Base by Base

Nieminuszczy J et al., Nature Communications, doi:10.1038/s41467-025-65594-2 - This study shows the CIP2A-TOPBP1 complex coordinates two mitotic double-strand break repair pathways, MiDAS and MMEJ, by recruiting SLX4/SMX components and Polθ to mitotic chromatin. Key terms: CIP2A, TOPBP1, SLX4, MiDAS, MMEJ.

Study Highlights:
TOPBP1 BRCT1/2 binds SLX4 phosphorylated at Thr1260, a CDK1-dependent modification that promotes recruitment of SLX4, MUS81 and ERCC1 to mitotic chromatin to drive MiDAS. CIP2A is required for mitotic chromatin localisation of both TOPBP1 and Polθ, enabling Polθ-dependent MMEJ. Loss of CIP2A impairs both MiDAS and MMEJ, increasing micronuclei, γH2AX and 53BP1 and reducing proliferation under replication stress. Pharmacological Polθ inhibition combined with disruption of the TOPBP1–SLX4 interaction further elevates genome instability and selectively limits growth of BRCA1/2-deficient cells.

Conclusion:
The CIP2A-TOPBP1 axis is a central mitotic DNA repair hub that integrates CDK1-dependent phosphorylation and Polθ recruitment to safeguard genome stability and represents a therapeutic vulnerability in HR-deficient tumors.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
The CIP2A-TOPBP1 axis facilitates mitotic DNA repair via MiDAS and MMEJ

First author:
Nieminuszczy J

Journal:
Nature Communications, doi:10.1038/s41467-025-65594-2

DOI:
10.1038/s41467-025-65594-2

Reference:
Nieminuszczy J, Kozik Z, Jakub N, Vorhauser J, Lane KA, Martin PR, Kowalski S, Lecot M, Kanellou A, Mansfeld J, Pearl LH, Oliver AW, Downs JA, Niedzwiedz W, Choudhary JS, Day M, et al. The CIP2A-TOPBP1 axis facilitates mitotic DNA repair via MiDAS and MMEJ. Nature Communications. 2025;16:10623. https://doi.org/10.1038/s41467-025-65594-2

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/

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/cip2a-topbp1-mitotic-repair

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-05.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing the CIP2A-TOPBP1 axis, MiDAS and MMEJ pathways, the SLX4 Thr1260 phosphorylation by CDK1, TOPBP1-SMX interactions, CIP2A’s regulation of Polθ and SMX components, and the BRCA1/2-deficient synthetic lethal context, plus experimental approaches referenced (co-IP/MS, CRISPR knock
- transcript topics: CIP2A-TOPBP1 axis as a mitotic DNA repair hub; MiDAS and SMX complex recruitment to mitotic chromatin; MMEJ and Polθ dependence in mitosis; CDK1-dependent phosphorylation of SLX4 Thr1260 and TOPBP1 interaction; TOPBP1 BRCT1/2-mediated SMX recruitment and AlphaFold modelling; CIP2A upstream regulation of SLX4 and Polθ localization

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CIP2A-TOPBP1 axis coordinates mitotic DNA repair by promoting MiDAS and MMEJ
- CDK1-dependent phosphorylation of SLX4 at Thr1260 enables TOPBP1 BRCT1/2 interaction and SMX recruitment for MiDAS
- TOPBP1 BRCT1/2 mediate binding to SMX components; BRCT0-2 suffices for interaction
- CIP2A loss impairs both MiDAS (MiDAS-like BIR) and MMEJ, reducing recruitment of SMX and Polθ
- Polθ recruitment to mitotic chromatin is CIP2A-dependent; CIP2A depletion reduces Polθ localization and MMEJ activity
- BRCA1/2-deficient cells exhibit synthetic lethality when CIP2A-TOPBP1 axis is disrupted

QC result: Pass.

Zhao X et al., Nature Communications - In developing neural progenitors PCM1 localizes to the mother centrosome and to Notch ligand-containing endosomes, promoting Par-3/dynein assembly and Rab5-to-Rab11 trafficking to bias posterior-directed endosome segregation and preserve progenitor fate. Key terms: PCM1, centrosome asymmetry, endosome dynamics, radial glia progenitors, Notch signaling.

