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  459: Cerebral palsy genetics: 515 candidate genes, evidence for 89 13.09.2026 24мин

  Arterbery et al., The American Journal of Human Genetics - Hundreds of genes have been reported as causes of cerebral palsy, yet there is no agreed model of what a pathogenic variant in a child with CP actually means. This study treats CP as a phenotypic feature that some genetic disorders make more likely, tests the reported genes against the population prevalence of CP across tens of thousands of published individuals, and finds statistical evidence of association for only 89 of 515, before applying that stratification to genome sequencing of 460 children with CP. Key terms: cerebral palsy, Mendelian disease, genome sequencing, Human Phenotype Ontology, gene-disease association. Study Highlights:Across 21 published genomic diagnostic cohorts, variants deemed causal of cerebral palsy had been reported in 515 genes, with no consensus on whether such variants cause CP, mimic it, or coexist with it. The authors modelled CP as a phenotypic feature with a known population prevalence and applied a Bonferroni-corrected binomial test to 280 genes drawn from 5,508 publications describing 43,897 individuals, rejecting the null hypothesis of no association for 86 genes, and for 89 when combined with the genes enriched across the CP sequencing cohorts. Genome sequencing of 460 children with CP from 453 families at Shriners Children's identified pathogenic or likely pathogenic variants in 60 genes in 15.8% of the children. Only 16 of those 60 genes had significant literature evidence for CP association, which still represented a 16.3-fold enrichment over the overlap expected by chance. The results support a stratified approach in which the strength of evidence for each gene shapes how a molecular finding in a child with CP is interpreted. Conclusion:A pathogenic variant found in a child with cerebral palsy does not carry the same weight for every gene: for most of the 515 genes reported so far, the literature does not yet provide statistical evidence that the associated disorder raises the likelihood of CP. Treating CP as a phenotype with graded genetic evidence offers a framework for attributing causality more carefully in precision genomic diagnosis, while leaving open that more genes may prove to be associated as data accumulate. Music:Enjoy the music based on this article at the end of the episode. Article title:A phenotypic paradigm for cerebral palsy genetics First author:Arterbery Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.08.007 Reference:Arterbery, A.S., Gargano, M.A., et al., and Robinson, P.N. (2026). A phenotypic paradigm for cerebral palsy genetics. The American Journal of Human Genetics 113, 1972-1986. https://doi.org/10.1016/j.ajhg.2026.08.007 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cerebral-palsy-genetics-phenotypic-model QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-09-13. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music
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  458: Somatic or inherited? Reading TP53 risk from shared DNA 10.09.2026 25мин

  MacGregor et al., The American Journal of Human Genetics - Pathogenic TP53 variants found in blood have long been read as inherited Li-Fraumeni alleles, but many turn out to be somatic clones that grew with age. Using whole-exome data from 469,391 UK Biobank participants, this study combines variant allele fraction with haplotype sharing to tell the two origins apart, and finds that in cancer-free middle-aged adults the risk is mostly somatic and mostly hematological. Key terms: TP53, clonal hematopoiesis, Li-Fraumeni syndrome, UK Biobank, variant classification. Study Highlights:Rare coding TP53 variants were called in 469,391 UK Biobank participants aged 40 to 70, and 1,753 nonsynonymous variants were sorted by variant allele fraction combined with haplotype sharing across individuals carrying the same allele. Of 55 unique pathogenic TP53 variants detected, only six were classified as germline, and most of those sit at positions linked to partial rather than complete loss of p53 function. Classic Li-Fraumeni alleles behaved like somatic clonal expansions: their prevalence rose with age at an odds ratio of 2.3 per decade, while likely germline variants showed no age trend. Incident cancer risk separated sharply by origin, with the signal for somatic and inconclusive variants driven almost entirely by blood cancers rather than solid tumors, reaching a hazard ratio of 16.5 for the high-allele-fraction inconclusive class. The prevalence of somatic expansion tracked missense pathogenicity, suggesting that clonal growth in blood is itself an in vivo readout of how much a variant damages p53. Conclusion:In a population cohort of healthy middle-aged adults, most apparently pathogenic TP53 variants detected in blood reflect somatic clonal expansion rather than inherited predisposition, and the cancer risk they carry is predominantly hematological. Distinguishing the two origins with allele fraction and shared haplotypes gives a scalable way to interpret TP53 variants outside the clinic, where classic Li-Fraumeni assumptions do not hold. Music:Enjoy the music based on this article at the end of the episode. Article title:Shared inheritance reveals landscape of somatic and germline cancer risk in TP53 First author:MacGregor Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.07.011 Reference:MacGregor, H.A.J., Blundell, J.R., and Easton, D.F. (2026). Shared inheritance reveals landscape of somatic and germline cancer risk in TP53. The American Journal of Human Genetics 113, 1916-1928. https://doi.org/10.1016/j.ajhg.2026.07.011 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/tp53-somatic-germline-cancer-risk-biobank QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-09-10. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the scientific body from the TP53 and Li-Fraumeni background through clonal hematopoiesis, the allele-f...
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  457: A deletion that raises Alzheimer risk, a duplication that lowers it 09.09.2026 24мин

  Quenez O et al., The American Journal of Human Genetics - Rare copy-number variants were called from 22,319 exomes covering early-onset Alzheimer disease, late-onset disease and unaffected controls, then tested gene by gene for a dosage effect. One locus came back with the cleanest signal in the field: at the central 22q11.21 region, deletions appeared only in early-onset cases, including one that arose de novo, while duplications piled up in controls, with late-onset cases sitting in between. Replication in nearly 400,000 further individuals confirmed it, and overexpressing SCARF2, one of the genes in the narrowed interval, increased amyloid-beta uptake in cells - the direction the protective duplications would predict. Key terms: copy-number variants, Alzheimer disease, 22q11.21, SCARF2, gene dosage. Study Highlights:The authors called rare copy-number variants from 22,319 harmonized exomes, comprising 4,150 early-onset Alzheimer cases at 65 years or younger, 8,519 late-onset cases and 9,650 unaffected controls, and found that early-onset cases carried an excess burden of rare CNVs affecting coding genes, driven particularly by deletions in genes already implicated in the disease. Pooling short truncating variants with deletions into a single loss-of-function analysis implicated ABCA1 with an odds ratio of 5.77 and ABCA7 deletions with an odds ratio of 2.29, and raised CTSB as a new candidate at an odds ratio of 5.03. An exome-wide gene-level dosage analysis then flagged 18 genes across five loci below a 10 percent false discovery rate, of which the central 22q11.21 region stood out: deletions were restricted to early-onset cases and absent from all 9,559 controls, duplications were enriched in controls, and late-onset cases fell in between, a gradient the authors narrowed to the SCARF2-KLHL22-MED15 interval. Replication across 33,977 additional cases and 362,322 controls confirmed the association at exome-wide significance, with duplications carrying an odds ratio of 0.34 and a mega-analysis p value of 5.52 times ten to the minus seven. Transfecting SCARF2 into microglial cells significantly increased uptake of fluorescent amyloid-beta with a p value of 2.2 times ten to the minus five, while uptake of inert latex beads did not change, arguing the effect is specific rather than a general boost in cell appetite. Conclusion:The same stretch of chromosome 22 pushes Alzheimer risk in opposite directions depending on how many copies you carry: losing one raises risk, gaining one lowers it. Duplications of the central 22q11.21 region emerge as one of the strongest risk-decreasing genetic factors described so far in terms of effect size, behind only the ultra-rare Icelandic APP variant, and unlike that variant they are found across multiple ancestries. The authors are careful about what this does not mean: the deletions are extremely rare, protection is relative rather than absolute, and they show it directly by pointing to duplication carriers who developed late-onset disease anyway while carrying other risk factors. Power is the central constraint, because each genome carries hundreds of rare coding point variants but typically only one rare coding CNV, and the analysis was restricted to individuals of European ancestry. Music:Enjoy the music based on this article at the end of the episode. Article title:Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk First author:Quenez O Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.07.013 Reference:Quenez O, Schramm C, Cassinari K, Nicolas A, Groeneveld J, Huguet G, et al. Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk. The American Journal of Human Genetics. 2026;113(10):1-19. doi:10.1016/j.ajhg.2026.07.013 Li...
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  456: Beyond exons: where heritability hides as traits get more polygenic 08.09.2026 45мин

