Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase [gamma] Inhibitors
Abstract not provided
Leahy, James W.↗
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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
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Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes
We found that Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. Here, we disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.
59 BASIC BIOLOGICAL SCIENCES↗
Discovery of Cyclic Acylguanidines as Highly Potent and Selective β-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I–Inhibitor Design and Validation
A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit, with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180° in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.
Zhu, Zhaoning↗
Lithium transport in amorphous Al2O3 and AlF3 for discovery of battery coatings
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energy storage (including batteries and capacitors↗
Discovery of a novel methanogen prevalent in thawing permafrost
Thawing permafrost promotes microbial degradation of cryo-sequestered and new carbon leading to the biogenic production of methane, creating a positive feedback to climate change. Here we determine microbial community composition along a permafrost thaw gradient in northern Sweden. Partially thawed sites were frequently dominated by a single archaeal phylotype, Candidatus ‘Methanoflorens stordalenmirensis’ gen. nov. sp. nov., belonging to the uncultivated lineage ‘Rice Cluster II’ (Candidatus ‘Methanoflorentaceae’ fam. nov.). Metagenomic sequencing led to the recovery of its near-complete genome, revealing the genes necessary for hydrogenotrophic methanogenesis. These genes are highly expressed and methane carbon isotope data are consistent with hydrogenotrophic production of methane in the partially thawed site. In addition to permafrost wetlands, ‘Methanoflorentaceae’ are widespread in high methane-flux habitats suggesting that this lineage is both prevalent and a major contributor to global methane production. In thawing permafrost, Candidatus ‘M. stordalenmirensis’ appears to be a key mediator of methane-based positive feedback to climate warming.
54 ENVIRONMENTAL SCIENCES↗
Systematic discovery of pseudomonad genetic factors involved in sensitivity to tailocins
Tailocins are bactericidal protein complexes produced by a wide variety of bacteria that kill closely related strains and may play a role in microbial community structure. Thanks to their high specificity, tailocins have been proposed as precision antibacterial agents for therapeutic applications. Compared to tailed phages, with whom they share an evolutionary and morphological relationship, bacterially produced tailocins kill their host upon production but producing strains display resistance to self-intoxication. Though lipopolysaccharide (LPS) has been shown to act as a receptor for tailocins, the breadth of factors involved in tailocin sensitivity, and the mechanisms behind resistance to self-intoxication, remain unclear. Here, we employed genome-wide screens in four non-model pseudomonads to identify mutants with altered fitness in the presence of tailocins produced by closely related pseudomonads. Our mutant screens identified O-antigen composition and display as most important in defining sensitivity to our tailocins. In addition, the screens suggest LPS thinning as a mechanism by which resistant strains can become more sensitive to tailocins. Furthermore, we validate many of these novel findings, and extend these observations of tailocin sensitivity to 130 genome-sequenced pseudomonads. This work offers insights into tailocin–bacteria interactions, informing the potential use of tailocins in microbiome manipulation and antibacterial therapy.
59 BASIC BIOLOGICAL SCIENCES↗
Computational strategies for design and discovery of nanostructured thermoelectrics
Abstract The contribution of theoretical calculations and predictions in the development of advanced high-performance thermoelectrics has been increasingly significant and has successfully guided experiments to understand as well as achieve record-breaking results. In this review, recent developments in high-performance nanostructured bulk thermoelectric materials are discussed from the viewpoint of theoretical calculations. An effective emerging strategy for boosting thermoelectric performance involves minimizing electron scattering while maximizing heat-carrying phonon scattering on many length scales. We present several important strategies and key examples that highlight the contributions of first-principles-based calculations in revealing the intricate but tractable relationships for this synergistic optimization of thermoelectric performance. The integrated optimization approach results in a fourfold design strategy for improved materials: (1) a significant reduction of the lattice thermal conductivity through multiscale hierarchical architecturing, (2) a large enhancement of the Seebeck coefficient through intramatrix electronic band convergence engineering, (3) control of the carrier mobility through band alignment between the host and second phases, and (4) design of intrinsically low-thermal-conductivity materials by maximizing vibrational anharmonicity and acoustic-mode Gruneisen parameters. These combined effects serve to enhance the power factor while reducing the lattice thermal conductivity. This review provides an improved understanding of how theory is impacting the current state of this field and helps to guide the future search for high-performance thermoelectric materials.
