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Refining minimal engineered receptors for specific activation of on-target signaling molecules.
Sci Rep
December 2024
Laboratory of Cell Vaccine, Microbial Research Center for Health and Medicine (MRCHM), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki-Shi, Osaka, 567-0085, Japan.
Since designer cells are attracting much attention as a new modality in gene and cell therapy, it would be advantageous to develop synthetic receptors that recognize artificial ligands and activate solely signaling molecules of interest. In this study, we refined the construction of our previously developed minimal engineered receptors (MERs) to avoid off-target activation of STAT5 while maintaining on-target activation of signaling molecules corresponding to tyrosine motifs. Among the myristoylated, cytoplasmic, and transmembrane types of MERs, the cytoplasmic type had the highest signaling efficiency, although there was off-target activation of STAT5 upon ligand stimulation.
View Article and Find Full Text PDFRegionally distinct GFAP promoter expression plays a role in off-target neuron expression following AAV5 transduction.
Sci Rep
December 2024
Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Astrocyte to neuron reprogramming has been performed using viral delivery of neurogenic transcription factors in GFAP expressing cells. Recent reports of off-target expression in cortical neurons following adeno-associated virus (AAV) transduction to deliver the neurogenic factors have confounded our understanding of the efficacy of direct cellular reprogramming. To shed light on potential mechanisms that may underlie the neuronal off-target expression of GFAP promoter driven expression of neurogenic factors in neurons, two regionally distinct cortices were compared-the motor cortex (MC) and medial prefrontal cortex (mPFC)-and investigated: (1) the regional tropism and astrocyte transduction with an AAV5-GFAP vector, (2) the expression of Gfap in MC and mPFC neurons; and (3) material transfer between astrocytes and neurons.
View Article and Find Full Text PDFTheranostic drugs represent an emerging path to deliver on the promise of precision medicine. However, bottlenecks remain in characterizing theranostic targets, identifying theranostic lead compounds, and tailoring theranostic drugs. To overcome these bottlenecks, we present the Theranostic Genome, the part of the human genome whose expression can be utilized to combine therapeutic and diagnostic applications.
View Article and Find Full Text PDFBAY 2413555 is a novel selective and reversible positive allosteric modulator of the type 2 muscarinic acetylcholine (M2) receptor, aimed at enhancing parasympathetic signaling and restoring cardiac autonomic balance for the treatment of heart failure (HF). This study tested the safety, tolerability and pharmacokinetics of this novel therapeutic option. REMOTE-HF was a multicenter, double-blind, randomized, placebo-controlled, phase Ib dose-titration study with two active arms.
View Article and Find Full Text PDFAI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer.
Nat Commun
December 2024
Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Pathogenic activating mutations in the fibroblast growth factor receptor 3 (FGFR3) drive disease maintenance and progression in urothelial cancer. 10-15% of muscle-invasive and metastatic urothelial cancer (MIBC/mUC) are FGFR3-mutant. Selective targeting of FGFR3 hotspot mutations with tyrosine kinase inhibitors (e.
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