  Fuhrer J et al., The American Journal of Human Genetics - Across 34 complex traits and disorders, a MiXeR-based framework partitions SNP heritability over 74 functional annotations and finds that exons carry only a minority of it, and steadily less as a trait becomes more polygenic. Exonic heritability falls from about 22 percent in less-polygenic somatic diseases and biomarkers to about 13 percent in highly polygenic psychiatric and cognitive traits, intergenic heritability rises by the same logic, and intronic heritability stays put. A new annotation contribution score shows the same axis in the annotations themselves: highly polygenic traits load on conservation and variant-effect scores, less-polygenic traits on promoter, transcription and chromatin marks. Key terms: polygenicity, SNP heritability, noncoding variation, functional annotation, complex traits. Study Highlights:The authors extended the MiXeR framework to model SNP effect-size variance across 74 binary functional annotations, applied it to 34 traits spanning psychiatric, neurological, cardiometabolic, anthropometric, hematological and immune phenotypes, and introduced a likelihood-based annotation contribution score that measures how much a single annotation adds to the full model rather than how enriched it is per SNP. Exons cover 2.55 percent of base pairs and account for a mean of 14.52 percent of heritability, with introns and intergenic regions together explaining the remaining 85.49 percent; introns alone typically carry about half. Regressing regional fractions on log polygenicity, the exonic fraction falls 4.38 percentage points and the intergenic fraction rises 4.87 percentage points per ten-fold increase in polygenicity, while the intronic slope is not significant, and the illustrative spread runs from 8.51 percent exonic in schizophrenia to 29.44 percent in sex-hormone-binding globulin. The contribution score peaks for mid-sized annotations covering roughly 10 to 15 percent of SNPs, so compact conservation tracks such as phastCons, GERP, CADD and Eigen dominate in highly polygenic traits while promoter and chromatin tracks such as H3K4me3 and CpG islands dominate in less-polygenic ones. Sensitivity analyses against sLDSC and sLD4M agreed closely, with heritability fractions correlating at r equals 0.996 and polygenicity estimates at Spearman r equals 0.91. Conclusion:The functional location of heritability is not a fixed property of the genome but tracks a trait's polygenicity: less-polygenic somatic traits concentrate heritability in coding and gene-proximal regulatory regions, while highly polygenic psychiatric and cognitive traits distribute it across dispersed distal regulatory elements. Because enrichment per SNP and total contribution can point in opposite directions, the authors argue both must be read together, and they note that coding variants explain a minority of heritability throughout, which argues for sequencing designs that maximize noncoding coverage. The analysis relies on European-ancestry reference panels, uses relatively broad annotations with incomplete chromosome X coverage, and depends on polygenicity estimates from two methods that nonetheless agreed closely. Music:Enjoy the music based on this article at the end of the episode. Article title:Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders First author:Fuhrer J Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.08.012 Reference:Fuhrer J, Shadrin AA, Hughes T, Parker N, Hindley G, Frei E, Nguyen D, Smeland OB, Djurovic S, Andreassen OA, Dale AM, Frei O. Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders. The American Journal of Human Genetics. 2026;113(10):1-13. doi:10.1016/j.ajhg.2026.08.012 License:This episode is based...
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  455: Agentic genomics: the bottleneck moves from code to judgment 07.09.2026 13мин

  Corpas M et al., Cell Genomics - A Perspective arguing that autonomous AI agents which discover, configure and chain bioinformatics operations from natural-language instructions have shifted the bottleneck in computational biology from building pipelines to validating their output. The authors define four necessary conditions for a system to count as agentic, propose a perturbation test that separates genuine runtime decision-making from pre-specified branching, survey four existing systems, and set out a three-tier validation framework in which none of the surveyed systems yet reaches clinical grade. Key terms: agentic genomics, AI agents, validation, skill libraries, equity in genomics. Study Highlights:The authors define agentic genomics through four necessary conditions — autonomy, domain constraint via validated skill libraries, iterative refinement, and natural-language mediation — and offer an empirically testable criterion: a system is not agentic if perturbed intermediate outputs fail to change its execution strategy. They distinguish the paradigm from workflow managers like Nextflow and Galaxy, from AutoML, from LLM-assisted scripting, and from general-purpose biomedical copilots. Four systems are surveyed and placed against a proposed three-tier validation framework of research grade, benchmarked and clinical grade; all four currently sit at research grade, and none has published the external multi-site evidence the clinical tier requires. The paper documents a concrete silent failure: in the early weeks of ClawBio, one skill given an empty input file containing no genomic data returned all-normal results including recommended dosages for 51 drugs, a path since closed by community audit. It also reports that a randomized trial of GPT-4-augmented diagnostic reasoning found no significant improvement over conventional resources, 76 percent versus 74 percent with p equal to 0.60, even though the model alone scored well above physicians. Conclusion:The central claim is that agentic genomics expands the capacity to produce analyses without expanding the capacity to judge them, so validation frameworks must be formalized and tiered, equity-aware defaults must be engineered rather than aspired to, and regulatory frameworks must accommodate non-deterministic software. The authors argue the paradigm is already in use and advancing, and that the open question is not whether it will be adopted but whether the field will build the standards to make it trustworthy first. Music:Enjoy the music based on this article at the end of the episode. Article title:Agentic genomics: From pipeline automation to autonomous validation First author:Corpas M Journal:Cell Genomics DOI:10.1016/j.xgen.2026.101305 Reference:Corpas M, Guio H, Fatumo S. Agentic genomics: From pipeline automation to autonomous validation. Cell Genomics. 2026;6(8):101305. doi:10.1016/j.xgen.2026.101305 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/agentic-genomics-validation-bottleneck QC:This episode was checked against the original article PDF and publication metadat...
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  454: Efavirenz retarda a doença priônica mexendo no colesterol do cérebro [PT] 02.09.2026 17мин

