Base by Base

Gustavo Barra
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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. 1 day ago

    450: ASOs que reduzem PrP prolongam a sobrevida [PT]

    Raymond GJ et al., JCI Insight - This episode covers a 2019 study showing that sequence-specific antisense oligonucleotides (ASOs) targeting the prion protein (PrP) mRNA, delivered by bolus intracerebroventricular injection, lower PrP levels in the CNS, slow neuropathology, and markedly extend survival in prion-infected wild-type mice when given prophylactically or even near symptom onset. Key terms: antisense oligonucleotide, prion disease, prion protein, intracerebroventricular, mouse model. Study Highlights: Two PrP-targeting ASOs (active ASO 1 and 2) reduced Prnp mRNA and PrP protein across brain regions and produced robust survival benefits in RML prion–infected wild-type mice, with prophylactic extension of lifespan by 61%–98%. A single bolus dose given at 120 days post-infection (near clinical onset) extended survival by 55% and slowed symptomatic progression. A non‑targeting control ASO showed no efficacy, indicating a sequence-specific, on‑target mechanism mediated by RNase H–dependent RNA lowering. Some tolerability issues were observed with particular ASO candidates at late-stage treatment, but at least one active ASO was both tolerated and effective. Conclusion: Bolus CNS delivery of sequence-specific PrP‑lowering ASOs lowers PrP, delays prion neuropathology, and substantially extends survival in infected mice, supporting further development of PrP‑lowering therapy and use of CSF PrP as a pharmacodynamic biomarker. Music: Enjoy the music based on this article at the end of the episode. Article title: Antisense oligonucleotides extend survival of prion-infected mice First author: Raymond GJ Journal: JCI Insight DOI: 10.1172/jci.insight.131175 Reference: Raymond GJ, Zhao HT, Race B, et al. Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight. 2019;4(16):e131175. doi:10.1172/jci.insight.131175. 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/450-prp-lowering-asos-prion-mice QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-24. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections describing ASOs targeting Prnp, PrP reduction, i.c.v. bolus delivery, prophylactic vs late-stage treatment in prion-infected mice, and the role of control ASOs and sequence specificity. - transcript topics: Antisense oligonucleotides targeting Prnp mRNA; PrP reduction and PrP biology; Intracerebroventricular bolus delivery vs continuous infusion; Prophylactic vs late-stage treatment in prion-infected mice; Sequence specificity and non-targeting control ASO; Pharmacodynamic biomarker: CSF PrP measurement 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: - ASOs targeting Prnp mRNA discussed as a therap...

  2. 1 day ago

    449: siRNA divalente para doença priônica [PT]

    Gentile JE et al., Nucleic Acids Research - Discovery and preclinical development of divalent siRNA candidates targeting PRNP, identifying 2439-s4 as a potent, durable human PRNP-lowering drug candidate with IND clearance. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, RNAi therapeutics. Study Highlights: Authors screened divalent siRNA libraries and identified mouse-targeting 1682-s4 that lowered brain PrP to ~49% and extended survival in prion-infected mice when dosed pre- or post-symptomatically. They generated human PRNP transgenic mouse lines (Tg25109, Tg26372) and nominated 2439-s4, which reduced whole-hemisphere human PrP to as low as 17% after a single dose. Mechanistic analysis showed that the s4 scaffold’s fixed 3' UU tail and exNA terminal linkages each contributed to superior potency and durability versus other scaffolds. GLP toxicology in rats and dogs found no significant adverse findings and the US FDA cleared an IND to advance 2439-s4 to clinical trials. Conclusion: Divalent siRNA 2439-s4 is a potent, durable PRNP-lowering candidate with favorable preclinical safety and regulatory clearance to proceed to clinical testing. Music: Enjoy the music based on this article at the end of the episode. Article title: Divalent siRNA for prion disease First author: Gentile JE Journal: Nucleic Acids Research DOI: 10.1093/nar/gkag287 Reference: Gentile JE, Corridon TL, Serack FE, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/divalent-sirna-prion-disease QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-24. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections covering PRNP biology, divalent siRNA mechanism (s4 scaffold with UU tail and exNA), lead sequences (1682-s4 and 2439-s4), human PRNP transgenic mice models, intrathecal delivery, RT-qPCR and ELISA readouts, PK/PD durability, prion-infected survival data, and IND status. - transcript topics: Prion biology and PRNP as therapeutic target; Divalent siRNA mechanism and s4 scaffold features (UU tail, exNA); Lead sequences 1682-s4 and 2439-s4 and in vivo screening; Transgenic human PRNP mice Tg25109 and Tg26372; Intrathecal delivery and brain distribution; Analytical readouts: RT-qPCR and PrP ELISA 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: - DOI canonical form 10.1093/nar/gkag287 - Article title: Divalent siRNA for prion disease - Journal: Nucleic Acids Research - License: Creative Commons Attribution 4.0 International License (CC BY 4.0) - Lead sequences identified: 1682-s4 (mouse Prnp) and 2439-...

