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RNA switch is a synthetic RNA-based technology that controls gene expression in response to cellular RNAs and proteins, thus enabling cell type-specific gene regulation and holding promise for gene therapy, regenerative medicine, and cell therapy. However, individual RNA switches often lack the specificity required for practical applications due to low ON/OFF ratios and difficulty in finding distinct and single biomolecule targets. To address these issues, we present "split RNA switches" that integrate outputs from multiple RNA switches by exploiting protein splicing. We show that split RNA switches significantly improve the ON/OFF ratio of microRNA-responsive ON switch system by canceling leaky OFF level in human cells. Using this approach, we achieve efficient cell purification using drug-resistance genes based on endogenous microRNA profiles and CRISPR-mediated genome editing with minimal off-target-cell effects. Additionally, we demonstrate RNA-based synthetic circuits using split RNA switches to enable the detection of multiple microRNAs and proteins with logical operations. Split RNA switches highlight the potential of post-translational processing as a versatile and comprehensive strategy for advancing mRNA-based therapeutic technologies.
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http://dx.doi.org/10.1038/s41467-025-60392-2 | DOI Listing |
MedComm (2020)
September 2025
Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Wuhan China.
RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine, and pseudouridine, serve as pivotal regulators of gene expression with significant implications for human health and disease. These dynamic modifications influence RNA stability, splicing, translation, and interactions, thereby orchestrating critical biological processes such as embryonic development, immune response, and cellular homeostasis. Dysregulation of RNA modifications is closely associated with a variety of pathologies.
View Article and Find Full Text PDFJ Neurochem
September 2025
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Memory formation involves a complex interplay of molecular and cellular processes, including synaptic plasticity mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). These processes rely on activity-dependent gene expression and local protein synthesis at synapses. A central unresolved question in neuroscience is how memories can be stably maintained over time, despite the transient nature of the proteins involved in their initial encoding.
View Article and Find Full Text PDFJ Infect Public Health
September 2025
AP-HP, Hospital Bichat - Claude-Bernard, Infectious and Tropical Diseases Department, IAME UMR 1137 INSERM, Université Paris Cité, France; IMEA, Hospital Bichat-Claude Bernard, Paris, France.
Background: Polymedication and comorbidities are frequent in aging people with HIV (PWH) and often associated with elevated incidences of adverse events (AEs) and drug-drug interactions (DDIs). The objective of this study was to evaluate the efficacy, safety and practicality of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), an antiretroviral (ARV) therapy with limited DDIs, in an elderly virologically-controlled PWH population.
Materials And Methods: This study was prospective, multicentric, single-arm conducted in HIV-1 controlled PWH aged over 65 years who switched from a ritonavir- or cobicistat-boosted containing regimen to B/F/TAF.
Cell Rep
September 2025
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA; Center for Neurogenetics, Weill Cornell Medicine, New York, NY, USA. Electronic address:
Progranulin-deficient frontotemporal dementia (GRN-FTD) is a major cause of familial FTD with TAR DNA-binding protein 43 (TDP-43) pathology, which is linked to exon dysregulation. However, little is known about this dysregulation in glial and neuronal cells. Here, using splice-junction-covering enrichment probes, we introduce single-nuclei long-read RNA sequencing 2 (SnISOr-Seq2), targeting 3,630 high-interest genes without loss of precision, and complete the first single-cell, long-read-resolved case-control study for neurodegeneration.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2025
Department of Radiation Oncology, Stanford University, Stanford, CA 94305.
Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation.
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