️ Episode 215: Protein Set Transformer for high-diversity viromics

In this episode of PaperCast Base by Base, we explore Protein Set Transformer (PST) is a protein-based genome language model that represents genomes as sets of proteins to improve genome and protein representations across diverse viral datasets

Study Highlights:
PST embeds proteins with ESM2, concatenates positional and strand vectors, contextualizes proteins with a multi-head attention encoder, and produces genome embeddings via a learnable weighted decoder pooling. The foundation PST-TL models were pretrained on >100k dereplicated viral genomes encoding >6M proteins using a triplet-loss objective with PointSwap augmentation and evaluated on IMG/VR v4 and MGnify soil virus test sets. PST-TL outperformed other protein- and nucleotide-based methods at recovering genome–genome relationships, including remote relationships, and its protein embeddings clustered structural capsid folds and late-gene functional modules. PST improved annotation transfer for hypothetical proteins via embedding and structure-aware clustering and boosted viral host-species prediction when used in a graph link-prediction framework.

Conclusion:
PST provides transferable genome- and protein-level embeddings that strengthen representation, annotation, and host-prediction tasks for diverse viral and microbial genomics applications

Music:
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Reference:
Martin, C., Gitter, A., Anantharaman, K. Protein Set Transformer: a protein-based genome language model to power high-diversity viromics. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66049-4

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.castos.com/episodes/protein-set-transformer

️ Episode 214: PI(4,5)P2 Asymmetry Enables Rapid FGF2 Secretion

In this episode of PaperCast Base by Base, we explore This study shows that an asymmetric transbilayer distribution of PI(4,5)P2 lowers the energy barrier for lipidic pore formation and accelerates unconventional secretion of Fibroblast Growth Factor 2

Study Highlights:
The authors generated asymmetric LUVs and GUVs by enzymatically converting outer-leaflet PI(4)P to PI(4,5)P2 using PIP5K1C and validated PI(4,5)P2 presence with FGF2-GFP and FGF2-Halo binding assays. GUV reconstitution assays revealed that outer-leaflet enrichment of PI(4,5)P2 shortened mean FGF2-dependent pore formation times from ~95 minutes to ~45 minutes without changing final pore frequency. In CHO-K1 cells, delivery of exogenous PI(4,5)P2 to the outer leaflet disrupted transbilayer asymmetry and acutely inhibited FGF2 secretion, an effect mirrored by PI(3,4)P2 and PI(3,4,5)P3 but not by PI(4)P or phosphatidylserine. Exogenously added PI(4,5)P2 was cleared from the cell surface within 40–60 minutes and FGF2 secretion recovered, supporting a reversible, asymmetry-dependent mechanism

Conclusion:
Transbilayer asymmetry of PI(4,5)P2 is a key biophysical determinant that lowers the energetic cost of membrane pore opening and is required for fast unconventional secretion of FGF2

Music:
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Reference:
Kaur, M., Lolicato, F., Nickel, W. Plasma membrane transbilayer asymmetry of PI(4,5)P2 drives unconventional secretion of Fibroblast Growth Factor 2. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66860-z

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Official website https://basebybase.com

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.castos.com/episodes/pi45p2-transbilayer-asymmetry

️ Episode 213: BRAIN-MAGNET: a functional atlas for non-coding variants

In this episode of PaperCast Base by Base, we explore BRAIN-MAGNET couples a ChIP-STARR-seq atlas of 148,198 neural regulatory elements with a validated convolutional neural network to predict enhancer activity and prioritize disease-relevant non-coding variants

Study Highlights:
The authors generated an activity-ranked functional genomics atlas of 148,198 non-coding regulatory elements in human neural stem cells. Comparative ChIP-STARR-seq revealed many elements are epigenetically primed in embryonic stem cells for later neural activity. BRAIN-MAGNET, a convolutional neural network trained on the atlas, predicts enhancer activity from DNA sequence and computes nucleotide-level contribution scores to identify functional motifs. The model outperformed other prioritization scores at tested loci and enabled prioritization and functional validation of both common GWAS SNPs and rare variants, including a putative RAB7A enhanceropathy.