  Ali T et al., JCI Insight - Um antirretroviral aprovado para HIV, dado por via oral em microdose, prolongou a sobrevida de camundongos que carregam a proteína priônica humana e foram infectados com príons de doença de Creutzfeldt-Jakob esporádica humana. O efavirenz age ativando a CYP46A1, a enzima cerebral que converte colesterol numa forma capaz de sair do cérebro — e não baixando a proteína priônica, como as abordagens dos episódios anteriores desta série. Termos-chave: efavirenz, CYP46A1, doença de Creutzfeldt-Jakob, metabolismo do colesterol cerebral, reposicionamento de medicamento. ⚠️ Importante: nada neste episódio é motivo para tomar efavirenz.O efavirenz é um antirretroviral de prescrição com efeitos colaterais reais, incluindo distúrbio do sono, sonhos vívidos, tontura e efeitos psiquiátricos. A dose usada neste estudo — cerca de 0,09 mg/kg por dia — é algo entre 300 e 400 vezes menor que a dose prescrita para HIV, e não é algo que alguém consiga aproximar por conta própria. Nenhum ser humano teve benefício demonstrado com efavirenz para doença priônica. Existe um ensaio de Fase 3 registrado como NCT07482085 no ClinicalTrials.gov, que ainda não reportou resultados. Se a doença priônica afeta você ou sua família, converse com um neurologista e pergunte sobre ensaios registrados — não sobre a farmácia.Este é o quarto episódio da nossa série sobre a doença de Creutzfeldt-Jakob, que começou como homenagem ao Lito Sousa. Todos os ensaios citados na série estão registrados publicamente no ClinicalTrials.gov. Destaques do estudo:Os autores inocularam camundongos tg650, que superexpressam a PrP humana, com príons MM1 de CJD esporádica humana e começaram o efavirenz oral em dose baixa aos 30 ou aos 130 dias após a infecção, prolongando a sobrevida em 17 e 23 dias respectivamente. Na fase clínica inicial, os animais tratados apresentaram menos PrPSc, menor teor de colesterol e de gotículas lipídicas no cérebro, e níveis mais altos de CYP46A1 e de 24S-hidroxicolesterol no cérebro e no soro. Superexpressar a CYP46A1 sozinha em células neuronais infectadas já reduziu a PrPSc e elevou o 24S-hidroxicolesterol, ligando o efeito antipriônico à enzima e não a outra propriedade do remédio. A dose usada foi de cerca de 0,09 mg/kg por dia, algo entre 300 e 400 vezes menor que a dose padrão prescrita para HIV. A eficácia no início tardio importa clinicamente, porque o paciente chega depois que os sintomas começaram. Conclusão:O efavirenz oral em dose baixa ativa a CYP46A1, restaura a renovação de colesterol no cérebro, reduz o acúmulo de PrPSc e prolonga a sobrevida num modelo humanizado de CJD esporádica, o que sustenta avaliar melhor esse medicamento reposicionado em doença priônica humana. Música:Ouça a música criada a partir deste artigo no final do episódio. Título do artigo:Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism Primeiro autor:Ali T Revista:JCI Insight DOI:10.1172/jci.insight.190296 Referência:Ali T, Cashion J, Hannaoui S, Ahmed-Hassan H, Schatzl H, Gilch S. Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism. JCI Insight. 2025;10(14):e190296. doi:10.1172/jci.insight.190296 Licença:Este episódio é baseado em um artigo de acesso aberto publicado sob a Licença Creative Commons Atribuição 4.0 Internacional (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Apoie:O Base by Base é independente e sem anúncios — sem patrocinadores, sem paywall. Se o episódio valeu o seu tempo, contribua e ajude a manter os artigos auditados e as músicas originais:❤️ Apoio mensal: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ Doação única: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Mais em basebybase.com
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  453: Efavirenz slows sCJD progression by reshaping brain cholesterol 31.08.2026 20мин

  Ali T et al., JCI Insight - Repurposed low-dose efavirenz slowed disease progression and extended survival in tg650 mice inoculated with MM1 sCJD prions by activating CYP46A1, raising 24S‑hydroxycholesterol and reducing PrPSc, brain cholesterol and lipid droplets at the early clinical stage. Key terms: efavirenz, CYP46A1, Creutzfeldt-Jakob disease, cholesterol metabolism, prion disease. ⚠️ Important: nothing in this episode is a reason to take efavirenz.Efavirenz is a prescription antiretroviral with real side effects, including sleep disturbance, vivid dreams, dizziness and psychiatric effects. The dose used in this study — about 0.09 mg/kg per day — is roughly 300 to 400 times lower than the dose prescribed for HIV, and is not something anyone can approximate on their own. No human being has yet been shown to benefit from efavirenz for prion disease. A Phase 3 trial is registered as NCT07482085 on ClinicalTrials.gov and has not reported results. If prion disease affects you or your family, talk to a neurologist and ask about registered trials — not about a pharmacy.This episode is the fourth in our series on Creutzfeldt-Jakob disease, which began as a dedication to Lito Sousa. Every trial named in the series is registered publicly on ClinicalTrials.gov. Study Highlights:Oral low-dose efavirenz given to human-PrP–overexpressing tg650 mice starting at 30 or 130 days postinoculation significantly slowed clinical progression and extended survival by 17 and 23 days, respectively. At the early clinical stage EFV-treated mice showed reduced PK-resistant PrPSc, decreased brain cholesterol and lipid droplets, and increased CYP46A1 expression with higher 24S‑hydroxycholesterol in brain and serum. Overexpression of CYP46A1 in prion-infected neuronal cells likewise reduced PrPSc, supporting a causal link between CYP46A1 activation and antiprion effects. Conclusion:Low-dose oral efavirenz activates CYP46A1, restores cholesterol turnover, reduces early PrPSc accumulation and lipid pathology, and extends survival in a humanized sCJD mouse model, supporting EFV as a candidate for further evaluation in human prion disease. Music:Enjoy the music based on this article at the end of the episode. Article title:Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism First author:Ali T Journal:JCI Insight DOI:10.1172/jci.insight.190296 Reference:Ali T, Cashion J, Hannaoui S, Ahmed-Hassan H, Schatzl H, Gilch S. Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism. JCI Insight. 2025;10(14):e190296. https://doi.org/10.1172/jci.insight.190296. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/efavirenz-prion-cjd-cholesterol QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-31. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's core biomedical claims about EFV's e...
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  452: Reduzir a PrP funciona em todas as linhagens [PT] 28.08.2026 28мин