Study Highlights:
Pcm1 is asymmetrically enriched at the posterior mother centrosome (Cep83+) in zebrafish radial glia progenitors and is also found on central-zone Notch ligand (Dld)-containing endosomes. In vivo time-lapse imaging and expansion microscopy show Pcm1 puncta move with Dld endosomes and promote posterior-directed polarized dynamics. Loss of pcm1 disrupts Rab5b-to-Rab11a trafficking, reduces Par-3 and dynein co-assembly on recycling endosomes, lowers Notch signaling, and shifts divisions toward neuron–neuron outcomes at the expense of progenitors. Similar PCM1–PARD3–CEP83–RAB11 associations and asymmetric PCM1 distribution are observed in human iPSC-derived neural rosettes and cortical organoids.

Conclusion:
PCM1 couples centrosome asymmetry to polarized recycling endosome trafficking to enforce asymmetric Notch signaling and maintain radial glia progenitor fate

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
PCM1 coordinates centrosome asymmetry with polarized endosome dynamics to regulate daughter cell fate

First author:
Zhao X

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65756-2

Reference:
Zhao X., Mouilleau V., Wang Y., Solak A.C., Garcia J.Q., Chen X., Shi X., Wilkinson C.J., Royer L.A., Dong Z. & Guo S. PCM1 coordinates centrosome asymmetry with polarized endosome dynamics to regulate daughter cell fate. Nature Communications. 2025;16:10728. https://doi.org/10.1038/s41467-025-65756-2

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/

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/pcm1-centrosome-endosome-asymmetry

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-04.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims and mechanisms described in the transcript: PCM1 association with centrosome age, Dld endosome polarization, Par-3/dynein loading on recycling endosomes, Rab5b→Rab11a maturation, cross-species conservation in hiPSC-derived neural progenitors, and clonal division outcomes.
- transcript topics: Asymmetric localization of PCM1 at the posterior mother centrosome (Cep83+); Delta-like endosome (Dld) polarization and Notch signaling asymmetry; Co-localization and interaction of Par-3 and dynein on recycling endosomes; Rab5b to Rab11a endosome maturation on Dld endosomes; Conservation of PCM1 asymmetry and endosome dynamics in hiPSC-derived neural progenitors; Clonal analysis of RGP divisions: P/P, P/N, N/N outcomes

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- PCM1 enriched at the posterior mother centrosome Cep83+
- PCM1 localizes to the central zone near Delta-containing endosomes (Dld) and moves with Dld endosomes
- Loss of pcm1 disrupts endosome dynamics and increases neuronal differentiation at the expense of progenitor self-renewal
- PCM1 facilitates the Rab5b to Rab11a transition and promotes Par-3 and dynein assembly on recycling endosomes
- Conserved PCM1–CEP83–RAB11 associations observed in human hiPSC-derived neural progenitors and organoids
- PCM1 acts as a bridge linking centrosome age to polarized endosome trafficking and Notch signaling to preserve progenitor fate

QC result: Pass.

Kutchukian C et al., Nature Communications - Disruption of the PIKfyve/Fig4/Vac14 complex drives ULK1-dependent trafficking of PI4KIIα and ATG9A to lysosomes, elevating lysosomal PI(4)P to promote membrane repair and induce mitochondrial fragmentation with increased respiration. Key terms: PIKfyve, PI4KIIα, PI(4)P, ULK1, lysosomal repair.

Study Highlights:
PIKfyve complex disruption or pharmacological inhibition reduces mTORC1 signaling, activating ULK1 and driving ATG9A-dependent trafficking of PI4KIIα from the TGN to lysosomes. PI4KIIα accumulation elevates lysosomal PI(4)P, recruiting OSBP/ORP proteins to transfer cholesterol and phosphatidylserine and enhance lysosomal membrane repair. Elevated lysosomal PI(4)P recruits ORP1L at ER–lysosome–mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria, Drp1 recruitment, mitochondrial fragmentation, and increased oxygen consumption. Inhibition of ULK1 or PI4KIIα or mitochondrial targeting of Sac1 reverses these lysosomal and mitochondrial phenotypes.

