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Lara MK et al et al., Nature Communications - Large GWAS in 836 outbred HS rats identifies six loci linked to cocaine self-administration traits, highlighting Ces1 carboxylesterase genes and other loci overlapping human substance-use genetics. Key terms: cocaine use disorder, GWAS, Heterogeneous Stock rats, Ces1, addiction-like behavior. Study Highlights:The study performed a genome-wide association analysis in 836 Heterogeneous Stock rats tested in extended-access cocaine self-administration paradigms and derived 27 behavioral traits. Six genome-wide significant loci were identified, including a chromosome 19 locus containing missense variants in Ces1c and Ces1d that are orthologous to human CES1 and associated with post-infusion interval. SNP-based heritability for traits was modest (h2 = 0.07–0.16) with the first LgA principal component showing the highest heritability (h2 = 0.16). Several loci contained coding variants and eQTL/sQTLs in brain regions, and one locus overlapped the rat homolog of human TRAK2. Conclusion:This largest-to-date rat GWAS of cocaine self-administration implicates drug-metabolizing carboxylesterases (Ces1c/Ces1d) and multiple neural genes in addiction-like behaviors, supports cross-species links to human SUD loci such as TRAK2, and highlights CES1-related pharmacological strategies as a potential avenue for follow-up. Music:Enjoy the music based on this article at the end of the episode. Article title:Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats First author:Lara MK et al Journal:Nature Communications DOI:10.1038/s41467-026-73694-w Reference:Lara MK et al., Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats. Nature Communications (2026). https://doi.org/10.1038/s41467-026-73694-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 On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/gwas-cocaine-hs-rats-ces1 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited portions of the transcript that cover: HS rat GWAS design and results; the chromosome 19 Ces1c/Ces1d locus and its link to post-infusion interval; metabolic role of Ces1 in cocaine breakdown; cross-species Trak2 findings; Rasd2/Gnas brain-region eQTLs; PC1 heritability; and broader discussion of implications an- transcript topics: Gwas in heterogeneous stock rats and six significant loci; Chromosome 19 Ces1c/Ces1d locus and post-infusion interval; Carboxylesterase Ces1 enzymes metabolizing cocaine; Trak2/TRAK2 cross-species overlap with human CUD; Rasd2 and Gnas expression in nucleus accumbens and cortex; LgA PC1 addiction-like behavior and heritability 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:- Six genome-wide significant associations identified for cocaine self-administration traits in HS rats- Chromosome 19 locus containing...

Dr. Sandra Kaufmann, The Kaufmann Anti-Aging Institute - Dr. Sandra Kaufmann — physician, scientist and athlete — set out to understand aging and fight it with science. This episode is a guided overview of her book, featured with the author's permission: why our cells age (mitochondria, genetic information systems, quality control and maintenance, immunity, and waste management) and the families of anti-aging molecules she reviews (resveratrol, astaxanthin, NAD, curcumin, metformin, melatonin and more) — framed as an informed, individualized approach rather than a quick fix. Key terms: aging, longevity, anti-aging molecules, cellular biology, Kaufmann Protocol. Study Highlights:The book maps aging onto cellular causes — declining mitochondria, genetic information systems, cellular quality control and maintenance, immune changes, and waste management — and then reviews the leading molecules and adjuvants that target these pathways. Dr. Kaufmann turns the science into the basis for an informed, personalized plan, stressing that it is not a diet or quick fix and that decisions about supplements should be made together with a physician. Conclusion:Aging has identifiable biological drivers, and a science-literate, individualized approach — discussed with a physician — can help people age more deliberately rather than passively. Presented as Dr. Kaufmann's perspective, featured with the author's permission. Title: The Kaufmann Protocol: Why We Age and How to Stop It Reference: Kaufmann, S.C. The Kaufmann Protocol: Why We Age and How to Stop It. Jacob Cerny (Ed.), Ross Goldstein (Illus.). Kaufmann Anti-Aging Institute, 2018. ISBN 978-0-692-08904-0. ISBN: 978-0-692-08904-0 License:This episode is a guided overview of the book "Why We Age and How to Stop It: The Kaufmann Protocol" by Dr. Sandra Kaufmann, featured and adapted with the kind permission of the author. 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/kaufmann-protocol-why-we-age QC:This episode is a guided overview of the book "Why We Age and How to Stop It — The Kaufmann Protocol" by Dr. Sandra Kaufmann, featured with the author's kind permission and reviewed for editorial accuracy. QC Summary:- verdict: pass- review mode: book overview (author-authorized)- framing: presented as the author's perspective and synthesis- note: educational content only — not medical advice; decisions about supplements should be made with a physician

Gätgens C et al., PNAS - This episode examines how DNA-intercalating molecules like daunorubicin block bacteriophage infection at an early stage, causing an abortive-infection-like outcome via toxic phage products and showing synergy with nucleic-acid targeting defenses. Key terms: daunorubicin, abortive infection, bacterial immunity, phage-host interactions, DNA intercalators. Study Highlights:Using the E. coli BASEL phage collection, the authors mapped taxon-specific phage sensitivities to daunorubicin and other intercalators. For the Tequintavirus Bas33, daunorubicin blocks infection after first-step transfer, restricting expression to pre-early genes and preventing genome replication. Continued expression of these pre-early host-takeover genes leads to host cell death driven by toxic phage products, a process described as mutual destruction. Daunorubicin can act synergistically with restriction-modification systems to prevent accumulation of toxic phage products and enable population survival. Conclusion:DNA-intercalating small molecules act as a chemical layer of bacterial antiphage defense that can block infection at defined stages and, depending on host context and additional immune systems, produce outcomes ranging from mutual destruction to population-level protection via synergy with nucleic-acid targeting defenses. Music:Enjoy the music based on this article at the end of the episode. Article title:DNA-intercalating antiphage molecules trigger abortive infection through mutual destruction and synergize with bacterial immunity First author:Gätgens C Journal:PNAS DOI:10.1073/pnas.2602073123 Reference:Gätgens C., Rackow B., Ernst L., et al. DNA-intercalating antiphage molecules trigger abortive infection through mutual destruction and synergize with bacterial immunity. PNAS. 2026;123(23):e2602073123. https://doi.org/10.1073/pnas.2602073123 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/daunorubicin-mutual-destruction QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the central mechanistic narrative and experimental results: daunorubicin action after first-step transfer, pre-early gene expression, mutual destruction phenotype, phage-specific sensitivity (Bas33 vs T4), and synergistic effects with RM systems EcoRV and EcoP1_I; plus methodological approaches and discussed li- transcript topics: DNA-intercalating chemical defense concept; Daunorubicin action on BASEL phage collection; First-step transfer and pre-early gene expression; Mutual destruction vs abortive infection phenotype; Phage taxonomic sensitivity patterns (Bas33 vs T4); Restriction-modification systems and daunorubicin synergy 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:- Daunorubicin blocks Bas33 infection after first-step transfer (FST), with transcription largely restricted to pre-ea...

PNAS - This study identifies crotonylation as a posttranslational modification of c-Myc that reduces its transcriptional and oncogenic activity. Key lysines K289 and K298 are crotonylated; loss of crotonylation (including a cancer-derived K298N mutant) enhances Skp2 binding and tumorigenesis. Key terms: c-Myc, crotonylation, Skp2, posttranslational modification, oncogenesis. Study Highlights:The authors mapped ten crotonylated lysine residues on c-Myc and identified K289 and K298 as critical sites. Mutating these residues (2R or 8R mutants) increased c-Myc transcriptional activity, cell proliferation, colony formation, and promoter occupancy. Mechanistically, loss of crotonylation strengthened c-Myc binding to the E3 ligase Skp2 and reduced binding to p14ARF, linking crotonylation status to Skp2-mediated activation and turnover. A cancer-derived K298N mutation recapitulated enhanced transcriptional activity and produced larger xenograft tumors in mice. Conclusion:Crotonylation at specific C-terminal lysines restrains c-Myc oncogenic activity by limiting Skp2 interaction; disruption of this modification (including K298N) promotes transcriptional activation and tumor growth. Music:Enjoy the music based on this article at the end of the episode. Article title:Crotonylation impedes c-Myc oncogenic activity Journal:PNAS DOI:10.1073/pnas.2530020123 Reference:https://doi.org/10.1073/pnas.2530020123 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/crotonylation-impedes-c-myc-activity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited core scientific narrative: discovery of c-Myc crotonylation in human cells, identification of K289 and K298, mutational analyses (2R/8R), mechanistic link to Skp2 and transcriptional activation, in vivo K298N mutation and xenograft data, gut microbiota and crotonyl-CoA biology, and structural context via AlphaF- transcript topics: c-Myc crotonylation in human cells; K289 and K298 crotonylation sites; crotonylation-deficient mutants 2R/8R and proliferation; Skp2 interaction and ARF competition; transcriptional activation and promoter occupancy; K298N cancer-derived mutant in vivo 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:- c-Myc is crotonylated in human cells at K289 and K298.- Crotonylation reduces binding of c-Myc to Skp2, dampening transcriptional activation.- Crotonylation-deficient mutants (2R and 8R) increase cellular proliferation and colony formation across multiple cell lines.- The cancer-derived K298N mutation shows increased transcriptional activity and oncogenic potential in vitro and in vivo.- K289R and K298R substitutions abolish crotonylation at these sites and enhance Skp2 binding while reducing ARF interaction.- AlphaFold predicts crotonylation drives a more compact, less disordered c-Myc conformation, imp...

Huang X et al., Proceedings of the National Academy of Sciences (PNAS) - This episode summarizes a PNAS study reporting CD163‑targeted lipid nanoparticles that deliver FAP‑specific CAR mRNA to liver macrophages in situ, producing CAR‑macrophages that clear activated hepatic stellate cells and promote fibrosis resolution in mouse models. Key terms: FAP‑CAR, macrophage, lipid nanoparticles, liver fibrosis, MMP12. Study Highlights:The authors engineered CD163 antibody–conjugated LNPs (αCD163/LNP‑FAPCAR) to selectively transduce liver macrophages with FAP‑targeting CAR mRNA, yielding in situ CAR‑macrophages. CAR‑M showed enhanced phagocytosis and cytotoxicity toward FAP+ hepatic stellate cells and activated Syk/MyD88/NF‑κB signaling, with induction of MMP12. In multiple mouse fibrosis models (CCl4, BDL, MCD diet), treatment reduced ECM and fibrosis markers, improved histology and hepatocyte regeneration, and reshaped macrophage subsets toward MMP12+ scar‑resolving states. Safety profiling showed no major organ toxicity in treated mice, though immunogenicity and off‑target distribution require further study. Conclusion:αCD163/LNP‑FAPCAR enables in situ generation of CAR‑macrophages that selectively eliminate FAP+ activated HSCs, reprogram macrophages toward reparative MMP12+ phenotypes, and reverse liver fibrosis in preclinical models, supporting further translational and safety evaluation. Music:Enjoy the music based on this article at the end of the episode. Article title:mRNA‑laden LNP‑enabled in situ CAR‑macrophage alleviates liver fibrosis via inhibiting activated HSCs and modulating the immune microenvironment First author:Huang X Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2534673123 Reference:Huang X, Wang J, Hao J, et al. mRNA‑laden LNP‑enabled in situ CAR‑macrophage alleviates liver fibrosis via inhibiting activated HSCs and modulating the immune microenvironment. Proc. Natl. Acad. Sci. U.S.A. 2026;123(22):e2534673123. doi:10.1073/pnas.2534673123. Published May 29, 2026. 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/in-situ-car-macrophage-liver-fibrosis QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections detailing αCD163/LNP-FAPCAR design, CAR-M macrophage generation in vivo, in vitro phagocytosis/cytotoxicity, in vivo fibrosis outcomes, scRNA-seq SAM/MMP12 reprogramming, human macrophage applicability, and safety considerations.- transcript topics: CD163-targeted LNPs delivering FAPCAR mRNA; CAR-M macrophage architecture (CD3zeta with CD28); In vitro phagocytosis and cytotoxicity against FAP+ cells; Syk/Myd88/NF-kB signaling and MMP12 induction; In vivo mouse liver fibrosis models and outcomes; Biodistribution and persistence of αCD163/LNP-FAPCAR 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:- Ta...

Andrade J et al., PNAS - Analysis of three long-term cohorts in the Philippines and Thailand shows antibody titers wane over years and that homotypic dengue reinfections are common and required to explain population-level age–titer patterns. Key terms: dengue, homotypic reinfection, antibody kinetics, cohort study, mathematical modelling. Study Highlights:The authors analyzed serology and PCR surveillance from three cohorts (N = 4,268) in Cebu, Philippines and Kamphaeng Phet, Thailand with up to 11 years of follow-up. Individual titers after infection show biexponential decay: a rapid short-term fall (~2 months half-life) followed by a slow long-term decline (half-life ~4–8 years) that slows with age. Catalytic models that allow waning homotypic immunity and reinfection are required to reproduce observed age-specific infection rates and mean titers, estimating many individuals experience multiple homotypic reinfections across life in high-endemic settings. Conclusion:Waning long-term antibody titers and consequent homotypic reinfections are a key feature of endemic dengue transmission; vaccines that mimic natural infection may not provide lifelong protection and control strategies should account for repeated immune-stimulating events across ages. Music:Enjoy the music based on this article at the end of the episode. Article title:Long-term antibody dynamics challenge the paradigm of lifelong homotypic immunity to dengue virus First author:Andrade J Journal:PNAS DOI:10.1073/pnas.2606206123 Reference:Andrade J, Mitard de Girardie A, Huang AT, et al. Long-term antibody dynamics challenge the paradigm of lifelong homotypic immunity to dengue virus. PNAS. 2026;123(22):e2606206123. doi:10.1073/pnas.2606206123 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/homotypic-reinfection-dengue QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-09. 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 dengue immunity dynamics, cohort data, subclinical infection prevalence, modeling of homotypic reinfection, age-related patterns, and public health/vaccine implications. Also checked limitations and caveats discussed in the article are echoed in the transcript.- transcript topics: DENV serotypes and lifelong immunity paradigm; Cohort data and serology methods (PRNT, HI); Subclinical infections and catalytic modeling; Two-phase antibody decay (short-term and long-term); Homotypic reinfection and population immunity; Age-specific infection risk and force of infection 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:- Three cohorts totaling N = 4,268 participants across Cebu, Philippines and Kamphaeng Phet, Thailand- Approximately 94% of infections are subclinical- Antibody titers show biexponential decay after infection: a rapid short-term drop followed by a slower long-term decline- Short-term h...

Peeters MKR et al., Proceedings of the National Academy of Sciences (PNAS) - A perspective outlining how genome doubling (polyploidy) reshapes genomes, phenotypes, and ecological interactions and how its immediate effects can be harnessed across agriculture, aquaculture, industrial biotechnology, and medicine to advance a sustainable bioeconomy. Key terms: polyploidy, bioeconomy, genetic diversity, stress tolerance, biotechnology. Study Highlights:Polyploidization (whole-genome duplication) often produces novel phenotypes by shifting gene expression, metabolism, and morphology, which can increase biomass, diversify metabolites, and enhance stress tolerance. The paper synthesizes applications across green, blue, white, and red bioeconomies, including crop improvement, algal biofuel and pharmaceutical production, polyploid industrial strains, and ploidy-based biocontainment in aquaculture. Practical methods discussed include induced polyploidy, doubled-haploid breeding, triploid sterility, and adaptive laboratory evolution. Outcomes are promising but variable and require careful phenotypic, ecological, and evolutionary assessment due to risks like genomic instability. Conclusion:Polyploidization is a shared mechanism that can generate increased genetic diversity, expanded metabolic capacity, and altered morphology useful across bioeconomy sectors, but its benefits are variable and must be paired with rigorous phenotypic and ecological evaluation to manage risks and guide responsible innovation. Music:Enjoy the music based on this article at the end of the episode. Article title:Polyploidy: A macromutational force pushing bioeconomic developments First author:Peeters MKR Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2522065123 Reference:Peeters MKR & Van de Peer Y (2026). Polyploidy: A macromutational force pushing bioeconomic developments. Proc. Natl. Acad. Sci. U.S.A. 123:e2522065123. https://doi.org/10.1073/pnas.2522065123 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/polyploidy-bioeconomy QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the core scientific content: mechanics of polyploidy, induction methods (Colchicine, DH breeding, triploidy, shocks), giga s effects, cross-domain applications (green/blue/white/red), and cancer-related polyploidy dynamics.- transcript topics: Polyploidy as a macro mutation and its continuum (auto- vs allo-polyploidy); Induction methods for polyploidy (Colchicine, chemical induction, DH breeding, triploidy, shocks); Gigas effect and biomass/bioproduct implications; Green bioeconomy: crops, biomass, and biofuels; Blue bioeconomy: triploid fish and polyploid algae; White bioeconomy: polyploid microbes in bioprocessing 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:- Polyploidy is a macromut...