  Minikel EV et al., Nucleic Acids Research - Este estudo testa a redução da proteína priônica (PrP) por oligonucleotídeos antisense (ASOs) em camundongos, variando doses, esquemas de aplicação, linhagens de príon e estágios da doença. O tratamento reduziu o RNA do Prnp, prolongou a sobrevida, atrasou os sintomas e reverteu biomarcadores de lesão neuronal e de gliose em vários cenários. O benefício apareceu mesmo com redução parcial, nas cinco linhagens testadas, e em alguns casos até depois do início dos sintomas. Termos-chave: proteína priônica, oligonucleotídeo antisense, neurodegeneração, biomarcadores, terapias. Destaques do estudo:A redução da PrP mediada por ASO prolongou a sobrevida e atrasou o início da doença tanto no esquema profilático quanto no tardio, em diferentes químicas de ASO. O benefício foi dose-dependente — uma redução de apenas cerca de 21 por cento do RNA já produziu ganho mensurável de sobrevida — e apareceu contra cinco linhagens distintas de príon adaptadas a camundongo, sem sinal de linhagens resistentes ao tratamento. Uma dose única aplicada depois da detecção da patologia reverteu a alta do neurofilamento leve no plasma e reduziu a bioluminescência de GFAP; a supressão crônica iniciada até o começo da neuropatologia alcançou benefício comparável ao de camundongos com apenas uma cópia funcional do gene da PrP. Alguns animais tratados já com sintomas francos tiveram sobrevida prolongada, embora a tolerabilidade de certas químicas de ASO em fase tardia tenha sido limitada. Conclusão:Reduzir a PrP por ASO, via mecanismo dependente de RNase H, é uma estratégia modificadora de doença amplamente eficaz nos modelos de príon em camundongo — atravessando linhagens e estágios — e justifica o desenvolvimento de terapias que baixem a PrP, com esquemas de dose apropriados. Música:Ouça a música criada a partir deste artigo no final do episódio. Título do artigo:Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints Primeiro autor:Minikel EV Revista:Nucleic Acids Research DOI:10.1093/nar/gkaa616 Referência:Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S, Carlson GA, Kavanaugh MP, Kriz J, Kim JB, Ma J, Wille H, Aiken J, McKenzie D, Doh-ura K, Beck M, O’Keefe R, Stathopoulos J, Caron T, Schreiber SL, Carroll JB, Kordasiewicz HB, Cabin DE, Vallabh SM. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Research. 2020;48(19):10615–10631. doi:10.1093/nar/gkaa616 Licença:Este episódio é baseado em um artigo de acesso aberto publicado sob a Licença Creative Commons Atribuição 4.0 Internacional (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Apoie:O Base by Base é independente e sem anúncios — sem patrocinadores, sem paywall. Se o episódio valeu o seu tempo, contribua e ajude a manter os artigos auditados e as músicas originais:❤️ Apoio mensal: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ Doação única: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Mais em basebybase.com No PaperCast Base by Base você acompanha o que há de mais recente em genômica, genômica funcional, genômica estrutural e proteômica. Link do episódio: https://basebybase.com/episodes/prion-protein-lowering-across-strains-pt QC:Este episódio foi conferido contra o PDF original do artigo e os metadados da publicação, para a edição publicada em 2026-08-28. Escopo do QC:- metadados do artigo e as afirmações científicas centrais da narração- exclui analogias, abertura/encerramento e música- cobertura da transcrição: Audited the transcript sections describing mechanism of action (RNase H–mediated PrP reduction), dose-response and minimal knockdown, cross-strain efficacy across five prion strains, treatmen...
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  451: Prion protein lowering is disease-modifying across stages and strains 25.08.2026 24мин

  Minikel EV et al., Nucleic Acids Research - This study uses antisense oligonucleotides (ASOs) to lower prion protein (PrP) RNA in mice and shows dose-dependent extension of survival, efficacy across multiple prion strains, reversal of molecular biomarkers, and benefit even when treatment is delayed into symptomatic stages. Key terms: prion protein, antisense oligonucleotide, neurodegeneration, biomarkers, survival. Study Highlights:Using ASOs to reduce PrP RNA in intracerebrally inoculated mice produced dose-dependent extension of survival in both prophylactic and delayed dosing paradigms. Less than 25% PrP suppression was sufficient to delay symptoms and extend survival. Treatment was effective across five distinct prion strains without evidence of drug-resistant prions. Biomarkers of neuronal injury (plasma NfL) and astrocytosis (GFAP bioluminescence) were reversed after ASO treatment, and chronic early dosing matched benefits seen in heterozygous PrP knockout animals. Conclusion:ASO-mediated PrP lowering is a robust, disease-modifying approach in mouse models of prion disease across strains and disease stages, supporting advancement of PrP-lowering therapeutics and use of CSF PrP and blood NfL as pharmacodynamic biomarkers. Music:Enjoy the music based on this article at the end of the episode. Article title:Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints First author:Minikel EV Journal:Nucleic Acids Research DOI:10.1093/nar/gkaa616 Reference:Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S, Carlson GA, Kavanaugh MP, Kriz J, Kim JB, Ma J, Wille H, Aiken J, McKenzie D, Doh-ura K, Beck M, O’Keefe R, Stathopoulos J, Caron T, Schreiber SL, Carroll JB, Kordasiewicz HB, Cabin DE, Vallabh SM. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Research. 2020;48(19):10615–10631. doi:10.1093/nar/gkaa616 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/prion-protein-lowering-stages-strains-endpoints QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-25. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections include PrP biology and PrP function; ASO mechanism and RNase H action; dose-response and minimal PrP knockdown; cross-strain efficacy across five mouse prion strains; biomarkers (plasma NfL and GFAP bioluminescence); therapeutic timing (prophylactic, early/delayed, late/symptomatic); resistance and tr- transcript topics: Prion protein biology and PrP function; ASO mechanism and RNase H action; Dose-response and minimal PrP knockdown; Cross-strain efficacy across five mouse prion strains; Biomarkers: plasma neurofilament light (NfL) and GFAP bioluminescence; Behavioral readouts: rotarod and nest-building QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata check...
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  450: ASOs que reduzem PrP prolongam a sobrevida [PT] 24.08.2026 24мин

