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. HÁ 23 H

    274: RPE-specific MCT2 gene delivery preserves cones and vision in rat and mouse models of retinitis pigmentosa

    Chandler LC et al., PNAS - AAV-mediated RPE expression of MCT2 in rat and mouse retinitis pigmentosa models increases RPE lactate uptake and prolongs cone photoreceptor survival and function. Study Highlights: Neonatal subretinal AAV8.Best1.MCT2 delivery was tested in multiple RP models (S334ter rats, FVB and P23H mice) and produced a statistically significant increase in surviving cones and transient preservation of optomotor visual acuity. The study combined AAV gene delivery with two-photon fluorescence lifetime imaging microscopy (FLIM) using LiLac and GlucoSnFR-TS biosensors to measure lactate and glucose in RPE tissue. MCT2 localized to apical and basolateral RPE membranes, MCT2-expressing RPE showed higher intracellular lactate and greater glucose accumulation consistent with increased lactate uptake and reduced glycolysis. These metabolic changes correlated with functional cone preservation across distinct genetic causes of RP, supporting a gene-agnostic metabolic rescue strategy. Conclusion: AAV-mediated, RPE-specific expression of MCT2 enhances lactate uptake into the RPE, shifts RPE metabolism toward higher intracellular lactate and glucose, and prolongs cone survival with transient preservation of cone-mediated function in multiple RP models. Music: Enjoy the music based on this article at the end of the episode. Reference: Chandler LC, Gardner A, Cepko CL. RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2421978122. https://doi.org/10.1073/pnas.2421978122 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/rpe-mct2-cone-survival Chapters (00:00:00) - Blending Genomics Into Your Life(00:00:28) - The starvation of RPE(00:02:48) - New science in retinal degeneration(00:03:56) - Gene therapy to save the retina(00:08:04) - Pigmented eyes to help sight?(00:10:25) - Genetics fixes blindness in mice(00:13:47) - A New way to save the brain(00:14:36) - Open the Gate, Let the Sugar Run

    19min

  2. HÁ 1 DIA

    273: CTVT-A acquires 15-Mb N-HT1 dicentric nuclear element via horizontal transfer

    Gori K et al., PNAS - In canine transmissible venereal tumor (CTVT), deep sequencing and cytogenetics identify a 15‑Mb horizontally transferred nuclear element (N-HT1) acquired ~2,000 years ago that is transcriptionally active. Study Highlights: The authors screened 174 transmissible tumor genomes, focusing on CTVT, DFT1, and DFT2, using deep short-read sequencing, long-read PacBio sequencing, structural variant analysis, and metaphase FISH. In CTVT-A they discovered a 15-Mb dicentric element (N-HT1) assembled from 11 fragments of six chromosomes that forms the short arm of a small submetacentric chromosome after centromeric fusion. Mutation density and CpG-based dating place N-HT1 acquisition about 2,000 years ago, and transcriptome allele deconvolution shows N-HT1 is transcriptionally active and adopts the CTVT expression profile. Functional interrogation found no clear oncogenic drivers on N-HT1, with at least one rescued gene (ARFGEF3) later inactivated, consistent with the element behaving as a likely neutral passenger. Conclusion: A single host-to-tumor nuclear horizontal transfer event was detected in sampled transmissible cancers: CTVT-A acquired a 15-Mb N-HT1 element that is transcriptionally active but shows no clear evidence of positive selection. Music: Enjoy the music based on this article at the end of the episode. Reference: Gori K., Baez-Ortega A., Strakova A., Stammnitz M.R., Wang J., Chan J., Hughes K., et al. Horizontal transfer of nuclear DNA in transmissible cancer. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2424634122. https://doi.org/10.1073/pnas.2424634122 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/ctvt-n-ht1-horizontal-transfer Chapters (00:00:00) - Blast by Bass(00:00:29) - Cancer Has Stealing DNA From Your Body(00:02:41) - Horizontal Transfer of nuclear DNA in transmissible cancer(00:07:24) - The ghost of a dog's genome(00:11:55) - Transmissible DNA in human cancer(00:14:08) - Step, Step, Close Hold

    19min

  3. HÁ 2 DIAS

    272: ADSL A429V reduces purine biosynthesis in brain and alters female mouse water-seeking behavior

