication and transcription of genomic DNA requires partial disassembly of nucleosomes to allow progression of polymerases. This presents both an opportunity to remodel the underlying chromatin and a danger of losing epigenetic information. Centromeric transcription is required for stable incorporation of the centromere-specific histone dCENP-A in M/G1 phase, which depends on the eviction of previously deposited H3/H3.3-placeholder nucleosomes. Here we demonstrate that the histone chaperone and transcription elongation factor Spt6 spatially and temporarily coincides with centromeric transcription and prevents the loss of old CENP-A nucleosomes in both Drosophila and human cells. Spt6 binds directly to dCENP-A and dCENP-A mutants carrying phosphomimetic residues alleviate this association. Retention of phosphomimetic dCENP-A mutants is reduced relative to wildtype, while non-phosphorylatable dCENP-A retention is increased and accumulates at the centromere. We conclude that Spt6 acts as a conserved CENP-A maintenance factor that ensures long-term stability of epigenetic centromere identity during transcription-mediated chromatin remodeling

Sustainable Sources of Biomass for Bioremediation of Heavy Metals in Waste Water Derived from Coal-Fired Power Generation

Biosorption of heavy metals using dried algal biomass has been extensively described but rarely implemented. We contend this is because available algal biomass is a valuable product with a ready market. Therefore, we considered an alternative and practical approach to algal bioremediation in which algae were cultured directly in the waste water stream. We cultured three species of algae with and without nutrient addition in water that was contaminated with heavy metals from an Ash Dam associated with coal-fired power generation and tested metal uptake and bioremediation potential. All species achieved high concentrations of heavy metals (to 8% dry mass). Two key elements, V and As, reached concentrations in the biomass of 1543 mg.kg−1 DW and 137 mg.kg−1 DW. Growth rates were reduced by more than half in neat Ash Dam water than when nutrients were supplied in excess. Growth rate and bioconcentration were positively correlated for most elements, but some elements (e.g. Cd, Zn) were concentrated more when growth rates were lower, indicating the potential to tailor bioremediation depending on the pollutant. The cosmopolitan nature of the macroalgae studied, and their ability to grow and concentrate a suite of heavy metals from industrial wastes, highlights a clear benefit in the practical application of waste water bioremediation

Minimising the risk posed by TiO2 nanomaterials used in sunscreen throughout the entire product lifecycle

Sunscreens are of emerging concern regarding both human and environmental health. While TiO2 nanoparticles used as UV-blockers may offer a safer alternative to organic filters, their fate and impact and resulting regulation are still under consideration, largely related to the potential risk of nanotechnology-based products. After leaving the skin either through bathing or cleaning, the TiO2 nanomaterials contained in the sunscreen can be released into rivers, lakes, sea shores, and/or sewage treatment plants. Their fate and impact in these different systems is largely determined by the surface properties, i.e. the coating type and lifetime. This project aims to develop the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. All stages of the cream life cycle must be considered in this light, from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environment. By considering each development stage of the sunscreen, from the choice of UV-blocker and its integration into a cosmetic formulation, to the knowledge of the risk involved in this choice all along the product lifecycle, an eco-design approach can be achieved and risk can be minimized. The present work combines industrial companies specialising in cosmetic formulation with academic research experts in the fields of exposure, toxicity and lifecycle assessment. Sunscreen fabrication, risk for the consumer by dermal exposure, risk for the direct aquatic environment and risk related to the end of life of the product are as many key steps of the sunscreen lifecycle that were investigated in this project

Coral reef structural complexity loss exposes coastlines to waves

Coral reefs offer natural coastal protection by attenuating incoming waves. Here we combine unique coral disturbance-recovery observations with hydrodynamic models to quantify how structural complexity dissipates incoming wave energy. We find that if the structural complexity of healthy coral reefs conditions is halved, extreme wave run-up heights that occur once in a 100-years will become 50 times more frequent, threatening reef-backed coastal communities with increased waves, erosion, and flooding

Coral reef structural complexity loss exposes coastlines to waves

Abstract Coral reefs offer natural coastal protection by attenuating incoming waves. Here we combine unique coral disturbance-recovery observations with hydrodynamic models to quantify how structural complexity dissipates incoming wave energy. We find that if the structural complexity of healthy coral reefs conditions is halved, extreme wave run-up heights that occur once in a 100-years will become 50 times more frequent, threatening reef-backed coastal communities with increased waves, erosion, and flooding