Sarabia Olivera L et al., PNAS - A perspective that surveys how diverse stresses trigger whole‑genome doubling (polyploidy) across fungi, plants, and animals, outlines common cell‑cycle mechanisms that produce polyploid cells, and evaluates the beneficial and detrimental consequences for genomes, cells, tissues, and applied contexts. Key terms: polyploidy, endocycles, oxidative stress, genome instability, regeneration. Study Highlights:The authors review evidence that many stresses — including temperature extremes, pharmacological agents, genotoxic insults, nutrient changes, infection, cell loss, and ROS — promote polyploidy across fungi, plants, and animals. Mechanistically, these stresses commonly act by perturbing the mitotic cell cycle via mitotic bypass, endoreplication, or failed cytokinesis. Polyploidy can enable tissue regeneration and buffer genomes but also increases genome instability, aneuploidy, and altered tissue function. Determining when polyploidy is adaptive versus harmful is presented as a key research priority for medicine and agriculture. Conclusion:Stress commonly induces polyploidy through conserved cell‑cycle alterations; its effects are context dependent, offering short‑term resilience or regeneration but often promoting genomic instability and long‑term functional costs, motivating cross‑discipline studies to understand mechanisms and applications. Music:Enjoy the music based on this article at the end of the episode. Article title:Growth under pressure: The pros and cons of polyploidy induced by stress First author:Sarabia Olivera L Journal:PNAS DOI:10.1073/pnas.2522063123 Reference:Sarabia Olivera L, Belato PB, Silva J, Selmecki A, Fox DT, Roeder AHK. Growth under pressure: The pros and cons of polyploidy induced by stress. PNAS. 2026;123(22):e2522063123. doi:10.1073/pnas.2522063123 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/growth-under-pressure-polyploidy-stress QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-04. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing (1) diverse stress triggers and cell-cycle bypass mechanisms leading to polyploidy, (2) ROS as a unifying stress signal, (3) consequences at genome, cellular, and tissue levels, and (4) implications for therapy and agriculture; compared with the canonical article.- transcript topics: Stress-induced polyploidy triggers; Mitotic bypass and cytokinesis failure; ROS signaling and DNA damage response; Genomic instability and aneuploidy; Tissue regeneration vs senescence; Clinical and agricultural implications 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:- Transcript describes diverse stresses triggering polyploidy (temperature, pharmacological, genotoxic, nutrient, infection, tissue loss).- ROS accumulation is presented as a universal master switch driving polyploidy.- Polyploi...

Haycocks JRJ et al., PNAS - This episode examines the discovery of CisR, a small RNA produced from the 3’UTR of prtV in Vibrio cholerae, which posttranscriptionally represses the CTXϕ-encoded cep mRNA via Hfq-mediated base-pairing. CisR accumulation is controlled by HapR and CRP and processed by RNase E, linking quorum sensing and carbon status to phage activation. We discuss the experimental evidence showing CisR lowers Cep protein levels and limits CTXϕ production under induction conditions. Key terms: small RNA, CTXϕ, Vibrio cholerae, Hfq, quorum sensing. Study Highlights:Researchers identified CisR as a ~50-nt sRNA derived from the 3’UTR of prtV that requires RNase E for processing and Hfq for stability and action. RIL-seq and reporter assays show CisR base-pairs with the cep mRNA ribosome binding site to inhibit translation, and deletion or overexpression of cisR respectively increases or decreases Cep levels and extracellular CTXϕ DNA after induction. Transcription of the vca0224-prtV-cisR operon is directly activated by HapR and CRP, linking CisR to quorum sensing and carbon catabolite signals. The work positions a core-genome sRNA as a posttranscriptional regulator that modulates a horizontally acquired phage life cycle. Conclusion:CisR is a 3’UTR-derived sRNA that integrates cell-density and metabolic signals to repress CTXϕ coat protein production via Hfq-dependent base-pairing with cep, thereby limiting phage production under stress and coordinating phage activation with host physiology. Music:Enjoy the music based on this article at the end of the episode. Article title:A 3’UTR-derived small RNA modulates the life cycle of the cholera toxin–encoding filamentous phage, CTXϕ First author:Haycocks JRJ Journal:PNAS DOI:10.1073/pnas.2535142123 Reference:Haycocks JRJ, O’Driscoll E, Sprenger M, Thriene K, Jung E-M, Siemers M, Lippegaus A, Krautwurst S, Grainger DC, Papenfort K. A 3’UTR-derived small RNA modulates the life cycle of the cholera toxin–encoding filamentous phage, CTXϕ. PNAS. 2026;123(23):e2535142123. doi:10.1073/pnas.2535142123 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/cisr-controls-ctxphi-life-cycle QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-03. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited the transcript sections describing CisR origin, CisR-cep interaction, HapR/CRP regulation, RIL-seq mapping, and functional impact on CTXϕ production under induction conditions.- transcript topics: CTXϕ life cycle and filamentous phage biology; CisR discovery from prtV 3’UTR and RNase E processing; HFQ and RIL-seq methodology to map RNA interactions; CisR-cep base-pairing and translational repression; HapR and CRP regulation of prtV-cisR transcription; CisR impact on CTXϕ production during MMC induction 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:- CisR is produced from the 3’...

Koprulu M et al., Cell - A 38-cohort proteogenomic meta-analysis of up to 78,664 people maps fine‑mapped protein quantitative trait loci (pQTLs) across 1,116 circulating proteins, uses machine learning to assign trans effector genes, and triangulates genetic and observational evidence to highlight disease mechanisms and therapeutic opportunities. Key terms: proteogenomics, protein QTLs, N-linked glycosylation, Mendelian randomization, drug repurposing. Study Highlights:The study meta-analyzed antibody-based proteomic data across 38 cohorts (n up to 78,664) and identified 24,738 fine-mapped pQTL credible sets for 1,116 proteins, including 5,040 cis and 19,698 trans pQTLs. Machine-learning effector-gene assignment for trans-pQTLs revealed enriched pathways and cell types that regulate plasma proteins, with N-linked glycosylation and liver/hepatocyte signals prominent. Systematic causal inference and triangulation with observational biomarker studies identified candidate drug targets and repurposing signals (e.g., TYK2, furin) but also showed limited concordance between cis genetic instruments and measured protein–disease associations. Conclusion:Large-scale multi-cohort proteogenomics uncovers widespread distal genetic regulation of the circulating proteome, identifies biological pathways and tissues that shape plasma protein levels (notably N-linked glycosylation and hepatic/immune contributors), and provides genetic evidence to prioritize biomarkers and drug targets while highlighting discordance between genetic and observational signatures that requires careful interpretation. Music:Enjoy the music based on this article at the end of the episode. Article title:Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome First author:Koprulu M Journal:Cell DOI:10.1016/j.cell.2026.03.049 Reference:Koprulu M., Smith-Byrne K., Ferolito B.R., et al., 2026. Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome. Cell 189, 3339–3357. https://doi.org/10.1016/j.cell.2026.03.049 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/multi-cohort-proteogenomics-pqtl-diseasome QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-02. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing trans-pQTL dominance, effector-gene mapping, N-linked glycosylation, tissue/cell-type enrichment, MR concordance issues, and clinical exemplars (TYK2 for RA, NT-proBNP for heart failure, extracellular furin).- transcript topics: Trans-pQTL paradigm and global regulatory architecture; Cis vs trans pQTL landscape and study scale; Olink proximity extension assay methodology; Effector gene assignment and pathway/cell-type enrichment; N-linked glycosylation as a key trans-regulatory pathway; Clinical translation: TYK2 and rheumatoid arthritis 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 <...

Nagahata Y et al., PNAS - A transcriptome-driven reconstruction of blood cell evolution shows modern animal blood lineages arose by repurposing an ancestral unicellular toolkit. The study traces macrophage-like origins, a bilaterian mast/killer split, and later deuterostome/vertebrate innovations. Key terms: blood cell evolution, macrophage, mast cell, Fos, thymus. Study Highlights:The authors used cross-species transcriptomics and TF-focused phylogenies to show that the metazoan blood cell program traces to a premetazoan toolkit governed by Fos, producing macrophage-like initial blood cells. They infer a first major bifurcation at the origin of Bilateria that gave rise to a mast/killer lineage equipped with granular proteases specialized for antiparasitic defense. Deuterostome and vertebrate ancestors then diversified this mast lineage into T/NK and erythrocyte/thrombocyte branches while B cells emerged from the macrophage branch, and a prototypic thymus formed at tunicate gill edges. Murine hematopoiesis retains vestiges of this history: macrophage and mast potentials are widely preserved and ancient HSC-like progenitors persist. Conclusion:Blood cell diversity in animals represents a Fos-mediated repurposing of an ancestral unicellular program, with macrophage-like cells as the earliest blood lineage and subsequent bilaterian and deuterostome innovations producing mast/killer, lymphoid, and erythroid branches. Music:Enjoy the music based on this article at the end of the episode. Article title:Animals have expanded the evolutionary legacy of unicellular ancestors in blood cells First author:Nagahata Y Journal:PNAS DOI:10.1073/pnas.2528110123 Reference:Nagahata Y, Ishidae T, Satou Y, Nishimura Y, Kaitani R, Leong JCK, Oda-Ishiie I, Carmona-Rivas M, Najle SR, Ruiz-Trillo I, Kohtsuka H, Abeg S, Ikuta K, Miura T, Kawamoto H, Casacuberta E, Ogasawara M, Irieda N. Animals have expanded the evolutionary legacy of unicellular ancestors in blood cells. PNAS. 2026;123(23):e2528110123. doi:10.1073/pnas.2528110123 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/base-by-base-382-blood-cell-evolution QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-02. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the spoken content describing the article’s core evolutionary timeline for blood cells, Fos-driven regulatory origins, macrophage-like ancestries, bilaterian mast/killer divergence, lineage branching to T/NK and erythrocyte/thrombocyte, B cell origin from macrophages, thymus evolution at gill edges, and implica- transcript topics: Origin of blood cells at the metazoan root and Fos-driven premetazoan toolkit; Cross-species transcriptomics and transcription factor phylogeny; Macrophage-like primitive blood cells; Divergence of mast/killer lineage at Bilateria origin and granzyme-containing cells; Erythrocyte/thrombocyte lineage derived from mast/killer cells; B cells arising from macrophages 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:

Battistoni G et al., PNAS - This paper presents BALI, a light-driven method that writes combinatorial DNA spatial barcodes directly onto biomolecules in tissue by iterative photocleavage and ligation, enabling user-defined, scalable spatial profiling of RNA, chromatin accessibility, or both from the same section and automation via a LightScribe instrument. Key terms: spatial multiomics, photocaged ligation, BALI, LightScribe, chromatin accessibility. Study Highlights:BALI uses a photocaged ligation root and patterned UV illumination to direct iterative DNA ligations that assemble combinatorial spatial barcodes in situ. The method achieves tunable spatial resolution down to ~3 µm and can scale barcode complexity from a few regions to theoretical millions by increasing barcode digits. As proof of concept, the authors profiled transcriptomes and chromatin accessibility in defined regions of embryonic and adult mouse brain and combined both readouts in a single-section multiomic workflow, showing concordance with established datasets. They also built the LightScribe instrument to automate combinatorial barcode writing and demonstrated automated encoding of hundreds of regions. Conclusion:BALI couples light-directed combinatorial ligation with standard sequencing workflows to offer histology-aware, tunable, and scalable spatial multiomic profiling with subcellular resolution and an accessible automation path, enabling targeted high-throughput studies across large sample sets. Music:Enjoy the music based on this article at the end of the episode. Article title:Spatially tuneable multiomic sequencing using light-driven combinatorial barcoding of molecules in tissues First author:Battistoni G Journal:PNAS DOI:10.1073/pnas.2527896123 Reference:Battistoni G, Torres-Garcia S, Sia CY, Corriero S, Boquetale C, Williams E, et al. Spatially tuneable multi-omics sequencing using light-driven combinatorial barcoding of molecules in tissues. Proc Natl Acad Sci U S A. 2026;123(21):e2527896123. doi:10.1073/pnas.2527896123 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/bali-light-driven-combinatorial-barcoding QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-01. 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 BALI method, UV uncaging, iterative ligation, LightScribe automation, and multiomic validation (RNA and ATAC) as well as scalability and cost considerations; compared these claims with the canonical article.- transcript topics: Spatial omics trade-offs and the need for histology-driven boundaries; BALI: Barcoding by Activated Linkage of Indexes; UV uncaging, ligation cycles, and barcode encoding; LightScribe automation with DMD mirrors; RNA profiling in embryonic mouse brain regions; Chromatin accessibility (ATAC) profiling in brain tissue 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:-...

Abadie FMC et al., Cell Genomics - Abadie et al. present prime‑SGE, a pooled prime‑editing framework that installs thousands of precise point mutations across multiple oncogenes and identifies drug‑resistance variants by sequencing integrated pegRNAs after positive‑selection with kinase inhibitors. The method resolved known resistance mutations (e.g., EGFR C797S, KRAS G12 variants), uncovered less-characterized candidates, compared resistance landscapes across covalent and non‑covalent EGFR inhibitors, and validated resistant edits in vivo. Key terms: prime editing, drug resistance, EGFR, KRAS, multiplex screening. Study Highlights:Prime‑SGE uses libraries of barcoded pegRNAs/epegRNAs delivered at low MOI into PEmax‑expressing, MLH1‑knockout cell lines to program thousands of point mutations and read out variant abundance by sequencing integrated guides after drug selection. In pooled screens across eight oncogenes and three EGFR inhibitors, prime‑SGE recovered established resistance mutations (EGFR C797S, KRAS G12 variants) and identified less-characterized hits (e.g., EGFR Q791, Y801). Distinct resistance landscapes emerged for covalent versus non‑covalent EGFR inhibitors, and barcodes showed many resistant clones arose from independent editing events. Prime‑edited resistant cells formed tumors in osimertinib-treated xenografts, demonstrating in vivo relevance. Conclusion:Prime‑SGE enables scalable, positive‑selection profiling of thousands of precise point mutations across the genome to identify and compare drug‑resistance variants, though sensitivity is limited by variable prime editing efficiency. The approach can prioritize resistance variants for follow-up and inform inhibitor development and choice. Music:Enjoy the music based on this article at the end of the episode. Article title:A multiplex, prime editing framework for identifying drug resistance variants at scale First author:Abadie FMC Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101167 Reference:Abadie FMC, Suiter CC, Smith NT, et al. A multiplex, prime editing framework for identifying drug resistance variants at scale. Cell Genomics. 2026;6:101167. doi:10.1016/j.xgen.2026.101167 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/prime-sge-drug-resistance-variants QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-29. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's sections describing Prime-SGE concept, the scale of edits, key resistance mutations (EGFR C797S, KRAS G12 variants, Q791, Y801), inhibitor contexts (osimertinib, sunvozertinib, CH7233163), in vivo xenograft validation, and limitations (editing efficiency, false negatives). 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:- Prime-SGE enables multiplexed installation of thousands of precise edits across multiple genes with readout by integrated pegRNA barcodes- Large-scale scr...