Conclusion:
A ULK1-dependent PI4KIIα–PI(4)P pathway links PIKfyve complex dysfunction to coordinated lysosomal membrane repair and adaptive mitochondrial remodeling

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis

First author:
Kutchukian C

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65798-6

Reference:
Kutchukian C., Casas M., Dixon R. E., Dickson E. J. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis. Nature Communications. 2025;16:10761. https://doi.org/10.1038/s41467-025-65798-6

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

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

Episode link: https://basebybase.com/episodes/pikfyve-lysosome-mitochondria

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of the paper's mechanism: acute PIKfyve disruption activates a ULK1-dependent PI4KIIα/ATG9A trafficking program, increases lysosomal PI(4)P, recruits OSBP/ORP proteins for membrane repair, enhances ER–lysosome–mitochondria three-way contacts with ORP1L and Drp1-driven mitochondrial fra
- transcript topics: ULK1-dependent trafficking of PI4KIIα and ATG9A from the TGN to lysosomes; PI(4)P redistribution to lysosomes and PI4KIIα relocation from the TGN; OSBP/ORP-mediated lipid transfer and lysosomal membrane repair (PITT pathway); ER–lysosome–mitochondria three-way contact sites and ORP1L/Drp1 recruitment; Mitochondrial fragmentation and enhanced respiration (Seahorse data); ULK1/mTOR signaling modulation

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Acute PIKfyve inhibition reduces mTORC1 signaling and ULK1 activation
- ULK1-dependent trafficking of PI4KIIα and ATG9A from the TGN to lysosomes
- PI(4)P redistribution to lysosomes via PI4KIIα relocation to lysosomes
- OSBP/ORP-mediated transfer of cholesterol and phosphatidylserine to lysosomal membranes (PITT pathway)
- ULK1-dependent recruitment of ORP1L at ER–lysosome–mitochondria three-way contacts and DRP1 recruitment
- PI(4)P-dependent lysosomal membrane repair and enhanced mitochondrial respiration

QC result: Pass.

Canalda-Baltrons A et al., Nature Communications - Long-read assemblies and a pangenome reference graph uncover widespread structural variants that shape Mycobacterium tuberculosis evolution and contribute to drug resistance. Key terms: structural variation, pangenome graph, Mycobacterium tuberculosis, drug resistance, long-read sequencing.

Study Highlights:
The authors built an M. tuberculosis pangenome reference graph from 859 high-quality long-read assemblies and identified 3,077 unique structural variants genome-wide. They developed miniwalk to genotype SVs from graph-mapped assemblies and showed higher precision for short-read SV genotyping (0.7 vs 0.46 for manta) at modest cost to recall. SVs cluster in GC-rich PE/PPE regions and include recurrent events such as a ppe25-ppe27 deletion fixed in L4.4 and diverse deletions of the copper exporter ctpV specific to sub-lineage L1.2.1 that alter copper-associated transcription. Genotyping 41,134 isolates revealed non-canonical SVs and SV-gene burdens associated with resistance to multiple first- and second-line drugs

Conclusion:
Structural variants are an important and previously underappreciated driver of M. tuberculosis evolution and drug resistance, and pangenome graph approaches improve their detection

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Genome graphs reveal the importance of structural variation in Mycobacterium tuberculosis evolution and drug resistance

First author:
Canalda-Baltrons A

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65779-9

Reference:
Canalda-Baltrons A., Theys D., Chang X., Viberg L. T., Sherry N. L., Coin L., Dunstan S. J., Silcocks M., Hall M. B. Genome graphs reveal the importance of structural variation in Mycobacterium tuberculosis evolution and drug resistance. Nature Communications. 2025;16:10746. https://doi.org/10.1038/s41467-025-65779-9

License:
CC BY 4.0 International License (CC-BY-4.0)

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/structural-variation-mtb-pangenome