  3. 1 day ago

    448: PrP‑lowering ASOs prolong survival in prion‑infected mice

    Raymond GJ et al., JCI Insight - This study tests antisense oligonucleotides (ASOs) targeting Prnp in wild‑type mice infected with RML prions and shows that sequence‑specific PrP lowering by bolus i.c.v. ASO dosing delays disease and extends survival, even when given near clinical onset. Key terms: prion disease, antisense oligonucleotide, PrP lowering, mouse model, intracerebroventricular delivery. Study Highlights: Two sequence‑specific ASOs targeting mouse Prnp lowered Prnp mRNA and PrP protein in brain and delayed neuropathology compared with a non‑targeting control. Prophylactic bolus i.c.v. dosing given every 2–3 months extended survival by 61%–98%. A single ASO dose at 120 days post‑infection, near expected symptom onset, extended survival by 55% and slowed symptomatic progression. Control ASO showed no benefit, supporting RNA‑lowering as the mechanism of action. Conclusion: Bolus intracerebroventricular delivery of PrP‑targeting ASOs lowers PrP via RNase H–mediated mRNA degradation, slows accumulation of misfolded PrP, and substantially extends survival in prion‑infected mice, including when treatment is initiated near clinical onset. Music: Enjoy the music based on this article at the end of the episode. Article title: Antisense oligonucleotides extend survival of prion‑infected mice First author: Raymond GJ Journal: JCI Insight DOI: 10.1172/jci.insight.131175 Reference: Raymond GJ, Tran Zhao H, Race B, Raymond LD, Williams K, Swayze EE, Graffam S, Le J, Caron T, Stathopoulos J, O’Keefe R, Lubke LDL, Reidenbach AG, Kraus A, Schreiber SL, Mazur C, Cabin DE, Carroll JB, Minikel EV, Kordasiewicz H, Caughey B, Vallabh SM. Antisense oligonucleotides extend survival of prion‑infected mice. JCI Insight. 2019;4(16):e131175. https://doi.org/10.1172/jci.insight.131175. 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/prp-lowering-asos-prolong-survival-ep448 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing PrP biology, ASO mechanism (RNA lowering vs aptameric), delivery strategy, prophylactic and late-stage efficacy, control experiments, neuropathology, and translational implications. - transcript topics: Prion biology and PrP involvement; ASO mechanism: RNA lowering vs aptameric effects; Delivery methods: bolus i.c.v. vs osmotic pumps; Prophylactic ASO efficacy in mice (onset delay, survival extension); scrambled control ASO vs active ASOs; Late-stage (120 dpi) ASO efficacy and ASO2 toxicity QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 5 - 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: - ASOs lowered Prnp mRNA and reduced PrP protein in brain regions - Prophylactic ASO... Chapters (00:00:00) - The genetic silencing approach to Creutzfeldt-Jak(00:02:27) - What is Prion Disease?(00:06:16) - How to Turn off prion disease's spread(00:11:54) - AsO 1, the scrambled ASO(00:12:47) - ASO2 delays the RML prion progression by nearly three(00:17:14) - The neuroscience of prion disease(00:21:11) - Thanks for listening to Prion Disease Podcasts(00:22:35) - Silence the Spark

