Nucleophilic Additions to 3-Azido-hexanal

Sakurai and Mukaiyama aldol additions were carried out with 3-Azido-hexanal under chelation and non-chelation conditions. The reactions were generally found to be diastereofacially selective in favor of the anti stereoisomer and showed simple diastereoselectivity in favor syn substitution. The relative stereochemistry of the addition products were deduced from NOE experiments on cyclic amines that were produced from intramolecular Schmidt, Staudinger/aza-Wittig, and catalytic hydrogenation reactions. The findings indicate that substituted N-heterocycles can be made diastereoselectively in a couple of steps from simple azido aldehydes by carefully selecting the reaction conditions

Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase

This is the published version.Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (∼26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC50s) of <1 μM. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited P. falciparum growth in vitro (50% effective concentration [EC50] of ≥0.6 and <6.8 μM). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against P. falciparum

A Laser-Plasma Ion Beam Booster Based on Hollow-Channel Magnetic Vortex Acceleration

Laser-driven ion acceleration can provide ultra-short, high-charge, low-emittance beams. Although undergoing extensive research, demonstrated maximum energies for laser-ion sources are non-relativistic, complicating injection into high-$\beta$ accelerator elements and stopping short of desirable energies for pivotal applications, such as proton tumor therapy. In this work, we decouple the efforts towards relativistic beam energies from a single laser-plasma source via a proof-of-principle concept, boosting the beam into this regime through only a few plasma stages. We employ full 3D particle-in-cell simulations to demonstrate the capability for capture of high-charge beams as produced by laser-driven sources, where both source and booster stages utilize readily available laser pulse parameters.Comment: 4 pages, 4 figures, submitted for peer revie

Laser-plasma ion beam booster based on hollow-channel magnetic vortex acceleration

Laser-driven ion acceleration provides ultrashort, high-charge, low-emittance beams, which are desirable for a wide range of high-impact applications. Yet after decades of research, a significant increase in maximum ion energy is still needed. This paper introduces a quality-preserving staging concept for ultraintense ion bunches that is seamlessly applicable from the nonrelativistic plasma source to the relativistic regime. Full three-dimensional particle-in-cell simulations prove robustness and capture of a high-charge proton bunch, suitable for readily available and near-term laser facilities. Published by the American Physical Society 202

A Potent and Selective Inhibitor of Cdc42 GTPase

Cdc42, a member of the Rho family of GTPases, has been shown to play a role in cell adhesion, cytoskeletal arrangement, phagocytosis and cell motility and migration, in addition to a host of other diverse biological processes. The function of Rho-family GTPases in disease pathogenesis has been well established and identification of small, cell permeable molecules that selectively and reversibly regulate Rho GTPases is of high scientific and potentially therapeutic interest. There has been limited success in identifying inhibitors that specifically interact with small Rho family GTPases. The identified probe, ML141 (CID-2950007), is demonstrated to be a potent, selective and reversible non-competitive inhibitor of Cdc42 GTPase suitable for in vitro assays, with low micromolar potency and selectivity against other members of the Rho family of GTPases (Rac1, Rab2, Rab7). Given the highly complementary nature of the function of the Rho family GTPases, Cdc42 selective inhibitors such as those reported here should help untangle the roles of the proteins in this family

Discovery of a Novel Compound with Anti-Venezuelan Equine Encephalitis Virus Activity That Targets the Nonstructural Protein 2

Abstract Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. To date, compounds reported as anti-VEEV or anti-alphavirus inhibitors have shown moderate activity. To discover new classes of anti-VEEV inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from live VEEV TC-83-induced cytopathic effect to screen a 340,000 compound library. Of those, we identified five novel anti-VEEV compounds and chose a quinazolinone compound, CID15997213 (IC50 = 0.84 µM), for further characterization. The antiviral effect of CID15997213 was alphavirus-specific, inhibiting VEEV and Western equine encephalitis virus, but not Eastern equine encephalitis virus. In vitro assays confirmed inhibition of viral RNA, protein, and progeny synthesis. No antiviral activity was detected against a select group of RNA viruses. We found mutations conferring the resistance to the compound in the N-terminal domain of nsP2 and confirmed the target residues using a reverse genetic approach. Time of addition studies showed that the compound inhibits the middle stage of replication when viral genome replication is most active. In mice, the compound showed complete protection from lethal VEEV disease at 50 mg/kg/day. Collectively, these results reveal a potent anti-VEEV compound that uniquely targets the viral nsP2 N-terminal domain. While the function of nsP2 has yet to be characterized, our studies suggest that the protein might play a critical role in viral replication, and further, may represent an innovative opportunity to develop therapeutic interventions for alphavirus infection. Author Summary Alphaviruses occur worldwide, causing significant diseases such as encephalitis or arthritis in humans and animals. In addition, some alphaviruses, such as VEEV, pose a biothreat due to their high infectivity and lack of available treatments. To discover small molecule inhibitors with lead development potential, we used a cell-based assay to screen 348,140 compounds for inhibition of a VEEV-induced cytopathic effect. The screen revealed a scaffold with high inhibitory VEEV cellular potency and low cytotoxicity liability. While most previously reported anti-alphavirus compounds inhibit host proteins, evidence supported that this scaffold targeted the VEEV nsP2 protein, and that inhibition was associated with viral replication. Interestingly, compound resistance studies with VEEV mapped activity to the N-terminal domain of nsP2, to which no known function has been attributed. Ultimately, this discovery has delivered a small molecule-derived class of potent VEEV inhibitors whose activity is coupled to the nsP2 viral protein, a novel target with a previously unestablished biological role that is now implicated in viral replication.This research was supported by the following funding sources: NIH R03MH087448-01A1, University of Louisville Internal Research Initiate grant to DHC, USAMRAA W81XWH-10-2-0064 and W81XWH-08-2-0024 to CBJ. Screening was provided by the Southern Research Specialized Screening Center (U54HG005034-0) and chemistry through the University of Kansas Specialized Chemistry Center (U54HG005031). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe

Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.This work was supported by National Science Foundation (NSF) Grant MCB0956027 and National Institutes of Health Grant R03 MH081231-01 from the Molecular Libraries Program (to A. W. N.); University of New Mexico Center for Molecular Discovery Molecular Libraries Probe Production Centers (UNMCMD MLPCN) National Institutes of Health Grants U54MH084690 and R01HL081062 (to L. A. S.); UNM National Center for Research Resources (NCRR) Grant 5P20RR016480 (to L. G. H.); National Institutes of Health Grant R21 CA170375-01 through the NCI (to A. W. N., L. G. H., and J. E. G.); National Institutes of Health Grants NS066429 and AI092130 (to T. B.); and University of Kansas Specialized Chemistry Center (KUSCC) MLPCN National Institutes of Health Grant U54HG005031 (to J. A.)

Mercury sources to Lake Ozette and Lake Dickey : highly contaminated remote coastal lakes, Washington State, USA

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Water, Air, & Soil Pollution 208 (2009): 275-286, doi:10.1007/s11270-009-0165-y.Mercury concentrations in largemouth bass and mercury accumulation rates in age-dated sediment cores were examined at Lake Ozette and Lake Dickey in Washington State. Goals of the study were to compare concentrations in fish tissues at the two lakes with lakes in a larger statewide dataset and evaluate factors influencing lake loading at Ozette and Dickey, which may include: catchment disturbances, coastal mercury cycling, and the role of trans-Pacific Asian mercury. Mercury fish tissue concentrations at the lakes were among the highest recorded in Washington State. Wet deposition and historical atmospheric monitoring from the area show no indication of enhanced deposition from Asian sources or coastal atmospheric processes. Sediment core records from the lakes displayed rapidly increasing sedimentation rates coinciding with commercial logging. The unusually high mercury flux rates and mercury tissue concentrations recorded at Lake Ozette and Lake Dickey appear to be associated with logging within the catchments

Identifying and Prioritizing Greater Sage-Grouse Nesting and Brood-Rearing Habitat for Conservation in Human-Modified Landscapes

BACKGROUND: Balancing animal conservation and human use of the landscape is an ongoing scientific and practical challenge throughout the world. We investigated reproductive success in female greater sage-grouse (Centrocercus urophasianus) relative to seasonal patterns of resource selection, with the larger goal of developing a spatially-explicit framework for managing human activity and sage-grouse conservation at the landscape level. METHODOLOGY/PRINCIPAL FINDINGS: We integrated field-observation, Global Positioning Systems telemetry, and statistical modeling to quantify the spatial pattern of occurrence and risk during nesting and brood-rearing. We linked occurrence and risk models to provide spatially-explicit indices of habitat-performance relationships. As part of the analysis, we offer novel biological information on resource selection during egg-laying, incubation, and night. The spatial pattern of occurrence during all reproductive phases was driven largely by selection or avoidance of terrain features and vegetation, with little variation explained by anthropogenic features. Specifically, sage-grouse consistently avoided rough terrain, selected for moderate shrub cover at the patch level (within 90 m(2)), and selected for mesic habitat in mid and late brood-rearing phases. In contrast, risk of nest and brood failure was structured by proximity to anthropogenic features including natural gas wells and human-created mesic areas, as well as vegetation features such as shrub cover. CONCLUSIONS/SIGNIFICANCE: Risk in this and perhaps other human-modified landscapes is a top-down (i.e., human-mediated) process that would most effectively be minimized by developing a better understanding of specific mechanisms (e.g., predator subsidization) driving observed patterns, and using habitat-performance indices such as those developed herein for spatially-explicit guidance of conservation intervention. Working under the hypothesis that industrial activity structures risk by enhancing predator abundance or effectiveness, we offer specific recommendations for maintaining high-performance habitat and reducing low-performance habitat, particularly relative to the nesting phase, by managing key high-risk anthropogenic features such as industrial infrastructure and water developments

The Surface Array planned for IceCube-Gen2

IceCube-Gen2, the extension of the IceCube Neutrino Observatory, will feature three main components: an optical array in the deep ice, a large-scale radio array in the shallow ice and firn, and a surface detector above the optical array. Thus, IceCube-Gen2 will not only be an excellent detector for PeV neutrinos, but also constitutes a unique setup for the measurement of cosmic-ray air showers, where the electromagnetic component and low-energy muons are measured at the surface and high-energy muons are measured in the ice. As for ongoing enhancement of IceCube’s current surface array, IceTop, we foresee a combination of elevated scintillation and radio detectors for the Gen2 surface array, aiming at high measurement accuracy for air showers. The science goals are manifold: The in-situ measurement of the cosmic-ray flux and mass composition, as well as more thorough tests of hadronic interaction models, will improve the understanding of muons and atmospheric neutrinos detected in the ice, in particular, regarding prompt muons. Moreover, the surface array provides a cosmic-ray veto for the in-ice detector and contributes to the calibration of the optical and radio arrays. Last but not least, the surface array will make major contributions to cosmic-ray science in the energy range of the transition from Galactic to extragalactic sources. The increased sensitivities for photons and for cosmic-ray anisotropies at multi-PeV energies provide a chance to solve the puzzle of the origin of the most energetic Galactic cosmic rays and will serve IceCube’s multimessenger mission