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-02.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive auditing of transcript segments describing: PRG construction and miniwalk SV genotyping; genome-wide SV landscape across lineages; ESX loci and ppe25-ppe27 deletion; copper exporter ctpV deletions in L1.2.1 with copper accumulation signals; DR associations across 41,134 isolates; and clinical implications.
- transcript topics: PRG construction and miniwalk SV genotyping; Genome-wide SV landscape across M. tuberculosis lineages; ESX secretion systems SVs and ppe25-ppe27 deletion; Copper homeostasis and ctpV deletions in L1.2.1; SV-based drug resistance associations across 41,134 isolates; Clinical implications and integration into sequencing pipelines

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- PRG built from 859 long-read Mtb assemblies; 821 assemblies used for SV genotyping
- Miniwalk SV genotyping on Illumina data yields precision 0.7 vs manta 0.46
- 3077 unique SVs identified across 821 isolates (1127 INS, 1694 DEL, 59 DUP, 58 INV, 139 CNVs)
- Largest SV ~66,582 bp inverted and translocated in lineage 9
- ppe25-ppe27 deletion in ESX-5 is the most frequent non-reference haplotype (9% overall; fixed in sub-lineage 4.4)
- Loss-of-function deletions of ctpV observed in L1.2.1 with transcriptional signals consistent with copper accumulation

QC result: Pass.

Pidathala S et al., Nature Communications - High-resolution cryo-EM structures of human SV2A reveal that orthosteric ligands induce an occluded MFS conformation and a secondary allosteric pocket modulates ligand binding. Key terms: SV2A, allosteric modulation, cryo-EM, levetiracetam, padsevonil.

Study Highlights:
The authors report sub-3 Å cryo-EM structures of human SV2A in the apo state and in complexes with levetiracetam, UCB-J, padsevonil, and the allosteric modulator UCB1244283. Levetiracetam and UCB-J bind the central cavity and drive inward movement of TM1 with Phe188 sealing the lumen, producing complete occlusion with levetiracetam and partial occlusion with UCB-J. UCB1244283 occupies a distinct allosteric site ~13 Å above the orthosteric pocket, reshapes the orthosteric site, lowers UCB-J Kd, increases Bmax, and slows ligand dissociation. Padsevonil binds both orthosteric and allosteric sites, precluding UCB1244283-mediated potentiation and illustrating overlapping but flexible allosteric interactions.

Conclusion:
SV2A uses orthosteric-induced occlusion combined with a secondary allosteric pocket to regulate ligand engagement, offering a structural blueprint for designing SV2A-specific modulators

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Structural pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily

First author:
Pidathala S

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65781-1

Reference:
Pidathala S., Chen X., Dai Y., Gorgulla C., Niu Y., Liu F., Lee C.-H. Structural pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily. Nature Communications. 2025;16:10748. https://doi.org/10.1038/s41467-025-65781-1

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

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

Episode link: https://basebybase.com/episodes/sv2a-allosteric-occlusion

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-01.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing SV2A mechanism, ligand-induced occlusion, orthosteric vs allosteric ligands, dual-binding Padsevonil, conditional engagement, and implications for MFS transporters; compared to the original article text.
- transcript topics: SV2A as a major facilitator superfamily transporter in brain; Cryo-EM methods and saposin nanoparticle reconstitution for SV2A; Levetiracetam and UCB-J binding to central cavity and induction of occlusion; TM1 inward movement and Phe188 sealing the central cavity; Allosteric site ~13 Å above orthosteric site; UCB1244283 mechanism; Padsevonil dual orthosteric/allosteric binding

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- SV2A is a major facilitator superfamily (MFS) transporter abundantly present in synaptic vesicles
- Sub-3 Å cryo-EM structures reported for SV2A in apo form and ligand-bound states
- Levetiracetam and UCB-J bind the central cavity and induce occlusion; levetiracetam causes complete occlusion, UCB-J partial occlusion
- UCB1244283 binds an allosteric site ~13 Å above the orthosteric site and stabilizes the occluded state while slowing ligand dissociation
- Padsevonil occupies both orthosteric and allosteric sites (dual binder)
- Allosteric modulation can be conditional, requiring orthosteric occupancy (conditional engagement)

QC result: Pass.