Mortazavi M et al., Cell Genomics - PaperCast Base by Base discusses a long-read whole-genome sequencing study of 267 individuals from 63 families that increased detection of structural variants and tandem repeats, resolved complex rearrangements, linked repeat expansions to methylation at FMR1, and estimated rare-variant contributions to ASD heritability. Key terms: long-read sequencing, structural variants, tandem repeats, autism, methylation. Study Highlights:The authors performed long-read WGS (PacBio HiFi and Oxford Nanopore) on 267 individuals and integrated calls with prior short-read data, increasing detection of gene-disrupting SVs by 33% and TRs by 38%. They discovered novel exonic de novo and somatic-mosaic SVs and characterized a previously undescribed class of nested DUP-DEL complex rearrangements. Joint phasing and methylation analysis identified deletions affecting imprinted genes (e.g., ADNP2) and showed that intermediate FMR1 CGG expansions (35–54 repeats) associate with allele-specific hypermethylation. Burden and heritability analyses indicate rare SVs, TRs, and damaging SNVs together explain a measurable fraction of ASD heritability, though power is limited by sample size. Conclusion:Long-read WGS uncovers substantial previously hidden structural and repeat variation and enables combined phased genetic and methylation analysis to improve functional interpretation in ASD, but larger cohorts and deeper coverage are needed to refine associations and heritability estimates. Music:Enjoy the music based on this article at the end of the episode. Article title:Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism First author:Mortazavi M Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101186 Reference:Mortazavi M., Guevara J., Diaz J., et al., 2026. Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism. Cell Genomics 6, 101186. https://doi.org/10.1016/j.xgen.2026.101186 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/long-read-wgs-autism-structural-repeat-variants QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-27. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited portions describing LR-WGS methodology, SV/TR detection gains, mosaic and de novo SVs (STK33), large balanced rearrangements, nested DUP-DEL SVs, imprinting (ADNP2), FMR1 gray-zone methylation, ASD heritability, and study limitations/future directions.- transcript topics: LR-WGS methods and methylation calling; Structural variants and tandem repeats detection gains; Mosaic and de novo SVs (STK33) and functional impact; Complex DUP-DEL rearrangements; Imprinted genes and ADNP2; FMR1 CGG repeats and methylation, XCI independence 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:- Cohort: LR-WGS perform...

Wijngaard R et al., The American Journal of Human Genetics - Researchers describe seven individuals with monoallelic PSMB8 missense variants that impair immunoproteasome assembly, causing early-onset immunodeficiency and variable systemic inflammation via a dominant-negative mechanism. Key terms: PSMB8, immunoproteasome, PRAAS-ID, immunodeficiency, proteasome assembly. Study Highlights:Seven individuals from five families carrying distinct monoallelic PSMB8 variants presented with neonatal-onset immunodeficiency, B cell lymphopenia, hypogammaglobulinemia, and variable inflammatory disease. Structural modeling predicted destabilization of proteasome interfaces, and complexome profiling plus native assays showed reduced fully assembled immunoproteasomes with accumulation of a ∼440-kDa assembly intermediate. Mutant PSMB8 precursors accumulated, incorporation into 20S/26S complexes was reduced, immunoproteasome-specific activity decreased, and integrated stress response genes were induced. These data support a shared dominant-negative mechanism disrupting immunoproteasome biogenesis and immune signaling. Conclusion:Monoallelic PSMB8 missense variants impair incorporation of β5i into assembling immunoproteasomes, stalling biogenesis, reducing immunoproteasome abundance and activity, and producing clinically variable immunodeficiency with systemic inflammation consistent with PRAAS-ID. Music:Enjoy the music based on this article at the end of the episode. Article title:Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly First author:Wijngaard R Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.04.015 Reference:Wijngaard R., van der Made C.I., Kalkan Uçar S., et al. Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly. Am J Hum Genet. 2026;113:1–19. doi:10.1016/j.ajhg.2026.04.015 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/monoallelic-psmb8-praas-id-immunoproteasome-assembly QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit of immunoproteasome biology, dominant-negative mechanism of monoallelic PSMB8 variants, complexome profiling findings (440-kDa assembly intermediate, reduced IP abundance), functional consequences (IP activity reduction, ISR activation), and clinical implications described in the transcript.- transcript topics: Immunoproteasome structure and SP/IP distinction; Dominant-negative PSMB8 variants and mechanism; Complexome profiling methodology and IP assembly intermediates; Impaired IP biogenesis and 440-kDa intermediate; ISR activation and immune signaling effects; Clinical features: B cell lymphopenia, hypogammaglobulinemia, leukocyte inclusions 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:- Monoallelic PSMB8 vari...

Malbranke C et al., Proceedings of the National Academy of Sciences (PNAS) - ProteomeLM is a transformer-based language model trained on complete proteomes that produces contextualized protein embeddings and attention signals which recover protein–protein interactions unsupervised and support supervised PPI and gene essentiality prediction across diverse taxa. Key terms: proteome language model, protein–protein interactions, gene essentiality, ProteomeLM, deep learning. Study Highlights:ProteomeLM was trained on ~32,000 proteomes using ESM‑C embeddings and a custom polar loss to reconstruct masked protein embeddings in proteome context. Its attention heads encode protein–protein interactions without supervision and distinguish direct physical binding, complex membership, and broader functional associations. As a fast first-pass filter it outperforms amino-acid coevolution (DCA) in recall while reducing compute by orders of magnitude. Downstream supervised models—ProteomeLM-PPI and ProteomeLM-Ess—achieve state-of-the-art cross-species PPI prediction and strong gene essentiality prediction that generalizes to held-out and synthetic minimal genomes. Conclusion:Representing proteins in whole-proteome context yields interpretable attention signals that capture functional and physical relationships, enabling rapid, accurate interactome screening and improved gene essentiality prediction across the tree of life. Music:Enjoy the music based on this article at the end of the episode. Article title:ProteomeLM: A proteome-scale language model enables accurate and rapid prediction of protein–protein interactions and gene essentiality across taxa First author:Malbranke C Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2524201123 Reference:Malbranke C, Zalaffi GP, Bitbol A-F. ProteomeLM: A proteome-scale language model enabling accurate and rapid prediction of protein–protein interactions and gene essentiality across taxa. Proc Natl Acad Sci U S A. 2026;123:e2524201123. doi:10.1073/pnas.2524201123 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/proteomelm-interactomes-essentiality QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited substantive scientific content in transcript: ProteomeLM architecture, functional encoding, polar loss, unsupervised PPI via attention, speed/screening benefits, supervised PPI (ProteomeLM-PPI), gene essentiality predictions (ProteomeLM-Ess), and cross-species/minimal cells.- transcript topics: ProteomeLM architecture and training on whole proteomes; Functional encoding using orthology (OrthoDB); Polar loss and avoiding reliance on coarse functional encoding; Attention coefficients encoding protein-protein interactions (PPI) in unsupervised manner; Unsupervised PPI detection and protein complex membership; Speed and scalability of whole-interactome screening vs DCA 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...

Ortiz-Rodríguez M et al., Proceedings of the National Academy of Sciences (PNAS) - Single-molecule optical tweezers and fluorescence reveal how the S. pombe Pif1-family helicase Pfh1 alternates ATP-dependent unwinding and ATP-modulated rewinding at replication-fork-like substrates, and how mitochondrial SSB spRim1 tunes those activities. Key terms: Pfh1 helicase, Pif1-family, DNA unwinding, spRim1, single-molecule. Study Highlights:Using single-molecule optical tweezers and fluorescence, the authors show Pfh1 performs ATP-dependent unwinding–rewinding cycles with an intrinsic ~20–22 bp processivity. Contacts with the translocating strand modulate apparent ATP affinity while engagement of the displaced strand limits maximum unwinding velocity. The mitochondrial SSB spRim1 binds the displaced strand, disrupts those contacts, and increases unwinding and rewinding velocities. Rewinding is ATP-dependent and proceeds via a sliding-back mechanism rather than strand switching. Conclusion:Pfh1 balances unwinding and rewinding through coordinated ATP-dependent interactions with both fork strands; binding of spRim1 to the displaced strand disrupts inhibitory helicase–strand contacts and accelerates fork dynamics, providing a mechanistic framework for how Pif1-family helicases promote replication fork progression without disrupting replisome organization. Music:Enjoy the music based on this article at the end of the episode. Article title:Regulation of Pfh1 helicase activity by nucleic acid interactions and mitochondrial SSB First author:Ortiz-Rodríguez M Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2602528123 Reference:Ortiz-Rodríguez M, Singh SP, Cao-García FJ, Galletto R, Ibarra B. Regulation of Pfh1 helicase activity by nucleic acid interactions and mitochondrial SSB. PNAS. 2026;123(21):e2602528123. doi:10.1073/pnas.2602528123 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/pfh1-helicase-unwinding-rewinding QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing Pfh1 unwinding/rewinding cycles, force and ATP dependencies, spRim1 modulation, DNA fork vs RNA–DNA fork experiments, and the proposed sliding-back mechanism and its biological relevance.- transcript topics: Pfh1 helicase function and 5'-3' directionality; Unwinding–rewinding cycles and ~20 bp processivity; ATP concentration and force dependencies (Km(f), Vmax); Role of spRim1 in DNA fork unwinding/rewinding; RNA–DNA fork experiments and strand-switching debate; Rewinding mechanism and ATP hydrolysis effects 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:- PfH1 operates via unwinding–rewinding cycles with coordination between fork strands- Intrinsic unwinding processivity is ~20 bp (not extending beyond ~22 bp per burst)- Unwinding veloc...

Douzgou Houge S et al., Human Genetics and Genomics Advances - This paper reports six individuals with biallelic loss-of-function DSCAM variants, delineating a recessive syndrome of moderate-to-severe neurodevelopmental delay with poor language, early focal seizures, hypotonia, short stature, and characteristic rotatory/vertical nystagmus with cone-pathway retinal dysfunction. Key terms: DSCAM, neurodevelopmental delay, nystagmus, retinal dysfunction, electroretinography. Study Highlights:The authors describe six patients (including four newly reported) with homozygous or compound heterozygous predicted loss-of-function variants in DSCAM. All individuals share moderate-to-severe neurodevelopmental delay, impaired language, frequent hypotonia, and short stature, with focal seizures in some. A consistent ophthalmic phenotype of rotatory/vertical nystagmus and poor vision was observed, and ERG in two patients showed relative rod preservation but marked cone-pathway dysfunction, implicating cone-associated bipolar cells. The clinical and electrophysiological findings align with animal models showing disrupted retinal lamination and mosaic spacing caused by loss of DSCAM. Conclusion:Biallelic DSCAM loss-of-function defines a rare recessive neurodevelopmental syndrome characterized by motor and cognitive impairment and a distinctive, developmentally origin retinal dysfunction primarily affecting the cone pathway detectable by ERG. Music:Enjoy the music based on this article at the end of the episode. Article title:Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction First author:Douzgou Houge S Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100622 Reference:Douzgou Houge S., Bredrup C., Wivestad Jansson R., Bojovic O., Aljamal B.M., Al-Otaibi M., Plomp A.S., Motazacker M.M., van Genderen M.M., Mellgren A., Alkuraya H., Hikmat O., Haukanes B.I., Alkuraya F.S., Douzgos Houge G. Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction. Human Genetics and Genomics Advances 7, 100622 (July 9, 2026). https://doi.org/10.1016/j.xhgg.2026.100622. 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/biallelic-dscam-neurodevelopmental-nystagmus QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: The transcript covers the study’s core claims: DSCAM function and retinal organization, genetic evidence for biallelic LoF variants, the neurodevelopmental phenotype, ERG findings showing cone pathway impairment with rod preservation, animal-model context, consanguinity patterns, and ASD-related discussions.- transcript topics: DSCAM role in retinal self-avoidance and patterning; Genetic identification of DSCAM LoF variants via trio exome sequencing; Clinical phenotype: neurodevelopmental delay, language impairment, seizures, hypotonia, short stature; Ophthalmic phenotype and ERG-based retinal function (cone vs rod); Cone-associated bipolar cells in the retina as the site of dysfunction; Animal-model evidence (chicken retina and DSCAM KO mice) for...

Wu X et al., Nature Biotechnology - The authors engineer synthetic PAM-containing DNA guides (crDNA) that bind Cas12a to form a deoxyribonucleoprotein (DNP) complex that recognizes and cleaves complementary RNA. Structural, biochemical and cellular data define a PAM-dependent activation route distinct from canonical RNA-guided systems and demonstrate applications in sensitive diagnostics and intracellular RNA knockdown. Key terms: DNA-guided Cas12a, crDNA, RNA targeting, SLEUTH diagnostic, RNA knockdown. Study Highlights:The team designed single-stranded PAM-bearing crDNA that assembles with Cas12a to form a stable DNP complex and recruit complementary RNA substrates. Cryo-EM and modeling show crDNA occupies the PI/WED/REC groove, preserves PAM engagement and positions an RNA–DNA heteroduplex for RuvC-mediated cleavage. DNA-guided Cas12a selectively binds and cleaves ssRNA, enables robust trans-cleavage across targets and orthologs, and supports an amplification-coupled SLEUTH diagnostic with attomolar sensitivity. In cells, phosphorothioate-stabilized crDNA with Cas12a produced sequence-specific knockdown of reporter and endogenous transcripts with minimal off-target signal. Conclusion:Cas12a can be reprogrammed into a DNA-guided, RNA-targeting effector: PAM-mediated crDNA engagement forms a catalytically competent complex that achieves sequence-specific RNA cleavage, enabling a new architecture for diagnostics and a proof-of-concept for intracellular RNA knockdown while highlighting stability and optimization challenges. Music:Enjoy the music based on this article at the end of the episode. Article title:DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage First author:Wu X Journal:Nature Biotechnology DOI:10.1038/s41587-026-03120-5 Reference:Wu X., Lam W.H., Zhao Z., Feng X., Zhai Y., Hsing I.-M. DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage. Nature Biotechnology (2026). doi:10.1038/s41587-026-03120-5 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-guided-cas12a-reprogrammed-to-target-rna QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-22. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing crDNA design and PAM activation, structural data from cryo-EM, RNA targeting and cleavage mechanics, SLEUTH diagnostic workflow and performance, and intracellular RNA knockdown in cells.- transcript topics: DNA-guided Cas12a concept and crDNA design; PAM-dependent activation and DNP formation; Cryo-EM structure and DNA–RNA duplex within Cas12a; Two-step binding kinetics (Kd1 and Kd2); Trans-cleavage activity and RNA targeting kinetics; SLEUTH diagnostic workflow and performance 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:- DNA-guided Cas12a can target RNA using crDNA with PAM-dependent activation- crDNA occupies PAM-inte...

