2,638 research outputs found
United States v. Hoskins: An Opportunity for the Second Circuit to Limit the Abusive Reach of the FCPA
Regioselective Reactions of Highly Substituted Arynes
The fully regioselective reactivity of four new highly substituted silyl aryl triflate aryne precursors in aryne acyl-alkylation, acyl-alkylation/condensation, and heteroannulation reactions is reported. The application of these more complex arynes provides access to diverse natural product scaffolds and obviates late-stage functionalization of aromatic rings
Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
Described in this report is the development of two unique methodologies exploiting the reactivity of arynes. Reaction of N-carbamoyl-functionalized enamine derivatives with benzyne affords substituted indolines. An orthogonal reactivity is uncovered when related enamine derivatives are modified as amides, such that isoquinolines are formed as the product of condensation with benzyne. This latter transformation is applied to a concise total synthesis of the opiate alkaloid papaverine
CRISPR/Cas9-based editing of a sensitive transcriptional regulatory element to achieve cell type-specific knockdown of the NEMO scaffold protein
The use of alternative promoters for the cell type-specific expression of a given mRNA/protein is a common cell strategy. NEMO is a scaffold protein required for canonical NF-κB signaling. Transcription of the NEMO gene is primarily controlled by two promoters: one (promoter B) drives NEMO transcription in most cell types and the second (promoter D) is largely responsible for NEMO transcription in liver cells. Herein, we have used a CRISPR/Cas9-based approach to disrupt a core sequence element of promoter B, and this genetic editing essentially eliminates expression of NEMO mRNA and protein in 293T human kidney cells. By cell subcloning, we have isolated targeted 293T cell lines that express no detectable NEMO protein, have defined genomic alterations at promoter B, and do not support activation of canonical NF-κB signaling in response to treatment with tumor necrosis factor. Nevertheless, noncanonical NF-κB signaling is intact in these NEMO-deficient cells. Expression of ectopic wildtype NEMO, but not certain human NEMO disease mutants, in the edited cells restores downstream NF-κB signaling in response to tumor necrosis factor. Targeting of the promoter B element does not substantially reduce NEMO expression (from promoter D) in the human SNU423 liver cancer cell line. Thus, we have created a strategy for selectively eliminating cell typespecific expression from an alternative promoter and have generated 293T cell lines with a functional knockout of NEMO. The implications of these findings for further studies and for therapeutic approaches to target canonical NF-κB signaling are discussed.Published versio
Scaffold proteins as dynamic integrators of biological processes
5R01GM117350-04 - NIH/National Institute of General Medical SciencesPublished versio
Benzannulated Bicycles by Three-Component Aryne Reactions
Triple crown: A pair of three-component coupling reactions between arynes, isocyanides, and either activated alkynes or phenyl esters generates unusual iminoindenones or phenoxy iminoisobenzofurans (see scheme), the latter of which may be advanced to o-ketobenzamides by performing direct hydrolysis. The synthetic utility of these compounds is demonstrated in a rapid preparation of substituted dibenzoketocaprolactams
Development of a mechanism to facilitate the safety stock planning configuration in ERP
Safety stock planning in ERP in general is dependent upon the planner having the experience to simulate planning scenarios. This paper focuses on the development of a mechanism to calculate adequate safety stocks in accordance with required service levels while enabling efficient configuration of the ERP safety stock parameters. The proposed mechanism could be of great benefit to industrial firms as it offers the ability to classify demand patterns, proposes replenishment strategies that are consistent with the demand profile, calculates key parameters and identifies the changes required to the ERP master data. The associated real world application is able to identify potential to save approximately £1.2 M in stock reductions and, more importantly, allows targeted actions to be implemented at material level. These results demonstrated that the proposed mechanism can be considered as a valuable new development for manufacturing industry to gain the competitive advantage
Atomic Dark Matter
We propose that dark matter is dominantly comprised of atomic bound states.
We build a simple model and map the parameter space that results in the early
universe formation of hydrogen-like dark atoms. We find that atomic dark matter
has interesting implications for cosmology as well as direct detection:
Protohalo formation can be suppressed below for weak scale dark matter due to Ion-Radiation interactions in the
dark sector. Moreover, weak-scale dark atoms can accommodate hyperfine
splittings of order 100 \kev, consistent with the inelastic dark matter
interpretation of the DAMA data while naturally evading direct detection
bounds.Comment: 17 pages, 3 figure
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Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis
The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of non-natural analogs
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