Feng H et al., Nat Commun - A comprehensive, unbiased benchmark compares five DNA foundation models across 57 datasets and multiple tasks, finding mean token embeddings improve classification and that model strengths vary by task and pre-training. Key terms: DNA foundation models, mean token embedding, sequence classification, variant effect, gene expression.

Study Highlights:
The study evaluated DNABERT-2, NT-v2, HyenaDNA, Caduceus-Ph, and GROVER on 57 datasets spanning sequence classification, gene expression prediction, variant effect quantification, and TAD recognition. Mean token embedding consistently and significantly outperformed summary-token and max pooling for sequence classification. Model performance was task-dependent: Caduceus-Ph excelled at human TFBS and promoter tasks, NT-v2 led pathogenic variant identification, HyenaDNA scaled efficiently and benefited from multi-species pre-training, while specialized models outperformed general foundations on QTL prediction. Zero-shot embeddings provided modest gene expression prediction and NT-v2 attention patterns did not reveal inherent TAD recognition.

Conclusion:
Mean token pooling yields more robust sequence-level representations and model choice should align with task, input length, and pre-training data for best genomic performance

Music:
Enjoy the music based on this article at the end of the episode.

First author:
Feng H

Journal:
Nat Commun

DOI:
10.1038/s41467-025-65823-8

Reference:
Feng H, Wu L, Zhao B, Huff C, Zhang J, Wu J, Lin L, Wei P & Wu C. Benchmarking DNA foundation models for genomic and genetic tasks. Nat Commun. 2025;16:10780. https://doi.org/10.1038/s41467-025-65823-8

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

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

Episode link: https://basebybase.com/episodes/dna-foundation-models-benchmark

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-31.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of core scientific claims: DNA foundation models benchmarking, pooling strategies (mean token embedding), zero-shot embeddings with a downstream classifier, VEQ dichotomy, multispecies pre-training and cross-species generalization, long-sequence performance, TAD recognition limitations
- transcript topics: DNA foundation models and zero-shot embeddings; Pooling strategies for sequence representations (mean token embedding vs summary/max pooling); Downstream classification using zero-shot embeddings (random forest); Variant effect quantification: pathogenic vs QTL (VEQ dichotomy); Multispecies pre-training and cross-species generalization; Cross-species transfer in promoter identification (Arabidopsis example)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Mean token embedding consistently improves sequence classification across all foundation models and yields measurable AUROC gains.
- Zero-shot embeddings with frozen weights are evaluated with a downstream random forest classifier to measure embedding quality without fine-tuning.
- VEQ dichotomy: generalists excel at pathogenic variant identification; specialized models excel at tissue-specific QTL predictions.
- Multispecies pre-training improves generalization; 14 of 49 tasks show statistically significant improvements, with some tasks favoring human-only pre-training.
- Cross-species transfer evidence: HyenaDNA pre-trained on human genomes shows cross-species transfer advantages (e.g., Arabidopsis promoter identification).
- NT-v2 self-attention does not inherently recognize higher-order chromatin structures (TADs) in zero-shot mode.

QC result: Pass.

Sun Z et al., Nature Communications - Mitochondrial NEK7 is imported via MTS peptides, binds SDHB to stabilize complex II conformation, prevent reverse electron transport and ROS, and thereby protects against spontaneous and experimentally induced liver fibrosis. Key terms: NEK7, SDHB, reverse electron transport, ROS, liver fibrosis.

Study Highlights:
NEK7 localizes to hepatocyte mitochondria through two internal mitochondrial targeting signal peptides and co‑localizes with SDHB. NEK7 binds SDHB and stabilizes complex II spatial conformation without changing SDHB abundance or complex assembly. Hepatocyte NEK7 deficiency induces reverse electron transport, increases mitochondrial membrane potential and mtROS, suppresses respiration, and triggers spontaneous liver fibrosis while worsening CCl4‑induced fibrosis. RET inhibitors or NEK7 overexpression restore mitochondrial function and substantially attenuate CCl4‑ and CDAHFD‑induced liver fibrosis.

Conclusion:
NEK7 maintains respiratory chain electron transport homeostasis via SDHB binding and is a candidate therapeutic target to prevent or treat liver fibrosis

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
NEK7 couples SDHB to orchestrate respiratory chain electron transport homeostasis that impedes liver fibrosis

First author:
Sun Z

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65790-0

Reference:
Sun Z., Le S., Hua H., Ren Y., Zhu W., Wang X., Gu W., Huang S., Zhong D., Sun Y., Zhang Y., Zhang A. & Jia Z. NEK7 couples SDHB to orchestrate respiratory chain electron transport homeostasis that impedes liver fibrosis. Nature Communications. 2025;16:10751. https://doi.org/10.1038/s41467-025-65790-0

License:
CC BY 4.0 / Creative Commons Attribution 4.0 International License

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/nek7-sdhb-mitochondria-fibrosis

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-30.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content for core mechanistic claims and experimental outcomes: mitochondrial localization of NEK7 via MTS, NEK7–SDHB binding and complex II stabilization, consequences of NEK7 deficiency (RET, mtROS, membrane potential, respiration), fibrosis phenotypes in hepatocyte NEK7 knockout mice, rescue by NEK
- transcript topics: NEK7 mitochondrial localization and mitochondrial targeting sequences (MTS); NEK7–SDHB interaction and stabilization of mitochondrial complex II; NEK7 deficiency effects: RET, mtROS, membrane potential, respiration impairment; Spontaneous liver fibrosis in hepatocyte NEK7 knockout mice; NEK7 overexpression mitigates CCl4- and CDAHFD-induced liver fibrosis; RET inhibitors and ROS scavengers mitigate NEK7-deficiency–driven fibrosis

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- NEK7 localizes to mitochondria in hepatocytes via two mitochondrial targeting signal peptides (MTS).
- NEK7 directly binds SDHB and stabilizes the spatial conformation of complex II, supporting forward electron transport.
- NEK7 deficiency in hepatocytes induces RET, increases mtROS, increases membrane potential, reduces respiration, and leads to spontaneous liver fibrosis.
- Overexpression of NEK7 reduces liver fibrosis in both CCl4- and CDAHFD-induced models and restores mitochondrial morphology/function.
- NEK7’s protective effect is independent of NLRP3 inflammasome activation in hepatocytes.
- RET inhibitors and ROS scavengers alleviate NEK7 deficiency–driven fibrosis in vivo and in vitro.

QC result: Pass.

Shraim R et al., Nat Commun - A GWIS of 338,977 UK Biobank White British participants using a cumulative weighted ambient UVB measure identified 307 independent loci for 25-hydroxyvitamin D, including 162 novel variants. Key terms: vitamin D, gene-environment interaction, ambient UVB, GWAS, circadian rhythm.

Study Highlights:
The study linked a cumulative and weighted ambient UVB (CW-D-UVB) dose from TEMIS to each participant’s residence and blood draw date to model gene-environment interaction on standardized log-transformed 25OHD in 338,977 White British UK Biobank participants. Genome-wide marginal, interaction, and joint tests identified 307 independent variants associated with 25OHD, 162 of which were novel to prior GWAS. SNP-heritability increased across CW-D-UVB quintiles from 8.48% in the lowest to 15.56% in the highest and was higher in participants reporting ≥3 hours outdoors. Functional annotation implicated known vitamin D genes, glucuronidation and lipid metabolism pathways, and circadian clock genes including BMAL1 and NPAS2, with replication showing concordant effect directions in European, LURIC, and ORCADES cohorts

Conclusion:
Incorporating a precise ambient UVB exposure measure increased power to detect genetic effects on vitamin D status and revealed GxE interactions linking vitamin D biology with lipid metabolism and circadian regulation

Music:
Enjoy the music based on this article at the end of the episode.

First author:
Shraim R

Journal:
Nat Commun

DOI:
10.1038/s41467-025-65820-x

Reference:
Shraim R, Timofeeva M, Wyse C, van Geffen J, van Weele M, Romero-Ortuno R, Lopez LM, Pilz S, März W, Fletcher BS, Kleber ME, Wilson JF, Theodoratou E, Dunlop MG, McManus R, Zgaga L. Genome-wide gene-environment interaction study uncovers 162 vitamin D status variants using a precise ambient UVB measure. Nat Commun. 2025;16:10774. https://doi.org/10.1038/s41467-025-65820-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

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

Episode link: https://basebybase.com/episodes/uvb-gxe-vitamin-d-variants

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-29.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of: (i) construction of the CW-D-UVB exposure metric and study scale; (ii) genome-wide and interaction results for 25OHD; (iii) heritability gradient with UVB; (iv) key genes and pathways (circadian clock, UGT glucuronidation, lipid metabolism); (v) replication across European UKB, LUR
- transcript topics: CW-D-UVB environmental exposure measurement; GWAS results for 25OHD (marginal, interaction, joint tests); Gene-environment interactions with UVB; SNP-based heritability gradient across UVB quintiles; Circadian clock genes BMAL1/ARNTL and NPAS2; UGT glucuronidation and lipid metabolism pathways

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CW-D-UVB: cumulative, weighted ambient UVB dose over 135 days prior to sampling
- Cohort: 338,977 UK Biobank participants of White British ancestry
- Identified 307 independent 25OHD variants; 162 novel variants
- SNP-based heritability (h2SNP) increases with ambient UVB: 8.48% in CW-D-UVB Q1 vs 15.56% in Q5; outdoors ≥3h: 11.01%
- 20 variants show GxE interaction with UVB exposure; novel interaction at COPB1 and PSMA1; circadian clock genes BMAL1/ARNTL and NPAS2 implicated
- Functional annotation: enrichment in lipid metabolism pathways and glucuronidation; liver-tissue enrichment

QC result: Pass.

Godin P et al., Nature Communications - A single intramuscular injection of an AAV9 vector encoding feline anti‑Müllerian hormone (fcMISv2) in prepubertal kittens produced sustained supraphysiological AMH, was well tolerated, and prevented breeding‑induced ovulation and pregnancy in adult females. Key terms: gene therapy, anti-Müllerian hormone, feline sterilization, adeno-associated virus, population control.

Study Highlights:
Twelve 2–3 month-old kittens received a single IM dose of AAV9-fcMISv2 (low or high dose) or empty AAV9 and were monitored for up to 21 months for females and 10 months for males. Treated animals showed rapid viral clearance, no clinically significant systemic inflammation or growth impairment, and no anti‑AMH antibody response. Females developed sustained elevated AMH, had reduced fecal estrogen and progestogen metabolites, increased circulating LH, lacked luteal phases, displayed altered estrous behavior, and none of the treated females became pregnant during a year-later 4‑month mating trial. Males completed puberty, maintained normal testis development, semen parameters, and in vitro fertilizing capacity, indicating preserved male fertility.

Conclusion:
Prepubertal intramuscular delivery of AAV9-fcMISv2 is a safe, durable, female-specific sterilant in domestic cats that prevents breeding-induced ovulation and pregnancy while sparing male reproductive function

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Gene therapy delivery of anti‑Müllerian hormone in prepubertal female domestic cats induces long-term sterilization.

First author:
Godin P

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65780-2

Reference:
Godin P., Nagykery N., Sicher N., Barnes J. L., Miller A. G., Bunner C., Thompson A. K., Kano M., Gao G., Wang D., Donahoe P. K., Rhodes L., Brake D. A., Conlon T. J., Swanson W. F., Vansandt L. M. & Pépin D. Gene therapy delivery of anti‑Müllerian hormone in prepubertal female domestic cats induces long-term sterilization. Nat Commun. 2025;16:10747. https://doi.org/10.1038/s41467-025-65780-2

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/

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/aav9-fcmisv2-sterilization-cats

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-28.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing vectored contraception, prepubertal kitten treatment, sustained AMH production, safety in both sexes, mating trial outcomes, hormonal and uterine changes, and observed behavioral aspects.
- transcript topics: Vectored contraception and AMH target; Prepubertal AAV9-fcMISv2 administration in kittens; Safety and immunogenicity in cats; Durable AMH production and pharmacokinetics; Block of ovulation and absence of luteal phases; Mating trial outcomes and pregnancy prevention

