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Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound ...from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was ...successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3nM; A2780 antiproliferative IC50=70nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This data article presents the multi-locus DNA alignments, morphometric data, and details on specimens examined to resolve the evolutionary history of Anodontoides and Strophitus, primarily generic ...placement and species boundaries. We sequenced 3 loci to create our molecular matrix: cytochrome c oxidase subunit I, NADH dehydrogenase subunit I, and the nuclear-encoded ribosomal internal transcribed spacer I. Aligned sequences were used in phylogenetic analyses and to identify diagnostic nucleotides for Strophitus pascagoulaensis, Strophitus radiatus, Strophitus sp. cf. pascagoulaensis, and Strophitus williamsi. Linear morphometrics (i.e. maximum height, length, and width) were also implemented to further evaluate species boundaries within Strophitus. For further details and experimental findings, please refer to the article published in Molecular Phylogenetics and Evolution (Smith et al., 2018) 1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Mitonuclear coevolution is common in eukaryotes, but bivalve lineages that have doubly uniparental inheritance (DUI) of mitochondria may be an interesting example. In this system, females ...transmit mtDNA (F mtDNA) to all offspring, while males transmit a different mtDNA (M mtDNA) solely to their sons. Molecular evolution and functional data suggest oxidative phosphorylation (OXPHOS) genes encoded in M mtDNA evolve under relaxed selection due to their function being limited to sperm only (vs. all other tissues for F mtDNA). This has led to the hypothesis that mitonuclear coevolution is less important for M mtDNA. Here, we use comparative phylogenetics, transcriptomics, and proteomics to understand mitonuclear interactions in DUI bivalves. We found nuclear OXPHOS proteins coevolve and maintain compatibility similarly with both F and M mtDNA OXPHOS proteins. Mitochondrial recombination did not influence mitonuclear compatibility and nuclear-encoded OXPHOS genes were not upregulated in tissues with M mtDNA to offset dysfunction. Our results support that selection maintains mitonuclear compatibility with F and M mtDNA despite relaxed selection on M mtDNA. Strict sperm transmission, lower effective population size, and higher mutation rates may explain the evolution of M mtDNA. Our study highlights that mitonuclear coevolution and compatibility may be broad features of eukaryotes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A series of HfxTa1-xC atomic compositions, where x = 0.0, 0.13, 0.25, 0.50, 0.75, 0.83, and 1.0, were computationally and experimentally studied in terms of their phase, hardness, and dislocation ...emission behavior. Using an ab initio evolutionary algorithm, the B1 rocksalt structure was found to be the 0 K ground state phase for the binary carbides whereas the ternary compounds were a mixture of metal-site ordered monoclinic, trigonal, and cubic structures. However, all experimental carbides were found to exhibit a B1 structure, with two B1 phases forming for Hf-rich ternary compositions. A modest rise in the elastic constant computationally predicted hardness was found with experimental mean values showing a similar trend from nanoindentation tests. With the presence of Ta, even in small amounts, in the Hf-rich ternary compositions, {111} slip was observed which is a change from the reported {110} slip for HfC. This change is explained by the promotion of an intrinsic stacking fault in the {111} planes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
With the growth of the healthcare industry, small scale power sources are needed to support advancements in medical implants, artificial organs, and sensors throughout the body. However, it remains a ...challenge to find safe, reliable, and stable power sources for these devices. In this study, a miniaturized reverse electrodialysis (RED) biopower cell design using physiological salinity concentration differences between renal bloodstreams is explored for its potential to be used as a power supply for implantable medical devices. Two small scale RED devices produced consistent power for up to three to ten days, depending on the device design. A two-fold decrease in the spacer thickness of the RED biopower cell almost doubled the average power density delivered (from 0.22 mW/m2 to 0.43 mW/m2) for a physiologically relevant salinity concentration difference. The use of an additional (ie. non-biological) salinity source to enhance the concentration difference more than doubled the average power density (from 0.43 mW/m2 to 0.90 mW/m2). In addition, the introduction of a biofouling agent, bovine serum albumin (BSA), was observed on the membrane but did not significantly affect the membrane performance.
•Physiologically relevant concentrations can generate power in a RED system.•Miniaturized RED power cell can provide stable power for more than three days.•Miniaturized RED power cell maintained power density even in the presence of BSA.•Reduced spacer thickness and larger salinity differences improve RED power density.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In experiments conducted at Sandia National Laboratories’ RITS-6 accelerator, the self-magnetic-pinch diode exhibits significant shot-to-shot variability. Specifically, for identical hardware ...operated at the same voltage, some shots exhibit a catastrophic drop in diode impedance. A study is underway to identify sources of shot-to-shot variations which correlate with diode impedance collapse. The scope of this report is limited to data collected at 4.5-MV peak voltage and sources of variability which occur away from the diode, such as sheath electron emission and trajectories, variations in pulsed power, load and transmission line alignment, and different field shapers. We find no changes in the transmission line hardware, alignment, or hardware preparation methods which correlate with impedance collapse. However, in classifying good versus poor shots, we find that there is not a continuous spectrum of diode impedance behavior but that the good and poor shots can be grouped into two distinct impedance profiles. In poor shots, the sheath current in the load region falls from 16%–30% of the total current to less than 10%. This result will form the basis of a follow-up study focusing on the variability resulting from diode physics.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
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