Conclusion:
The NCRE atlas and BRAIN-MAGNET provide a functionally validated resource to interpret non-coding genetic variation relevant to neurodevelopment and neurological disease

Music:
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Reference:
Deng R, Perenthaler E, Nikoncuk A, Yousefi S, Lanko K, Schot R, Maresca M, Medico-Salsench E, Sanderson LE, Parker MJ, van Ijcken WFJ, Park J, Sturm M, Haack TB, Roshchupkin GV, Mulugeta E, Barakat TS. BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants. Cell. 2026 Jan 22;189:1–20. https://doi.org/10.1016/j.cell.2025.10.029

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Official website https://basebybase.com

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 212: Zonal control of mutant β-catenin tumorigenesis

This study shows that hepatic zonation determines whether mutant β-catenin drives proliferation and liver cancer by forcing differentiation to a non-permissive zone 3 fate or, when reversed, enabling MAPK- and mTOR-dependent growth

Study Highlights:
β-catenin exon 3 mutations cooperate with exogenous MYC to produce a proliferative translatome that supports tumour outgrowth. Differentiation to an extreme zone 3 GLUL+Lgr5+ hepatocyte fate suppresses the pro-growth translatome and is refractory to WNT/MYC-driven tumorigenesis. Early proliferative lesions that progress show reduced WNT activation, elevated MAPK signalling and engagement of an IGFBP2–mTOR–cyclin D1 axis, and inhibition of IGFBP2, mTOR or Yap/Taz impairs lesion formation and tumorigenesis. High-level WNT activation from Apc loss is less compatible with tumour formation, whereas MAPK activation (BrafV600E) antagonizes zone 3 differentiation to permit Lgr5+ hepatocyte transformation that can be suppressed by PORCN or BRAF inhibitors

Conclusion:
Hepatocyte zonal identity dictates susceptibility to WNT-driven HCC, and escape from WNT-induced zone 3 differentiation plus activation of MAPK/mTOR pro-growth pathways is required for tumour initiation

Music:
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Reference:
Raven A. et al. Hepatic zonation determines tumorigenic potential of mutant β-catenin. Nature. 2025. https://doi.org/10.1038/s41586-025-09733-1

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 211: Retention Elements in Cancer Cells

In this episode of PaperCast Base by Base, we explore the discovery of genetic elements that promote the retention of extrachromosomal DNA (ecDNA) in cancer cells, enhancing their survival and evolution.

Study Highlights:
Researchers identified a family of genomic elements known as retention elements that tether ecDNA to mitotic chromosomes, facilitating its transmission to daughter cells during division. The study utilized a novel genome-scale assay called Retain-seq, revealing thousands of retention elements that enhance the persistence of ecDNA. These elements are primarily located at gene promoters and are characterized by high CpG density, which is crucial for their function. The findings suggest that retention elements play a significant role in the maintenance of oncogenic ecDNA across generations of cancer cells.

Conclusion:
Understanding the mechanisms of ecDNA retention may provide insights into cancer evolution and potential therapeutic targets.

Music:
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Reference:
Sankar, V., Hung, K. L., Gnanasekar, A., Wong, I. T.-L., Shi, Q., Kraft, K., Jones, M. G., He, B. J., Yan, X., Belk, J. A., Liu, K. J., Agarwal, S., Wang, S. K., Henssen, A. G., Mischel, P. S., & Chang, H. Y. (2025). Genetic elements promote retention of extrachromosomal DNA in cancer cells. Nature. https://doi.org/10.1038/s41586-025-09764-8

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

Castos player https://basebybase.castos.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 210: Tumour-Reactive CD8 T Cell Clusters in Human Melanoma
In this episode of PaperCast Base by Base, we explore how tumour-reactive CD8 T cells organize into stable clusters with melanoma cells and antigen-presenting cells, and how these structures can be isolated from patient samples to boost anti-tumour immunity.

Study Highlights:
The authors used conventional and imaging flow cytometry to identify heterotypic clusters in which CD8 T cells were physically conjugated to tumour cells and antigen-presenting cells across 21 human melanoma metastases. Single-cell RNA and TCR sequencing showed that clustered CD8 T cells were more clonally expanded and displayed gene expression signatures of tumour reactivity, activation and exhaustion, whereas single CD8 T cells were enriched for naive and bystander-like states. Specific melanoma and myeloid subpopulations with strong antigen-presentation, interferon signalling and chemokine expression were preferentially engaged in these clusters, highlighting non-random, ligand–receptor-driven interactions in the tumour microenvironment. When expanded ex vivo, T cells derived from clusters produced more cytokines and showed markedly higher cytotoxicity against autologous melanoma cells than T cells from singlets. In mouse models bearing patient-derived melanomas, adoptive transfer of cluster-derived T cells led to stronger T cell infiltration, activation and tumour control than transfer of T cells expanded from single-cell gates.

Conclusion:
Heterotypic CD8 T cell clusters represent a powerful and previously overlooked source of tumour-reactive T cells and TCRs that could be harnessed to refine and enhance adoptive T cell therapies, including TIL-based treatment strategies.

Music:
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Reference:
Ibáñez-Molero S, Veldman J, Nieto JS, Traets JJH, George A, Hoefakker K, Karomi A, Harkes R, van den Broek B, Pack SM, Tas L, Visser NL, van Hal-van Veen SE, Alóndiga-Mérida P, Alkemade M, Seignette IM, Tissier R, Nieuwland M, van Baalen M, Poźniak J, Mul E, Tol S, Stenqvist S, Nilsson LM, Nilsson JA, Haanen JBAG, van Houdt WJ, Peeper DS. Tumour-reactive heterotypic CD8 T cell clusters from clinical samples. Nature. 2025. https://doi.org/10.1038/s41586-025-09754-w

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Official website https://basebybase.com

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️ Episode 209: PERT: Prime Editing tRNAs for Nonsense Mutations

In this episode of PaperCast Base by Base, we explore how prime editing can reprogram endogenous tRNAs into potent suppressor tRNAs, enabling a single therapeutic strategy to rescue many different genetic diseases caused by premature stop codons.

Study Highlights:
The authors introduce PERT, a prime editing-mediated strategy that permanently converts selected endogenous tRNAs into optimized suppressor tRNAs capable of reading through premature termination codons. Through large-scale screening of thousands of engineered tRNA variants and careful tuning of promoter, leader, terminator and tRNA sequence elements, they identify sup-tRNAs that efficiently restore protein production even when expressed from a single genomic copy. In human cell models of Batten disease, Tay–Sachs disease, Niemann–Pick type C1 and cystic fibrosis, installation of a single optimized sup-tRNA restores substantial fractions of enzyme activity or full-length protein across many different nonsense mutations. In mouse models, including a Hurler syndrome model carrying a pathogenic stop codon, in vivo delivery of a prime editor that converts a native tRNA into a suppressor tRNA leads to durable enzyme restoration and broad correction of disease pathology, while transcriptome, proteome and off-target analyses show minimal detectable disruption of normal stop codons or global gene expression.

Conclusion:
This work positions PERT as a promising, disease-agnostic genome-editing platform in which a single, well-characterized prime editing agent could eventually treat diverse genetic disorders caused by nonsense mutations.

Music:
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Reference:
Pierce SE, Erwood S, Oye K, An M, Krasnow N, Zhang E, Raguram A, Seelig D, Osborn MJ, Liu DR. Prime editing-installed suppressor tRNAs for disease-agnostic genome editing. Nature. 2025. https://doi.org/10.1038/s41586-025-09732-2

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode Slug: pert-prime-editing-suppressor-trnas

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Keywords: prime editing, suppressor tRNA, nonsense mutations, therapeutic genome editing, disease-agnostic strategy

️ Episode 208: ZAK, Collided Ribosomes, and the Stress Switch

In this episode of PaperCast Base by Base, we explore how collided ribosomes activate the MAP3K ZAK to drive the ribotoxic stress response and shape cell fate decisions under translational stress.

Study Highlights:
Using biochemistry, cryo-electron microscopy and crosslinking-based RNA mapping, the authors define how ZAK is constitutively recruited to ribosomes and how this engagement changes upon stress-induced ribosome collisions. They show that ZAK contacts the 40S subunit through a C-terminal eS27 pin and rRNA patches and anchors to RACK1 via a RACK1-interacting helix, while a collision-sensitive FPxL-containing RACK1-interacting motif becomes engaged only when two ribosomes collide. Disome formation brings two RACK1 molecules into proximity, allowing ZAK SAM domains to dimerize across the collision interface and enabling kinase activation, with pathogenic and engineered SAM variants revealing how this interface tunes activity on and off the ribosome. The study also identifies the ribosome-binding protein SERBP1 as a negative regulator that competes with ZAK for the FPxL-binding site on RACK1, thereby preventing inappropriate activation during basal translation.

Conclusion:
This work provides a structural and mechanistic blueprint for how ribosome collisions are translated into ZAK kinase activation, offering new entry points to modulate stress signalling in disease contexts.

Music:
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Reference:
Huso VL, Niu S, Catipovic MA, Saba JA, Denk T, Park E, Cheng J, Berninghausen O, Becker T, Green R, Beckmann R. ZAK activation at the collided ribosome. Nature. 2025. https://doi.org/10.1038/s41586-025-09772-8

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode Slug: zak-collided-ribosome-stress-switch

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 207: Semantic Design of de novo Genes with Evo

In this episode of PaperCast Base by Base, we explore how a genomic language model called Evo can use genomic context to design entirely new DNA sequences that encode functional genes and multi-component defence systems.

Study Highlights:
Researchers trained the Evo genomic language model on long prokaryotic and phage DNA sequences and used genomic neighbourhoods as prompts to autocomplete new genes whose functions mirror those of their neighbours. They experimentally validated Evo-designed toxin–antitoxin systems and type III toxin–antitoxin modules, discovering novel protein toxins, protein antitoxins and RNA antitoxins that strongly modulate bacterial survival despite low or absent sequence similarity to natural proteins. Using prompts from anti-CRISPR operons, they generated diverse anti-CRISPR proteins that block SpCas9 activity and protect cells from phage infection, including candidates that cannot be confidently assigned to any known protein family. Finally, they scaled this semantic design strategy to build SynGenome, a public resource of more than 120 billion base pairs of Evo-generated DNA organised by gene ontology and domain annotations to enable function-guided exploration across many biological pathways.

Conclusion:
This work shows that genomic language models can move beyond imitating nature, using semantic relationships in genomes to design de novo functional genes and systems that expand the sequence space available for protein engineering and synthetic biology.

Music:
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Reference:
Merchant AT, King SH, Nguyen E, Hie BL. Semantic design of functional de novo genes from a genomic language model. Nature. 2025. https://doi.org/10.1038/s41586-025-09749-7

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

Castos player https://basebybase.castos.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 206: Wild Birds and the North American H5N1 Epizootic
In this episode of PaperCast Base by Base, we explore how wild migratory birds have shaped the ecology and spread of the 2021–2023 highly pathogenic H5N1 epizootic across North America, and what this means for wildlife conservation and poultry health.

Study Highlights:
Using 1,818 haemagglutinin gene sequences from wild birds, domestic birds, and mammals collected across North America, the authors reconstruct the timing and routes of highly pathogenic H5N1 spread using Bayesian phylogeographical and phylodynamic models. They show that North America experienced around nine separate virus introductions, mainly via the Atlantic and Pacific migratory flyways, and that wild migratory Anseriformes sustained long-distance transmission across flyways. Non-canonical hosts such as raptors, songbirds, owls, and mammals were often infected but rarely acted as sources for onward transmission, functioning largely as dead-end hosts. In agriculture, the study estimates at least 46 and up to 113 independent introductions from wild birds into domestic poultry, with viral lineages persisting on farms for several months but rarely spilling back into wildlife. Comparisons between backyard and commercial flocks suggest that backyard birds tend to be infected slightly earlier and more frequently than commercial poultry, highlighting their potential value as early sentinels of increased viral circulation.

Conclusion:
Together, these findings indicate that managing future H5N1 waves in North America will require sustained surveillance in wild migratory birds and stronger measures at the wild–agriculture interface, rather than relying solely on rapid culling of infected farms.

Music:
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Reference:
Damodaran L, Jaeger AS, Moncla LH. Ecology and spread of the North American H5N1 epizootic. Nature. 2025. https://doi.org/10.1038/s41586-025-09737-x

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

Castos player https://basebybase.castos.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.