benzo-15-crown-5/2,3,5,6,8,9,11,12-Octahydro-1,4,7,10,13-benzopentaoxacyclopentadecine/Benzo-15-crown 5-Ether/1,4,7,10,13-Benzopentaoxacyclopentadecin, 2,3,5,6,8,9,11,12-octahydro-/2,5,8,11,14-pentaoxabicyclo[13.4.0]nonadeca-1(19),15,17-triene/2,3,5,6,8,9,11,12-Octahydrobenzo[b][1,4,7,10,13]pentaoxacyclopentadecine/2,3-Benzo-1,4,7,10,13-pentaoxacyclopentadec-2-ene
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Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models. Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells. AURKA inhibitors may provide a therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harbouring SMARCA4/BRG1-inactivating mutations.
SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers
Vural Tagal,1 Shuguang Wei,1 Wei Zhang,2,3 Rolf A. Brekken,3,4,5 Bruce A. Posner,1,5 Michael Peyton,3 Luc Girard,3,4 TaeHyun Hwang,6 David A. Wheeler,7 John D. Minna,3,4,5,8 Michael A. White,5,9 Adi F. Gazdar,2,3,5 and Michael G. Rotha,1,5
Synesthesia is a condition in which normal stimuli can trigger anomalous associations. In this study, we exploit synesthesia to understand how the synesthetic experience can be explained by subtle changes in network properties. Of the many forms of synesthesia, we focus on colored sequence synesthesia, a form in which colors are associated with overlearned sequences, such as numbers and letters (graphemes). Previous studies have characterized synesthesia using resting-state connectivity or stimulus-driven analyses, but it remains unclear how network properties change as synesthetes move from one condition to another. To address this gap, we used functional MRI in humans to identify grapheme-specific brain regions, thereby constructing a functional “synesthetic” network. We then explored functional connectivity of color and grapheme regions during a synesthesia-inducing fMRI paradigm involving rest, auditory grapheme stimulation, and audiovisual grapheme stimulation. Using Markov networks to represent direct relationships between regions, we found that synesthetes had more connections during rest and auditory conditions. We then expanded the network space to include 90 anatomical regions, revealing that synesthetes tightly cluster in visual regions, whereas controls cluster in parietal and frontal regions. Together, these results suggest that synesthetes have increased connectivity between grapheme and color regions, and that synesthetes use visual regions to a greater extent than controls when presented with dynamic grapheme stimulation. These data suggest that synesthesia is better characterized by studying global network dynamics than by individual properties of a single brain region.
Neural Networks of Colored Sequence Synesthesia
Steffie N. Tomson, Manjari Narayan, Genevera I. Allen, David M. Eagleman
2013 Aug 28;
In this work, the purification and characterization of an extracellular elicitor protein, designated AsES, produced by an avirulent isolate of the strawberry pathogen Acremonium strictum, are reported. The defense eliciting activity present in culture filtrates was recovered and purified by ultrafiltration (cutoff, 30 kDa), anionic exchange (Q-Sepharose, pH 7.5), and hydrophobic interaction (phenyl-Sepharose) chromatographies. Two-dimensional SDS-PAGE of the purified active fraction revealed a single spot of 34 kDa and pI 8.8. HPLC (C2/C18) and MS/MS analysis confirmed purification to homogeneity. Foliar spray with AsES provided a total systemic protection against anthracnose disease in strawberry, accompanied by the expression of defense-related genes (i.e. PR1 and Chi2-1). Accumulation of reactive oxygen species (e.g. H2O2 and O2˙̄) and callose was also observed in Arabidopsis. By using degenerate primers designed from the partial amino acid sequences and rapid amplification reactions of cDNA ends, the complete AsES-coding cDNA of 1167 nucleotides was obtained. The deduced amino acid sequence showed significant identity with fungal serine proteinases of the subtilisin family, indicating that AsES is synthesized as a larger precursor containing a 15-residue secretory signal peptide and a 90-residue peptidase inhibitor I9 domain in addition to the 283-residue mature protein. AsES exhibited proteolytic activity in vitro, and its resistance eliciting activity was eliminated when inhibited with PMSF, suggesting that its proteolytic activity is required to induce the defense response. This is, to our knowledge, the first report of a fungal subtilisin that shows eliciting activity in plants. This finding could contribute to develop disease biocontrol strategies in plants by activating its innate immunity
Mass Spectrometry (MS), Plant Defense, Protein Purification, Protein Sequence, Serine Protease, Acremonium strictum, Elicitor, Fragaria x ananassa, Subtilisin, cDNA Sequencing
Purification and Characterization of AsES Protein: A SUBTILISIN SECRETED BY ACREMONIUM STRICTUM IS A NOVEL PLANT DEFENSE ELICITOR
Nadia R. Chalfoun, Carlos F. Grellet-Bournonville, Martin G. Martinez-Zamora, Araceli Diaz-Perales, Atilio P. Castagnaro, Juan C. Diaz-Ricci
2013 May 17;