    Ju X-C et al., PNAS - Human-specific ADSL A429V substitution and a common regulatory haplotype reduce ADSL activity and raise purine substrates in the brain, altering mouse behavior. Study Highlights: Model: mice humanized for ADSL carrying the modern-human A429V (with R428Q) were compared to wild-type littermates using ultraperformance LC–Orbitrap metabolomics and automated IntelliCage behavioral assays. Mechanistic/quantitative result: SAICAr and S-Ado concentrations increased up to ~2-fold in liver and 1.8–5.4-fold across cerebrum regions, and these increases correlated negatively with Adsl mRNA expression across tissues. Human genetics: a 7.8-kb haplotype (including rs8135371) at >97% carrier frequency is associated with lower ADSL expression, higher S-Ado in cerebrospinal fluid, and signals of positive selection. Functional implication: female humanized mice accessed water more efficiently under restricted conditions, linking reduced ADSL activity to altered behavior. Conclusion: Two genetic changes on the modern human lineage—a nearly fixed A429V amino acid substitution and a common regulatory haplotype—have reduced ADSL activity and expression, increasing purine substrates particularly in the brain and producing measurable behavioral effects in mice. Music: Enjoy the music based on this article at the end of the episode. Reference: Ju X-C, Huttner W, Ågren R, Machado LC, Xing J, Lee S-Y, Siepel A, Azama C, Roy MC, Pääbo S, Endo T, Fukunaga I, Zeberg H. The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior. Proc. Natl. Acad. Sci. U.S.A. 2025.122:e2508540122. https://doi.org/10.1073/pnas.2508540122 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/adsl-a429v-purine-brain

    22min

  4. HÁ 4 DIAS

    271: Rising EA PGI prediction of educational attainment across 1946–1970 British birth cohorts and socioeconomic interaction

    Morris TT et al., PNAS - EA and cognition polygenic indexes (PGIs) in three British birth cohorts show EA PGI associations with years of education increased from 1946–1970 and were strongest in advantaged socioeconomic backgrounds. Study Highlights: Using three nationally representative British birth cohorts born 1946, 1958, and 1970, the authors analyzed polygenic indexes for educational attainment (EA) and cognition. They generated PGIs with clumping-and-thresholding (PRSice2) and LDpred2, used multiple imputation and inverse probability weighting, and estimated linear models including cohort-by-PGI interactions. EA PGI associations increased from approximately 0.44 to 0.67 years of education per 1-SD and incremental R2 rose from 3.5% to 5.1% across cohorts, while cognition PGI associations were broadly stable. There was strong evidence of gene–environment interaction: returns to EA genetic liability were disproportionately larger among those born into more advantaged socioeconomic backgrounds. Conclusion: Across three British birth cohorts born 1946–1970, genetic liability indexed by an EA PGI became more predictive of years of completed education while cognition PGI prediction remained stable, and EA PGI effects were amplified in advantaged socioeconomic contexts. Music: Enjoy the music based on this article at the end of the episode. Reference: Morris TT, Wright L, Shireby G, Bann D. Genetic associations with education have increased and are patterned by socioeconomic context: Evidence from 3 studies born 1946–1970. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2516460123. https://doi.org/10.1073/pnas.2516460123 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/ea-pgi-cohort-socioeconomic-interaction Chapters (00:00:00) - Genetics and the socioeconomic gap(00:04:36) - The genetic link between school and success(00:07:42) - Genetics and educational success(00:11:42) - The Wealthy Kids and the Poor(00:12:56) - The genetics of intelligence and personality(00:15:38) - Open Access: Science Podcast(00:16:31) - Inheritance

    20min

  5. HÁ 4 DIAS

    270: Human Topoisomerase IIIα–RMI1–RMI2 (TRR) processively relaxes negatively supercoiled DNA measured by optical tweezers