  Raymond GJ et al., JCI Insight - This episode covers a 2019 study showing that sequence-specific antisense oligonucleotides (ASOs) targeting the prion protein (PrP) mRNA, delivered by bolus intracerebroventricular injection, lower PrP levels in the CNS, slow neuropathology, and markedly extend survival in prion-infected wild-type mice when given prophylactically or even near symptom onset. Key terms: antisense oligonucleotide, prion disease, prion protein, intracerebroventricular, mouse model. Study Highlights:Two PrP-targeting ASOs (active ASO 1 and 2) reduced Prnp mRNA and PrP protein across brain regions and produced robust survival benefits in RML prion–infected wild-type mice, with prophylactic extension of lifespan by 61%–98%. A single bolus dose given at 120 days post-infection (near clinical onset) extended survival by 55% and slowed symptomatic progression. A non‑targeting control ASO showed no efficacy, indicating a sequence-specific, on‑target mechanism mediated by RNase H–dependent RNA lowering. Some tolerability issues were observed with particular ASO candidates at late-stage treatment, but at least one active ASO was both tolerated and effective. Conclusion:Bolus CNS delivery of sequence-specific PrP‑lowering ASOs lowers PrP, delays prion neuropathology, and substantially extends survival in infected mice, supporting further development of PrP‑lowering therapy and use of CSF PrP as a pharmacodynamic biomarker. Music:Enjoy the music based on this article at the end of the episode. Article title:Antisense oligonucleotides extend survival of prion-infected mice First author:Raymond GJ Journal:JCI Insight DOI:10.1172/jci.insight.131175 Reference:Raymond GJ, Zhao HT, Race B, et al. Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight. 2019;4(16):e131175. doi:10.1172/jci.insight.131175. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/450-prp-lowering-asos-prion-mice QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-24. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections describing ASOs targeting Prnp, PrP reduction, i.c.v. bolus delivery, prophylactic vs late-stage treatment in prion-infected mice, and the role of control ASOs and sequence specificity.- transcript topics: Antisense oligonucleotides targeting Prnp mRNA; PrP reduction and PrP biology; Intracerebroventricular bolus delivery vs continuous infusion; Prophylactic vs late-stage treatment in prion-infected mice; Sequence specificity and non-targeting control ASO; Pharmacodynamic biomarker: CSF PrP measurement QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- ASOs targeting Prnp mRNA discussed as a therap...
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  449: siRNA divalente para doença priônica [PT] 24.08.2026 28мин

  Gentile JE et al., Nucleic Acids Research - Discovery and preclinical development of divalent siRNA candidates targeting PRNP, identifying 2439-s4 as a potent, durable human PRNP-lowering drug candidate with IND clearance. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, RNAi therapeutics. Study Highlights:Authors screened divalent siRNA libraries and identified mouse-targeting 1682-s4 that lowered brain PrP to ~49% and extended survival in prion-infected mice when dosed pre- or post-symptomatically. They generated human PRNP transgenic mouse lines (Tg25109, Tg26372) and nominated 2439-s4, which reduced whole-hemisphere human PrP to as low as 17% after a single dose. Mechanistic analysis showed that the s4 scaffold’s fixed 3' UU tail and exNA terminal linkages each contributed to superior potency and durability versus other scaffolds. GLP toxicology in rats and dogs found no significant adverse findings and the US FDA cleared an IND to advance 2439-s4 to clinical trials. Conclusion:Divalent siRNA 2439-s4 is a potent, durable PRNP-lowering candidate with favorable preclinical safety and regulatory clearance to proceed to clinical testing. Music:Enjoy the music based on this article at the end of the episode. Article title:Divalent siRNA for prion disease First author:Gentile JE Journal:Nucleic Acids Research DOI:10.1093/nar/gkag287 Reference:Gentile JE, Corridon TL, Serack FE, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/divalent-sirna-prion-disease QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-24. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections covering PRNP biology, divalent siRNA mechanism (s4 scaffold with UU tail and exNA), lead sequences (1682-s4 and 2439-s4), human PRNP transgenic mice models, intrathecal delivery, RT-qPCR and ELISA readouts, PK/PD durability, prion-infected survival data, and IND status.- transcript topics: Prion biology and PRNP as therapeutic target; Divalent siRNA mechanism and s4 scaffold features (UU tail, exNA); Lead sequences 1682-s4 and 2439-s4 and in vivo screening; Transgenic human PRNP mice Tg25109 and Tg26372; Intrathecal delivery and brain distribution; Analytical readouts: RT-qPCR and PrP ELISA QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- DOI canonical form 10.1093/nar/gkag287- Article title: Divalent siRNA for prion disease- Journal: Nucleic Acids Research- License: Creative Commons Attribution 4.0 International License (CC BY 4.0)- Lead sequences identified: 1682-s4 (mouse Prnp) and 2439-...
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  448: PrP‑lowering ASOs prolong survival in prion‑infected mice 23.08.2026 25мин

  Raymond GJ et al., JCI Insight - This study tests antisense oligonucleotides (ASOs) targeting Prnp in wild‑type mice infected with RML prions and shows that sequence‑specific PrP lowering by bolus i.c.v. ASO dosing delays disease and extends survival, even when given near clinical onset. Key terms: prion disease, antisense oligonucleotide, PrP lowering, mouse model, intracerebroventricular delivery. Study Highlights:Two sequence‑specific ASOs targeting mouse Prnp lowered Prnp mRNA and PrP protein in brain and delayed neuropathology compared with a non‑targeting control. Prophylactic bolus i.c.v. dosing given every 2–3 months extended survival by 61%–98%. A single ASO dose at 120 days post‑infection, near expected symptom onset, extended survival by 55% and slowed symptomatic progression. Control ASO showed no benefit, supporting RNA‑lowering as the mechanism of action. Conclusion:Bolus intracerebroventricular delivery of PrP‑targeting ASOs lowers PrP via RNase H–mediated mRNA degradation, slows accumulation of misfolded PrP, and substantially extends survival in prion‑infected mice, including when treatment is initiated near clinical onset. Music:Enjoy the music based on this article at the end of the episode. Article title:Antisense oligonucleotides extend survival of prion‑infected mice First author:Raymond GJ Journal:JCI Insight DOI:10.1172/jci.insight.131175 Reference:Raymond GJ, Tran Zhao H, Race B, Raymond LD, Williams K, Swayze EE, Graffam S, Le J, Caron T, Stathopoulos J, O’Keefe R, Lubke LDL, Reidenbach AG, Kraus A, Schreiber SL, Mazur C, Cabin DE, Carroll JB, Minikel EV, Kordasiewicz H, Caughey B, Vallabh SM. Antisense oligonucleotides extend survival of prion‑infected mice. JCI Insight. 2019;4(16):e131175. https://doi.org/10.1172/jci.insight.131175. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/prp-lowering-asos-prolong-survival-ep448 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing PrP biology, ASO mechanism (RNA lowering vs aptameric), delivery strategy, prophylactic and late-stage efficacy, control experiments, neuropathology, and translational implications.- transcript topics: Prion biology and PrP involvement; ASO mechanism: RNA lowering vs aptameric effects; Delivery methods: bolus i.c.v. vs osmotic pumps; Prophylactic ASO efficacy in mice (onset delay, survival extension); scrambled control ASO vs active ASOs; Late-stage (120 dpi) ASO efficacy and ASO2 toxicity QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- ASOs lowered Prnp mRNA and reduced PrP protein in brain regions- Prophylactic ASO...
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  447: Divalent siRNA for prion disease 23.08.2026 23мин

