Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation

Differentiation of naive CD4+ T cells into T helper type 1 (Th1) effector cells requires both T cell receptor (TCR) signaling and cytokines such as interleukin-12 and interferon gamma (IFN-gamma). Here, we report that a third cytokine signal, mediated by the Janus family tyrosine kinase 3 (Jak3) and signal transducer and activator of transcription 5 (STAT5) pathway, is also required for Th1 cell differentiation. In the absence of Jak3-dependent signals, naive CD4+ T cells proliferate robustly but produce little IFN-gamma after Th1 cell polarization in vitro. This defect is not due to reduced activation of STAT1 or STAT4 or to impaired upregulation of the transcription factor T-bet. Instead, we find that T-bet binding to the Ifng promoter is greatly diminished in the absence of Jak3-dependent signals, correlating with a decrease in Ifng promoter accessibility and histone acetylation. These data indicate that Jak3 regulates epigenetic modification and chromatin remodeling of the Ifng locus during Th1 cell differentiation

Identification and characterization of small-molecule inhibitors of Tie2 kinase

Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC 50 value at 0.3 μM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders

Parameters Governing Ruthenium Sawhorse-Based Decarboxylation of Oleic Acid

Ruthenium-catalyzed decarboxylation of 9-cis-octadecenoic is a path to produce biobased olefins. Here, a mechanistic study of this reaction was undertaken utilizing a closed reaction system and a pressure reactor. The proposed mechanism of an isomerization followed by a decarboxylation reaction was consistent with a mathematical kinetic model. That same model was able to accurately predict CO₂ evolution. Additionally, computational chemistry was used to determine that the barrier of the oleic acid decarboxylation reaction is 249 kJ mol^–1. Using the new information, the efficacy of the decarboxylation reaction was improved to an overall catalytic efficiency of 850 total turnovers

Parameters Governing Ruthenium Sawhorse-Based Decarboxylation of Oleic Acid

Ruthenium-catalyzed decarboxylation of 9-cis-octadecenoic is a path to produce biobased olefins. Here, a mechanistic study of this reaction was undertaken utilizing a closed reaction system and a pressure reactor. The proposed mechanism of an isomerization followed by a decarboxylation reaction was consistent with a mathematical kinetic model. That same model was able to accurately predict CO₂ evolution. Additionally, computational chemistry was used to determine that the barrier of the oleic acid decarboxylation reaction is 249 kJ mol^–1. Using the new information, the efficacy of the decarboxylation reaction was improved to an overall catalytic efficiency of 850 total turnovers

Sulfonamido-aryl ethers as bradykinin B1 receptor antagonists.

The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM