Base by Base

Gustavo Barra
  • 1.0 (1)
  • LIFE SCIENCES
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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

  1. 1D AGO

    248: Disruption of PIKfyve triggers lysosomal repair and mitochondrial adaptation

    ️ Episode 248: Disruption of PIKfyve triggers lysosomal repair and mitochondrial adaptation In this episode of PaperCast Base by Base, we explore 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 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. 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.castos.com/episodes/pikfyve-lysosome-mitochondria Episode Slug: pikfyve-lysosome-mitochondria Keywords: PIKfyve, PI4KIIα, PI(4)P, ULK1, lysosomal repair

    21 min

  2. 2D AGO

    247: Genome graphs reveal structural variation in M. tuberculosis

    ️ Episode 247: Genome graphs reveal structural variation in M. tuberculosis In this episode of PaperCast Base by Base, we explore Long-read assemblies and a pangenome reference graph uncover widespread structural variants that shape Mycobacterium tuberculosis evolution and contribute to drug resistance 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. 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: 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.castos.com/episodes/structural-variation-mtb-pangenome Episode Slug: structural-variation-mtb-pangenome Keywords: structural variation, pangenome graph, Mycobacterium tuberculosis, drug resistance, long-read sequencing

    21 min

  3. 3D AGO

    246: SV2A structural pharmacology and allosteric occlusion

    ️ Episode 246: SV2A structural pharmacology and allosteric occlusion In this episode of PaperCast Base by Base, we explore 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 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. 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 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 link: https://basebybase.castos.com/episodes/sv2a-allosteric-occlusion Episode Slug: sv2a-allosteric-occlusion Keywords: SV2A, allosteric modulation, cryo-EM, levetiracetam, padsevonil

    17 min

  4. 4D AGO

    245: Benchmarking DNA foundation models

    ️ Episode 245: Benchmarking DNA foundation models In this episode of PaperCast Base by Base, we explore 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. 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. 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 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 link: https://basebybase.castos.com/episodes/dna-foundation-models-benchmark Episode Slug: dna-foundation-models-benchmark Keywords: DNA foundation models, mean token embedding, sequence classification, variant effect, gene expression

    19 min

  5. 5D AGO

    244: NEK7 couples SDHB to preserve mitochondrial electron transport and limit liver fibrosis

    ️ Episode 244: NEK7 couples SDHB to preserve mitochondrial electron transport and limit liver fibrosis In this episode of PaperCast Base by Base, we explore 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 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. 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: 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 link: https://basebybase.castos.com/episodes/nek7-sdhb-mitochondria-fibrosis Episode Slug: nek7-sdhb-mitochondria-fibrosis Keywords: NEK7, SDHB, reverse electron transport, ROS, liver fibrosis Chapters (00:00:00) - How to prevent and treat liver scarring?(00:02:07) - Liver fibrosis: The mystery of NEK7(00:07:58) - Liver fibrosis: NeK7 protection(00:14:14) - Keep It Moving Forward

    18 min

  6. 6D AGO

    243: Genome-wide UVB GxE study finds 162 vitamin D variants

    ️ Episode 243: Genome-wide UVB GxE study finds 162 vitamin D variants In this episode of PaperCast Base by Base, we explore 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 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. 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 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 link: https://basebybase.castos.com/episodes/uvb-gxe-vitamin-d-variants Episode Slug: uvb-gxe-vitamin-d-variants Keywords: vitamin D, gene-environment interaction, ambient UVB, GWAS, circadian rhythm Chapters (00:00:00) - Quantifying the genetics of vitamin D(00:05:54) - The genetic basis of vitamin D deficiency(00:08:45) - Vitamin D genetic risk in winter(00:11:26) - Genetic determinants of vitamin D(00:12:48) - I'm Made of Clockwork Sun Lines

    18 min

  7. 12/28/2025

    242: AAV9-fcMISv2 gene therapy prevents pregnancy in female cats

    ️ Episode 242: AAV9-fcMISv2 gene therapy prevents pregnancy in female cats In this episode of PaperCast Base by Base, we explore 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 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. 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. Keywords: gene therapy, anti-Müllerian hormone, feline sterilization, adeno-associated virus, population control Chapters (00:00:00) - A single shot, long term contraceptive for cats(00:05:29) - The AMH treatment in cats(00:07:31) - AMH completely abrogated ovulation in cats(00:08:53) - Gene therapy for women's uterine health(00:09:31) - African cats: Sterilization by blocking ovulation(00:12:53) - Signal to Stillness

    18 min

  8. 12/27/2025

    241: Wagyu T2T reveals a cattle X neocentromere

    ️ Episode 241: Wagyu T2T reveals a cattle X neocentromere In this episode of PaperCast Base by Base, we explore 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 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. 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: 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 link: https://basebybase.castos.com/episodes/wagyu-t2t-x-neocentromere Episode Slug: wagyu-t2t-x-neocentromere Keywords: cattle genomics, neocentromere, centromere evolution, telomere-to-telomere, structural variants Chapters (00:00:00) - Finding the dark matter of cattle genetics(00:05:26) - The cattle genome: a mutational puzzle(00:10:09) - Strange centromere on the cattle X chromosome

    19 min
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About

Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time. Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.

Information

  • Creator
    Gustavo Barra
  • Years Active
    2025 - 2026
  • Episodes
    248
  • Rating
    Clean
  • Copyright
    © Gustavo Barra
  • Show Website
    Base by Base