  Gentile JE et al., Nucleic Acids Research - This study develops and tests divalent siRNA molecules that lower prion protein (PrP) in the brain, identifies a potent human-targeting candidate (2439-s4), demonstrates survival benefit in prion-infected mice with a mouse-targeting tool compound, and reports IND-enabling toxicology supporting clinical testing. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, transgenic mouse. Study Highlights:The authors identify a mouse Prnp-targeting divalent siRNA (1682-s4) that lowers brain PrP to ~49% residual and extends survival in RML prion–infected mice (2.7-fold when dosed presymptomatically, 64% increase after a single symptomatic dose). They generate two transgenic mouse lines expressing full human PRNP (Tg25109, Tg26372) and use them to discover human-targeting siRNA 2439, optimized as 2439-s4, which lowers whole-hemisphere human PrP to 17% residual at 348 μg and to 49% at 52 μg. Chemical features—an exNA terminal linkage and a fixed 3' UU tail—each contribute substantially to potency, and a single dose shows durability out to months while 1–2% of CSF dose is retained in brain. GLP toxicology in rats and dogs identified no major liabilities and the FDA cleared an IND to advance 2439-s4 to human trials. Conclusion:Divalent siRNA can achieve deep, durable PrP lowering in the CNS, confer disease-modifying benefit in a mouse prion model, and yield a clinical candidate (2439-s4) with supportive nonclinical toxicology and regulatory clearance for a first-in-human study. Music:Enjoy the music based on this article at the end of the episode. Article title:Divalent siRNA for prion disease First author:Gentile JE Journal:Nucleic Acids Research DOI:10.1093/nar/gkag287 Reference:Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZC, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/divalent-sirna-prion-disease QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections covering: divalent siRNA mechanism and CNS delivery; mouse Prnp knockdown and survival data for 1682-s4; human PRNP targeting with 2439-s4 in transgenic mice; scaffold optimization (exNA, fixed tail, PS); PK/PD and IND-enabling GLP tox; and FDA IND clearance.- transcript topics: Divalent siRNA mechanism and CNS delivery; Mouse Prnp knockdown and survival in prion model with 1682-s4; Human PRNP transgenic mouse models Tg25109/Tg26372 and lead candidate 2439-s4; Chemical scaffold optimization (PS reductions, exNA, fixed UU tail); IND-enabling GLP toxicology and FDA IND clearance; PK/PD metrics (IC50 ~1.2 μg/g; tissue retention 1–2% dose) QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata is...
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  446: Cilia, Synuclein, and Survival: G51D Mice Reveal a Shared Parkinson’s Pathway 23.08.2026 28мин

  Lin Y‑E et al., PNAS - Knock‑in SncaG51D/G51D mice show selective loss of primary cilia in specific striatal interneurons, astrocytes, piriform cortex PV cells and olfactory basal stem cells, with concomitant reduction in Hedgehog‑dependent neurotrophic signaling linked to Parkinson’s disease vulnerabilities. Key terms: alpha-synuclein, primary cilia, neurotrophic signaling, Parkinson’s disease, G51D mouse. Study Highlights:Using SncaG51D/G51D knock‑in mice, the authors document selective loss of primary cilia in striatal cholinergic and parvalbumin interneurons and in ALDH1L1+ astrocytes while medium spiny neuron ciliation is preserved. Cilia loss associates with reduced Ptch1 expression and decreased production of neurotrophic factors (GDNF, NRTN, BDNF), indicating impaired Hedgehog signaling. PV neurons in the piriform cortex and horizontal basal cells in the olfactory epithelium also lose cilia and show reduced NRTN, whereas multiciliated olfactory sensory neurons remain intact. Higher phospho-Ser129 α‑synuclein correlates with reduced ciliation within ChAT neurons but does not predict vulnerability across all cell types. Conclusion:G51D α‑synuclein drives cell type–selective loss of primary cilia and impaired cilia‑dependent neurotrophic signaling, highlighting disrupted ciliary signaling as a convergent pathogenic pathway in Parkinson’s disease. Music:Enjoy the music based on this article at the end of the episode. Article title:Selective loss of primary cilia and neurotrophic signaling in G51D α- synuclein mice highlights a common pathway to Parkinson’s disease First author:Lin Y‑E Journal:PNAS DOI:10.1073/pnas.2619797123 Reference:Lin Y‑E, Chiang C‑Y, et al., Selective loss of primary cilia and neurotrophic signaling in G51D α‑synuclein mice highlights a common pathway to Parkinson’s disease. Proc Natl Acad Sci U S A. 2026;123:e2619797123. doi:10.1073/pnas.2619797123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cilia-synuclein-g51d-parkinsons-pathway QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive auditing of the transcript’s reporting of the G51D α-synuclein mouse model findings, including: cell-type–specific cilia loss, Hedgehog signaling impairment, neurotrophic factor downregulation, olfactory system involvement (piriform cortex and olfactory epithelium), pS129-α-synuclein correlations, and thera- transcript topics: G51D α-synuclein knock-in mouse model; Cell-type specific loss of primary cilia in striatum (ChAT and PV interneurons) and astrocytes; Hedgehog signaling impairment and Ptch1 transcription; Downregulation of neurotrophic factors: GDNF, NRTN, BDNF; Olfactory system involvement: piriform cortex PV neurons and Neurturin downregulation; Olfactory epithelium ciliopathy: horizontal basal cells vs olfactory sensory neurons QC Summary:- factual score: 10/10- metadata score: 10/10- supported core...
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  445: Why Thymine Survived the UV: Photodamage Pathways Explained 22.08.2026 26мин

  Khosh Abady K et al., PNAS - Spectroscopic comparison of thymine and uracil under 265 nm UVC shows thymine is more photoreactive and absorbs more primordial UVC, yet channels damage into reversible CPDs rather than irreversible (6-4) lesions, supporting an evolutionary 'molecular sunscreen' role. Key terms: UV photodamage, thymine, uracil, cyclobutane pyrimidine dimer, origin of life. Study Highlights:The authors used absorption, fluorescence, and Raman spectroscopy with 265 nm UVC irradiation to compare thymine and uracil photochemistry under controlled conditions. Thymine shows a faster overall absorbance decay (k = 0.174 min−1) than uracil (k = 0.064 min−1) and ~9% broader, redshifted absorption that increases overlap with primordial UVC. Thymine exhibits ~4.5× stronger intrinsic fluorescence and produces higher-amplitude photoproduct fluorescence while accumulating irreversible (6-4) photoproducts more slowly (k = 1.56 min−1) than uracil (k = 2.04 min−1). Raman markers distinguish CPD and (6-4) pathways and indicate thymine preferentially funnels damage into reversible CPD formation amenable to nonenzymatic self-repair. Conclusion:Thymine, though more photoreactive and exposed to higher primordial UVC flux, appears evolutionarily selected to localize UV damage into reversible lesions (CPDs) and provide molecular 'sunscreen' protection while enabling nonenzymatic self-repair, complementing later biochemical fidelity mechanisms. Music:Enjoy the music based on this article at the end of the episode. Article title:UV photodamage pathways and the evolutionary selection of thymine over uracil in early genetic systems First author:Khosh Abady K Journal:PNAS DOI:10.1073/pnas.2615278123 Reference:Khosh Abady K, Karpourazar N, Rentzepis PM. UV photodamage pathways and the evolutionary selection of thymine over uracil in early genetic systems. PNAS. 2026. doi:10.1073/pnas.2615278123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/uv-photodamage-thymine-vs-uracil QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-22. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections: background on RNA world and thymine vs uracil, experimental design with frozen-state bases, absorption/fluorescence/Raman results, and interpretation including CPD vs (6-4) pathways, molecular sunscreen hypothesis, evolutionary implications, and applications to pathogen detection/UV disinfe- transcript topics: RNA world background and thymine vs uracil photochemistry; Experimental design: frozen-ice state, 130 µM concentration, 265.3 nm narrowband UVC LED, -15 °C; Absorption spectra and photodegradation kinetics (k values for thymine and uracil); Fluorescence kinetics and photoproduct formation; Raman signatures for CPD and (6-4) photoproducts; Methyl group effects on base stacking and CPD bias QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged f...
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  444: Many-eyes or Sentinels? How Cost Curvature Shapes Collective Vigilance 19.08.2026 24мин