McGowan J et al., PLOS Genetics - Genome and transcriptome sequencing of an uncultured Oligohymenophorea ciliate (PL0344) reveals a novel nuclear genetic code in which UAA translates as lysine and UAG as glutamic acid, supported by suppressor tRNAs and phylogenomic context. Key terms: genetic code, ciliate, UAA, UAG, suppressor tRNA. Study Highlights:The authors assembled a macronuclear genome from low-input G&T-Seq data for Oligohymenophorea sp. PL0344 and found widespread in-frame UAA and UAG codons. Codetta and PhyloFisher analyses predict UAA→lysine and UAG→glutamic acid, and multiple corresponding suppressor tRNA genes were identified. UGA remains as a stop and is enriched as tandem stops in the 3' UTR, suggesting selection to limit readthrough. Phylogenomic mapping shows numerous independent genetic code changes across ciliates, making this the first reported case where UAA and UAG specify different amino acids. Conclusion:This study documents a previously unknown nuclear genetic code variant in a ciliate where UAA and UAG have distinct sense meanings, expanding known genetic code diversity and highlighting the need to consider noncanonical codes in genome annotation and evolutionary analyses. Music:Enjoy the music based on this article at the end of the episode. Article title:Identification of a non-canonical ciliate nuclear genetic code where UAA and UAG code for different amino acids First author:McGowan J Journal:PLOS Genetics DOI:10.1371/journal.pgen.1010913 Reference:McGowan J, Kilias ES, Alacid E, Lipscombe J, Jenkins BH, Gharbi K, et al. (2023) Identification of a non-canonical ciliate nuclear genetic code where UAA and UAG code for different amino acids. PLoS Genet 19(10): e1010913. https://doi.org/10.1371/journal.pgen.1010913 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/non-canonical-ciliate-code-373 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-21. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited the transcript sections that discuss genetic code reassignments (UAA/UAG), suppressor tRNAs, UGA handling (stop/Sec), tandem stop codons, sequencing approach (G&T-Seq), and phylogenetic context.- transcript topics: Canonical vs noncanonical genetic code in ciliates; UAA and UAG reassignment to Lys and Glu; Suppressor tRNA genes and wobble binding; G&T-Seq single-cell genome/transcriptome methodology; UGA stop codon usage and tandem stop codons; Phylogenomics and independent genetic code changes in ciliates 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:- UAA codon reassigned to lysine and UAG codon reassigned to glutamic acid in PL0344- Presence of multiple suppressor tRNA genes corresponding to UAA (Lys) and UAG (Glu)- tRNA-SeC(UCA) identified, suggesting UGA can encode selenocysteine in addition to stop- UGA codons enriched in the 3'-UTR downstream of g... Chapters (00:00:10) - What Really Happens to the Universal Code of Life?(00:05:57) - Quantifying the genome of a single ciliate(00:12:31) - The UGA Stop Sign

Kajonius PJ et al., Scientific Reports - This episode examines a twin-study analysis from the German TwinLife panel showing that cognitive ability at age 23 predicts socioeconomic status at age 27, and that much of this longitudinal association is explained by genetic factors rather than shared or unique environments. Key terms: cognitive ability, IQ, socioeconomic status, genetics, twin study. Study Highlights:Using TwinLife panel data, IQ measured at 23 predicted educational and occupational outcomes at 27 with phenotypic correlations typically above .30. Univariate twin models estimated IQ heritability at about 75% and substantial heritability for SES measures. Bivariate Cholesky decompositions found that genetics accounted for 69–98% of the IQ–SES association and that genetic correlations exceeded environmental correlations. These results held across two education and two occupation measures. Conclusion:In this emerging-adult sample, both IQ and SES showed sizable heritability and the longitudinal link from IQ to future SES was largely attributable to shared genetic influences, suggesting that research and policy should account for genetic contributions when interpreting individual socioeconomic trajectories. Music:Enjoy the music based on this article at the end of the episode. Article title:Longitudinal associations between cognitive ability and socioeconomic status are partially genetic in nature First author:Kajonius PJ Journal:Scientific Reports DOI:10.1038/s41598-026-37786-3 Reference:Kajonius PJ. Longitudinal associations between cognitive ability and socioeconomic status are partially genetic in nature. Scientific Reports. 2026;16:4315. doi:10.1038/s41598-026-37786-3 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/genes-iq-ses-twinlife QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-20. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited sections covering: study design (TwinLife, MZ/DZ twins), measurement (CFT-20-R IQ at 23; education and occupation SES at 27), main results (heritability estimates; 69–98% genetic explanation of IQ–SES link; C factor minimal), pleiotropy pathways (direct and mediated), and discussion of limitations- transcript topics: TwinLife study and sample characteristics; Measurement of IQ and SES; Univariate and bivariate twin-model analyses (ACE/AE; Cholesky/related description); Genetic and environmental contributions to IQ and SES; Genetic overlap and pleiotropy pathways; Limitations and policy implications 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:- IQ23 heritability around 75%- SES27 heritability for education around 49% (AE) and 66% (Casmin); occupation around 32% (ACE) and 71% (AE)- Genetic factors explained 69–98% of the IQ–SES longitudinal association- Occupational SES shows up to 98% genetic overlap with IQ- Common environment (C...

Han et al., Nature Communications - This study uses paired single-nucleus chromatin accessibility and gene expression profiling across Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy to map disease-dynamic cis-regulatory elements (CREs). Dynamic chromatin changes concentrate genetic risk in glial cell states and co-regulated regulatory modules. Integrating GWAS, sn-eQTLs and MPRA validates functional noncoding variants that tune lysosomal, lipid and vesicular pathways. Experimental CRISPRa and histology support a stress-inducible SOX10-driven glial program linked to resilience. Key terms: snATAC-seq, tauopathies, microglia, chromatin accessibility, SOX10. Study Highlights:The authors profiled matched snATAC-seq and snRNA-seq from three brain regions across AD, PiD and PSP and defined cell-type-specific CREs and 50 subclusters. Disease-dynamic peaks concentrated in glia and disproportionately capture GWAS heritability, with PiD-linked mg.C4 microglia and PSP-linked ast.C1 astrocytes identified as risk-associated states. MPRA in microglial models and sn-eQTL integration validated functional regulatory variants that converge on MEF2C/SOX10 and SNARE-centered modules affecting lysosomal, sphingolipid and trafficking pathways. CRISPRa induction of SOX10 in iPSC-derived microglia under synaptosome stress recapitulated mg.C4 programs, and RNAscope/IHC confirmed SOX10+/PLP1+ glial states in human tissue. Conclusion:Dynamic, disease-context-specific chromatin remodeling in glia concentrates genetic risk into co-regulated regulatory modules that modulate lysosomal, lipid and vesicular pathways; these modules nominate SOX10-, MEF2- and SNARE-centered circuits as candidate modulators of glial resilience across tauopathies. Music:Enjoy the music based on this article at the end of the episode. Article title:Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states First author:Han Journal:Nature Communications DOI:10.1038/s41467-026-73007-1 Reference:Han, X., Rosenberg, G.M., Kisling, V.M. et al. Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73007-1 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/epigenomic-glial-genetic-risk-tauopathies QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-19. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing glial states mg.C4 microglia and ast.C1 astrocytes, regulatory networks (MEF2C/MEF2D), SOX10's role and ectopic expression, MPRA validation, CRISPRaSOX10 experiments, dynamic CREs and heritability findings, and study limitations.- transcript topics: Glial states mg.C4 microglia and ast.C1 astrocytes across tauopathies; MEF2C/MEF2D regulatory modules linking to lysosomal and phagocytic pathways; SOX10 as a stress-responsive regulator and ectopic expression in glia; MPRA validation of regulatory variants in microglia (frVars); CRISPRa SOX10 activation in hiPSC-derived microglia and recapitulation of mg.C4 programs; Dynamic CREs and GWAS heritability enrichment across disorders

Yang X et al., Proceedings of the National Academy of Sciences - Genetic and pharmacologic inhibition of ICMT suppresses proliferation, invasion, and tumor growth in BRAFV600E-driven models and identifies INPP5E as an ICMT-dependent CAAX substrate whose membrane targeting supports melanoma growth. Key terms: ICMT, INPP5E, BRAFV600E, melanoma, UCM-1336. Study Highlights:ICMT genetic knockdown or pharmacologic inhibition (UCM-1336) reduced proliferation and invasion of BRAFV600E-mutant melanoma cells, decreased tumor growth in xenografts and mouse models, and retained activity in BRAF-inhibitor-resistant cells. ICMT inhibition reduced INPP5E carboxyl methylation, displaced INPP5E from membranes to the cytosol, and increased cellular PI(4,5)P2. Forced membrane targeting of INPP5E (Lyn-INPP5E) partially rescued proliferation and tumor growth during ICMT suppression. These results implicate an ICMT–INPP5E axis that supports BRAFV600E-driven tumor growth without measurable suppression of MAPK signaling. Conclusion:ICMT-dependent methylation and membrane targeting of INPP5E contribute to BRAFV600E-driven tumor growth, and ICMT inhibition (genetic or with UCM-1336) impairs melanoma growth including in BRAF-inhibitor-resistant models, highlighting ICMT as a context-dependent therapeutic vulnerability. Music:Enjoy the music based on this article at the end of the episode. Article title:ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E First author:Yang X Journal:Proceedings of the National Academy of Sciences DOI:10.1073/pnas.2601795123 Reference:Yang X, Qiao X, Schmidt S, et al. ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E. PNAS. 2026;123(20):e2601795123. doi:10.1073/pnas.2601795123 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/icmt-inpp5e-brafv600e-membrane-targeting QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections describing ICMT/CAAX processing, INPP5E as an ICMT substrate, membrane targeting and PI(4,5)P2 effects, rescue experiments, in vitro/in vivo models, and therapeutic implications.- transcript topics: ICMT and CAAX protein processing; INPP5E as an ICMT substrate and its membrane localization; Impact of ICMT inhibition on BRAFV600E melanoma cell proliferation and invasion; MAPK signaling independence from ICMT inhibition; In vivo models and genetic/pharmacologic ICMT suppression; Rescue experiments with Lyn-INPP5E and rescue implications 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:- ICMT inhibition reduces BRAFV600E-driven melanoma cell proliferation and invasion in vitro and tumor growth in vivo.- INPP5E is an ICMT-dependent CAAX substrate; ICMT inhibition reduces INPP5E methylation and displaces it from membranes.- Displa...

White MC et al., PNAS - This episode reviews a PNAS study showing that the kinase NEK2 is upregulated by EBV and its latency proteins and that NEK2 inhibition with the irreversible inhibitor JH295 selectively kills EBV-positive non-Hodgkin lymphoma cells, lowers drug resistance, and reduces tumor burden in mouse models. Key terms: NEK2, EBV, non-Hodgkin lymphoma, LMP1, drug resistance. Study Highlights:EBV infection and the latency proteins EBNA1, LMP1, and EBNA2 increase NEK2 expression in human B cells and patient tumors. Genetic depletion or pharmacologic inhibition of NEK2 with JH295 selectively kills EBV-positive NHL cells and induces inflammatory, ROS-associated cell death with gasdermin D cleavage. NEK2 inhibition reduces LMP1 and c-myc expression, decreases ABC transporter expression and MRP1-mediated drug efflux, and sensitizes cells to doxorubicin. In xenograft and cord blood-humanized mouse models JH295 lowered tumor burden, reduced tumor incidence, and prolonged survival without observable toxicity. Conclusion:NEK2 is a promising therapeutic target in EBV-positive non-Hodgkin lymphoma; NEK2 inhibition by JH295 both kills malignant cells and reduces drug resistance and viral oncoprotein expression in preclinical models. Music:Enjoy the music based on this article at the end of the episode. Article title:NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma First author:White MC Journal:PNAS DOI:10.1073/pnas.2535550123 Reference:White MC, Lange PT, Stewart J, Damania B. NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2026;123:e2535550123. doi:10.1073/pnas.2535550123 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/nek2-drives-ebv-positive-nhl QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-16. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript passages on EBV-induced NEK2 upregulation, NEK2 inhibition mechanisms (ROS, gasdermin D), downstream effects (LMP1, c-Myc, beta-catenin, Bcl-2 family), MRP1/ABC transporters and drug resistance, and in vivo xenograft and cord blood–humanized mouse results.- transcript topics: EBV-induced NEK2 upregulation in primary B cells; EBV latency proteins EBNA1, LMP1, EBNA2 drive NEK2 expression; JH295 NEK2 inhibitor and EBV+ NHL selectivity; Inflammatory cell death: ROS accumulation and gasdermin D cleavage; Downregulation of LMP1, c-Myc, beta-catenin; Bcl-2 family modulation; MRP1/MDR transporters and drug resistance reversal 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:- EBV latency proteins EBNA1, LMP1, EBNA2 independently drive NEK2 upregulation- Primary EBV infection increases NEK2 expression in human B cells- NEK2 inhibition with JH295 induces inflammatory, ROS-associated cell death with gasdermin D cleavage in EBV-positi...

Jhaldiyal A et al., PNAS - This episode summarizes a PNAS study showing that PARP1 activation links Aβ1-42 toxicity to DNA damage, amyloid accumulation, neuroinflammation, and cognitive deficits, and that genetic or pharmacologic PARP1 suppression reduces pathology in cells and 5XFAD mice. Key terms: PARP1, poly(ADP-ribose), Alzheimer's disease, amyloid beta, neurodegeneration. Study Highlights:CSF poly(ADP-ribose) (PAR) is elevated in patients with MCI and AD and negatively correlates with the Aβ42/40 ratio. Oligomeric Aβ1-42 activates PARP1 in primary cortical neurons, causing DNA damage and cell death that are prevented by PARP1 inhibitors or PARP1 genetic deletion. In 5XFAD mice, PARP1 knockout halves plaque burden, preserves synapses and neurons, reduces glial activation and inflammatory gene expression, and rescues spatial learning and memory. Mechanistically, PARP1 deficiency lowers BACE1, alters γ-secretase subunits (PSEN1 up, nicastrin down), and increases the Aβ-degrading enzyme NEP2. Conclusion:PARP1 is a critical mediator of Aβ-driven toxicity, amyloid accumulation, neuroinflammation, and cognitive decline in a familial AD model, and its inhibition may be a promising disease-modifying strategy. Music:Enjoy the music based on this article at the end of the episode. Article title:PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model First author:Jhaldiyal A Journal:PNAS DOI:10.1073/pnas.2525028123 Reference:Jhaldiyal A., Kumari M., Guttman L. C., et al. PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model. PNAS (2026). DOI: 10.1073/pnas.2525028123 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/parp1-amyloid-neurodegeneration-5xfad QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-16. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing CSF PAR elevation, Aβ42-induced PARP1 activation in neurons, in vitro neuroprotection by PARP inhibitors, in vivo 5XFAD/PARP1−/− outcomes (plaque burden, neuronal survival, gliosis, cognitive tests), APP metabolism changes, NEP2 involvement, inflammation, and translational cav- transcript topics: CSF PAR elevation in MCI and AD and relation to Aβ42/40; Oligomeric Aβ42 activates PARP1 and induces DNA damage; Pharmacologic/genetic PARP1 inhibition confers neuroprotection in vitro; 5XFAD/PARP1−/− mice: reduced amyloid plaque burden and neuronal loss; APP processing changes: BACE1 reduction, PSEN1/nicastrin alterations, NEP2 up; Neuroinflammation and gliosis attenuation with PARP1 loss 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:- CSF PAR levels are elevated in MCI and AD and inversely correlate with the Aβ42/40 ratio- Oligomeric Aβ1-42 activates PARP1 and induces DNA damage; PARP1 inhibition...