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Prepubertal AAV9-fcMISv2 injection yields sustained supraphysiological AMH production and sterilization in female kittens
- Single low- or high-dose intramuscular injection with follow-up up to 21 months in females and ~9–10 months in males
- 100% pregnancy prevention in treated females during a mating trial (no pregnancies in treated group vs controls)
- No anti-AMH antibodies detected in treated cats
- Males show normal puberty, testicular development, and fertility parameters
- Treated females exhibit smaller uterine horn diameters post-puberty, suggesting protective effects

QC result: Pass.

Pineda PS et al., Nature Communications - A telomere-to-telomere Wagyu assembly uncovers a natural neocentromere on the cattle X formed by inverted repeats and transposable element expansion, adds hundreds of new genes, and improves variant discovery. Key terms: cattle genomics, neocentromere, centromere evolution, telomere-to-telomere, structural variants.

Study Highlights:
The UOA_Wagyu_1 haplotype-resolved assembly includes a complete X chromosome and four T2T autosomes, adding 431 Mb relative to the ARS-UCD2.0 reference and annotating 738 new protein-coding genes. The cattle X centromere spans ~12 Mb and is a natural neocentromere composed mainly of highly identical inverted repeats and transposable elements, lacking canonical bovine satellite arrays and showing low CENP-A signal. The BTAX centromere exhibits CpG depletion and elevated TpG consistent with TE expansion followed by methylation and CpG deamination, and all 37 centromeric protein-coding genes are expressed in testes. Using UOA_Wagyu_1_Y increased mapping rates for Wagyu reads and enabled discovery of 49,610 structural variants from 20 animals, revealing Wagyu-specific SV and PAV hotspots overlapping genes enriched for olfactory transduction.

Conclusion:
A breed-specific T2T cattle genome reveals a dynamic, TE-rich X neocentromere with testis-expressed genes and substantially improves structural variant discovery for Wagyu populations

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Insights into natural neocentromere evolution from a cattle T2T X chromosome

First author:
Pineda PS

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65778-w

Reference:
Pineda PS, MacPhillamy C, Ren Y, Chen T, Zhong L, Adelson DL, Dessaix C, Perez-Silva J, Haggerty L, Martin FJ, Bottema CDK, Pitchford WS, Rosen BD, Smith TPL, Low WY. Insights into natural neocentromere evolution from a cattle T2T X chromosome. Nature Communications. 2025;16:10745. https://doi.org/10.1038/s41467-025-65778-w

License:
CC BY 4.0 International License

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

Official website https://basebybase.com

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

Episode link: https://basebybase.com/episodes/wagyu-t2t-x-neocentromere

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's core scientific claims as presented in the article, focusing on BTAX assembly, centromere architecture, epigenetics, neocentromere formation, gene content within BTAX, X-Y PAR, and improvements in SV discovery and mapping.
- transcript topics: BTAX assembly and haplotype-resolved X chromosome (UOA_Wagyu_1_Y); BTAX centromere structure: inverted repeats and TE content; absence of bovine satellites; Epigenetic features: CENP-A signal, methylation, CpG/TpG dynamics; Two-step model for neocentromere formation: TE expansion followed by CpG deamination; BTAX centromere gene content: 37 centromere genes, 24 newly identified; testes expression; Wagyu SV discovery and improved mapping rates using the Wagyu reference

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- BTAX centromere is a natural neocentromere located on the cattle X chromosome
- BTAX centromere consists primarily of highly identical inverted repeats and transposable elements
- BTAX centromere lacks bovine satellite repeats
- BTAX centromere exhibits low CENP-A signal and CpG depletion with low methylation relative to TpG dinucleotides
- Two-step model for neocentromere formation: TE expansion followed by CpG deamination
- BTAX contains 37 centromere genes; 24 of these are newly identified; all centromere genes are expressed in testes

QC result: Pass.