Transformational advances in genomic sequencing capabilities, vastly improved HLA class I epitope prediction algorithms and powerful delivery platforms have facilitated the clinical development of vaccines targeting neoa...Transformational advances in genomic sequencing capabilities, vastly improved HLA class I epitope prediction algorithms and powerful delivery platforms have facilitated the clinical development of vaccines targeting neoantigens encoded by tumor mutations. Early clinical trials indicate that vaccination against neoantigens can induce robust and durable T cell immunity that may persist for decades. mRNA vaccines, originally developed for cancer applications, have demonstrated considerable promise due to their efficacy and scalable production, as evidenced during the SARS-CoV-2 pandemic. However, the optimal cancer vaccine platform and delivery strategy is not yet known, as current approaches have not been compared head-to-head and substantial technological advances to improve immunogenicity and potentially clinical efficacy are achievable. For example, lipid-based formulations, while necessary for the effective delivery of mRNA vaccines, may also improve the immunogenicity of peptides and other delivery strategies. Here we review the current state of neoantigen vaccines in the clinic and highlight emerging opportunities for advancement in the field.
Cellular metabolites have emerged as noncanonical RNA caps. Despite its early discovery as an RNA cap, the dephospho-CoA (dpCoA) cap remains largely uncharacterized because of a lack of detection technologies. Here we us...Cellular metabolites have emerged as noncanonical RNA caps. Despite its early discovery as an RNA cap, the dephospho-CoA (dpCoA) cap remains largely uncharacterized because of a lack of detection technologies. Here we use biochemical and structural analysis to identify Arabidopsis NUDT11 as a specific decapping enzyme toward dpCoA-RNA. Leveraging this specificity, we develop biochemical and transcriptomic methods to quantify and profile dpCoA-RNA across the genome, revealing that dpCoA-RNAs exist across species and exhibit tissue-specific and/or condition-specific variations. In Arabidopsis, dpCoA-RNAs possess distinct transcription start sites and respond more rapidly to high light intensity as compared to 7-methylguanosine (mG)-capped RNAs. Moreover, Arabidopsis dpCoA-RNAs can reach up to 15% of mG-capped RNAs in abundance and are associated with translating ribosomes. We further demonstrate that an in vitro transcribed dpCoA-RNA is translated in human cells. This study uncovers a dynamic dpCoA cap that may potentially influence gene expression and establishes a toolkit for future investigations.
Organisms that permit hypermutation of target genes without off-target mutagenesis of the host genome enable the accelerated, continuous evolution of genes for new or enhanced functions. We develop and optimize an orthog...Organisms that permit hypermutation of target genes without off-target mutagenesis of the host genome enable the accelerated, continuous evolution of genes for new or enhanced functions. We develop and optimize an orthogonal DNA replication system in Escherichia coli that uses components from bacteriophage Φ29. The minimal system requires just two Φ29 genes to maintain the replicon and replicons can be efficiently engineered in vivo. We generate a highly mutagenic Φ29 DNA polymerase that introduces mutations at a frequency approaching 10 per base per generation (one mutation in a 1-kb gene every ten generations). Our system is stable for hundreds of generations and enables the continuous, accelerated evolution of new gene functions. We demonstrate the rapid evolution of a tetracycline resistance gene to confer resistance to tigecycline at higher levels than achieved with previously reported systems. We further evolve a 1,000-fold increase in β-lactamase activity for a third-generation cephalosporin in just 3 days.
Agentic artificial intelligence (AI) systems are emerging as teams of intelligent computational experts capable of rivaling human performance in labor-intensive tasks, including literature review, hypothesis formulation,...Agentic artificial intelligence (AI) systems are emerging as teams of intelligent computational experts capable of rivaling human performance in labor-intensive tasks, including literature review, hypothesis formulation, data analysis and model interpretation. These systems are poised to accelerate labor-intensive biomedical research by making autonomous decisions based on contextual information and expert feedback. Agentic AI systems have been developed for various applications, including drug discovery, data analysis and biomarker identification; however, several distinct challenges remain for making these systems broadly deployable in biomedical research. Here we discuss three key algorithms and seven foundational building-block characteristics that contribute to the development of agentic AI systems. We highlight their biomedical applications, design considerations and the challenges and opportunities associated with deploying agentic AI systems to advance collaborative scientific research.
Wei X, Xu Y, Yang D
… +16 more, Kim K, Yi L, Luo W, Lin X, Xiang Y, Williams AB, Wang X, Srivas S, Tan C, Zhang K, Li W, Li YE, Yue F, Huang ZJ, Jung I, Diao Y
Nat Biotechnol
· 2026 Feb · PMID 41714417
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The three-dimensional (3D) organization of cis-regulatory elements (CREs) is critical in transcription control. However, capturing transcriptome, epigenome and 3D genome from the same single cells remains challenging. He...The three-dimensional (3D) organization of cis-regulatory elements (CREs) is critical in transcription control. However, capturing transcriptome, epigenome and 3D genome from the same single cells remains challenging. Here we present scHiCAR (single-cell Hi-C with assay for transposase-accessible chromatin and RNA sequencing), a plate-based combinatorial barcoding method that simultaneously profiles mRNA, open chromatin and chromosome conformation capture from the same cells. Compared to existing single-cell 3D genome methods, scHiCAR more efficiently enriches long-range cis-interactions anchored at candidate CREs (cCREs). Applied to 1.62 million mouse brain cells and complemented with a deep-learning-based loop caller, scHiCAR accurately defines cell-type-specific transcriptomes, accessible cCREs and 5-kb-resolution enhancer-promoter pairs across 22 brain cell types. scHiCAR also performs robustly in challenging tissues such as skeletal muscle, enabling trimodal single-cell-level analysis of gene regulation dynamics during muscle stem cell regeneration. By providing a scalable and cost-effective system for single-cell trimodal analysis of gene-regulatory landscapes in complex tissues, scHiCAR reveals gene-locus-specific regulatory roles of 3D genome reorganization in transcriptional control.
Wagner A, Margalit N, Fishman Y
… +13 more, Indri SS, Upcher A, Baranov M, Nativ-Roth E, Hughes CE, Kariuki BM, Haataja JS, Schertel L, Yates JR, Harris KDM, Place AR, Mojzes P, Palmer BA
Highly reflective biogenic crystals such as guanine have potential as biocompatible alternatives to toxic inorganic optical materials. However, controlling the structural and optical properties of these sparingly soluble...Highly reflective biogenic crystals such as guanine have potential as biocompatible alternatives to toxic inorganic optical materials. However, controlling the structural and optical properties of these sparingly soluble crystals in vitro is challenging. Engineered microbial cells have been used widely to generate high-value metabolites, but the biosynthesis of functional crystalline materials has not been achieved. Here we harness microalgae for the biosynthesis of difficult-to-crystallize molecular materials. We show that dinoflagellates can rapidly accumulate many nitrogen heterocycles from aqueous solutions into nitrogen-storage crystals, revealing a general mechanism for their metabolism of dissolved organic nitrogen. We manipulate this innate crystallization behavior to generate crystals with tailored morphologies and optical properties, including birefringent xanthine spherulites-a biogenic analog of TiO nanoparticles. Our results show how microalgae may be exploited as cellular factories for producing molecular crystals from aqueous solutions, under ambient conditions, harnessing the intrinsic control mechanisms of crystal-forming cells, with possible further applications in the crystallization of pharmaceuticals and bioremediation of toxicants.