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Resolving the molecular basis of a Mendelian condition remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion and structural variant calling and diploid de novo genome assembly. This permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility and full-length transcript information in a single long-read sequencing run.
View Article and Find Full Text PDFGenetically-encoded targeted protein degradation technology to remove endogenous condensation-prone proteins and improve crop performance.
Nat Commun
January 2025
State Key Laboratory of Hybrid Rice, Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei, China.
Effective modulation of gene expression in plants is achievable through tools like CRISPR and RNA interference, yet methods for directly modifying endogenous proteins remain lacking. Here, we identify the E3 ubiquitin ligase E3TCD1 and develope a Targeted Condensation-prone-protein Degradation (TCD) strategy. The X-E3TCD1 fusion protein acts as a genetically engineered degrader, selectively targeting endogenous proteins prone to condensation.
View Article and Find Full Text PDFRedirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
Cell Metab
January 2025
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address:
Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo.
View Article and Find Full Text PDFNoncoding variants and sulcal patterns in congenital heart disease: Machine learning to predict functional impact.
iScience
February 2025
Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
Neurodevelopmental impairments associated with congenital heart disease (CHD) may arise from perturbations in brain developmental pathways, including the formation of sulcal patterns. While genetic factors contribute to sulcal features, the association of noncoding variants (ncDNVs) with sulcal patterns in people with CHD remains poorly understood. Leveraging deep learning models, we examined the predicted impact of ncDNVs on gene regulatory signals.
View Article and Find Full Text PDFFunctional expression of Cry proteins on the surface of spores.
J Pestic Sci
November 2024
Bacillus Tech LLC.
The Cry1Fa insecticidal protein from (Bt) was expressed on the surface of (Bs) spores to create transgenic Bs spores referred to as Spore-Cry1Fa. Cry1Fa, along with its leader sequence, was connected to the carboxyl end of a Bs spore outercoat protein, CotC, through a flexible linker. The Arg-27 residue of the Cry1Fa protein was mutated to Leu to prevent detachment from the spores due to protease digestion.
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