  4. 1 day ago

    447: Divalent siRNA for prion disease

    Gentile JE et al., Nucleic Acids Research - This study develops and tests divalent siRNA molecules that lower prion protein (PrP) in the brain, identifies a potent human-targeting candidate (2439-s4), demonstrates survival benefit in prion-infected mice with a mouse-targeting tool compound, and reports IND-enabling toxicology supporting clinical testing. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, transgenic mouse. Study Highlights: The authors identify a mouse Prnp-targeting divalent siRNA (1682-s4) that lowers brain PrP to ~49% residual and extends survival in RML prion–infected mice (2.7-fold when dosed presymptomatically, 64% increase after a single symptomatic dose). They generate two transgenic mouse lines expressing full human PRNP (Tg25109, Tg26372) and use them to discover human-targeting siRNA 2439, optimized as 2439-s4, which lowers whole-hemisphere human PrP to 17% residual at 348 μg and to 49% at 52 μg. Chemical features—an exNA terminal linkage and a fixed 3' UU tail—each contribute substantially to potency, and a single dose shows durability out to months while 1–2% of CSF dose is retained in brain. GLP toxicology in rats and dogs identified no major liabilities and the FDA cleared an IND to advance 2439-s4 to human trials. Conclusion: Divalent siRNA can achieve deep, durable PrP lowering in the CNS, confer disease-modifying benefit in a mouse prion model, and yield a clinical candidate (2439-s4) with supportive nonclinical toxicology and regulatory clearance for a first-in-human study. Music: Enjoy the music based on this article at the end of the episode. Article title: Divalent siRNA for prion disease First author: Gentile JE Journal: Nucleic Acids Research DOI: 10.1093/nar/gkag287 Reference: Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZC, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/divalent-sirna-prion-disease QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections covering: divalent siRNA mechanism and CNS delivery; mouse Prnp knockdown and survival data for 1682-s4; human PRNP targeting with 2439-s4 in transgenic mice; scaffold optimization (exNA, fixed tail, PS); PK/PD and IND-enabling GLP tox; and FDA IND clearance. - transcript topics: Divalent siRNA mechanism and CNS delivery; Mouse Prnp knockdown and survival in prion model with 1682-s4; Human PRNP transgenic mouse models Tg25109/Tg26372 and lead candidate 2439-s4; Chemical scaffold optimization (PS reductions, exNA, fixed UU tail); IND-enabling GLP toxicology and FDA IND clearance; PK/PD metrics (IC50 ~1.2 μg/g; tissue retention 1–2% dose) QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata checks passed: 4 - metadata is... Chapters (00:00:02) - Basses by Bass(00:00:28) - The science of Creutzfeldt Jakob Disease(00:05:56) - Turning off the prion protein(00:13:13) - Quantum therapy for prion disease(00:20:18) - CJD Foundation on Lito Sousa(00:21:32) - Cut the Thread

  5. 1 day ago

    446: Cilia, Synuclein, and Survival: G51D Mice Reveal a Shared Parkinson’s Pathway

    Lin Y‑E et al., PNAS - Knock‑in SncaG51D/G51D mice show selective loss of primary cilia in specific striatal interneurons, astrocytes, piriform cortex PV cells and olfactory basal stem cells, with concomitant reduction in Hedgehog‑dependent neurotrophic signaling linked to Parkinson’s disease vulnerabilities. Key terms: alpha-synuclein, primary cilia, neurotrophic signaling, Parkinson’s disease, G51D mouse. Study Highlights: Using SncaG51D/G51D knock‑in mice, the authors document selective loss of primary cilia in striatal cholinergic and parvalbumin interneurons and in ALDH1L1+ astrocytes while medium spiny neuron ciliation is preserved. Cilia loss associates with reduced Ptch1 expression and decreased production of neurotrophic factors (GDNF, NRTN, BDNF), indicating impaired Hedgehog signaling. PV neurons in the piriform cortex and horizontal basal cells in the olfactory epithelium also lose cilia and show reduced NRTN, whereas multiciliated olfactory sensory neurons remain intact. Higher phospho-Ser129 α‑synuclein correlates with reduced ciliation within ChAT neurons but does not predict vulnerability across all cell types. Conclusion: G51D α‑synuclein drives cell type–selective loss of primary cilia and impaired cilia‑dependent neurotrophic signaling, highlighting disrupted ciliary signaling as a convergent pathogenic pathway in Parkinson’s disease. Music: Enjoy the music based on this article at the end of the episode. Article title: Selective loss of primary cilia and neurotrophic signaling in G51D α- synuclein mice highlights a common pathway to Parkinson’s disease First author: Lin Y‑E Journal: PNAS DOI: 10.1073/pnas.2619797123 Reference: Lin Y‑E, Chiang C‑Y, et al., Selective loss of primary cilia and neurotrophic signaling in G51D α‑synuclein mice highlights a common pathway to Parkinson’s disease. Proc Natl Acad Sci U S A. 2026;123:e2619797123. doi:10.1073/pnas.2619797123 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/cilia-synuclein-g51d-parkinsons-pathway QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantive auditing of the transcript’s reporting of the G51D α-synuclein mouse model findings, including: cell-type–specific cilia loss, Hedgehog signaling impairment, neurotrophic factor downregulation, olfactory system involvement (piriform cortex and olfactory epithelium), pS129-α-synuclein correlations, and thera - transcript topics: G51D α-synuclein knock-in mouse model; Cell-type specific loss of primary cilia in striatum (ChAT and PV interneurons) and astrocytes; Hedgehog signaling impairment and Ptch1 transcription; Downregulation of neurotrophic factors: GDNF, NRTN, BDNF; Olfactory system involvement: piriform cortex PV neurons and Neurturin downregulation; Olfactory epithelium ciliopathy: horizontal basal cells vs olfactory sensory neurons QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core... Chapters (00:00:20) - What is the silent process of Parkinson's disease?(00:03:16) - Parkinson's disease: The genetic mystery(00:07:35) - Parkinson's in a mouse(00:13:05) - Parkinson's neurodegeneration causes loss of smell(00:16:43) - Parkinson's disease's toxic alpha synuclein paradox(00:24:03) - Parkinson's disease: The cellular blackout(00:25:47) - Bring Back the Signal, Let it Come Alive