    Spakmana D et al., H., Hickson I. D., Peterman E. J. G., Wuite G. J. L., King G. A. Mechanistic basis for relaxation of DNA supercoils by human topoisomerase IIIα–RMI1–RMI2. Proc. Natl. Acad. Sci. U.S.A - Optical tweezers and fluorescence imaging show human Topoisomerase IIIα–RMI1–RMI2 (TRR) processively relaxes highly negatively supercoiled DNA faster than PICH loops. Study Highlights: Using torsionally constrained end-closed λ-DNA in a multichannel flow cell, the authors combined Optical DNA Supercoiling (ODS), dual-trap optical tweezers, and fluorescence imaging to measure supercoiling density and visualize TRR binding in real time. They find TRR relaxes hyper-negatively supercoiled DNA in a highly processive manner, with single TRR complexes performing thousands (>3,000) of strand-passage reactions and exhibiting a force-dependent rate described by an Arrhenius relation (δ ≈ 1.1–1.4 nm in ensemble and single-molecule fits). Ensemble TRR activity was ~10-fold lower than E. coli TopoI under the same conditions, while single- complex rates indicate a single TRR can relax PICH-generated negative loops within the reported loop lifetime. These results support a mechanistic role for TRR in relaxing PICH-generated negative supercoils that could facilitate ultrafine anaphase bridge resolution. Conclusion: Human topoisomerase IIIα–RMI1–RMI2 (TRR) relaxes highly negatively supercoiled DNA in a force-dependent, highly processive manner and can act within the lifetime of PICH-generated negative loops, supporting a role in ultrafine anaphase bridge resolution. Music: Enjoy the music based on this article at the end of the episode. Reference: Spakmana D., Biebricher A. S., Bizard A. H., Hickson I. D., Peterman E. J. G., Wuite G. J. L., King G. A. Mechanistic basis for relaxation of DNA supercoils by human topoisomerase IIIα–RMI1–RMI2. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2406949123. Published January 23, 2026. https://doi.org/10.1073/pnas.2406949123 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/trr-supercoil-relaxation-optical-tweezers Chapters (00:00:00) - The Great Divide: When will the bridge break?(00:02:41) - Deep Dive: The mechanism of DNA supercoils by human to(00:03:49) - The Hidden Story of DNA(00:08:02) - How fast does TRR work on DNA?(00:12:40) - Why TRR Stuck to the DNA(00:17:30) - Who is the bouncer of DNA?

    22min

  6. HÁ 5 DIAS

    269: Mlh1–Pms1 endonuclease creates single-strand gaps to excise mispairs in S. cerevisiae MMR

    Palacio T et al., PNAS - Reconstituted Saccharomyces cerevisiae mismatch repair shows the Mlh1–Pms1 endonuclease directly generates single-strand gaps to excise mispairs independent of Exo1 and Rad27. Study Highlights: We reconstituted Saccharomyces cerevisiae mismatch repair with purified Msh2–Msh6 or Msh2–Msh3, Mlh1–Pms1, PCNA, RFC, RPA, and DNA polymerases and analyzed products by restriction mapping, Mung Bean nuclease, electron microscopy, and APOBEC3A deamination. The Mlh1–Pms1 endonuclease, activated by RFC-loaded PCNA and Mn2+, generates strand-specific single-strand gaps on the preexisting nicked strand. Electron microscopy and deamination mapping revealed a broad distribution of gap sizes with a peak around 128 ± 17 nucleotides and most gaps under 500 nucleotides. These gaps can be filled by DNA Polε or low levels of DNA Polδ, providing an Exo1- and Rad27-independent route for mispair excision and explaining redundancy among excision pathways. Conclusion: Mlh1–Pms1 catalyzes strand-specific single-strand gap formation that mediates Exo1- and Rad27-independent mispair excision in reconstituted S. cerevisiae mismatch repair. Music: Enjoy the music based on this article at the end of the episode. Reference: Palacio T, Calil FA, Bowen N, Griffith JD, Putnam CD, Kolodner RD. DNA mismatch repair mediated by Mlh1–Pms1 endonuclease-catalyzed mispair excision. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2528670122. https://doi.org/10.1073/pnas.2528670122 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/mlh1-pms1-gap-excision Chapters (00:00:00) - Base by Bass(00:00:29) - Who is the real repairman of DNA?(00:02:39) - The spell-checker for our DNA(00:04:23) - The ghost mechanic of DNA repair(00:07:02) - The secret to DNA repair(00:09:48) - How DNA repair works: The 3 pathways(00:13:43) - How to Stop cancer with a single drug

    21min

  7. HÁ 6 DIAS

    268: M493I in human β-cardiac myosin: SRX disruption, slow ADP release, and enhanced actin attachment