36 MATERIALS SCIENCE↗
Fundamental form of the electrostatic δf-PIC algorithm and discovery of a converged numerical instability
The δf particle-in-cell algorithm has been a useful tool in studying the physics of plasmas, particularly turbulent magnetized plasmas in the context of gyrokinetics. The reduction in noise due to not having to resolve the full distribution function indicates an efficiency advantage over the standard (“full-f”) particle-in-cell. Despite its successes, the algorithm behaves strangely in some circumstances. In this work, we document a fully resolved numerical instability that occurs in the simplest of multiple-species test cases: the electrostatic Ω{sub H} mode. There is also a poorly understood numerical instability that occurs when one is under-resolved in particle number, which may require a prohibitively large number of particles to stabilize. Both of these are independent of the time-stepping scheme, and we conclude that they exist if the time advancement were exact. The exact analytic form of the algorithm is presented, and several schemes for mitigating these instabilities are also presented.
70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
Discovery of ferromagnetism with large magnetic anisotropy in ZrMnP and HfMnP
ZrMnP and HfMnP single crystals are grown by a self-flux growth technique, and structural as well as temperature dependent magnetic and transport properties are studied. Both compounds have an orthorhombic crystal structure. ZrMnP and HfMnP are ferromagnetic with Curie temperatures around 370 K and 320 K, respectively. The spontaneous magnetizations of ZrMnP and HfMnP are determined to be 1.9 μ{sub B}/f.u. and 2.1 μ{sub B}/f.u., respectively, at 50 K. The magnetocaloric effect of ZrMnP in terms of entropy change (ΔS) is estimated to be −6.7 kJ m{sup −3} K{sup −1} around 369 K. The easy axis of magnetization is [100] for both compounds, with a small anisotropy relative to the [010] axis. At 50 K, the anisotropy field along the [001] axis is ∼4.6 T for ZrMnP and ∼10 T for HfMnP. Such large magnetic anisotropy is remarkable considering the absence of rare-earth elements in these compounds. The first principle calculation correctly predicts the magnetization and hard axis orientation for both compounds, and predicts the experimental HfMnP anisotropy field within 25%. More importantly, our calculations suggest that the large magnetic anisotropy comes primarily from the Mn atoms, suggesting that similarly large anisotropies may be found in other 3d transition metal compounds.
71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
The top quark, 20 years after its discovery
The heaviest of nature’s elementary particles plays an outsized role in many fundamental processes. But because the top quark is so massive, it eluded experimental detection for nearly two decades.
71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
Moving beyond the constraints of chemistry via crystal structure discovery with isotropic multiwell pair potentials
The rigid constraints of chemistry-dictated by quantum mechanics and the discrete nature of the atom-limit the set of observable atomic crystal structures. What structures are possible in the absence of these constraints? Here, we systematically crystallize one-component systems of particles interacting with isotropic multiwell pair potentials. We investigate two tunable families of pairwise interaction potentials. Our simulations self-assemble a multitude of crystal structures ranging from basic lattices to complex networks. Sixteen of the structures have natural analogs spanning all coordination numbers found in inorganic chemistry. Fifteen more are hitherto unknown and occupy the space between covalent and metallic coordination environments. The discovered crystal structures constitute targets for self-assembly and expand our understanding of what a crystal structure can look like.
crystal structures↗
PSR J2030+3641: RADIO DISCOVERY AND GAMMA-RAY STUDY OF A MIDDLE-AGED PULSAR IN THE NOW IDENTIFIED FERMI-LAT SOURCE 1FGL J2030.0+3641
In a radio search with the Green Bank Telescope of three unidentified low Galactic latitude Fermi Large Area Telescope (LAT) sources, we have discovered the middle-aged pulsar J2030+3641 associated with 1FGL J2030.0+3641 (2FGL J2030.0+3640). Following the detection of gamma-ray pulsations using a radio ephemeris, we have obtained a phase-coherent timing solution based on gamma-ray and radio pulse arrival times which spans the entire Fermi mission. With a rotation period of 0.2 s, a spin-down luminosity of 3 Multiplication-Sign 10{sup 34} erg s{sup -1}, and a characteristic age of 0.5 Myr, PSR J2030+3641 is a middle-aged neutron star with spin parameters similar to those of the exceedingly gamma-ray-bright and radio-undetected Geminga. Its gamma-ray flux is 1% that of Geminga, primarily because of its much larger distance, as suggested by the large integrated column density of free electrons, DM = 246 pc cm{sup -3}. We fit the gamma-ray light curve, along with limited radio polarimetric constraints, to four geometrical models of magnetospheric emission, and while none of the fits have high significance some are encouraging and suggest that further refinements of these models may be worthwhile. We argue that not many more non-millisecond radio pulsars may be detected along the Galactic plane that are responsible for LAT sources, but that modified methods to search for gamma-ray pulsations should be productive-PSR J2030+3641 would have been found blindly in gamma rays if only {approx}> 0.8 GeV photons had been considered, owing to its relatively flat spectrum and location in a region of high soft background.