  6. 3 days ago

    445: Why Thymine Survived the UV: Photodamage Pathways Explained

    Khosh Abady K et al., PNAS - Spectroscopic comparison of thymine and uracil under 265 nm UVC shows thymine is more photoreactive and absorbs more primordial UVC, yet channels damage into reversible CPDs rather than irreversible (6-4) lesions, supporting an evolutionary 'molecular sunscreen' role. Key terms: UV photodamage, thymine, uracil, cyclobutane pyrimidine dimer, origin of life. Study Highlights: The authors used absorption, fluorescence, and Raman spectroscopy with 265 nm UVC irradiation to compare thymine and uracil photochemistry under controlled conditions. Thymine shows a faster overall absorbance decay (k = 0.174 min−1) than uracil (k = 0.064 min−1) and ~9% broader, redshifted absorption that increases overlap with primordial UVC. Thymine exhibits ~4.5× stronger intrinsic fluorescence and produces higher-amplitude photoproduct fluorescence while accumulating irreversible (6-4) photoproducts more slowly (k = 1.56 min−1) than uracil (k = 2.04 min−1). Raman markers distinguish CPD and (6-4) pathways and indicate thymine preferentially funnels damage into reversible CPD formation amenable to nonenzymatic self-repair. Conclusion: Thymine, though more photoreactive and exposed to higher primordial UVC flux, appears evolutionarily selected to localize UV damage into reversible lesions (CPDs) and provide molecular 'sunscreen' protection while enabling nonenzymatic self-repair, complementing later biochemical fidelity mechanisms. Music: Enjoy the music based on this article at the end of the episode. Article title: UV photodamage pathways and the evolutionary selection of thymine over uracil in early genetic systems First author: Khosh Abady K Journal: PNAS DOI: 10.1073/pnas.2615278123 Reference: Khosh Abady K, Karpourazar N, Rentzepis PM. UV photodamage pathways and the evolutionary selection of thymine over uracil in early genetic systems. PNAS. 2026. doi:10.1073/pnas.2615278123 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/uv-photodamage-thymine-vs-uracil QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-22. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections: background on RNA world and thymine vs uracil, experimental design with frozen-state bases, absorption/fluorescence/Raman results, and interpretation including CPD vs (6-4) pathways, molecular sunscreen hypothesis, evolutionary implications, and applications to pathogen detection/UV disinfe - transcript topics: RNA world background and thymine vs uracil photochemistry; Experimental design: frozen-ice state, 130 µM concentration, 265.3 nm narrowband UVC LED, -15 °C; Absorption spectra and photodegradation kinetics (k values for thymine and uracil); Fluorescence kinetics and photoproduct formation; Raman signatures for CPD and (6-4) photoproducts; Methyl group effects on base stacking and CPD bias QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 5 - claims flagged f... Chapters (00:00:00) - Base by Base(00:00:29) - Why DNA vs RNA was the ultimate solar hard drive(00:06:02) - The UV glow of early life(00:10:51) - Thiine protects the DNA from UV damage(00:16:00) - Molecular sunscreen: The UV protection(00:21:19) - How DNA protected its ancestors from the sun(00:24:26) - Make It Bend, Don't Let It Break