Singh P et al., PNAS - This paper compares alternative splicing (AS) and gene expression (GE) across 200 transcriptomes from oral and pharyngeal jaws of 18 haplochromine cichlid species across Lakes Victoria, Malawi, and Tanganyika. The authors show that rapid changes in AS, often from low-frequency ancestral isoforms and some novel isoforms, contributed more to early trophic diversification than shifts in GE. Key terms: alternative splicing, adaptive radiation, cichlids, gene regulation, craniofacial development. Study Highlights:Using 200 jaw transcriptomes spanning three East African cichlid radiations, the authors found that alternative splicing (AS) diverged faster than gene expression (GE) and was enriched for craniofacial and jaw morphogenesis genes. Most adaptive isoforms were present at low levels in nonradiating ancestral lineages and increased in frequency in radiating lineages, consistent with standing splice variation fueling rapid adaptation. A subset of novel isoforms evolved rapidly, some within a few thousand years, and mapped to candidate craniofacial genes such as col21a1. Younger radiations (Victoria, Malawi) showed stronger AS divergence while the older Tanganyika radiation displayed more GE differences. Conclusion:Ancestral alternative splice variation, supplemented by rapidly evolved novel isoforms, provided a labile reservoir of protein-coding diversity that likely enabled the extremely rapid trophic diversification of African cichlid radiations; integrating splicing into regulatory perspectives is essential to understand rapid adaptive evolution. Music:Enjoy the music based on this article at the end of the episode. Article title:Ancestral splice variation is a key substrate for rapid diversification in African cichlids First author:Singh P Journal:PNAS DOI:10.1073/pnas.2516477123 Reference:Singh P., Ahi E.P., Duenser A., Durdevic M., Gessl W., Schaeffer S., Gall J., Seehausen O., Sturmbauer C. Ancestral splice variation is a key substrate for rapid diversification in African cichlids. PNAS. 2026;123(20):e2516477123. doi:10.1073/pnas.2516477123 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/ancestral-splice-variation-african-cichlids QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing AS vs GE dynamics, ancestral standing variation, novel isoforms (col21a1), lake-by-lake evolutionary patterns, and convergent/trophic evolution; cross-checked against the original article.- transcript topics: Adaptive radiation and jaw anatomy in African cichlids; Gene expression vs alternative splicing (GE vs AS); Ancestral standing variation and novel isoforms; Temporal patterns: young vs old radiations (Victoria/Malawi vs Tanganyika); Key genes: col21a1 and craniofacial pathways; Convergent vs divergent regulation across radiations 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...

Han YJ et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study showing that the BRCA1 pseudogene BRCA1P1 produces circular RNAs that suppress antiviral innate immunity in human cancers; depleting BRCA1P1 activates interferon-stimulated genes, increases apoptosis and chemosensitivity, and enhances immune clearance in preclinical models. Key terms: BRCA1P1, pseudogene, circular RNA, antiviral immunity, breast cancer. Study Highlights:BRCA1P1 is expressed broadly across human cancer cell lines and is elevated in breast tumors. The majority of BRCA1P1 transcripts are circular RNAs that bind the NF-κB subunit RelA to attenuate NF-κB–driven antiviral gene transcription. Loss of BRCA1P1 by ASO or CRISPR induces ISGs, IFNβ and TNF, increases apoptosis and sensitivity to chemotherapy, and enhances macrophage phagocytosis. In patient-derived organoids and humanized mouse xenografts BRCA1P1 depletion reduces tumor viability and increases T cell and M1 macrophage infiltration. Conclusion:BRCA1P1-derived circular RNAs act as immunosuppressive regulators of antiviral and antitumor immunity in human cancers, and targeting BRCA1P1 activates antiviral programs that reduce tumor growth and boost immune infiltration. Music:Enjoy the music based on this article at the end of the episode. Article title:Regulation of antiviral and antitumor immunity by the BRCA1 pseudogene in human cancers First author:Han YJ Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2528911123 Reference:Han YJ, Zhang J, Shariff M, Wu S, Khramtsova G, Nguyen LC, Peiffer DS, Li N, Lewicka A, Moore M, Piccirilli JA, Olopade OI. Regulation of antiviral and antitumor immunity by the BRCA1 pseudogene in human cancers. Proc Natl Acad Sci U S A. 2026;123(19):e2528911123. doi:10.1073/pnas.2528911123 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/brca1p1-pseudogene-antiviral-immunity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing BRCA1P1 background, circular RNA nature, RelA/NF-κB interaction, depletion experiments (ASO/CRISPR), pancancer expression, antiviral gene upregulation, apoptosis, chemotherapy sensitivity, immune infiltration, PDOs, and humanized mouse models, plus clinical implications and de- transcript topics: BRCA1P1 background and primate-specificity; BRCA1P1 circular RNA and RelA/NF-κB interaction; BRCA1P1 depletion methods (ASO, CRISPR) and pancancer scope; Antiviral gene induction and cytokine responses; Apoptosis and chemotherapy sensitivity after BRCA1P1 loss; Macrophage phagocytosis and T cell infiltration 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:- BRCA1P1 is a primate-specific, chimeric BRCA1/RPLP1 pseudogene; majority of BRCA1P1 transcripts are circular RNAs (~70-80%).- BRC...

Bourgeois et al., Nature Communications - This study used enhanced CRISPR base editor screens, structural biology, biochemical assays, and in vitro/in vivo selection to map MEN1 mutations that drive resistance to five clinical menin inhibitors and to explain their mechanisms. Key terms: MEN1, menin inhibitors, CRISPR base editing, drug resistance, KMT2A. Study Highlights:CRISPR base editor screens tiled MEN1 and profiled resistance to five clinical menin inhibitors, revealing shared (M327 I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) substitutions. Co-crystal structures of mutant menin bound to each inhibitor explain resistance via steric clashes or disrupted interactions and correlate with measured Ki and cellular IC50 shifts. Orthogonal in vitro selection and PDX experiments show many predicted mutations arise spontaneously under drug pressure and that higher inhibitor potency or dosing can suppress or overcome some resistant clones. The particular amino acid substitution at a residue critically determines the magnitude and breadth of resistance. Conclusion:Enhanced CRISPR base editing combined with structural and biological validation maps a mutational landscape in MEN1 that can produce pan-class or drug-specific resistance to menin inhibitors; these data can guide clinical monitoring, choices between inhibitors, dosing strategies, and next-generation inhibitor design. Music:Enjoy the music based on this article at the end of the episode. Article title:CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials First author:Bourgeois Journal:Nature Communications DOI:10.1038/s41467-026-72685-1 Reference:Bourgeois, W., Rice, H.E., Wenge, D.V. et al. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72685-1 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/papercast-base-by-base-menin-mutations-365 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15. 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 CRISPR base editor screen identifying MEN1 mutations that affect five clinical menin inhibitors, including shared vs inhibitor-specific mutations, biochemical and structural validation, and in vivo PDX confirmation, as well as dose-related resistance dynamics and limitatio- transcript topics: Menin-KMT2A interaction and menin inhibitors in leukemia; CRISPR base editor screen design and MV4;11 cells; Shared and inhibitor-specific MEN1 mutations (M327, G331, T349, C334R, E368K/V, V372A); Biochemical binding: TR-FRET and Ki shifts; Structural insights: co-crystal structures; In vivo validation: PDX models 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:- Five inhibitors tested: DS-1594, JNJ-6617, KO-539...

Kalinowski A et al., PNAS - This study reports that C4 protein is enriched in human neutrophils and monocytes and that neutrophil C4 protein levels correlate with C4A gene copy number specifically in people with schizophrenia, linking peripheral innate immunity to disease-related biology. Key terms: schizophrenia, complement C4, neutrophils, monocytes, innate immunity. Study Highlights:Using public gene-expression data and fresh whole blood, the authors show C4 protein is primarily localized to neutrophils and monocytes. In a clinical cohort, neutrophil C4 protein positively correlated with C4A gene copy number in schizophrenia (Spearman rho = 0.63). Neutrophil and classical monocyte C4 protein were reduced in schizophrenia versus controls, and neutrophil C4 associated with perceived stress and symptom measures. Findings support a peripheral, cell-associated source of complement activation in schizophrenia. Conclusion:Neutrophils are a peripheral cellular reservoir of C4 that links C4A gene copy number to complement protein levels in schizophrenia, implicating innate immune cell mechanisms as potential contributors and targets for disease modification. Music:Enjoy the music based on this article at the end of the episode. Article title:Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes First author:Kalinowski A Journal:PNAS DOI:10.1073/pnas.2536376123 Reference:Kalinowski A., Macaubas C., Guo H., et al. Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes. PNAS. 2026;123(20):e2536376123. doi:10.1073/pnas.2536376123 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/peripheral-c4-schizophrenia-neutrophil-link QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-11. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit of the transcript’s core scientific narrative: peripheral C4 biology in SZ (cellular localization, genetic associations, plasma vs cellular activation), links to symptoms/stress, and translational implications, with attention to study limitations.- transcript topics: Innate immunity and C4 in schizophrenia; C4 protein expression in neutrophils and monocytes; C4A gene copy number correlates with neutrophil C4 protein in SZ; Plasma C4 vs cell-associated C4 activation; Clinical associations: perceived stress and PANSS; Limitations and confounds (medication, BMI, sample size) 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:- C4 protein is expressed and localized in neutrophils and monocytes (cellular localization, not plasma only)- C4A gene copy number correlates with neutrophil C4 protein in schizophrenia (Spearman rho ≈ 0.63; P ≈ 0.012)- In schizophrenia, neutrophil C4 protein is lower than controls after adjustment (BMI or related covariates; notable P-values in exploratory anal...

Zhou Z et al., Nature Communications - This study develops a Lorentzian deconvolution model of cfDNA fragment length distributions across bodily fluids, identifies a ~159 bp component that demarcates intra- vs inter-nucleosomal fragments, and shows that intra-nucleosomal fragmentation entropy distinguishes tumor-derived ctDNA from non-tumor shortening. Key terms: cell-free DNA, fragmentomics, nucleosome, ctDNA, size deconvolution. Study Highlights:The authors modeled cfDNA size profiles as sums of Cauchy–Lorentz distributions with ~10 bp periodicity and applied deconvolution across plasma, saliva, urine, CSF and lymphatic fluid. A distinct ~159 bp component emerged as a pivot between intra- and inter-nucleosomal fragments. Tumor-derived ctDNA shows increased intra-nucleosomal fragmentation entropy and inverse amplitude changes across the 159 bp boundary, whereas phagocytosis-associated shortening increases intra-nucleosomal amplitude without raising entropy. The intra/inter-nucleosomal entropy ratio improved cancer detection performance relative to standard size-ratio metrics across multiple cohorts. Conclusion:Size deconvolution using Lorentzian components reveals nucleosomal structure in cfDNA, identifies a 159 bp demarcation between fragmentation regimes, and provides an entropy-based metric that enhances ctDNA detection while separating tumor-associated fragmentation from phagocyte-related signals. Music:Enjoy the music based on this article at the end of the episode. Article title:Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations First author:Zhou Z Journal:Nature Communications DOI:10.1038/s41467-026-72925-4 Reference:Zhou Z, Cooper WN, Cheng Z, et al. Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72925-4 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ 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/cfdna-size-deconvolution-nucleosomal-origins QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-09. 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 discussion of cfDNA fragmentology, Lorentzian deconvolution, the 159 bp pivot, entropy vs amplitude distinctions, Li-Fraumeni context, phagocytosis vs tumor fragmentation, and diagnostic performance metrics.- transcript topics: cfDNA fragmentomics basics; Lorentzian size deconvolution and nucleosome structure; 159 bp boundary between intra- and inter-nucleosomal cfDNA; intra-/inter-nucleosomal amplitude and entropy ratios; ctDNA fragmentation entropy as cancer signature; phagocytosis vs tumor-derived fragmentation 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:- cfDNA size profiles deconvoluted into Lorentzian components across multiple fluids with ~10 bp periodicity- a ~159 bp component d...

Kearns FL et al., PNAS - Simulations and HDXMS reveal how the D614G substitution alters internal communication in SARS-CoV-2 spike, enabling faster receptor-binding-domain opening through newly engaged allosteric pathways. Key terms: D614G, SARS-CoV-2 spike, RBD opening, allostery, weighted ensemble simulations. Study Highlights:Weighted ensemble simulations of Ancestral, Delta, and Omicron BA.1 spikes show distinct RBD opening landscapes and identify two S1 linkers (N2R and a previously underappreciated antiparallel R2N) that connect the NTD to the RBD. In the Ancestral spike a D614–K854 salt bridge constrains the R2N and must break before RBD opening; D614G abolishes that constraint, increasing local flexibility and enabling communication through both linkers. Delta and Omicron BA.1, both carrying D614G, open faster and use balanced N2R/R2N signaling; Omicron also forms a K856–D568 salt bridge and can adopt a unique “peel” conformation. Hydrogen–deuterium exchange mass spectrometry on VLPs confirms altered dynamics around the 614-proximal region consistent with the simulations. Conclusion:Ablation of the D614–K854 salt bridge by D614G relieves local frustration, opens an additional allosteric lane via the R2N linker alongside N2R, and accelerates RBD opening—providing a mechanistic link between the D614G substitution and increased infectivity; Omicron BA.1 further tunes this network with compensatory interactions. Music:Enjoy the music based on this article at the end of the episode. Article title:D614G reshapes allosteric networks and opening mechanisms of SARS - CoV - 2 spikes First author:Kearns FL Journal:PNAS DOI:10.1073/pnas.2504793123 Reference:Kearns FL, Bogetti AT, Calvó-Tusell C, et al. D614G reshapes allosteric networks and opening mechanisms of SARS-CoV-2 spikes. PNAS. 2026;123(19):e2504793123. doi:10.1073/pnas.2504793123 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/d614g-reshapes-allosteric-networks QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the spoken content for alignment with the PNAS article's core findings: D614G reshapes spike allostery, dual N2R/R2N pathways, D614-K854 salt-bridge dynamics, Delta/Omicron opening differences, Omicron peel state, and HDXMS corroboration; plus methodological details (WE/MA binning, glycans, and limitations).- transcript topics: D614G impact on RBD opening dynamics; Weighted Ensemble simulations (WE) and minimal adaptive binning (MAB); N2R and R2N flexible linkers as allosteric pathways; D614-K854 salt bridge role and congestion; Variant-specific opening pathways: Delta and Omicron; Omicron BA.1 peel state and K856-D568 salt bridge 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:- D614G abolishes the D614-K854 salt bridge, increasing local flexibility and accelerating RBD opening via dual N2R and R2N l...

Beckner RL et al., PNAS - This episode examines a PNAS study using Chiral Inversion Mutagenesis (ChIM) to scan low-complexity domains (LCDs) of Emerin and neurofilament light chain (NEFL). Targeted L-to-D amino acid inversions reveal position-dependent, chirality-sensitive hotspots that control LCD self-association. Key terms: chiral inversion, low-complexity domains, Emerin, neurofilament light chain, synthetic protein chemistry. Study Highlights:The authors applied synthetic protein chemistry to introduce site-specific L-to-D Cα inversions (ChIM) in LCDs of Emerin (EMD) and NEFL. ChIM scans identified discrete enantioselective hotspots—EMD residues ~191–203 and NEFL residues ~22–41—where D substitutions strongly reduce self-association measured by GST pulldown and turbidity assays. Minimal inversions, including single D substitutions, can abrogate EMD self-association, while an all-D mirror-image C-terminal fragment restored activity, implicating backbone geometry and secondary-structure involvement. These results show that polypeptide homochirality and transient structure underpin certain LCD–LCD interactions. Conclusion:Cα stereochemistry is a determinant of LCD self-association at specific sequence hotspots, and ChIM provides a positional-resolution chemical approach to identify backbone-constrained elements that mediate oligomerization of disordered domains. Music:Enjoy the music based on this article at the end of the episode. Article title:Chiral inversion mutagenesis identifies geometrically constrained residues within self - associating low - complexity domains First author:Beckner RL Journal:PNAS DOI:10.1073/pnas.2535888123 Reference:Beckner RL, Kim L, Carter C, Walterscheid A, Liszczak G. Chiral inversion mutagenesis identifies geometrically constrained residues within self-associating low-complexity domains. Proc Natl Acad Sci U S A. 2026;123(19):e2535888123. doi:10.1073/pnas.2535888123 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/chiral-inversion-lcd-hotspots-361 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-08. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the spoken sections describing: ChIM methodology; Emerin LCD hotspot mapping (188–201) with 3×Pro and 3×D scans; single-residue effects (1×D) and all-D mirror-image rescue; NEFL head domain hotspot (22–41) with 5×D scans; assay descriptions (GST pulldown, turbidity); cross-β/anti-selective interactions; drug-de- transcript topics: Chiral inversion mutagenesis (ChIM) methodology; Emerin (EMD) LCD self-association hotspot mapping (188–201) with Pro/ D-inversions; NEFL head domain hotspot mapping (22–41) with 5×D inversions; Mutational scan results: 3×D, 1×D, 5×D variants and effects on pulldown/turbidity; Mirror-image (all-D) fragment rescue for Emerin; Assays: GST pulldown and turbidity measurements 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 Audite...