  Pilgrim C et al., PNAS - A minimal analytical model shows that whether animal groups adopt distributed low-level vigilance (many-eyes) or concentrated high-vigilance roles (sentinels) depends on how individual vigilance costs scale with effort. The same dichotomy appears in selfish and cooperative groups and explains switching, edge effects, and turn-taking. Key terms: collective vigilance, many-eyes, sentinel behavior, vigilance costs, behavioral ecology. Study Highlights:The authors derive a minimal model where collective vigilance benefit is a function of summed individual vigilance and costs depend on individual effort. When vigilance costs are convex (steepening) many-eyes strategies with equal low vigilance across individuals are optimal; when costs are concave (flattening) sentinel strategies with vigilance concentrated in one or a few individuals are optimal. This outcome holds in both selfish (game-dynamic) and cooperative (group-optimal) contexts and is supported by simulations. Extensions reproduce behavioral switching with S-shaped costs, edge effects from heterogeneous costs, and turn-taking when energy state dynamics are included. Conclusion:The curvature of individual vigilance costs determines whether groups distribute vigilance across many members or concentrate it in sentinels; habitat structure that creates flattening costs (vantage points) favors sentinels, while uniform habitats with steepening costs favor many-eyes. Music:Enjoy the music based on this article at the end of the episode. Article title:Many-eyes and sentinels in selfish and cooperative groups First author:Pilgrim C Journal:PNAS DOI:10.1073/pnas.2536017123 Reference:Pilgrim C, Bate AM, Sigalou A, Aellen M, Morford J, Warren E, Krupenye C, Biro D, Mann RP. Many-eyes and sentinels in selfish and cooperative groups. PNAS. 2026;123(33):e2536017123. doi:10.1073/pnas.2536017123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/many-eyes-or-sentinels-cost-curvature-vigilance QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-19. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing the minimal model fi = b(S) − c(vi); S = ∑vi; cost-curvature (convex vs concave); environmental structure; selfish vs cooperative results; behavioral switching (sigmoidal costs); edge effects; turn-taking; energy-state dynamics; and discussed limitations.- transcript topics: Model of collective vigilance (fi = b(S) − c(vi)); Cost curvature and environmental structure (convex vs concave); Selfish vs cooperative group outcomes; Behavioral switching with sigmoidal costs; Edge effects and spatial positioning; Energy-state dynamics and turn-taking QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title
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  443: 5D‑ASO boosts exon 51 skipping and restores dystrophin in DMD models 18.08.2026 19мин

  Feng P et al., PNAS - This paper describes a bipartite antisense oligonucleotide (5D‑ASO) design that appends a short 5′ splice site decoy tail to improve exon skipping, demonstrating robust efficacy for DMD exon 51 in cells, mice, and cynomolgus monkeys with a favorable safety profile. Key terms: antisense oligonucleotide, exon skipping, Duchenne muscular dystrophy, U1 snRNA decoy, dystrophin restoration. Study Highlights:The authors developed a bipartite ASO approach (5D‑ASO) that appends a short 5′ splice site–complementary tail to enhance exon skipping. An optimal 7–8 nt decoy appended to exon 51 ASOs markedly increased exon skipping in human cells and in multiple genetically modified mouse models, restoring dystrophin and improving muscle function. The lead MOE/PS 5D‑ASO showed durable tissue retention, dose‑dependent efficacy, and an overall favorable safety profile in mice and cynomolgus monkeys. The method was operative across multiple genes and exon targets, indicating broad applicability. Conclusion:Appending a short 5′ splice site decoy to exon‑targeting ASOs substantially increases exon‑skipping potency and therapeutic benefit in preclinical DMD models, supporting further clinical development of 5D‑ASO designs. Music:Enjoy the music based on this article at the end of the episode. Article title:An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy First author:Feng P Journal:PNAS DOI:10.1073/pnas.2606494123 Reference:Feng P., Gao P., Meng S., Yuan Y., Krainer A.R., Hua Y. An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy. PNAS. 2026;123(33):e2606494123. doi:10.1073/pnas.2606494123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/base-by-base-443-5d-aso-dmd QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the core narrative: Duchenne muscular dystrophy background; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy action; in vitro exon 51 skipping in RD cells; in vivo huEx51/huΔ52 mice data including dystrophin restoration; cynomolgus monkey efficacy/safety; off-target considerations; delivery- transcript topics: DMD background and dystrophin function; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy mechanism and splicing repression; In vitro exon skipping in RD cells (Etep-L8c and MOE-Etep); In vivo exon 51 skipping in huEx51/huΔ52 mice and dystrophin restoration; Cynomolgus monkey exon 51 skipping and safety QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- 5D-ASO tail acts as a decoy to misdirect U1 snRNP...
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  442: When pumps go missing: Ca2+ control of PMCA2 in Tmc1 deafness mutants 17.08.2026 22мин