  7. 6 days ago

    444: Many-eyes or Sentinels? How Cost Curvature Shapes Collective Vigilance

    Pilgrim C et al., PNAS - A minimal analytical model shows that whether animal groups adopt distributed low-level vigilance (many-eyes) or concentrated high-vigilance roles (sentinels) depends on how individual vigilance costs scale with effort. The same dichotomy appears in selfish and cooperative groups and explains switching, edge effects, and turn-taking. Key terms: collective vigilance, many-eyes, sentinel behavior, vigilance costs, behavioral ecology. Study Highlights: The authors derive a minimal model where collective vigilance benefit is a function of summed individual vigilance and costs depend on individual effort. When vigilance costs are convex (steepening) many-eyes strategies with equal low vigilance across individuals are optimal; when costs are concave (flattening) sentinel strategies with vigilance concentrated in one or a few individuals are optimal. This outcome holds in both selfish (game-dynamic) and cooperative (group-optimal) contexts and is supported by simulations. Extensions reproduce behavioral switching with S-shaped costs, edge effects from heterogeneous costs, and turn-taking when energy state dynamics are included. Conclusion: The curvature of individual vigilance costs determines whether groups distribute vigilance across many members or concentrate it in sentinels; habitat structure that creates flattening costs (vantage points) favors sentinels, while uniform habitats with steepening costs favor many-eyes. Music: Enjoy the music based on this article at the end of the episode. Article title: Many-eyes and sentinels in selfish and cooperative groups First author: Pilgrim C Journal: PNAS DOI: 10.1073/pnas.2536017123 Reference: Pilgrim C, Bate AM, Sigalou A, Aellen M, Morford J, Warren E, Krupenye C, Biro D, Mann RP. Many-eyes and sentinels in selfish and cooperative groups. PNAS. 2026;123(33):e2536017123. doi:10.1073/pnas.2536017123 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/many-eyes-or-sentinels-cost-curvature-vigilance QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-19. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript sections describing the minimal model fi = b(S) − c(vi); S = ∑vi; cost-curvature (convex vs concave); environmental structure; selfish vs cooperative results; behavioral switching (sigmoidal costs); edge effects; turn-taking; energy-state dynamics; and discussed limitations. - transcript topics: Model of collective vigilance (fi = b(S) − c(vi)); Cost curvature and environmental structure (convex vs concave); Selfish vs cooperative group outcomes; Behavioral switching with sigmoidal costs; Edge effects and spatial positioning; Energy-state dynamics and turn-taking 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

  8. 18 Aug

    443: 5D‑ASO boosts exon 51 skipping and restores dystrophin in DMD models

    Feng P et al., PNAS - This paper describes a bipartite antisense oligonucleotide (5D‑ASO) design that appends a short 5′ splice site decoy tail to improve exon skipping, demonstrating robust efficacy for DMD exon 51 in cells, mice, and cynomolgus monkeys with a favorable safety profile. Key terms: antisense oligonucleotide, exon skipping, Duchenne muscular dystrophy, U1 snRNA decoy, dystrophin restoration. Study Highlights: The authors developed a bipartite ASO approach (5D‑ASO) that appends a short 5′ splice site–complementary tail to enhance exon skipping. An optimal 7–8 nt decoy appended to exon 51 ASOs markedly increased exon skipping in human cells and in multiple genetically modified mouse models, restoring dystrophin and improving muscle function. The lead MOE/PS 5D‑ASO showed durable tissue retention, dose‑dependent efficacy, and an overall favorable safety profile in mice and cynomolgus monkeys. The method was operative across multiple genes and exon targets, indicating broad applicability. Conclusion: Appending a short 5′ splice site decoy to exon‑targeting ASOs substantially increases exon‑skipping potency and therapeutic benefit in preclinical DMD models, supporting further clinical development of 5D‑ASO designs. Music: Enjoy the music based on this article at the end of the episode. Article title: An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy First author: Feng P Journal: PNAS DOI: 10.1073/pnas.2606494123 Reference: Feng P., Gao P., Meng S., Yuan Y., Krainer A.R., Hua Y. An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy. PNAS. 2026;123(33):e2606494123. doi:10.1073/pnas.2606494123 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 is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming: ❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01 ☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at 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/base-by-base-443-5d-aso-dmd QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-18. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the core narrative: Duchenne muscular dystrophy background; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy action; in vitro exon 51 skipping in RD cells; in vivo huEx51/huΔ52 mice data including dystrophin restoration; cynomolgus monkey efficacy/safety; off-target considerations; delivery - transcript topics: DMD background and dystrophin function; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy mechanism and splicing repression; In vitro exon skipping in RD cells (Etep-L8c and MOE-Etep); In vivo exon 51 skipping in huEx51/huΔ52 mice and dystrophin restoration; Cynomolgus monkey exon 51 skipping and safety 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: - 5D-ASO tail acts as a decoy to misdirect U1 snRNP...

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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
    451
  • Rating
    Clean
  • Copyright
    © Gustavo Barra
  • Show Website
    Base by Base

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