Graff A et al., PNAS - A PNAS study linking global population-genetic data and structural linguistic features finds an inverse correlation: regions with lower genetic diversity show higher structural linguistic diversity, after controlling for geography, phylogeny, and environment. Key terms: linguistic diversity, population genetics, Wright's F, language contact, structural typology. Study Highlights:The authors merged global genomic samples (Wright’s F / homozygosity) with curated structural linguistic datasets and estimated local structural entropy per grid cell. Using Bayesian GAMMs that adjust for spatial, phylogenetic, environmental, and sampling confounds, they find that higher excess homozygosity (lower genetic diversity) predicts higher structural linguistic entropy. The genetic predictor outperforms other covariates and the effect is robust across grid resolutions and sensitivity checks, though it varies by region and by specific linguistic features. The pattern supports a model where isolation promotes linguistic diversification while contact and admixture promote homogenization. Conclusion:An inverse, regionally variable correlation between local human genetic diversity and structural linguistic diversity suggests isolation-driven hotspots are key windows into the flexibility and evolution of language structure. Music:Enjoy the music based on this article at the end of the episode. Article title:An inverse correlation between structural linguistic and human genetic diversity First author:Graff A Journal:PNAS DOI:10.1073/pnas.2526762123 Reference:Graff A., Ringen E.J., Zakharko T., Stoneking M., Shimizu K.K., Bickel B., Barbieri C. An inverse correlation between structural linguistic and human genetic diversity. Proc. Natl. Acad. Sci. U.S.A. 2026;123(18):e2526762123. doi:10.1073/pnas.2526762123 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/inverse-correlation-linguistic-genetic-diversity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-07. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections describing inverse relationship between local genetic diversity and structural linguistic diversity, methods (F coefficient, entropy, geodesic hex grids), magnitude of effects, regional patterns, and study limitations; cross-checks with article content performed.- transcript topics: Inverse relationship between genetic diversity and linguistic structural diversity; Genetic metric Wright's F and linguistic entropy (normalized Shannon entropy); Geodesic hex grid methodology and grid resolutions (500 km and 300 km); Regional variation and strongest signals (North-Central Asia, Southeast Asia); Feature-level impact and percent of features affected by genetic diversity; Limitations: correlation vs causation and blind spots of genetic data 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:- Inverse correlation betwee...

Avery NG et al., PNAS - This episode covers a PNAS study reporting the de novo design of miniprotein inhibitors targeting porcine deltacoronavirus (PDCoV). The lead minibinder, MB11, binds the PDCoV RBD with picomolar affinity, broadly neutralizes diverse deltacoronaviruses, and resists multiple biochemical stresses. Key terms: Porcine deltacoronavirus, miniprotein inhibitor, MB11, protein design, neutralization. Study Highlights:Researchers used computational design (BindCraft and AlphaFold3) to generate miniprotein inhibitors targeting the PDCoV receptor-binding domain and screened candidates by BLI and pseudovirus neutralization. MB11 binds the PDCoV RBD with KD ~155 pM and neutralizes PDCoV and several distantly related DCoVs with superior potency to known antibodies. Cryo-EM shows MB11 occludes receptor-binding loops and sterically blocks APN engagement, explaining broad neutralization. Deep mutational scanning indicates a high barrier to escape and biochemical tests show MB11 retains function after high temperature and low pH exposure but is susceptible to pepsin. Conclusion:MB11 is a promising preclinical PDCoV inhibitor combining ultrapotent, broad neutralization, mechanistic receptor blockade, and favorable stability, supporting further development for pandemic preparedness. Music:Enjoy the music based on this article at the end of the episode. Article title:Computational design of an ultrapotent deltacoronavirus miniprotein inhibitor First author:Avery NG Journal:PNAS DOI:10.1073/pnas.2533456123 Reference:Avery NG, Yoshiyama CN, Taylor AL, Park Y-J, Asarnow D, Perruzza L, Brown JT, Corti D, Benigni F, Starr TN, Veesler D. Computational design of an ultrapotent deltacoronavirus miniprotein inhibitor. PNAS. 2026;123:e2533456123. doi:10.1073/pnas.2533456123 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/mb11-pdcoronavirus-minibinder QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-06. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the sections covering MB11 design (BindCraft/AF3), binding measurements (BLI), neutralization assays (PDCoV and related DCoVs), cryo-EM structural validation, deep mutational scanning escape analysis, biophysical stability tests (heat/acid/enzymes), and delivery/manufacturing implications discussed.- transcript topics: Computational minibinder design (BindCraft and AlphaFold3); Biolayer interferometry binding screening; Pseudovirus neutralization assays and breadth across DCoVs; Cryo-EM structure and mechanism of entry inhibition; Deep mutational scanning and viral escape barriers; Biophysical stability under heat, low pH, and proteases 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:- MB11 has KD ≈ 155 pM to PDCoV RBD (binds with high affinity).- MB11 neutralizes PDCoV pseudovirus with IC50 ≈ 216 pM.- MB11 shows broad neutralization across DCoVs, including SparrowC...

Mantecon M et al., Human Genetics and Genomics Advances - This episode reviews a brief communication reporting a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Functional studies in patient fibroblasts show decreased CHCHD4 protein, marked assembly defects of mitochondrial complexes I and IV, and broad downregulation of electron transport and complex I biogenesis. Lentiviral expression of wild-type CHCHD4 restored OXPHOS proteins and assembly, linking CHCHD4 deficiency to human mitochondrial disease. Key terms: CHCHD4, mitochondrial disease, OXPHOS, complex I, protein import. Study Highlights:A single infant carried a paternal c.5C>T (p.Ser2Phe) CHCHD4 variant and a maternal deletion encompassing CHCHD4, resulting in markedly reduced CHCHD4 protein and severe lactic acidosis with neurological regression. Fibroblast analyses revealed decreased complex I and IV subunits, assembly defects on BN-PAGE, and widespread downregulation of mitochondrial proteins by proteomics, with respiratory electron transport and complex I biogenesis identified as the main dysregulated pathways. Lentiviral overexpression of wild-type CHCHD4 in patient cells restored CHCHD4 levels, rescued complex I and IV protein abundance and assembly, and reversed many proteomic changes, supporting causality. Conclusion:Biallelic CHCHD4 deficiency causes a severe early-onset mitochondrial disease by impairing mitochondrial protein import and assembly of complexes I and IV; restoration of CHCHD4 rescues the molecular defects. Additional cases are needed to define the clinical spectrum and the functional impact of specific variants. Music:Enjoy the music based on this article at the end of the episode. Article title:Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease First author:Mantecon M Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100615 Reference:Mantecon M, Chhuon C, Roger K, et al. Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease. Human Genetics and Genomics Advances. 2026;7:100615. doi:10.1016/j.xhgg.2026.100615 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/biallelic-chchd4-oxphos-defect QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the sections describing CHCHD4 function in the MIA pathway, the pediatric case with biallelic CHCHD4 variants, AlphaFold structural predictions for Ser2Phe, lentiviral complementation rescuing OXPHOS defects, and the proteomics results including selective vulnerability and clinical implications.- transcript topics: MIA pathway and CHCHD4 function in mitochondrial protein import; Genetic case and inheritance pattern (p.Ser2Phe with maternal CHCHD4 deletion); AlphaFold structural prediction of Ser2Phe destabilizing CHCHD4; Functional complementation rescue with WT CHCHD4 in patient fibroblasts; Proteomics results showing OXPHOS defects and selective vulnerability; Clinical implications: CHCHD4 deficiency as a novel cause of mitochondrial disease QC... Chapters (00:00:20) - A cellular blackout: The nuclear power plant(00:02:22) - Mitochondrial dysfunction: The power grid of the cell(00:06:39) - Mitochondrial disease 8, Genetic Errors(00:12:29) - The CRISPR-based diagnosis of iron deficiency(00:18:27) - Bring the light back in mitochondrial disease

Lassen F et al., The American Journal of Human Genetics - Meta-analysis of up to 948,690 exome- or whole-genome-sequenced individuals across six biobanks used statistical phasing to infer compound-heterozygous genotypes, increasing detectable bi-allelic damaging genotypes by 19% and identifying 58 significant gene-trait associations, 17 of which show stronger recessive effects. Key terms: recessive genetics, compound heterozygous, biobank meta-analysis, loss-of-function, statistical phasing. Study Highlights:The study combined data from UKB, All of Us, 100kGP, Genes & Health, BioMe, and BBJ totaling 948,690 samples and phased rare variants to detect compound-heterozygous genotypes. Phasing increased the number of bi-allelic damaging genotypes by 19% and identified 5,563 genes with bi-allelic pLoF genotypes. Gene-based recessive testing across 41 traits found 58 significant associations after meta-analysis and Cauchy combination, with 17 instances showing stronger recessive than additive effects, including HBB with heart failure and LECT2 with height. The federated, cross-biobank approach improved power and highlighted the value of diverse ancestries for discovering recessive effects. Conclusion:Federated meta-analysis across multiple biobanks combined with statistical phasing substantially increases discovery of rare recessive gene-trait associations and expands the catalog of human gene knockouts, demonstrating the importance of phasing and diverse cohorts for recessive-effect discovery. Music:Enjoy the music based on this article at the end of the episode. Article title:Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases First author:Lassen F Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.04.005 Reference:Lassen F.H. et al., 2026. Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases. The American Journal of Human Genetics 113, 1–17. https://doi.org/10.1016/j.ajhg.2026.04.005 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/recessive-coding-associations-six-biobanks QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-03. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing: the role of statistical phasing to identify compound-heterozygous genotypes, the scale across six biobanks (~950k individuals), the rise in bi-allelic genotypes, and key recessive gene–trait associations (HBB, LECT2, ENSG00000267561, PYGM, ODAD1), plus pleiotropy and conditional- transcript topics: Introduction to human knockouts and biobank-scale data; Compound heterozygosity and the need for phasing; Statistical phasing across six biobanks and study scale; Gene-based recessive associations across 41 traits; Notable associations: HBB with heart failure and lipids; LECT2 with height; ENSG00000267561 with height; BTNL9 association with HDL-C and triglycerides 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<... Chapters (00:00:11) - The Hidden World of Human Knockouts(00:06:52) - The genetic knockouts of the UK and Japan(00:09:47) - The Mendelian genetic mystery of heart disease(00:12:28) - The HBB Paradox(00:17:54) - The genetic determinants of healthcare(00:19:00) - What Happens to Medicine When we Sequence a Billion People?

Sanders CG et al et al., PNAS - Surveillance-derived influenza D virus (IDV) isolates were tested across cell lines, primary airway cultures, and precision-cut lung slices to assess human compatibility. IDV replicated to high titers in human respiratory models while eliciting muted interferon responses, highlighting a potential zoonotic threat and the need for enhanced surveillance. Key terms: influenza D virus, zoonosis, human airway, interferon evasion, surveillance. Study Highlights:A panel of six genetically diverse IDV isolates replicated efficiently in MDCK and A549 cell lines, primary well-differentiated human bronchial epithelial cultures, porcine airway cultures, and precision-cut lung slices. IDV induced markedly reduced IRF activation and lower IFN-λ1 and ISG expression compared to human influenza A virus, indicating limited innate immune sensing. Pretreatment with IFN-β potently restricted IDV replication, showing the virus is sensitive to an established antiviral state. Active surveillance at US swine exhibitions recovered multiple genetically distinct IDV strains spanning several clades. Conclusion:IDV readily infects and replicates in human respiratory tissues while limiting innate sensing, supporting intensified surveillance and mechanistic studies to evaluate its zoonotic and pandemic potential. Music:Enjoy the music based on this article at the end of the episode. Article title:Efficient replication of influenza D virus in the human airway underscores zoonotic potential First author:Sanders CG et al Journal:PNAS DOI:10.1073/pnas.2530325123 Reference:Sanders CG et al., Efficient replication of influenza D virus in the human airway underscores zoonotic potential. PNAS (2026) Vol. 123 No. 17 e2530325123. doi:10.1073/pnas.2530325123 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/influenza-d-human-airway-zoonotic-potential QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-03. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited the transcript sections describing field surveillance, in vitro and tissue-level replication in human/porcine models, innate immune responses, receptor usage, and zoonotic implications as reported in the canonical article.- transcript topics: Field surveillance and isolation of IDV from exhibition swine; IDV replication in MDCK cells and A549 cells; Primary human and porcine airway epithelial cultures (ALI); Precision-cut lung slices (PCLS) and tissue-level replication; Innate immune sensing and interferon responses (IRF, IFN-λ1, ISGs); Interferon-β pretreatment and antiviral state 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:- IDV replicates to high titers in MDCK cells and in immortalized human lung cells (A549).- IDV replicates efficiently in primary well-differentiated human airway epithelial cultures (ALI) and in porcine ALI cultures, with comparable rep... Chapters (00:00:11) - What Really Happens to Human Vibes?(00:02:04) - Disclosing the source of influenza D(00:06:08) - Human and pig lung viruses(00:12:16) - How influenza spreads like a stealthy virus(00:17:35) - Human Influenza: The Secret to Its Spread

Costantino L et al., PNAS - Costantino et al. dissect how Eco1-mediated acetylation of Smc3 (K112, K113) and cohesin ATPase activity separately regulate chromatin loop size, loop positioning, and sister chromatid tethering in budding yeast using Micro-C XL, ChIP, and biochemical ATPase assays. Key terms: cohesin, acetylation, ATPase, chromatin loops, sister chromatid cohesion. Study Highlights:Using a panel of budding yeast mutants, the authors show that acetylation of either Smc3 K112 or K113 is sufficient to produce positioned chromatin loops, while loss of both (Eco1 depletion) leads to expanded, unpositioned loops despite normal cohesin binding. K113 acetylation is required for sister chromatid cohesion (tethering), but cohesion-defective K113R mutants still form positioned loops, indicating looping can occur without tethering. K112 acetyl-mimic reduces loader-stimulated ATPase yet retains wild-type loop architecture, whereas hyper-ATPase mutants convert random loops into more positioned loops. The DE (low-ATPase) mutant produces long, unpositioned loops despite normal cohesin binding and Pds5 recruitment, indicating separable mechanisms downstream of acetylation and Pds5. Conclusion:Acetylation and ATPase activity separately tune cohesin's functions: acetylation at Smc3 K112/K113 helps position loops and control ATPase responsiveness, K113 acetylation is essential for tethering, and ATPase level biases cohesin toward random versus positioned loops, supporting active loop extrusion as the primary loop-forming mechanism. Music:Enjoy the music based on this article at the end of the episode. Article title:Cohesin acetylation and ATPase activity control cohesion and loop architecture through distinct mechanisms First author:Costantino L Journal:PNAS DOI:10.1073/pnas.2531218123 Reference:Costantino L, Ye T, Boardman K, Xiang S, Luo J, Mu Y, Ma W, Koshland D. Cohesin acetylation and ATPase activity control cohesion and loop architecture through distinct mechanisms. PNAS. 2026;123(17):e2531218123. doi:10.1073/pnas.2531218123. 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/cohesin-acetylation-atpase-loop-architecture QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-30. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing cohesin functions (loop extrusion and tethering), Eco1-mediated Smc3 acetylation at K112/K113, ATPase regulation by Scc2/Scc4, mutations (K112R, K113R, K112Q, K113Q, DE, TI), Micro-C XL method and CARs, Pds5 involvement, and the active loop extrusion model versus loop capture.- transcript topics: Cohesin functions: loop extrusion and sister chromatid tethering; Smc3 K112/K113 acetylation and Eco1; ATPase regulation by loader Scc2/Scc4 and acetylation; Mutant analyses: K112R, K113R, K112Q, K113Q, ECO1-AID, TI, DE; Micro-C XL methodology and CARs/positioned loops; Pds5 binding and loop regulation 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_titl... Chapters (00:00:20) - Base by Base: The motor of cell division(00:05:37) - The chemical engine of cell cohesion(00:06:57) - Cohesin's passive loop capture model(00:10:22) - How does DNA cohesion work?(00:11:30) - Two Marked Tracks