Coral reef structural complexity loss exposes coastlines to waves

Coral reefs offer natural coastal protection by attenuating incoming waves. Here we combine unique coral disturbance-recovery observations with hydrodynamic models to quantify how structural complexity dissipates incoming wave energy. We find that if the structural complexity of healthy coral reefs conditions is halved, extreme wave run-up heights that occur once in a 100-years will become 50 times more frequent, threatening reef-backed coastal communities with increased waves, erosion, and flooding

Eco-SUN for Eco-design of sunscreen using titanium dioxide nanoparticles

Among cosmetics and personal care products, sunscreen products are of emerging concern regarding both human and environmental health. The fate and impact of mineral nanoparticulate UV-blockers, such as TiO2 nanomaterials, is under consideration from a regulatory perspective due to their potential impact. Once leaving the skin either through bathing or everyday usage and cleaning, the nanomaterials contained in the sunscreen can be released into rivers, lakes, sea shores, and/or sewage treatment plants. The nanomaterial behaviour, fate and impact in these different systems is largely determined by its surface properties, (e.g. the nanomaterial coating type) and lifetime. Here we present the first result of the Eco-SUN research program aimed at developing the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. Different stages of the cream lifecycle are considered from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environments. Reducing the potential release and / or toxicity of the nanomaterial from the cream is a decisive criterion for its eco-design. Different relevant TiO2 UV-blockers have been selected to integrate a typical o/w formulation as case studies. The resulting sunscreen were characterised in terms of nanomaterial localisation, sun protection factor and photo-passivation. The risk for the consumer by dermal exposure was assessed using skin biopsies. Inflammation and skin penetration were evaluated. The risk for the aquatic environment directly expose was assessed both in terms of exposure and hazard. The release of nanomaterials from the sunscreen upon normal usage was studied in laboratory through simulated aging procedure. Two biological models, sea urchin and coral colonies, were selected as relevant endpoints to assess the marine ecotoxicity of the byproducts formed. Finally, the risk related to the end of life of the sunscreen through the removal with cleaning water followed by drainage to sewage treatment plants was evaluated by considering two opposite fate scenarios: (i) nanomaterial concentration in sewadge sludge later spread as fertilizer in agriculture, and (ii) nanomaterial suspension maintained in the treated water and released in river water. Thus, fate and impact in soil and river ecosystems were also studied

Lifecycle and ompact of sunscreens using TiO2 nanomaterials

Among cosmetics and personal care products, sunscreen products are of emerging concern regarding both human and environmental health. The fate and impact of mineral nanoparticulate UV-blockers, such as TiO2 nanomaterials, is under consideration from a regulatory perspective due to their potential impact. Once leaving the skin either through bathing or everyday usage and cleaning, the nanomaterials contained in the sunscreen can be released into rivers, lakes, sea shores, and/or sewage treatment plants. The nanomaterial behaviour, fate and impact in these different systems is largely determined by its surface properties, (e.g. the nanomaterial coating type) and lifetime. Here we present the first result of the Eco-SUN research program aimed at developing the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. Different stages of the cream lifecycle are considered from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environments. Reducing the potential release and / or toxicity of the nanomaterial from the cream is a decisive criterion for its eco-design. Different relevant TiO2 UV-blockers have been selected to integrate a typical o/w formulation as case studies. The resulting sunscreen were characterised in terms of nanomaterial localisation, sun protection factor and photo-passivation. The risk for the consumer by dermal exposure was assessed using skin biopsies. Inflammation and skin penetration were evaluated. The risk for the aquatic environment directly expose was assessed both in terms of exposure and hazard. The release of nanomaterials from the sunscreen upon normal usage was studied in laboratory through simulated aging procedure. Two biological models, sea urchin and coral colonies, were selected as relevant endpoints to assess the marine ecotoxicity of the byproducts formed. Finally, the risk related to the end of life of the sunscreen through the removal with cleaning water followed by drainage to sewage treatment plants was evaluated by considering two opposite fate scenarios: (i) nanomaterial concentration in sewadge sludge later spread as fertilizer in agriculture, and (ii) nanomaterial suspension maintained in the treated water and released in river water. Thus, fate and impact in soil and river ecosystems were also studied