392: GWAS of Cocaine Self-Administration in Heterogeneous Stock Rats

392: GWAS of Cocaine Self-Administration in Heterogeneous Stock Rats

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 Ces1c and Ces1d associated with post-infusion interval - Ces1 enzymes metabolize cocaine and influence duration/intensity of effects - Trak2 is the rat ortholog of human TRAK2 and overlaps human CUD GWAS signals - Rasd2 and Gnas show brain-region eQTLs related to cocaine response - LgA PC1 addiction-like behavior explains ~55% of variance with SNP-based heritability up to 0.16 QC result: Pass.

391: The Kaufmann Protocol — Why We Age and How to Stop It

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

390: Daunorubicin, Mutual Destruction, and Layered Antiphage Defense

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-early genes - Pre-early gene products drive host DNA degradation leading to a mutual destruction outcome - Bas33 is daunorubicin-sensitive, whereas the model Tevenvirinae phage T4 shows resistance to daunorubicin - A1 and A2 pre-early genes reside in the first 9% of Bas33 genome and are involved in host takeover; transcription of these genes is affected by daunorubicin - EcoP1_I RM system provides strong synergy with daunorubicin, with eight recognition sites in the pre-early region contributing to protection - Synergy between daunorubicin and RM systems can shift outcomes from Abi-like cell death to population survival QC result: Pass.

389: Crotonylation impedes c-Myc oncogenic activity

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, impairing Skp2 binding. QC result: Pass.

388: Base by Base | Episode 388 — In situ CAR‑macrophage alleviates liver fibrosis

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: - Targeting activated HSCs via FAP expression using CAR-M strategy - CD163-targeted LNPs deliver FAPCAR mRNA to hepatic macrophages in situ - CAR design includes CD3ζ signaling and CD28 costimulation - In vitro CAR-M show markedly increased phagocytosis and cytotoxicity toward FAP+ cells - In vivo mouse models show reduced hydroxyproline, ALT, ECM deposition and improved histology - scRNA-seq reveals expansion of MMP12+ scar-associated macrophages (SAM) QC result: Pass.