Schubert HA et al., PNAS - This episode reviews a global analysis showing that shifts in population sex composition have reversed historical sex gaps in fertility. Using UN World Population Prospects 2024 data and regression and standardization methods, the authors estimate male total fertility rates and project widening differences through 2100 driven by masculinized reproductive-age populations. Key terms: male fertility, sex ratio, total fertility rate, sex-selective abortion, population structure. Study Highlights:The authors estimate male and female total fertility rates using UN WPP2024 data combined with a regression-based model and demographic standardization. They identify a global crossover in 2024 when female TFRs first exceeded male TFRs and project growing disparities through 2100, especially in East Asia. Key drivers are higher sex ratios at birth, declining mortality, and a narrowing male–female mortality gap, with sex-selective abortion amplifying effects in some countries. The analysis highlights social consequences such as rising male childlessness and offers policy recommendations to mitigate sex imbalances. Conclusion:Masculinization of reproductive-age populations has flipped historical fertility patterns so that female TFRs now often exceed male TFRs, a gap expected to widen in many regions and to carry social and policy implications related to childlessness and partnership markets. Music:Enjoy the music based on this article at the end of the episode. Article title:Masculinization of populations reverses sex differences in fertility First author:Schubert HA Journal:PNAS DOI:10.1073/pnas.2533317123 Reference:Schubert HA, Spoorenberg T, Dudel C, Skirbekk VF. Masculinization of populations reverses sex differences in fertility. Proc Natl Acad Sci U S A. 2026;123:e2533317123. doi:10.1073/pnas.2533317123 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/353-masculinization-populations-fertility QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-30. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing historical sex differences in fertility, the 2024 crossover, drivers (birth sex ratio, mortality decline, sex-selective abortion), the age-gap Model 3 estimation approach, regional variations (East Asia vs Sub-Saharan Africa), war shocks, and policy implications.- transcript topics: Historical fertility gender gaps and denominator effects; Birth sex ratio and sex-selective abortion; Mortality decline and sex mortality gap; Model 3 age-gap estimation of male TFR; Global crossover year 2024 and 2100 projections; Regional variations: East Asia vs Sub-Saharan Africa 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:- Global crossover year: 2024- 2100 projection: <10% of countries have higher TFRm- Three drivers of masculinization: birth sex ratio, mortality decline... Chapters (00:00:12) - The feminization of the population(00:05:45) - The demographic structure of human populations(00:07:15) - The Real Story Behind Global Fertility(00:12:47) - Maternal mortality in the US and Europe(00:13:19) - How Does War Affect Male Fertility?(00:17:27) - What Actually Happens to Men When They're Out of the Marriage(00:21:46) - The Future of Families Is Shaping(00:23:42) - A Place to Be After the Crossover

Tibbe D et al., The American Journal of Human Genetics - This study identifies bi-allelic hypomorphic WDHD1 variants in 17 subjects with a clinical spectrum from fetal lethality to microcephalic primordial dwarfism and characterizes cellular defects in patient-derived cells linked to replisome dysfunction. Key terms: WDHD1, microcephalic primordial dwarfism, replication stress, sister chromatid cohesion, splicing variants. Study Highlights:Researchers found bi-allelic WDHD1 variants in 17 subjects presenting with intrauterine growth retardation, microcephaly and a spectrum of organ abnormalities including neonatal acute liver failure. Several intronic variants cause aberrant splicing and markedly reduced WDHD1 protein levels in fibroblasts. Subject-derived cells showed slowed replication fork progression, impaired G1-to-S transition, increased spontaneous DNA damage, abnormal nuclear morphology, and elevated premature sister chromatid separation, supporting a role for WDHD1 in replisome stability and cohesion. Conclusion:Hypomorphic bi-allelic WDHD1 variants cause an autosomal recessive microcephalic primordial dwarfism spectrum by reducing WDHD1 protein and impairing replication fork stability, genome integrity, and sister chromatid cohesion, establishing WDHD1 as essential for normal human growth and development. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism First author:Tibbe D Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.010 Reference:Tibbe D., Vogt M.R., Holling T., et al. Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism. The American Journal of Human Genetics. 2026. https://doi.org/10.1016/j.ajhg.2026.03.010 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/wdhd1-microcephalic-primordial-dwarfism QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-10. 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 WDHD1 function as replisome scaffold; intronic WDHD1 variants and splicing; DNA fiber assay and replication fork dynamics; γH2AX signaling; nuclear morphology; PCS; and liver pathology in MPD.- transcript topics: WDHD1 as replisome scaffold; intronic WDHD1 variants and splicing; DNA fiber assay and replication fork speed; γH2AX DNA damage signaling; nuclear morphology and lamin B1; premature sister chromatid separation (PCS) 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:- 17 subjects from 14 families with bi-allelic WDHD1 variants and MPD spectrum- intronic WDHD1 variants cause aberrant splicing and markedly reduced WDHD1 protein levels in patient-derived cells- WDHD1 acts as replisome scaffolding to stabilize replication forks and maintain genome integrity- replication fork progression is slowed and there is increased sp...

Katzourou IK et al., The American Journal of Human Genetics - Population analysis of ~459,000 UK Biobank participants shows that carriers of neurodevelopmental CNVs (ND-CNVs) have higher odds of co-occurring internalizing (depression, anxiety, somatic) and cardiometabolic conditions (hypertension, dyslipidemia, obesity, T2D, CKD). Effects are stronger for deletions than duplications, greater in females, and linked to the number of haploinsufficient genes within deletions. Key terms: copy-number variants, multimorbidity, internalizing disorders, cardiometabolic, UK Biobank. Study Highlights:Using CNV calls and linked EHRs in the UK Biobank, the authors tested associations between 54 ND-CNVs and combinations of internalizing and cardiometabolic conditions (ICM-MM). Aggregated ND-CNV carriers (n≈7,546; ~1.6%) had higher odds of ICM-MM (OR range 1.21–1.57) and a higher ICM-MM frequency (14.2% vs 11.5%). Deletions showed stronger effects than duplications and the number of haploinsufficient genes in deletions was associated with greater ICM-MM risk. No robust interactions were detected between ND-CNV status and polygenic risk scores after multiple testing correction. Conclusion:ND-CNVs increase risk of internalizing–cardiometabolic multimorbidity at the population level, especially for deletions and in females, suggesting the need for heightened clinical monitoring of carriers. Music:Enjoy the music based on this article at the end of the episode. Article title:Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank First author:Katzourou IK Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.021 Reference:Katzourou IK, LINC consortium, Barroso I, et al. Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank. The American Journal of Human Genetics. 2026;113:1–11. https://doi.org/10.1016/j.ajhg.2026.02.021 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/nd-cnv-internalizing-cardiometabolic-multimorbidity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-08. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections covering ND-CNV–ICM-MM association, UK Biobank design and CNV calling, dosage-sensitivity (haploinsufficient vs triplosensitive), deletion vs duplication effects (notably 16p11.2), sex differences, PRS interaction analyses, and clinical implications including multidisciplinary care and casca- transcript topics: Definition of ND-CNVs and ICM-MM; UK Biobank cohort size, CNV calling methods (PennCNV); Dosage sensitivity: haploinsufficient vs triplosensitive genes; Deletion vs duplication effects on ICM-MM and obesity; 16p11.2 region emphasis; Sex differences in ND-CNV associations 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:<...

Sapp JC et al., The American Journal of Human Genetics - A longitudinal study of recipients of medically actionable secondary genomic findings develops a Bayesian approach that integrates variant, family genotypic, and phenotypic data to estimate the probability that a secondary finding represents a true clinicomolecular diagnosis, with a detailed analysis of BRCA1/BRCA2 families and implications for screening policy and clinical management. Key terms: secondary findings, BRCA1, BRCA2, Bayesian risk assessment, population genomic screening. Study Highlights:The team enrolled 227 secondary findings recipients and completed genotyping and deep phenotyping for 163 probands, using cascade testing and variant reclassification. They piloted a Bayesian method combining prior population prevalence, variant pathogenicity, and family genotype–phenotype data to estimate clinicomolecular diagnosis (CMD) probabilities for BRCA1/2 families. CMD probabilities varied widely (26.2% to >99.9%) and over half of BRCA1/2 families met NCCN diagnostic testing criteria, indicating underuse of diagnostic testing. Conclusion:In opportunistic secondary findings contexts the posterior probability that a patient has the implicated monogenic disease can differ substantially from variant pathogenicity; integrating familial genotypic and phenotypic data via Bayesian methods refines risk estimates and should guide shared decision-making, management strategies, and policy for population genomic screening. Music:Enjoy the music based on this article at the end of the episode. Article title:Measuring disease likelihood in genomic ascertainment First author:Sapp JC Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.009 Reference:Sapp JC, Lewis KL, Modlin EW, et al. Measuring disease likelihood in genomic ascertainment. The American Journal of Human Genetics. 2026;113:1–12. doi:10.1016/j.ajhg.2026.03.009 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/measuring-disease-likelihood-genomic-ascertainment QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-07. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing the Bayesian CMD approach, the BRCA1/BRCA2 findings, the Family 8334 case, NCCN criteria implications, and study design/limitations.- transcript topics: ACMG secondary findings context and selection bias; Bayesian probability model for CMD; Cascade testing and family data integration; BRCA1 vs BRCA2 variant distribution and penetrance; NCCN criteria and clinical testing underutilization; Study design and recruitment (163 probands from 41 sources) 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:- CMD probability range across BRCA1/BRCA2 families: 26.2% to 100%- Baseline posterior probability for BRCA2-related CMD: 58.2%- Posterior CMD probability for family 8334: 99.2%- Average CMD...

Massilania D et al., PNAS - We summarize a PNAS study reporting a ~37× genome from a ~110,000-year-old male Neandertal (Denisova 17) from Denisova Cave. The genome shows D17 is closely related to an earlier Denisova Neandertal (D5), both carry Denisovan introgressed segments, and Neandertal groups displayed high regional differentiation and small, isolated populations in the Altai. Key terms: Neandertal, Denisova Cave, genome sequencing, population structure, Denisovan admixture. Study Highlights:The authors generated a high-coverage (~37-fold) autosomal genome from a ~110,000-year-old male Neandertal (D17) from Denisova Cave and dated it to ~110 kya. D17 is more closely related to an older Denisova Neandertal (D5) than to European or other Altai Neandertals and both D5 and D17 contain Denisovan-derived genomic segments. Patterns of homozygosity indicate smaller, more isolated groups in Altai Neandertals compared with later European Neandertals. Estimated FST shows Eastern and Western Neandertals were as genetically differentiated as the most divergent present-day human populations, implying rapid drift under small effective sizes. Conclusion:A high-coverage Altai Neandertal genome reveals Denisovan admixture in older eastern Neandertals, small and isolated group sizes in the Altai, and pronounced east–west Neandertal population differentiation exceeding that seen among modern human populations. Music:Enjoy the music based on this article at the end of the episode. Article title:A high-coverage Neandertal genome from the Altai Mountains reveals population structure among Neandertals First author:Massilania D Journal:PNAS DOI:10.1073/pnas.2534576123 Reference:Massilania D, Peyrégne S, Iasi LN M, de Filippo C, Mafessoni F, Mesab AB, Sümer AP, Swiel Y, Popli D, Silverman S, Boylea MJ, Kozlikind MB, Shunkov MV, Derevianko AP, Higham T, Douka K, Meyer M, Zeberg H, Kelso J, Pääbo S. A high-coverage Neandertal genome from the Altai Mountains reveals population structure among Neandertals. PNAS. 2026;123(13):e2534576123. doi:10.1073/pnas.2534576123 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/d17-altai-neandertal-genome-structure QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit focused on the transcript sections describing: specimen, sequencing coverage, population structure, Denisovan admixture, autozygosity and small group sizes, FST differentiation, and dating of D17/D5 lineages, plus migration/replacement dynamics.- transcript topics: Denisova 17 (D17) DNA extraction and high-coverage genome (~37x); Relationship among Neandertals (D17, D5, Chag8, Vi33.19) and Denisovans; Denisovan introgression into D17 and D5; lack of clear Denisovan signal in Chag8; Autozygosity and small population sizes (<50 individuals) in Eastern Neandertals; Genetic differentiation (FST ~0.30) between Eastern and Western Neandertals; Molecular dating and age estimates for D17 (~110 kya) and Y-chromosome lineage QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata c...

Law C-T et al., Cell Genomics - Law and Burns introduce TiMEstamp, a comparative-genomics pipeline that dates LINE-1 insertions from multiple sequence alignments and discovers hundreds of LINE-1 chimeric insertions fused to diverse RNAs across mammalian evolution. Key terms: LINE-1, TiMEstamp, chimeric insertions, retrotransposition, comparative genomics. Study Highlights:The authors developed TiMEstamp to infer TE insertion times from multispecies MSAs and to detect contemporaneous 5′ sequences fused to LINE-1. They compiled a large catalog of LINE-1 chimeras (reported >700 events) including known U6/LINE-1 cases and newly identified partners such as tRNA, 28S rRNA, 7SL, Y RNA, Alu elements, and mRNA 5′ transductions. Alu/LINE-1 chimeras (452 events) and 17 mRNA/lncRNA 5′ transductions were characterized with TSDs, EN motifs, and orientation/length patterns. They also show that promoter co-option (e.g., RAP1GDS1 driving a spliced intronic L1PA2) can restore retrotransposition competence. Conclusion:Comparative MSA-based timing reveals widespread, recurrent recombination between LINE-1 RNA and diverse cellular RNAs, producing chimeric insertions that have contributed to transposon diversification and provide mechanisms (RNA ligation, template switching, twin priming, promoter co-option) that may influence TE evolution and somatic/germline retrotransposition. Music:Enjoy the music based on this article at the end of the episode. Article title:Comparative genomics reveals LINE-1 recombination with diverse RNAs First author:Law C-T Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101165 Reference:Law C-T and Burns K.H., 2026. Comparative genomics reveals LINE-1 recombination with diverse RNAs. Cell Genomics 6, 101165. https://doi.org/10.1016/j.xgen.2026.101165 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/line1-recombination-diverse-rnas QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections covering the TiMEstamp workflow and data (MSA across mammals), discovery of chimeric LINE-1 insertions (tRNA halves, 28S rRNA, 7SL, Y RNA, 7SK), Alu/LINE-1 chimeras, mRNA/lncRNA 5' transductions (MAP3K13, FHIT), RAP1GDS1 promoter co-option, twin priming and trans-splicing mechanisms, and study limitati- transcript topics: LINE-1 retrotransposition mechanics (TPRT); TiMEstamp methodology and MSA dating; Chimeric LINE-1 insertions with non-LINE-1 RNAs (tRNA halves, 28S rRNA, 7SL, Y RNA, 7SK RNA); Alu/LINE-1 chimeras and temporal activity; 5′ transductions involving mRNAs/lncRNAs (MAP3K13, FHIT, RAP1GDS1); RAP1GDS1 promoter co-option and transcriptional rescue 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:- TiMEstamp uses MSAs across mammals to date LINE-1 insertions and identify contemporaneous adjacencies- Chimeric LINE-1 insertions involve diverse RNAs including tR...

