Application and development of zero-valent iron (ZVI) for groundwater and wastewater treatment

Zero-valent iron has been used for more than 130 years for water treatment. It is based on redox reactions as well as on sorption to the corrosion products of iron. It is successfully applied for the removal of metals and organic pollutants from groundwater and wastewater. There are different variations how zero-valent iron can be used, especially (i) permeable reactive barriers, (ii) fluidized bed reactors and (iii) nanoscale zero-valent iron. Permeable reactive barriers are used for in situ treatment of groundwater in trench-like constructions or in a funnel and gate system. Their advantages are low maintenance cost, inexpensive construction and prevention of excavation wastes, and their disadvantages are surface passivation and clogging of pores by corrosion products. Zero-valent iron nanoparticles are injected directly in contaminated soil or groundwater. Their advantages are a higher reactivity than coarse-grained zero-valent iron and their mobility in the subsurface to reach the contaminated areas. However, they also have some major disadvantages like fast ageing in the system, phytotoxicity, agglomeration during migration and high costs. The latest development is a fluidized bed process (“ferrodecont process”) which avoids the passivation and clogging observed in permeable reactive barriers as well as the high costs and toxicity issues of nanoscale zero-valent iron. First results of this technology for Cr(VI) and organically contaminated groundwaters and metal removal from industrial wastewaters are highly promising

Designing a solution to enable agency-academic scientific collaboration for disasters

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ecology and Society 22 (2017): 18, doi:10.5751/ES-09246-220218.As large-scale environmental disasters become increasingly frequent and more severe globally, people and organizations that prepare for and respond to these crises need efficient and effective ways to integrate sound science into their decision making. Experience has shown that integrating nongovernmental scientific expertise into disaster decision making can improve the quality of the response, and is most effective if the integration occurs before, during, and after a crisis, not just during a crisis. However, collaboration between academic, government, and industry scientists, decision makers, and responders is frequently difficult because of cultural differences, misaligned incentives, time pressures, and legal constraints. Our study addressed this challenge by using the Deep Change Method, a design methodology developed by Stanford ChangeLabs, which combines human-centered design, systems analysis, and behavioral psychology. We investigated underlying needs and motivations of government agency staff and academic scientists, mapped the root causes underlying the relationship failures between these two communities based on their experiences, and identified leverage points for shifting deeply rooted perceptions that impede collaboration. We found that building trust and creating mutual value between multiple stakeholders before crises occur is likely to increase the effectiveness of problem solving. We propose a solution, the Science Action Network, which is designed to address barriers to scientific collaboration by providing new mechanisms to build and improve trust and communication between government administrators and scientists, industry representatives, and academic scientists. The Science Action Network has the potential to ensure cross-disaster preparedness and science-based decision making through novel partnerships and scientific coordination.The authors thank the David and Lucile Packard Foundation for a grant to undertake this project and enable participation of a wide range of participants and interviewees. We thank the Center for Ocean Solutions and ChangeLabs for their oversight and support

PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KIR2.1 channels, but increases channel protein expression

Background: The inward rectifier potassium current IK1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of function mutations V93I and D172N associate with increased IK1, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC50 = 14 nM with inside-out patch clamp methodology) and specific IK1 inhibitor that interacts with the cytoplasmic pore region of the KIR2.1 ion channel, encoded by KCNJ2. At 10 μM, PA-6 increases wild-type (WT) KIR2. 1 expression in HEK293T cells upon chronic treatment. We hypothesized that PA-6 will interact with and inhibit V93I and D172N KIR2.1 channels, whereas impact on channel expression at the plasma membrane requires higher concentrations. Methods: Molecular modelling was performed with the human KIR2.1 closed state homology model using FlexX. WT and mutant KIR2.1 channels were expressed in HEK293 cells. Patch clamp single cell electrophysiology measurements were performed in the whole cell and inside-out mode of the patch clamp method. KIR2.1 expression level and localization were determined by western blot analysis and immunofluorescence microscopy, respectively. Results: PA-6 docking in the V93I/D172N double mutant homology model of KIR2.1 demonstrated that mutations and drug-binding site are >30 Å apart. PA-6 inhibited WT and V93I outward currents with similar potency (IC50 = 35.5 and 43.6 nM at +50 mV for WT and V93I), whereas D172N currents were less sensitive (IC50 = 128.9 nM at +50 mV) using inside-out patch-clamp electrophysiology. In whole cell mode, 1 μM of PA-6 inhibited outward IK1 at −50 mV by 28 ± 36%, 18 ± 20% and 10 ± 6%, for WT, V93I and D172N channels respectively. Western blot analysis demonstrated that PA-6 (5 μM, 24 h) increased KIR2.1 expression levels of WT (6.3 ± 1.5 fold), and V93I (3.9 ± 0.9) and D172N (4.8 ± 2.0) mutants. Immunofluorescent microscopy demonstrated dose-dependent intracellular KIR2.1 accumulation following chronic PA-6 application (24 h, 1 and 5 μM). Conclusions: 1) KCNJ2 gain-of-function mutations V93I and D172N in the KIR2.1 ion channel do not impair PA-6 mediated inhibition of IK1, 2) PA-6 elevates KIR2.1 protein expression and induces intracellular KIR2.1 accumulation, 3) PA-6 is a strong candidate for further preclinical evaluation in treatment of congenital SQT3 and AF

Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels. Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships. Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27-37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2-3 μM), while Q52R inhibition was 15-20% at 10 μM. Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity

Computational Identification of Novel Kir6 Channel Inhibitors

KATP channels consist of four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodilation of arterial smooth muscle cells. Abnormal channel function resulting from inherited gain or loss-of-function mutations in either the Kir6.x and/or SUR subunits are associated with severe diseases such as neonatal diabetes, congenital hyperinsulinism, or Cantú syndrome (CS). CS is an ultra-rare genetic autosomal dominant disorder, caused by dominant gain-of-function mutations in SUR2A or Kir6.1 subunits. No specific pharmacotherapeutic treatment options are currently available for CS. Kir6 specific inhibitors could be beneficial for the development of novel drug therapies for CS, particular for mutations, which lack high affinity for sulfonylurea inhibitor glibenclamide. By applying a combination of computational methods including atomistic MD simulations, free energy calculations and pharmacophore modeling, we identified several novel Kir6.1 inhibitors, which might be possible candidates for drug repurposing. The in silico predictions were confirmed using inside/out patch-clamp analysis. Importantly, Cantú mutation C166S in Kir6.2 (equivalent to C176S in Kir6.1) and S1020P in SUR2A, retained high affinity toward the novel inhibitors. Summarizing, the inhibitors identified in this study might provide a starting point toward developing novel therapies for Cantú disease

Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency

Multi-layered omics approaches can help define relationships between genetic factors, biochemical processes and phenotypes thus extending research of inherited diseases beyond identifying their monogenic cause 1. We implemented a multi-layered omics approach for the inherited metabolic disorder methylmalonic aciduria (MMA). We performed whole genome sequencing, transcriptomic sequencing, and mass spectrometry-based proteotyping from matched primary fibroblast samples of 230 individuals (210 affected, 20 controls) and related the molecular data to 105 phenotypic features. Integrative analysis identified a molecular diagnosis for 84% (177/210) of affected individuals, the majority (148) of whom had pathogenic variants in methylmalonyl-CoA mutase (MMUT). Untargeted analysis of all three omics layers revealed dysregulation of the TCA cycle and surrounding metabolic pathways, a finding that was further corroborated by multi-organ metabolomics of a hemizygous Mmut mouse model. Integration of phenotypic disease severity indicated downregulation of oxoglutarate dehydrogenase and upregulation of glutamate dehydrogenase, two proteins involved in glutamine anaplerosis of the TCA cycle. The relevance of disturbances in this pathway was supported by metabolomics and isotope tracing studies which showed decreased glutamine-derived anaplerosis in MMA. We further identified MMUT to physically interact with both, oxoglutarate dehydrogenase complex components and glutamate dehydrogenase providing evidence for a multi-protein metabolon that orchestrates TCA cycle anaplerosis. This study emphasizes the utility of a multi-modal omics approach to investigate metabolic diseases and highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA. Take home message Combination of integrative multi-omics technologies with clinical and biochemical features leads to an increased diagnostic rate compared to genome sequencing alone and identifies anaplerotic rewiring as a targetable feature of the rare inborn error of metabolism methylmalonic aciduria

Roadmap on Electronic Structure Codes in the Exascale Era

Electronic structure calculations have been instrumental in providing many important insights into a range of physical and chemical properties of various molecular and solid-state systems. Their importance to various fields, including materials science, chemical sciences, computational chemistry and device physics, is underscored by the large fraction of available public supercomputing resources devoted to these calculations. As we enter the exascale era, exciting new opportunities to increase simulation numbers, sizes, and accuracies present themselves. In order to realize these promises, the community of electronic structure software developers will however first have to tackle a number of challenges pertaining to the efficient use of new architectures that will rely heavily on massive parallelism and hardware accelerators. This roadmap provides a broad overview of the state-of-the-art in electronic structure calculations and of the various new directions being pursued by the community. It covers 14 electronic structure codes, presenting their current status, their development priorities over the next five years, and their plans towards tackling the challenges and leveraging the opportunities presented by the advent of exascale computing

Roadmap on electronic structure codes in the exascale era

Electronic structure calculations have been instrumental in providing many important insights into a range of physical and chemical properties of various molecular and solid-state systems. Their importance to various fields, including materials science, chemical sciences, computational chemistry, and device physics, is underscored by the large fraction of available public supercomputing resources devoted to these calculations. As we enter the exascale era, exciting new opportunities to increase simulation numbers, sizes, and accuracies present themselves. In order to realize these promises, the community of electronic structure software developers will however first have to tackle a number of challenges pertaining to the efficient use of new architectures that will rely heavily on massive parallelism and hardware accelerators. This roadmap provides a broad overview of the state-of-the-art in electronic structure calculations and of the various new directions being pursued by the community. It covers 14 electronic structure codes, presenting their current status, their development priorities over the next five years, and their plans towards tackling the challenges and leveraging the opportunities presented by the advent of exascale computing

Roadmap on Electronic Structure Codes in the Exascale Era

Electronic structure calculations have been instrumental in providing many important insights into a range of physical and chemical properties of various molecular and solid-state systems. Their importance to various fields, including materials science, chemical sciences, computational chemistry and device physics, is underscored by the large fraction of available public supercomputing resources devoted to these calculations. As we enter the exascale era, exciting new opportunities to increase simulation numbers, sizes, and accuracies present themselves. In order to realize these promises, the community of electronic structure software developers will however first have to tackle a number of challenges pertaining to the efficient use of new architectures that will rely heavily on massive parallelism and hardware accelerators. This roadmap provides a broad overview of the state-of-the-art in electronic structure calculations and of the various new directions being pursued by the community. It covers 14 electronic structure codes, presenting their current status, their development priorities over the next five years, and their plans towards tackling the challenges and leveraging the opportunities presented by the advent of exascale computing