    Cail RC et al., PNAS - Recombinant human β-cardiac myosin M493I studied by optical trapping and stopped-flow kinetics disrupts the super-relaxed state and increases actin attachment and contractile force. Study Highlights: System: recombinant human β-cardiac heavy meromyosin (cHMM) expressed in C2C12 cells. Methods: ensemble actin gliding, stopped-flow kinetics, NADH ATPase, mantATP single-turnover, and single-molecule three-bead optical trap assays. Main results: M493I preserves Pi release and the two-step 4.7–5 nm working stroke but slows ADP release ~5-fold, doubles steady-state ATPase Vmax, reduces SRX occupancy (KSRX/DRX from ~0.33 to ~0.53), and prolongs actin attachment with increased high-force, long-duration interactions. Functional implication: the combined increase in DRX head availability and prolonged AM·ADP lifetimes produce higher sustained force and faster actin reattachment consistent with a mechanism for HCM hypercontractility and impaired relaxation. Conclusion: The M493I relay-helix mutation disrupts the SRX off state and, together with slowed ADP release and prolonged actin attachment, increases myosin head availability and force production, explaining its hypercontractile HCM phenotype. Music: Enjoy the music based on this article at the end of the episode. Reference: Cail RC, Barua B, Báez-Cruz FA, Winkelmann DA, Goldman YE, Ostap EM. A myosin hypertrophic cardiomyopathy mutation disrupts the super- relaxed state and boosts contractility by enhanced actin attachment. Proc. Natl. Acad. Sci. U.S.A. 2025;122:e2521561122. https://doi.org/10.1073/pnas.2521561122 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/m493i-beta-myosin-srx-disruption Chapters (00:00:00) - Heart Hypertrophic Cardiomyopathy: The genetic puzzle(00:04:48) - Myosin motors: Do they Pull or Float?(00:07:50) - Heart Disease: M493I mutant causes heart to slow(00:12:16) - Heart dysrhythmias: The sticky insomniac motor(00:17:54) - Hold on Hold On

    22min

  8. 22 DE JAN.

    267: DNA base-pair opening modes and soliton-like loops revealed by hydrogen exchange

    Englander SW et al., PNAS - Hydrogen exchange (H-T and NMR H-H) on DNA and RNA reveals two distinct base-pair opening modes: single-base microsecond openings and multi-base millisecond soliton-like loops. Study Highlights: Systems studied include long polynucleotides (DNA, duplex RNA, synthetic long duplexes) and short oligonucleotides; key methods are H-T (tritium) exchange, stopped-flow H-D, and NMR H-H (water relaxation) measurements. H-T exchange of long polymers reports opening-limited EX1 imino exchange with kop ~1/s, reclosing kcl ~20/s and Kop ~10^-2 consistent with multi-base open loops with ms lifetimes. NMR H-H on short oligos reports catalyzable EX2 behavior dominated by single base-pair openings with kcl ~10^6/s and Kop ~10^-6 and microsecond lifetimes. The selective detection implies short oligonucleotides cannot host extensive loops while multi-base soliton-like loops in polynucleotides could dynamically expose sequences for protein or nucleic acid recognition. Conclusion: Both H-T and NMR H-H exchange provide accurate but complementary views: long polynucleotides exhibit frequent multi-base, ms-lived open loops (Kop ~10^-2, kcl ~20/s) while short oligonucleotides reveal rare single-base, μs-lived openings (Kop ~10^-6, kcl ~10^6/s). Music: Enjoy the music based on this article at the end of the episode. Reference: Englander SW. Nucleic acid base pair open states by hydrogen exchange. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2520855122. https://doi.org/10.1073/pnas.2520855122 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/dna-basepair-opening-soliton Chapters (00:00:00) - Papercast: The mystery of DNA(00:02:42) - Breaking down the mystery of DNA(00:03:26) - How does DNA open? The '(00:07:43) - DNA is Not Like Longer Strands(00:11:32) - The physics of DNA replication(00:16:10) - I'm 1% Open

    21min
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Sobre

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.

Informações

  • Criado por
    Gustavo Barra
  • Anos de atividade
    2025 - 2026
  • Episódios
    274
  • Classificação
    Livre
  • Copyright
    © Gustavo Barra
  • Site do podcast
    Base by Base