79 ASTRONOMY AND ASTROPHYSICS↗
DISCOVERY OF GAMMA-RAY PULSATIONS FROM THE TRANSITIONAL REDBACK PSR J1227-4853
The 1.69 ms spin period of PSR J1227−4853 was recently discovered in radio observations of the low-mass X-ray binary XSS J12270−4859 following the announcement of a possible transition to a rotation-powered millisecond pulsar state, inferred from decreases in optical, X-ray, and gamma-ray flux from the source. We report the detection of significant (5σ) gamma-ray pulsations after the transition, at the known spin period, using ∼1 year of data from the Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope. The gamma-ray light curve of PSR J1227−4853 can be fit by one broad peak, which occurs at nearly the same phase as the main peak in the 1.4 GHz radio profile. The partial alignment of light-curve peaks in different wavebands suggests that at least some of the radio emission may originate at high altitude in the pulsar magnetosphere, in extended regions co-located with the gamma-ray emission site. We folded the LAT data at the orbital period, both pre- and post-transition, but find no evidence for significant modulation of the gamma-ray flux. Analysis of the gamma-ray flux over the mission suggests an approximate transition time of 2012 November 30. Continued study of the pulsed emission and monitoring of PSR J1227−4853, and other known redback systems, for subsequent flux changes will increase our knowledge of the pulsar emission mechanism and transitioning systems.
79 ASTRONOMY AND ASTROPHYSICS↗
Designing rules and probabilistic weighting for fast materials discovery in the Perovskite structure
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bio-inspired↗
DISCOVERY OF A GeV BLAZAR SHINING THROUGH THE GALACTIC PLANE
The Fermi Large Area Telescope (LAT) discovered a new gamma-ray source near the Galactic plane, Fermi J0109+6134, when it flared brightly in 2010 February. The low Galactic latitude (b = -1.{sup 0}2) indicated that the source could be located within the Galaxy, which motivated rapid multi-wavelength follow-up including radio, optical, and X-ray observations. We report the results of analyzing all 19 months of LAT data for the source, and of X-ray observations with both Swift and the Chandra X-ray Observatory. We determined the source redshift, z = 0.783, using a Keck Low-Resolution Imaging Spectrometer observation. Finally, we compiled a broadband spectral energy distribution (SED) from both historical and new observations contemporaneous with the 2010 February flare. The redshift, SED, optical line width, X-ray absorption, and multi-band variability indicate that this new GeV source is a blazar seen through the Galactic plane. Because several of the optical emission lines have equivalent width >5 A, this blazar belongs in the flat-spectrum radio quasar category.
79 ASTRONOMY AND ASTROPHYSICS↗
MAGIC DISCOVERY OF VERY HIGH ENERGY EMISSION FROM THE FSRQ PKS 1222+21
Very high energy (VHE) {gamma}-ray emission from the flat spectrum radio quasar (FSRQ) PKS 1222+21 (4C 21.35, z = 0.432) was detected with the MAGIC Cherenkov telescopes during a short observation ({approx}0.5 hr) performed on 2010 June 17. The MAGIC detection coincides with high-energy MeV/GeV {gamma}-ray activity measured by the Large Area Telescope (LAT) on board the Fermi satellite. The VHE spectrum measured by MAGIC extends from about 70 GeV up to at least 400 GeV and can be well described by a power-law dN/dE {proportional_to} E {sup -}{Gamma} with a photon index {Gamma} = 3.75 {+-} 0.27{sub stat} {+-} 0.2{sub syst}. The averaged integral flux above 100 GeV is (4.6 {+-} 0.5) x 10{sup -10} cm{sup -2} s{sup -1} ({approx}1 Crab Nebula flux). The VHE flux measured by MAGIC varies significantly within the 30 minute exposure implying a flux doubling time of about 10 minutes. The VHE and MeV/GeV spectra, corrected for the absorption by the extragalactic background light (EBL), can be described by a single power law with photon index 2.72 {+-} 0.34 between 3 GeV and 400 GeV, and is consistent with emission belonging to a single component in the jet. The absence of a spectral cutoff constrains the {gamma}-ray emission region to lie outside the broad-line region, which would otherwise absorb the VHE {gamma}-rays. Together with the detected fast variability, this challenges present emission models from jets in FSRQs. Moreover, the combined Fermi/LAT and MAGIC spectral data yield constraints on the density of the EBL in the UV-optical to near-infrared range that are compatible with recent models.
79 ASTRONOMY AND ASTROPHYSICS↗