Impacts of groundwater management on energy resources and greenhouse gas emissions in California.

California faces significant energy and water infrastructure planning challenges in response to a changing climate. Immediately following the most severe recorded drought, the state experienced one of its wettest water years in recorded history. Despite the recent severe wet weather, much of the state's critical groundwater systems have not recovered from the drought. The recent Sustainable Groundwater Management Act (SGMA) aims to eliminate future depletion risks, but may force California basins to seek alternative water sources by limiting groundwater withdrawals during droughts. These alternative water resources, such as recycled water or desalination, can have significantly higher energy demands in treatment and supply than local groundwater or surface water resources. This research developed potential scenarios of water supply sources for five overdrafted groundwater basins, and modeled the impacts of these scenarios on energy demands and greenhouse gas (GHG) emissions for water supply systems. Our results reveal that energy demands and GHG emissions in different water supply scenarios can vary substantially between basins, but could increase statewide energy consumption as much as 2% and GHG emissions by 0.5. These results highlight the need to integrate these energy and GHG impacts into water resource management. Better understanding these considerations enables water supply planners to avoid potential unintended consequences (i.e., increased energy demands and GHG emissions) of enhancing drought resilience.

Assessing Location and Scale of Urban Nonpotable Water Reuse Systems for Life-Cycle Energy Consumption and Greenhouse Gas Emissions.

Nonpotable water reuse (NPR) is one option for conserving valuable freshwater resources. Decentralization can improve distribution system efficiency by locating treatment closer to the consumer; however, small treatment systems may have higher unit energy and greenhouse-gas (GHG) emissions. This research explored the trade-off between residential NPR systems using a life-cycle approach to analyze the energy use and GHG emissions. Decentralized and centralized NPR options are compared to identify where decentralized systems achieve environmental advantages over centralized reuse alternatives, and vice versa, over a range of scales and spatial and demographic conditions. For high-elevation areas far from the centralized treatment plant, decentralized NPR could lower energy use by 29% and GHG emissions by 28%, but in low-elevation areas close to the centralized treatment plant, decentralized reuse could be higher by up to 85% (energy) and 49% (GHG emissions) for the scales assessed (20-2000 m3/day). Direct GHG emissions from the treatment processes were found to be highly uncertain and variable and were not included in the analysis. The framework presented can be used as a planning support tool to reveal the environmental impacts of integrating decentralized NPR with existing centralized wastewater infrastructure and can be adapted to evaluate different treatment technology scales for reuse.

Life-Cycle Energy Use and Greenhouse Gas Emissions of a Building-Scale Wastewater Treatment and Nonpotable Reuse System.

Treatment and water reuse in decentralized systems is envisioned to play a greater role in our future urban water infrastructure due to growing populations and uncertainty in quality and quantity of traditional water resources. In this study, we utilized life-cycle assessment (LCA) to analyze the energy consumption and greenhouse gas (GHG) emissions of an operating Living Machine (LM) wetland treatment system that recycles wastewater in an office building. The study also assessed the performance of the local utility's centralized wastewater treatment plant, which was found to be significantly more efficient than the LM (79% less energy, 98% less GHG emissions per volume treated). To create a functionally equivalent comparison, the study developed a hypothetical scenario in which the same LM design flow is recycled via centralized infrastructure. This comparison revealed that the current LM has energy consumption advantages (8% less), and a theoretically improved LM design could have GHG advantages (24% less) over the centralized reuse system. The methodology in this study can be applied to other case studies and scenarios to identify conditions under which decentralized water reuse can lower GHG emissions and energy use compared to centralized water reuse when selecting alternative approaches to meet growing water demands.

Design, structure-activity relationship, and in vivo characterization of the development candidate NVP-HSP990.

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.

Save water to save carbon and money: developing abatement costs for expanded greenhouse gas reduction portfolios.

The water-energy nexus is of growing interest for researchers and policy makers because the two critical resources are interdependent. Their provision and consumption contribute to climate change through the release of greenhouse gases (GHGs). This research considers the potential for conserving both energy and water resources by measuring the life-cycle economic efficiency of greenhouse gas reductions through the water loss control technologies of pressure management and leak management. These costs are compared to other GHG abatement technologies: lighting, building insulation, electricity generation, and passenger transportation. Each cost is calculated using a bottom-up approach where regional and temporal variations for three different California water utilities are applied to all alternatives. The costs and abatement potential for each technology are displayed on an environmental abatement cost curve. The results reveal that water loss control can reduce GHGs at lower cost than other technologies and well below California's expected carbon trading price floor. One utility with an energy-intensive water supply could abate 135,000 Mg of GHGs between 2014 and 2035 and save--rather than spend--more than $130/Mg using the water loss control strategies evaluated. Water loss control technologies therefore should be considered in GHG abatement portfolios for utilities and policy makers.

Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2 isoform of pyruvate kinase (PKM2).

Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic 'Warburg effect' characteristic of aberrant metabolism. In this Letter, we describe the optimization of a weakly active screening hit to a structurally novel series of small molecule 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as potent PKM2 activators.

Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors.

A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/ß-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/ß-catenin transcriptional complex.

Epigenetic drug discovery: targeting DNA methyltransferases.

Epigenetic modification of DNA leads to changes in gene expression. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in disease states such as cancer. Disrupting gene expression patterns through promoter methylation has been implicated in many malignancies and supports DNMTs as attractive therapeutic targets. This review focuses on the rationale of targeting DNMTs in cancer, the historical approach to DNMT inhibition, and current marketed hypomethylating therapeutics azacytidine and decitabine. In addition, we address novel DNMT inhibitory agents emerging in development, including CP-4200 and SGI-110, analogs of azacytidine and decitabine, respectively; the oligonucleotides MG98 and miR29a; and a number of reversible inhibitors, some of which appear to be selective against particular DNMT isoforms. Finally, we discuss future opportunities and challenges for next-generation therapeutics.

Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors.

Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties. A series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines, which potently inhibit PI3K, were discovered. Within this series a compound, 17, was identified with suitable pharmacokinetic (PK) properties, which allowed for the establishment of a PI3K PK/pharmacodynamic-efficacy relationship as determined by in vivo inhibition of AKT(Ser473) phosphorylation and tumor growth inhibition in a mouse A2780 tumor xenograft model.

Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.

Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.

Identification and structure-activity relationship of 2-morpholino 6-(3-hydroxyphenyl) pyrimidines, a class of potent and selective PI3 kinase inhibitors.

PI3 Kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration, and differentiation. The PI3 kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations, and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe a novel series of PI3K inhibitors sharing a pyrimidine core and showing significant potency against class I PI3 kinases in the biochemical assay and in cells. The discovery, synthesis and SAR of this chemotype are described.

Verbal medication orders in the OR.

Medication errors are the fourth most commonly reported sentinel event, and changes in practice are needed to provide a safe environment for patients in the OR. Existing measures for preventing medication errors in the OR have focused on labeling medication containers on and off the sterile field. Very little attention, however, has been given to the potential for errors caused by verbal orders in the OR or to developing processes to prevent such errors. Simple solutions for improving the safety of verbal medication orders include instituting a read-back system in which verbal orders are written on a dry-erase board and verified by the ordering physician, requesting clarification of questionable orders, and reducing distractions in the OR.

Implementing a smallpox vaccination program aboard an aircraft carrier.

OBJECTIVE: To determine the feasibility of implementing a smallpox vaccination program aboard an aircraft carrier in conjunction with anthrax vaccination. METHODS: Retrospective review of smallpox vaccination program conducted from January 17, 2003 to February 19, 2003. Morbidity and loss of manpower were the major endpoints. RESULTS: There were 5,204 sailors available for vaccination. There were 243 (4.7%) medical exemptions and 24 administrative exemptions. During the program, 4,931 sailors were vaccinated. There were five reportable complications. Three sailors had autoinoculation, one sailor had localized cellulitis, and one patient had a positive beta human chorionic gonadotropin during vaccination. None of the complications required medical evacuation. Only two sailors required time off from duty. CONCLUSIONS: Smallpox vaccination can be accomplished rapidly and safely aboard an aircraft carrier. There was not an increase in adverse events compared to historical data despite the close-quarter conditions. Smallpox and anthrax vaccinations can be completed simultaneously with minimal morbidity.

Structure-based design of a parallel synthetic array directed toward the discovery of irreversible inhibitors of human rhinovirus 3C protease.

Utilizing the tools of parallel synthesis and structure-based design, a new class of Michael acceptor-containing, irreversible inhibitors of human rhinovirus 3C protease (HRV 3CP) was discovered. These inhibitors are shown to inhibit HRV-14 3CP with rates of inactivation ranging from 886 to 31 400 M(-1) sec(-1). These inhibitors exhibit antiviral activity when tested against HRV-14 infected H1-HeLa cells, with EC(50) values ranging from 1.94 to 0.15 microM. No cytotoxicity was observed at the limits of the assay concentration. A crystal structure of one of the more potent inhibitors covalently bound to HRV-2 3CP is detailed. These compounds were also tested against HRV serotypes other than type 14 and were found to have highly variable activities.

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics.

The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).