Jiang P et al., Cell Genomics - This episode reviews a Cell Genomics study that uses ssDNA '2-end' and novel '4-end' sequencing to profile native 5′ and 3′ termini of plasma cfDNA. The work identifies PREM/POEM markers, links 3′ ends to methylation, and shows improved HCC detection. Key terms: cfDNA fragmentomics, 3' end motifs, 4-end sequencing, hepatocellular carcinoma, DNASE1L3. Study Highlights:The authors adapted single-stranded library preparation (2-end sequencing) to measure native 5′ (EM5) and 3′ (EM3) end motifs and defined flanking PREM and POEM motifs. Combining size‑stratified PREM, EM5, EM3, and POEM features raised hepatocellular carcinoma (HCC) detection to an AUC of 0.95. Fragmentomics-based methylation analysis of 3′ ends (3′ FRAGMA) improved HCC detection further (AUC 0.97). A novel 4-end sequencing approach captured all four termini of double‑stranded cfDNA, yielding 4‑end motif models with AUC up to 0.98 and revealing coordinated nuclease activity, notably DNASE1L3 involvement. Conclusion:Holistic end profiling of cfDNA—integrating native 5′ and 3′ ends, flanking motifs, methylation-informed fragmentomics, and four‑end resolution—enhances cancer detection performance and provides mechanistic insight into coordinated nuclease-mediated fragmentation, warranting larger validation studies. Music:Enjoy the music based on this article at the end of the episode. Article title:Holistic determination of ends of cfDNA molecules First author:Jiang P Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101142 Reference:Jiang P., Ma M.-J. L., Qiao R., et al. Holistic determination of ends of cfDNA molecules. Cell Genomics. 2026;6:101142. doi:10.1016/j.xgen.2026.101142 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/holistic-cfdna-ends-episode-333 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-04. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript’s substantive description of 2-end sequencing (EM5/EM3), PREM/POEM, 3'-FRAGMA, 4-end sequencing, nuclease signatures (DNASE1L3, DNASE1, DFFB), HCC diagnostic performance (AUC values), fragment-size context, and translational limitations as reported in the article.- transcript topics: 2-end sequencing preserving native ends (EM5/EM3); Pre-end (PREM) and post-end motifs (POEM); 4-end sequencing with stem-loop adapters and PacBio SMRT; 3'-FRAGMA methylation analysis; Nuclease-specific end motifs and coordinated fragmentation (DNASE1L3, DNASE1, DFFB); HCC detection performance and AUC values 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:- 2-end sequencing preserves native 5' and 3' ends (EM5/EM3) by omitting end-repair during library prep- PREM and POEM motifs are defined and analyzed as end-motif neighbors around EM5 and EM3- 4-end sequencing enables simultaneous assessment of all four termini using stem-loop adapters and PacBio SMRT sequencing<...

Liao Y et al., PNAS - Human dermal fibroblasts from young and old donors were embedded in 3D collagen and exposed to mechanical tension and TGF-β. Combining bulk RNA‑seq, ATAC‑seq, imaging, and perturbations, the study shows that matrix tension amplifies TGF‑β responses in young but not aged cells and identifies AP‑1 as a central chromatin-associated regulator required for fibroblast activation. Key terms: chromatin accessibility, mechanotransduction, aging, TGF-β signaling, AP-1. Study Highlights:Young fibroblasts under matrix tension mount a strong, synergistic transcriptional response to TGF‑β while aged fibroblasts exhibit blunted or divergent responses. Age-dependent differences in chromatin accessibility, notably at distal regulatory elements, correlate with these transcriptional outcomes. AP‑1 family motifs are highly enriched in TGF‑β- and age-responsive accessible regions and cooperate with age-specific TFs. Inhibiting AP‑1 activity prevents JUNB recruitment to RNA polymerase II and suppresses myofibroblast activation. Conclusion:3D chromatin accessibility acts as a dynamic filter of mechanical and biochemical signals during aging; AP‑1 and its regulatory network drive the age-specific chromatin remodeling that permits synergistic tension + TGF‑β responses in young fibroblasts, and AP‑1 inhibition blocks this activation, suggesting a potential therapeutic axis. Music:Enjoy the music based on this article at the end of the episode. Article title:Chromatin accessibility regulates age- dependent nuclear mechanotransduction First author:Liao Y Journal:PNAS DOI:10.1073/pnas.2522217123 Reference:Liao Y, Land M, Gupta R, Yu L, Sornapudi TR, Shivashankar GV. Chromatin accessibility regulates age-dependent nuclear mechanotransduction. PNAS. 2026;123(13):e2522217123. doi:10.1073/pnas.2522217123. Published March 26, 2026. 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/base-by-base-332-chromatin-age-mechanotransduction QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-02. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive auditing covered the study’s central mechanistic story: aging as a chromatin-filter for mechanochemical signaling; AP-1 as master regulator; age-specific TF partnerships; the 3D collagen tension model; ATAC-seq/RNA-seq integration; and AP-1 perturbation experiments.- transcript topics: Aging as chromatin-based signaling filter; 3D collagen gel tension model with glass ring; TGF-β signaling and mechanical tension synergy; AP-1 as master regulator; age-specific partners (JUNB vs HOXB13); ATAC-seq and RNA-seq integration; Perturbation experiments (siJUNB, T-5224, kinase inhibitors) 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:- Young fibroblasts exhibit synergistic gene expression enhancement to combined mechanical tension and TGF-β; aging cells show a blunted/divergent response- Quantified...

Tan et al et al., The American Journal of Human Genetics - This report identifies bi-allelic NDUFA5 variants in four individuals from three families causing an isolated mitochondrial complex I deficiency with variable multisystem features. The study combines genomic, transcriptomic, proteomic, biochemical, structural modeling, and zebrafish functional data to support pathogenicity. Key terms: NDUFA5, complex I deficiency, mitochondriopathy, proteomics, zebrafish model. Study Highlights:Bi-allelic NDUFA5 variants were found in four individuals from three unrelated families presenting with a variable multisystem phenotype including congenital heart defects, hematological abnormalities, and Leigh-like neurological features. Multi-tissue RNA-seq and RT-PCR revealed aberrant splicing and NMD, while proteomics and BN-PAGE demonstrated reduced NDUFA5 protein, isolated complex I deficiency, and stalled assembly at a Q/P intermediate. CRISPR-Cas9 ndufa5 zebrafish crispants showed developmental delays, locomotor deficits, reduced survival, and epileptiform neural activity, corroborating functional impact. Conclusion:Combined clinical, molecular, and animal-model evidence supports that bi-allelic NDUFA5 variants cause a recessive mitochondriopathy with isolated complex I deficiency and variable multisystem involvement; NDUFA5 should be considered in molecular reanalysis of undiagnosed complex I disorders. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency First author:Tan et al Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.003 Reference:Tan et al., 2026, The American Journal of Human Genetics 113, 1–14, May 7, 2026. https://doi.org/10.1016/j.ajhg.2026.03.003 License:CC BY (http://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/ndufa5-complex-i-mitochondriopathy QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-31. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing NDUFA5 variants, splicing consequences, proteomics/BN-PAGE findings, zebrafish model outcomes, and the diagnostic paradigm shift.- transcript topics: Complex I biology and mitochondrial energy metabolism; Gene discovery via GeneMatcher and patient cohorts; NDUFA5 variant classes and their consequences; RNA sequencing and exon skipping due to synonymous variant; Protein abundance and complex I assembly defects; Blue native PAGE and assembly intermediates 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:- Bi-allelic NDUFA5 variants cause a mitochondrial complex I deficiency with multisystem disease- Two distinct variant classes observed: frameshift + missense in Family 1; start-loss + synonymous splice variant in Family 2; homozygous synonymous splice variant in Family 3- RNA-seq reveals aberrant splicing and nonsense-mediated decay for some alleles; exon 3 skipping yields a 39-amino-acid in-frame deletion- Proteomics shows ma...

Chaldebas M et al., The American Journal of Human Genetics - Chaldebas et al. present 5ULTRA, a computational pipeline that integrates uORF databases, Kozak-motif features, splicing prediction, and a random-forest score to detect and prioritize 5′ UTR variants predicted to alter protein translation. The score correlates with proteomic and MPRA measures and is applied to population, somatic, GWAS, and rare-disease datasets to nominate candidate functional variants. Key terms: 5' UTR, uORF, Kozak motif, translation regulation, machine learning. Study Highlights:The authors developed 5ULTRA to annotate SNVs, indels, and splicing variants that create/disrupt uORFs or alter Kozak strength, integrating comprehensive uORF databases and SpliceAI. A random-forest 5ULTRA score trained on HGMD and gnomAD distinguishes likely translation-impacting variants and achieved strong cross-validation performance and AUC = 0.82 on an independent ClinVar test. The score correlates with cis-pQTL effect sizes (Spearman rho = 0.57) and with MPRA ribosome-load measurements (rho = 0.78). Genome-wide screening found thousands of candidate variants, highlighted rare/conserved signals in disease genes, and nominated examples in cancer, GWAS loci, and rare infections. Conclusion:5ULTRA provides a validated, transcript-aware framework to detect and prioritize 5′ UTR variants that modulate translation, offering mechanistic hypotheses for noncoding variant interpretation in rare disease, cancer, and complex-trait genetics; the tool and data are publicly available under a CC BY license. QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-30. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive auditing focused on the scientific content described in the transcript and its alignment with the AJHG article: 5ULTRA architecture, features, SpliceAI integration, validation metrics, somatic/GWAS/infectious disease applications, limitations, and open-source availability.- transcript topics: 5′ UTR regulatory elements (Kozak motif, uORFs) and translation initiation; 5ULTRA methodology and data integration (MANE transcripts, uORFdb, Ribo-uORF, SpliceAI); Machine-learning scoring (17 features; PhyloP conservation as key predictor; uORF/k Kozak annotations); Model validation (ClinVar, cross-validation AUC, accuracy); Correlation with proteomics and MPRA data (cis-pQTL, ΔMRL); Somatic cancer applications (NRAS and ABI1 examples; splicing effects; N-terminal extensions) 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:- 5ULTRA identifes and prioritizes 5′ UTR variants that affect translation via uORFs and Kozak motifs- 17 features used by the 5ULTRA random forest model; PhyloP conservation of uORF start codon as the strongest predictor- Genome-wide analysis: ~28 million 5′ UTR variants; ~137k predicted to affect translation via URFs or Kozak changes- ClinVar independent test AUC ≈ 0.82 and ClinVar threshold-based accuracy ≈ 80.8%- Cross-validation 5-fold AUC ≈ 0.981; MPRA and pQTL data show concordant translation effects (ΔMRL, Spearman ρ values ~0.78; 5ULTRA vs cis-pQTL ρ ≈ 0.57) QC result: Pass. Chapters (00:00:08) - Genome Wide Detection of Human 5 UTR Variants(00:06:41) - How a Deep Learning Algorithm Can Identify Dangerous Human Variants(00:12:35) - 5 Ultra: The computational genetics of cancer(00:18:46) - How to decode the secrets of the human genome

Mualim KS et al., Proceedings of the National Academy of Sciences - This study develops spatiotemporal population-genetic models calibrated with genomic data to predict how habitat loss and fragmentation drive changes in nucleotide diversity (π). The authors translate IUCN, Living Planet Index, and GBF indicators into estimates of current and future genetic diversity loss across thousands of species. Key terms: genetic diversity, habitat loss, fragmentation, WFmoments, conservation indicators. Study Highlights:The authors built WFmoments and SLiM-based spatiotemporal frameworks and calibrated them with population-scale genomic data from 29 species to model π dynamics after habitat loss. They translated demographic proxies from the IUCN Red List, Living Planet Index, and GBF indicators for 4,611 species to estimate genetic diversity declines. Short-term π loss is often modest, but mid- and long-term losses lag behind habitat declines and can be substantially larger, with average estimates ranging from ~1–13% already lost and mid-term projections much higher under some datasets. Habitat fragmentation can inflate species-wide π while reducing within-population diversity, and recovery of genetic diversity after restoration is slow. Conclusion:Habitat protection alone is insufficient to guarantee long-term genetic health; conservation should incorporate genetic monitoring, connectivity restoration, and policies informed by spatiotemporal genetic forecasts. Music:Enjoy the music based on this article at the end of the episode. Article title:Large future genetic diversity losses are predicted from conservation indicators even with habitat protection First author:Mualim KS Journal:Proceedings of the National Academy of Sciences DOI:10.1073/pnas.2514371123 Reference:Mualim KS, Spence JP, Weiß C, Selmoni O, Lin M, Exposito-Alonso M. Large future genetic diversity losses are predicted from conservation indicators even with habitat protection. Proc. Natl. Acad. Sci. U.S.A. 2026. doi:10.1073/pnas.2514371123 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/predicting-genetic-diversity-losses-329 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-30. 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 article’s methods (WFmoments, GDAR), habitat-loss scenarios (edge contraction vs fragmentation), key results (short-term vs long-term π losses, wallund/Wahlund effect), real-world examples (Miami Blue Butterfly, Torrey Pine, E. melliodora), and global-scale predictions; excluded- transcript topics: Genetic diversity concept (π) and proxies; WFmoments framework and GDAR; Edge contraction vs fragmentation habitat-loss patterns; Wahlund/Wahlund-like effects and fragmentation inflation; Spatial population structure (FST) and migration; Empirical calibration: 29 species and 4,611 species predictions 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- licen... Chapters (00:00:20) - What's the Hidden Crisis of Genetic Diversity?(00:06:09) - How Human Development Is Wiping Out Genetic Diversity(00:11:02) - The Walland Effect on species(00:13:13) - The ticking time bomb of genetic diversity

Zhou A et al., Human Genetics and Genomics Advances - Comparing LD‑pruning, COJO, SuSiE and PCA in haptoglobin (HP) cis‑region data, the study finds including non‑lead variants substantially increases variance explained (R2) and MR precision. Key terms: haptoglobin, cis-Mendelian randomization, LD-pruning, SuSiE, COJO. Study Highlights:The study analyzed circulating haptoglobin (HP) using Fenland protein GWAS summary statistics with LD from UK Biobank, compared four variant selection methods (modified LD‑pruning, COJO, SuSiE, PCA), and extended results with simulations and 15 additional gene regions. In the HP region, incorporating non‑lead variants produced a median proportional gain in R2 of 145.1% and a median reduction in MR standard error of 36.3% relative to the lead variant alone. In simulations with one or two causal variants the methods recovered the expected genetic variance (≈40%) and, when causal variants were removed, non‑lead‑inclusive methods recovered more variance than lead‑only. The functional implication supported by the data is that including correlated non‑lead variants can materially increase instrument strength and precision in cis‑MR, but may raise risks of pleiotropy and numerical instability. Conclusion:Variant selection methods that incorporate correlated non‑lead variants reliably improve instrument strength (R2) and MR precision in cis‑MR compared with the lead‑variant‑only approach; comparisons with the lead variant are advised to detect instability. Music:Enjoy the music based on this article at the end of the episode. Article title:Variant selection to maximize variance explained in cis-Mendelian randomization First author:Zhou A Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100573 Reference:Zhou A, Karhunen V, Tian H, Pott J, Patel A, Slob EAW, Burgess S. Variant selection to maximize variance explained in cis-Mendelian randomization. Human Genetics and Genomics Advances. 2026 Apr 9;7:100573. https://doi.org/10.1016/j.xhgg.2026.100573. 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/hp-variant-selection-cis-mr QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-27. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing: (1) the four variant selection methods and their rationale; (2) HP region results including R2 gains and SE reductions; (3) simulation studies with known causal variance (40%); (4) extension to 15 gene regions; (5) pleiotropy concerns and safeguards; (6) practical recommendat- transcript topics: Four variant selection methods (LD-pruning, COJO, SuSiE, PCA); Modified LD-pruning with adjusted R2 and LD-matrix checks; HP region results: variance explained (R2) gains and MR precision; Simulations with known causal variance (40%); Two-causal-variant scenario and lead variant variance explained; Extension to 15 additional gene regions 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- articl... Chapters (00:00:20) - How a single matrix can cripple genomics(00:01:34) - Deep Dive: The Search for genetic instruments without breaking the math(00:05:59) - The Hidden Problem with Standard LD Pruning(00:11:13) - The Lead Variants vs Non-Lead variants in disease prediction(00:15:27) - Multivariant Analysis: The Right Mix of Variants