  Rolseth AB et al., Proceedings of the National Academy of Sciences (PNAS) - This study links reduced Ca2+ entry through mutant TMC1 mechanotransducer channels to decreased PMCA2 pump density in outer hair cell stereocilia. PMCA2 turnover is rapid in the early postnatal period and is regulated by stereociliary Ca2+ via insertion from an apical vesicular pool; Neuroplastin (NPTN) later stabilizes the pump complex. Persistent pump reduction at hearing onset may contribute to hair cell mitochondrial dysfunction and death in Tmc1 mutants. Key terms: TMC1, PMCA2, hair cells, Ca2+ regulation, neuroplastin. Study Highlights:Tmc1 point mutations that reduce MET channel Ca2+ permeability show markedly decreased PMCA2 immunolabeling in outer hair cell bundles. PMCA2 density scaled with calculated Ca2+ entry, and experimental lowering of extracellular Ca2+ or pharmacological block of endocytosis or PtdIns(4,5)P2 synthesis reduced PMCA2 during the first postnatal week. PMCA2 is supplied from an apical vesicular pool, turns over rapidly before P11, and NPTN expression lags PMCA2 by ~2 days and less Ca2+ sensitivity, consistent with a stabilizing accessory role. The lower PMCA2 density persists at hearing onset and may contribute to mitochondrial dysfunction and subsequent hair cell death. Conclusion:Reduced stereociliary Ca2+ influx through mutant TMC1 channels decreases Ca2+-regulated insertion and rapid turnover of PMCA2 from an apical vesicular pool during early postnatal development. Because PMCA2 becomes less plastic after ~P11 and NPTN-mediated stabilization follows PMCA2 expression, early pump loss is maintained into hearing onset and may exacerbate intracellular Ca2+ dysregulation, mitochondrial impairment, and hair cell apoptosis in Tmc1 mutants. Music:Enjoy the music based on this article at the end of the episode. Article title:Ca2+ regulation of PMCA2 calcium pump expression in hair cells of Tmc1 deafness mutants First author:Rolseth AB Journal:Proceedings of the National Academy of Sciences (PNAS) DOI:10.1073/pnas.2607733123 Reference:Rolseth AB, Beurg M, Konrad DE, Augusta BK, Fettiplace R. Ca2+ regulation of PMCA2 calcium pump expression in hair cells of Tmc1 deafness mutants. Proc Natl Acad Sci U.S.A. 2026;123:e2607733123. doi:10.1073/pnas.2607733123. License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ca2-regulation-pmca2-tmc1 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-17. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the core scientific narrative in the transcript: MET Ca2+ permeability reductions in Tmc1 mutants, Ca2+-dependent PMCA2 regulation and vesicle trafficking, dynamic turnover and endocytosis, NPTN's stabilizing role, pharmacological perturbations (Pitstop2, PAO, GSK-1), endolymphatic potential effects at hearing- transcript topics: MET channel Ca2+ permeability in Tmc1 mutants; PMCA2 density regulation and Ca2+ entry relationship; Ca2+-dependent PMCA2 turnover and vesicle tra...
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  441: Evolutionary mapping of Cav1.3 functional sites 14.08.2026 24мин

  Tang X et al., PNAS - The authors apply an evolutionary sequence-covariation model to the Cav1.3 (CACNA1D) α1-subunit, map predicted pathogenicity onto structural models, and validate five predicted sites by patch-clamp electrophysiology and structural analysis. Predictions recapitulate known functional regions, reveal previously unrecognized clusters, and the tested variants produce diverse functional outcomes from nonconducting channels to gain- and loss-of-function gating changes. Key terms: Cav1.3, evolutionary modeling, CACNA1D, voltage-gated calcium channel, variant pathogenicity. Study Highlights:An evolutionary epistasis model predicted context-dependent conserved residues across Cav1.3 and recapitulated known functional sites. Mapping scores onto structural models highlighted novel clusters outside classical pore and voltage-sensor regions. Electrophysiological testing of five predicted variants confirmed diverse functional effects, including nonconducting (N745A), left-shifted activation (S635I, A376V, R1401A), and right-shifted or slowed gating (F1362A; Q1156E increased inactivation). The combined evolutionary, structural, and biophysical approach provides a scalable framework to prioritize and interpret CACNA1D variants. Conclusion:Evolutionary sequence-covariation combined with structural modeling and electrophysiology identifies novel functionally critical residues across Cav1.3 and enables rapid prioritization of pathogenic CACNA1D variants; the approach is generalizable to other ion channels but requires experimental follow-up to define gain- versus loss-of-function. Music:Enjoy the music based on this article at the end of the episode. Article title:Identification of novel functional sites in the Cav1.3 calcium channel α1-subunit using evolutionary modeling First author:Tang X Journal:PNAS DOI:10.1073/pnas.2602636123 Reference:Tang X, Hermenean HC, Yakimchyka A, Tuluc P, Ortner NJ, Liedl KR. Identification of novel functional sites in the Cav1.3 calcium channel α1-subunit using evolutionary modeling. PNAS. 2026;123(32):e2602636123. doi:10.1073/pnas.2602636123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/evolutionary-modeling-cav1-3-functional-sites QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-14. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the core scientific sections: evolutionary modeling predictions, structure mapping onto Cav1.3 models, electrophysiology validation in tsA-201 cells, and the functional effects of Cav1.3 variants (N745A, S635I, A376V, F1362A, R1401A, Q1156E); also reviewed limitations and clinical interpretation.- transcript topics: Evolutionary sequence covariation and context-dependent conservation in Cav1.3; Mapping pathogenicity scores onto Cav1.3 cryo-EM structures; Electrophysiological validation of Cav1.3 variants in tsA-201 cells; Functional consequences of specific Cav1.3 variants (N745A, S635I, A376V, F1362A, R1401A, Q1156E); Limitations...
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  440: DENV-4: Suppressing DNA Repair and Causing Genome Damage 12.08.2026 23мин

  Lamkina EN et al., PNAS - This episode reviews a PNAS brief report showing that DENV-4 infection induces marked DNA damage in infected cells while broadly suppressing transcription of DNA repair pathways, with selective upregulation of a mutagenic translesion polymerase and suppressed ATR expression. The findings raise concerns about long-term molecular "scars" after dengue infection that could influence cancer and postdengue syndromes. Key terms: Dengue, DENV-4, DNA damage, DNA repair, Genome instability. Study Highlights:Using Vero E6 and HUH-7 cells infected at MOI 0.1 and followed up to 5 days, the authors detected a large increase in γH2AX signaling indicating DNA damage. A 96-gene qPCR panel showed widespread suppression of DNA repair and DDR transcripts across multiple pathways while mismatch repair proteins remained stable. ATR protein expression was reduced and the mutagenic polymerase POLι was upregulated, telomere length and TRF2 were unchanged, and LC3 I/II levels decreased. The authors propose these changes create durable molecular vulnerabilities that warrant patient-based validation. Conclusion:DENV-4 causes significant host DNA damage while repressing many DNA repair transcripts, a combination that may leave lasting molecular scars and elevate long-term disease risk, but confirmation in patient samples is needed. Music:Enjoy the music based on this article at the end of the episode. Article title:DENV-4 infection suppresses transcription of DNA repair genes First author:Lamkina EN Journal:PNAS DOI:10.1073/pnas.2536909123 Reference:Lamkina EN, Reich J, Victora JA, et al. DENV-4 infection suppresses transcription of DNA repair genes. PNAS. 2026;123(32):e2536909123. doi:10.1073/pnas.2536909123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/base-by-base-denv4-dna-repair QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the main scientific narrative: DENV-4 infection at MOI 0.1 in Vero E6 and HUH-7 cells; γH2AX DNA damage; broad suppression of DDR/DNA repair transcription with selective maintenance of MMR; ATR suppression; telomere length/TRF2 status; autophagy marker LC3 I/II; POLι upregulation; serotype-specific contrasts; a- transcript topics: DENV-4 infection setup in vitro (MOI 0.1, 5 days, Vero E6 and HUH-7); γH2AX DNA damage signaling in infected cells; Broad suppression of DDR/DNA repair transcripts (BER, HR, NHEJ, NER) with MMR largely unchanged; ATR suppression and its consequence for DNA repair coordination; Telomere length and TRF2 status in infected cells; Maintenance of MMR proteins (MLH1, MSH2, MSH6) despite widespread suppression 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_jou...